immuno Flashcards
What would a C1 protein deficieny cause?
C1 inhibitor (C1-INH) protein deficiency
causes hereditary angioedema
C1-INH is a multifunctional serine protease inhibitor
probable mechanism is uncontrolled release of bradykinin resulting in oedema of tissues
What would a C5 deficiency cause?
C5-9 deficiency
encodes the membrane attack complex (MAC)
particularly prone to Neisseria meningitidis infection
What does IL-6 do?
Endogenous pyrogen
Stimulates acute phase protein production
Also secreted by Th2
What is the major chemotactic factor for neutrophils?
IL-8
Describe the basic process of antigen recognition in the lymph node
Dendrite phagocytoses pathogen
Undergoes ‘licensing’ and upregulates CCR7 (chemotactic receptor) that sends them to the spleen or lymph node
In paracortex of spleen LN, activates the naive t-cell to either CD8 killer or memory cell or
CD4 (TH1, Th2, Th17, T-reg, or TFH)
What are the roles of, and cytokines required for differentiation of activated CD4+ T-Cells?
Th1 - activates macrophages via IFN-gamma, activates B-Cells. Requires IL-12 and IFN-gamma to become this.
Th2. Recruits and activates granulocytes. Requires IL-4 to become this.
TFH (T follicular helper). Allows B-Cells to differentiate, class switch, and proliferate with help of Th1 or Th2. Requires IL-6 alone.
T-Reg. Regulates T-cells by inhibiting immature dendrite entry into the lymph node. Requires IGF-B alone.
Th17. Secretes IL-17, causes epithelial cells to recruit more leukocytes to the affected area. Requires IGF-B and IL-6 to become this.
What does CD4+ Th1 do?
Th1 -
activates macrophages via IFN-gamma, activates B-Cells.
Secretes IFN-gamma and TNF-_beta_
Requires IL-12 and IFN-gamma to become this.
What does CD4+ Th2 do?
Th2.
Recruits and activates granulocytes (mast cells and eosinophils) and B-cells.
Secretes IL-4 (autocrine), IL-5 (eosinophils & mast cells), IL-6 (major inflam mediator) IL-10, and IL-13
Requires IL-4 to become this.
What does CD4+ Th17 do?
Secretes IL-17, causes epithelial cells to recruit more leukocytes to the affected area. Requires IGF-B and IL-6 to become this.
What does CD4+ T-reg do?
Regulates T-cells by inhibiting immature dendrite entry into the lymph node. Requires IGF-B alone.
What does CD4+ TFH (T follicular helper) do?
Allows B-Cells to differentiate, class switch, and proliferate with help of Th1 or Th2. Requires IL-6 alone.
What is the general mechanism of severe combined immunodeficiency?
Most cases of SCID are due to mutations in the gene encoding the common gamma chain (γc), a protein that is shared by the receptors for interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. These interleukins and their receptors are involved in the development and differentiation of T and B cells. Because the common gamma chain is shared by many interleukin receptors, mutations that result in a non-functional common gamma chain cause widespread defects in interleukin signalling. The result is a near complete failure of the immune system to develop and function, with low or absent T cells and NK cells and non-functional B cells.
OR
Janus kinase-3 (JAK3) is an enzyme that mediates transduction downstream of the γc signal. Mutation of its gene causes SCID
What are the general features of severe combined immunodeficiency?
- absence of functional t-lymphocytes
- defective antibody response as t-cells can’t kill or activate B-cell
- most severe form of primary immunodeficiency
- known as the ‘bubble boy disease’
- severe infections of all types
- BMT is tx, it’s rare.
What is the mechanism of the second most commonest form of SCID?
- defective enzyme, adenosine deaminase (ADA)
- necessary for the breakdown of purines.
- causes accumulation of dATP –> inhibition of the activity of ribonucleotide reductase, the enzyme that reduces ribonucleotides to generate deoxyribonucleotides.
Without functional ribonucleotide reductase, lymphocyte proliferation is inhibited and the immune system is compromised.
What does IL-3 do?
- stimulates myeloid progenitor cells or lymphoid (with IL-7) progenitors - works just like GM-CSF
- secreted by activated T-cells and basophils
Describe the process of B-cell activation in the presence of antigen
- B-Cell MHC2 presents antigen to T-helper cell TCR
- CD40 is coexpressed on the B-Cell and attaches to the CD40 ligand on the Thelper which stimulates B-cell proliferation and differentiation
- T-cell releases IL-4, IL-5, and IL-6 which also activates the B-cell in the dark zone of the germinal centre.
- The immature B-Cell undergoes somatic hypermutation (alteration of binding specificity and affinity of resultant antibodies) and affinity maturation (only the high affinity antibodies survive) and turns into a centroblast.
- The centroblast expresses CXRCR4 and CXCR5 which attract it to chemokines in the light zone where it becomes a centrocyte.
- Once in the light zone, they die if they’re of low affinity mutation, if high, the T-helper follicular cells will bind it and signal it to class switch, differentiate, and proliferate.
- Either becomes Memory B-Cell (IgG), or to plasma cell (which goes to the BM and secrete antibodies).
What are the three main roles of antibodies?
Neutralisation - prevents pathogen adhesion
Opsonization - promotes phagocytosis
Complement activation –> activates MAC destruction
What is Pathogen Associated Molecular Pattern (PAMP)?
All bugs have it, allows leukocytes to recognise it and start immune response.
Local mast cells will also release histamine in the presence of PAMP
Local macropahges will release cytokines too –> blood vessels will extrude monocytes into the tissues where they become macrophages, and neutrophils
What is diapedesis?
The process through which neutrophils extrude through the blood vessels (migrate)
How does opsonisation occur?
Plasmin and kinin activate complement cascade which then either opsonise the pathogen allowing easily elimination by phagocytes, or destroy the pathogen by rupturing it’s membrane.
How does the innate immune system recognise pathogens?
Specific PAMPs - only on pathogenic microbes - LPS, lipoproteins, peptidoglycans, lipoprotease, and lipotechoic acids (LTAs) are some examples.
They can be cell wall, flagella, or even DNA/RNA and are essential for pathogen survival.
via Pathogen Recognition Receptors
3 types - intracellular, extracellular, or secretory (for tagging) and all trigger the innate response (phagocytosis, opsonisation, complement, release cytokines and inflammatory mediators)
Describe the extracellular pathogen receptor protein
Sits on innate immune cells i.e. macrophages.
- binds PAMP (i.e. cell wall)
- tells cell to engulf pathogen and release lysosomic granules - this is done by mannose and scavenger receptors
- OR signals nucleus to release cytokines/IFNs (if virus has invaded the cell) via toll-like-receptors
Describe the intracellular cellular pathogen receptor protein
Sits inside innate immune cells i.e. macrophages.
- most famous is the nod-like receptor
- cell gets infected by pathogen ie virus
- releases cytokines
- aptoptoses if fully infected
Describe the secreted cellular pathogen receptor protein
Secreted by the liver and immune cells
Once secreted, no relation to those cells
Activates complement cascade via complementary receptors
What are the cytokines and receptors involved in diapedesis of neutrophils?
Macrophage releases TNF-a at site of injury
Activates endothelial receptors - selectins and Ig SuperFamily
Macrophages secrete CXCL8 or IL-8 which is a chemokine that shows the neutrophil the way to the site of injury
Neutrophil then passes through the vessel wall by binding the receptors. The neutrophil expresses a special carbohydrain chain, an IL-8 receptor, and an Integrin.
Rolling–> Adhesion –> Binding
Special carbohydrate chain binds to the selectin (it’s like a leg) - ‘adhesion’
and then
Integrin binds Ig Superfamily (I-CAM-1 and ICAM-2 (superfamilies are usually called ICAM)
IL-8 binds IL-8 which lead the way
What is the difference between MHC1 & MHC2?
MHC 1
All nucleated cells (so NOT red blood cells)
1 leg in phospholipid membrane
Binds small antigenic peptides which are tightly bound
B2 domain stays constant
4 microglobulins (alpha 1, 2, 3 and B2) - 1 never changes (B2 - represents MHC1), which the MHC1 molecule, other makeup the cleft (binding site). The alpha portion of the binding site will then change to fit the specific antigen.
Antigen sits in cleft, CD8 receptor on T-cell ‘checks’ if the MHC is class 1 (via the beta domain)
Cell mediated immunity is then activated.
MHC 2
Antigen presenting cells only (phags, macrcophage, dendritic cell)
2 legs in phospholipid membrane
Binds large antigenic peptides which are loosely bound
Presents antigen to T-helper cell so it can get help
4 microglobulins - alpha 1&2 (different to MHC1 alpha), B1&2 - specific to a particular antigen
Binds CD4 D1-D2 domain (which binds the beta 1&2) after checking if an MHC2 molecule.
T-Cell receptor then checks the antigen fits and then binds it
Initiates adaptive and cell mediated immunity.
How does MHC-1 present an antigen?
Bacteria ends cytosol via lipid membrane
Antigen winds up in the cytosol
Proteosome activated which chops up the bacteria into identical peptides
Peptides enter the ER within the cell via the TAP-transport channel
Calnexin sits inside the ER bound next to an incomplete MHC1 (missing a b2 domain) which allows B2 to attach.
Calnexin then dissociates after B2 has been attached
MHC1 then requires binding of calreticulin, ERPs and tapsin, which allows a peptide (the antigen) to load and attach to the alpha domains of the MHC1 molecule
MHC1 then leaves the ER in an endosome.
It then surfaces on the infected cell, ready to present to CD8 t-cells.
How does MHC-2 present an antigen?
Pathogen gets phagocytosed through a cell via endocytosis.
Pathogen sits in endosome
Lysosomes release acid into endosome, the pathogen is degraded into small peptides.
On the other side of the cell, the ER contains the MHC2 which is all synthesised and ready to go, but it’s binding site is blocked by a protein called Li.
Blocked MHC2 leaves in an endosome, and Li breaks down in the now acidic environment, leavning a fragment ‘CLIP’ still bound.
HLMDM then binds MHC2, releasing CLIP, completing the MHC2
The peptide containing endosome, binds to the endosome containing MHC2, and binds it
MHC2 then fuses with the cell membrane, now presenting the antigen to T-helper cells.
How do toll-like receptors work?
Pathogen recognition receptors found on cell membranes
Bind PAMPs
Signalling receptors with end result: Secrete cytokines/chemokines to ‘warn’ other cells in area, attract other mediators
TLR-4 main pathogen recognition factor, on macrophages.
- binds LPS (major cell wall component of g- bacteria)
- requires MD2 and CD14 (macrophage engulfing receptor) cobinding to function
- activates NFKB or IRF (interferon regulatory factor) –> cytokine transcription and production
Viruses get bound by the endosomal TLR (need 2 TLRs to activate lower domains) –> IRF –> IFNa and b get produced which target other cells in area, protecting them from taking in the virus
What are scavenger receptors?
Pathogen recognition receptor that binds PAMPs and different types of LDLs
Co-receptors of TLRs
Expressed on macrophages and assist in phagocytosis –> pathogen sits in phagosome stuck to SR –> lysosome fuses and acidifies ‘phagolysosome’, destroying pathogen
On platelets, macrophages, smooth muscle
Bind LDLs using scavenger receptor –> becomes foam cell, and attach to vessel wall
If this constantly occurs –> atherosclerosis
What does the complement pathway do?
Opsonisation (C3b)
MAC (C3b)
Inflammation (C3a)
In general - activated complement mediators ending in B kill stuff, while those ending in A, enhance inflammation
How does the lectin and classical complement pathways differ from the alternative pathway?
- When the classical and lectin pathways activate C3b, they do so via the C4b2a variant of C3a convertase - this activates the alternative pathway.
- The aforementioned pathways are activated by antigen, the alternative is activated by C3b via C3b convertase
- The alternative pathway enhances the classical and lectin pathways.
- The C3 convertase produced by activated of the alternative pathway is C3bBb, not C4b2a.
How does the lectin and classical complement pathways differ from the alternative pathway?
- When the classical and lectin pathways activate C3b, they do so via the C4b2a variant of C3a convertase - this activates the alternative pathway.
- The aforementioned pathways are activated by antigen, the alternative is activated by C3b via C3b convertase
- The alternative pathway enhances the classical and lectin pathways.
- The C3 convertase produced by activated of the alternative pathway is C3bBb, not C4b2a.
What are the complement proteins specific to the classical complement pathway?
C1 q and R - these get activated to split C4
C2
C4 (which forms C3 convertase with C2a)
What are the complement proteins specific to the classical complement pathway?
C1 q and R - these get activated to split C4
C2
C4 (which forms C3 convertase with C2a)
What are the complement proteins specific to the lectin complement pathway?
Mannose binding lectin - binds mannose
Filcolin - binds oligosaccharides
C4 and C2 (which when activated form C4B2a or C3 convertase)
What are the complement proteins specific to the lectin complement pathway?
Mannose binding lectin - binds mannose
Filcolin - binds oligosaccharides
C4 and C2 (which when activated form C4B2a or C3 convertase)
What are the complement proteins specific to the lectin alternative pathway?
Factor D (classical pathway) - complexes with factor B and C3b to form C3bBb (convertase)
Properdin (lectin pathway) - complexes with Factor-B and C3b to form C3bBb
Factor B complexes with C3b as well as Factor D (classical) or Properdin (Lectin pathway)
Factor B is used from both classical and lectin pathways.
Both complexes form C3bBb which is a C3 convertase produced only by the alternative pathway
What are the complement proteins specific to the lectin alternative pathway?
Factor D (classical pathway) - complexes with factor B and C3b to form C3bBb (convertase)
Properdin (lectin pathway) - complexes with Factor-B and C3b to form C3bBb
Factor B complexes with C3b as well as Factor D (classical) or Properdin (Lectin pathway)
Factor B is used from both classical and lectin pathways.
Both complexes form C3bBb which is a C3 convertase produced only by the alternative pathway
Describe how the classical pathway activates C3
- Complement protein C1 binds antigen-antibody complex at the Fc part via C1q
- C4 and C2 are cleaved, forming the C4b2a complex or C3 Convertase
- C3 convertase splits C3a and C3b
- C3b then activates the alternate pathway, enhancing the classical
- Further C3 is split into C3a and C3b.
Describe how the classical pathway activates C3
- Complement protein C1 binds antigen-antibody complex at the Fc part via C1q
- C4 and C2 are cleaved, forming the C4b2a complex or C3 Convertase
- C3 convertase splits C3a and C3b
- C3b then activates the alternate pathway, enhancing the classical
- Further C3 is split into C3a and C3b.
Describe how the lectin pathway activates C3
- Mannose binding lectin binds mannose (single sugar) or Filcolin binds oligosaccharide
- This activates C1 to split C4 and C2, forming the C4b2a complex, or C3 convertase
- C3 convertase splits C3a and C3b
- C3b activates the alternative pathway which makes another C3 convertase, C3bBb which makes LOTS of C3 convertase
- Reaction ramped up, C3 begins to be split into C3a and C3b at a much higher rate
Describe how the lectin pathway activates C3
- Mannose binding lectin binds mannose (single sugar) or Filcolin binds oligosaccharide
- This activates C1 to split C4 and C2, forming the C4b2a complex, or C3 convertase
- C3 convertase splits C3a and C3b
- C3b activates the alternative pathway which makes another C3 convertase, C3bBb which makes LOTS of C3 convertase
- Reaction ramped up, C3 begins to be split into C3a and C3b at a much higher rate
Describe how the alternative pathway activates C3
- Small amount of C3b generated by activation of lectin or classical pathway.
- Properdin complexes with Factor B and C3b or, Factor D cleaves Factor B to form and stabilise C3bBb, a type of C3 convertase specific to the alternative pathway.
- Production of C3bBb ramps up C3 convertase production, enhancing cleavage of C3a and C3b.
Describe how the alternative pathway activates C3
- Small amount of C3b generated by activation of lectin or classical pathway.
- Properdin complexes with Factor B and C3b or, Factor D cleaves Factor B to form and stabilise C3bBb, a type of C3 convertase specific to the alternative pathway.
- Production of C3bBb ramps up C3 convertase production, enhancing cleavage of C3a and C3b.
Describe the role of C3a protein in the complement system
With C5a, causes mast cells to degranulate and release histamine
This attracts leukocytes (macrophages) and causes vascular permeability
Describe the role of C3a protein in the complement system
With C5a, causes mast cells to degranulate and release histamine
This attracts leukocytes (macrophages) and causes vascular permeability
Describe the role of C5a protein in the complement system
Causes mast cells to release histamine and attract leukocytes and icnrease vascular permeability
Attaches to the macrophage C5a receptor, allowing the macrophage to then bind an opsonised pathogen via it’s CR1 receptor (which binds the C3b that coats the pathogen).
Describe the role of C5a protein in the complement system
Causes mast cells to release histamine and attract leukocytes and icnrease vascular permeability
Attaches to the macrophage C5a receptor, allowing the macrophage to then bind an opsonised pathogen via it’s CR1 receptor (which binds the C3b that coats the pathogen).
Describe the role of C3b protein in the complement system
- Opsonisation. Coats the bacteria in itself via it’s thioester bond, then attaches to the macrophage CR1 receptor with the help of the C5a-C5a-receptor on the macrophage, which then allows the macrophage to phagocytose the pathogen.
- Complexes with C4b2a (the main C3 convertase) to form C4b2a3b or C3-C5 convertase to cleave C5 into C5a and C5b (the terminal stage and beginning of the MAC attack)
Describe the role of C3b protein in the complement system
- Opsonisation. Coats the bacteria in itself via it’s thioester bond, then attaches to the macrophage CR1 receptor with the help of the C5a-C5a-receptor on the macrophage, which then allows the macrophage to phagocytose the pathogen.
- Complexes with C4b2a (the main C3 convertase) to form C4b2a3b or C3-C5 convertase to cleave C5 into C5a and C5b (the terminal stage and beginning of the MAC attack)
Describe the role of C5 protein in the complement system
Cleaved by C3/C5 convertase (C4b2a3b convertase)
C5a - histamine release from mast cells, binds macrophages to activate CR1 receptor to bind C3b opsonised pathogens –> phagocytosis
C5b - terminal stage of complement pathway - binds C6/7/8 and 9 proteins to form a pore that lyses the cell.
Describe the role of C5 protein in the complement system
Cleaved by C3/C5 convertase (C4b2a3b convertase)
C5a - histamine release from mast cells, binds macrophages to activate CR1 receptor to bind C3b opsonised pathogens –> phagocytosis
C5b - terminal stage of complement pathway - binds C6/7/8 and 9 proteins to form a pore that lyses the cell.
What are the key regulators of the complement pathway?
C1-inhibitor
C4bBp - blocks formation of C3 convertase in the classical pathway
Factor H - blocks formation of C3 convertase in the alternative pathway
Membrane cofactor protein (MCP/CD46) - Cell bound blocker of C3 convertase in classical and alt pathways
Decay Accelerating Factor (DAF) - membrane anchored, dissociates C3 convertase from both classic and alternate pathways
What are the key regulators of the complement pathway?
C1-inhibitor
C4bBp - blocks formation of C3 convertase in the classical pathway
Factor H - blocks formation of C3 convertase in the alternative pathway
Membrane cofactor protein (MCP/CD46) - Cell bound blocker of C3 convertase in classical and alt pathways
Decay Accelerating Factor (DAF) - membrane anchored, dissociates C3 convertase from both classic and alternate pathways
What is the main function of C1 inhibitor?
Inhibits the complement system to prevent spontaneous activation.
Irreversibly binds C1r and C1s proteases in the C1 complex of the classical pathway of complement, as well as the MASP-1 and MASP2 proteases in MBL complexes of the lectin pathway, thereby preventing downstream cleavage of C4 and C2.
Also inhibits proteases of fibrinloytic, clotting, and kinin pathways.
Most important inhibitor of plasma kallikrein, FXIA and FXIIa.
What is the main function of C1 inhibitor?
Inhibits the complement system to prevent spontaneous activation.
Irreversibly binds C1r and C1s proteases in the C1 complex of the classical pathway of complement, as well as the MASP-1 and MASP2 proteases in MBL complexes of the lectin pathway, thereby preventing downstream cleavage of C4 and C2.
Also inhibits proteases of fibrinloytic, clotting, and kinin pathways.
Most important inhibitor of plasma kallikrein, FXIA and FXIIa.
Which complement protein deficiency is most reliable in the diagnosis of acquired angioedema and why?
How can you distinguish it from hereditary angioedema?
Screening is conducted by determining the C4 level, which is decreased during the attack as well as in between the attacks.
If the C4 level was normal and suspicion is high, the test should be repeated.
When clinical suspicion of acquired angioedema is high, qualitative and functional values of C1-INH should be obtained at the same time.
Antigenic levels of C1q are usually low (in acquired) and are useful to distinguish hereditary angioedema from acquired angioedema.
Which complement protein deficiency is most reliable in the diagnosis of acquired angioedema and why?
How can you distinguish it from hereditary angioedema?
Screening is conducted by determining the C4 level, which is decreased during the attack as well as in between the attacks.
If the C4 level was normal and suspicion is high, the test should be repeated.
When clinical suspicion of acquired angioedema is high, qualitative and functional values of C1-INH should be obtained at the same time.
Antigenic levels of C1q are usually low (in acquired) and are useful to distinguish hereditary angioedema from acquired angioedema.
What cytokines do macrophages and dendritic cells secrete when bound to antigen, and what does each do?
IL-6 - activates B and T cells, stimulates liver to make more immune proteins
CXCL-8 (IL-8) - chemokine that attracts more leukocytes
IL-12 - activates NK and differentiation of naive CD4 cells into Th1 cell
TNF-a - stimulates the inflammatory response
IL-1b - vascular permeability
What cytokines do macrophages and dendritic cells secrete when bound to antigen, and what does each do?
IL-6 - activates B and T cells, stimulates liver to make more immune proteins
CXCL-8 (IL-8) - chemokine that attracts more leukocytes
IL-12 - activates NK and differentiation of naive CD4 cells into Th1 cell
TNF-a - stimulates the inflammatory response
IL-1b - vascular permeability
What immune components does the liver secrete?
Fibrinogen
CRP
Complement proteins
Mannose binding lectin
Usually does so after signalling from an activated macrophage
What immune components does the liver secrete?
Fibrinogen
CRP
Complement proteins
Mannose binding lectin
Usually does so after signalling from an activated macrophage
What are the actions of an activated macrophage?
- stimulates hypothalamus, fat, and muscle to increase body temp
- cytokines target bone marrow epithelial cells to produce more neutrophils
- most importantly - secreted TNF-a stimulates dendritic cells to migrate into the lymph nodes to initiate adaptive immunity. Most important link between innate and adaptive system.
What are the actions of an activated macrophage?
- stimulates hypothalamus, fat, and muscle to increase body temp
- cytokines target bone marrow epithelial cells to produce more neutrophils
- most importantly - secreted TNF-a stimulates dendritic cells to migrate into the lymph nodes to initiate adaptive immunity. Most important link between innate and adaptive system.
In terms of dendritic cells, what does licensing refer to?
Dendrite attaches to antigen on it’s MHC complex
Starts expressing CCR7 which is like a magnet to chemokines (CCL21) coming from the lymph node
Makes the dendrite migrate to the lymph node where it can activate the dendritic cell.
In terms of dendritic cells, what does licensing refer to?
Dendrite attaches to antigen on it’s MHC complex
Starts expressing CCR7 which is like a magnet to chemokines (CCL21) coming from the lymph node
Makes the dendrite migrate to the lymph node where it can activate the dendritic cell.
How does an NK cell work?
Lymphocytes with no immune memory
Same lineage as t-cells (lymphoid progenitor)
Always activated, do not require Thelper involvement - like cops on the street!
Normal Cell
- MHC1 expressed normally and attaches to KIR (CD94)
- AR ligand on normal cell interacts with AR on NK cell
- nothing happens
Virus-infected or malignant cell
- MHC1 is downregulated or absent
(important)
- still express AR ligand
- NK cell attaches to AR ligand but no signal from MHC1
- NK cell starts secreting chemical mediators and kill the infected cell.
How does an NK cell work?
Lymphocytes with no immune memory
Same lineage as t-cells (lymphoid progenitor)
Always activated, do not require Thelper involvement - like cops on the street!
Normal Cell
- MHC1 expressed normally and attaches to KIR (CD94)
- AR ligand on normal cell interacts with AR on NK cell
- nothing happens
Virus-infected or malignant cell
- MHC1 is downregulated or absent
(important)
- still express AR ligand
- NK cell attaches to AR ligand but no signal from MHC1
- NK cell starts secreting chemical mediators and kill the infected cell.
How does an NK cell kill it’s target after it detects a target?
Fas pathway
Fas-ligand on the NK cell attaches to the cell Fas receptor, pulling the two together
NK cells release granzyme and perforin from cytoplasm are endocytosed onto infected cell
Perforin forms a pore
Granzyme B exits the vesicle with the help of perforin which initiates the killing mechanism
- makes the mitochondria release cytochrome C into the cytoplasm –> indicates the cell to apoptose
- THEN procaspase is disinhibited by granzyme to cleave Caspase 3 which causes apoptosis.
Cytotoxic killer T-cells do the same but need to be activated by Thelper cells. NK do not require this.
How does an NK cell kill it’s target after it detects a target?
Fas pathway
Fas-ligand on the NK cell attaches to the cell Fas receptor, pulling the two together
NK cells release granzyme and perforin from cytoplasm are endocytosed onto infected cell
Perforin forms a pore
Granzyme B exits the vesicle with the help of perforin which initiates the killing mechanism
- makes the mitochondria release cytochrome C into the cytoplasm –> indicates the cell to apoptose
- THEN procaspase is disinhibited by granzyme to cleave Caspase 3 which causes apoptosis.
Cytotoxic killer T-cells do the same but need to be activated by Thelper cells. NK do not require this.
Describe the process of T-cell development
- Lymphoid progenitor moves from BM to thymus (cortex)
- At this stage it is ‘double negative 1’ (DN1). Thymic epithelial cell helps it become a precursor T-cel (DN2), at which point it loses its ability to become anything else.
- Then it becomes a thymocyte and expresses a TCR (DNIII)
- Then it becomes DN4 and proliferates into a double positive thymocyte (CD4+CD8
- It then has one of three fates
a) The thymic epithelial cell ignores it and it dies from neglect (the majority)
b) the thymic epithelial cell expresses MHC but it doesn’t recognise it ‘self’ and it apoptoses
c) the thymic epithelial cell expresses MHC (either one or 2) and it differentiates into a single positive naive T-Cell - If the thymic epithelial cell expressed MHC2 it becomes a CD4+ T-cell in the medulla
- If the thymic epithelial cell expressed MHC1 it becomes a CD8+T-cell in the medulla
- In the medulla a dendritic APC will either present an antigen (the t-cells will be scanning for it), or, more commonly, the T-cell will then migrate to a peripheral lymphoid organ ie the LN or the spleen.
Describe the process of T-cell development
- Lymphoid progenitor moves from BM to thymus (cortex)
- At this stage it is ‘double negative 1’ (DN1). Thymic epithelial cell helps it become a precursor T-cel (DN2), at which point it loses its ability to become anything else.
- Then it becomes a thymocyte and expresses a TCR (DNIII)
- Then it becomes DN4 and proliferates into a double positive thymocyte (CD4+CD8
- It then has one of three fates
a) The thymic epithelial cell ignores it and it dies from neglect (the majority)
b) the thymic epithelial cell expresses MHC but it doesn’t recognise it ‘self’ and it apoptoses
c) the thymic epithelial cell expresses MHC (either one or 2) and it differentiates into a single positive naive T-Cell - If the thymic epithelial cell expressed MHC2 it becomes a CD4+ T-cell in the medulla
- If the thymic epithelial cell expressed MHC1 it becomes a CD8+T-cell in the medulla
- In the medulla a dendritic APC will either present an antigen (the t-cells will be scanning for it), or, more commonly, the T-cell will then migrate to a peripheral lymphoid organ ie the LN or the spleen.
What are the different parts of a peripheral lymphoid organ and what lives in them?
Medulla - plasma cells and macrophages
Paracortex - naive T-cells
Cortex - Naive b-cells, germinal centre/follicle
What are the different parts of a peripheral lymphoid organ and what lives in them?
Medulla - plasma cells and macrophages
Paracortex - naive T-cells
Cortex - Naive b-cells, germinal centre/follicle
How do the acute phase proteins work?
CRP and SAP - opsonins
SAA - recruits immune cells, induces ECM degrading enzymes
Fibrinogen, prothrombin, factove VII, VWF - trap microbes in clots
Plasminogen - degrades the clots
Ferritin - binds iron, inhibits microbe iorn uptake
Hepcidin - internalises ferroportin, stops release of iron bound by ferritin within intestinal enterocytes and macrophages
Haptoglobin - binds haemoglobin, inhibits microbe iron uptake
Alpha1-antitryupsin - downregulates inflammation
How do the acute phase proteins work?
CRP and SAP - opsonins
SAA - recruits immune cells, induces ECM degrading enzymes
Fibrinogen, prothrombin, factove VII, VWF - trap microbes in clots
Plasminogen - degrades the clots
Ferritin - binds iron, inhibits microbe iorn uptake
Hepcidin - internalises ferroportin, stops release of iron bound by ferritin within intestinal enterocytes and macrophages
Haptoglobin - binds haemoglobin, inhibits microbe iron uptake
Alpha1-antitryupsin - downregulates inflammation
What are ‘negative’ acute phase proteins?
They go down inflammation
Albumin, transferrin, transthyretin, retinol binding protein, antithrombin, transcortin
Downregulation saves amino acids to produce positive acute phase proteins more efficiently
What are ‘negative’ acute phase proteins?
They go down inflammation
Albumin, transferrin, transthyretin, retinol binding protein, antithrombin, transcortin
Downregulation saves amino acids to produce positive acute phase proteins more efficiently
How do ESR and CRP differ?
CRP - short T1/2, returns to normal with treatment.
ESR - longer T1/2, will stay elevated longer.
I.e. Lupus - raised ESR but normal CRP in active disease.
May also indicate liver failure.
How do ESR and CRP differ?
CRP - short T1/2, returns to normal with treatment.
ESR - longer T1/2, will stay elevated longer.
I.e. Lupus - raised ESR but normal CRP in active disease.
May also indicate liver failure.
What are Witebsky’s postulates?
For a disease to be regarded as an autoimmune disease it needs:
- Direct evidence from transfer of pathogenic antibody or pathogenic T cells
- Indirect evidence based on reproduction of the autoimmune disease in experimental animals
- Circumstantial evidence from clinical clues
- Genetic architecture clustering with other autoimmune diseases
What are Witebsky’s postulates?
For a disease to be regarded as an autoimmune disease it needs:
- Direct evidence from transfer of pathogenic antibody or pathogenic T cells
- Indirect evidence based on reproduction of the autoimmune disease in experimental animals
- Circumstantial evidence from clinical clues
- Genetic architecture clustering with other autoimmune diseases
Which acute phase protein rises first and gets the highest?
CRP
Which acute phase protein rises first and gets the highest?
CRP
What is the pathophysiology of sarcoidosis?
- increased macrophage and CD4 helper T-cell activation, resulting in accelerated inflammation
- paradoxical immune response to antigen challenges such as tuberculin is suppressed - suggests a state of anergy.
The anergy may also be responsible for the increased risk of infections and cancer.
The regulatory T-lymphocytes in the periphery of sarcoid granulomas appear to suppress IL-2 secretion, which is hypothesized to cause the state of anergy by preventing antigen-specific memory responses.
What is the pathophysiology of sarcoidosis?
- increased macrophage and CD4 helper T-cell activation, resulting in accelerated inflammation
- paradoxical immune response to antigen challenges such as tuberculin is suppressed - suggests a state of anergy.
The anergy may also be responsible for the increased risk of infections and cancer.
The regulatory T-lymphocytes in the periphery of sarcoid granulomas appear to suppress IL-2 secretion, which is hypothesized to cause the state of anergy by preventing antigen-specific memory responses.
What is a surrogate light chain?
Light chain that sits on the Pre-B IgM until real ones are made
What is a surrogate light chain?
Light chain that sits on the Pre-B IgM until real ones are made
What is the role of somatic hypermutation?
Somatic hypermutation –> higher affinity antibody. Occurs in germinal centre after activation.
What is the role of somatic hypermutation?
Somatic hypermutation –> higher affinity antibody. Occurs in germinal centre after activation.
What do eosinophils do?
Degranulate to release an array of cytotoxic granule cationic proteins. These include:
major basic protein (MBP)
eosinophil cationic protein (ECP)
eosinophil peroxidase (EPO)
eosinophil-derived neurotoxin (EDN)
Major basic protein, eosinophil peroxidase, and eosinophil cationic protein are toxic to many tissues.
Eosinophil cationic protein and eosinophil-derived neurotoxin are ribonucleases with antiviral activity.
Major basic protein induces mast cell and basophil degranulation
What do eosinophils do?
Degranulate to release an array of cytotoxic granule cationic proteins. These include:
major basic protein (MBP)
eosinophil cationic protein (ECP)
eosinophil peroxidase (EPO)
eosinophil-derived neurotoxin (EDN)
Major basic protein, eosinophil peroxidase, and eosinophil cationic protein are toxic to many tissues.
Eosinophil cationic protein and eosinophil-derived neurotoxin are ribonucleases with antiviral activity.
Major basic protein induces mast cell and basophil degranulation
What is C3 nephritic factor?
C3 nephritic factor is an autoantibody to the alternate complement pathway’s C3 convertase, C3bBb.
C3NF stabilises this enzyme leading to an increase in the rate that C3 is activated.
The outcome of this is a markedly reduced C3 serum level.
Presence of the autoantibody leads to uncontrolled activation of C3 leading to very low C3 levels but normal C4. The presence of this complement profile (very low C3 normal C4) in patients with appropriate renal symptoms is almost characteristic of the presence of C3 Nef.
The antibody can be seen in membranoproliferative glomerulonephritis, MPGN and partial lipodystrophy.
This assay is only indicated in patients with very low C3 levels.
What is C3 nephritic factor?
C3 nephritic factor is an autoantibody to the alternate complement pathway’s C3 convertase, C3bBb.
C3NF stabilises this enzyme leading to an increase in the rate that C3 is activated.
The outcome of this is a markedly reduced C3 serum level.
Presence of the autoantibody leads to uncontrolled activation of C3 leading to very low C3 levels but normal C4. The presence of this complement profile (very low C3 normal C4) in patients with appropriate renal symptoms is almost characteristic of the presence of C3 Nef.
The antibody can be seen in membranoproliferative glomerulonephritis, MPGN and partial lipodystrophy.
This assay is only indicated in patients with very low C3 levels.
What does ‘C3 tickover’ refer to?
Activation of the alternative complement pathway.
It is initiated by the spontaneous hydrolysis of C3, which is abundant in the blood plasma. “Tickover” occurs through the spontaneous cleavage of the thioester bond in C3 to form C3(H2O).
This change in shape allows the binding of plasma protein Factor B, which allows Factor D to cleave Factor B into Ba and Bb.
What does ‘C3 tickover’ refer to?
Activation of the alternative complement pathway.
It is initiated by the spontaneous hydrolysis of C3, which is abundant in the blood plasma. “Tickover” occurs through the spontaneous cleavage of the thioester bond in C3 to form C3(H2O).
This change in shape allows the binding of plasma protein Factor B, which allows Factor D to cleave Factor B into Ba and Bb.
In the complement cascade, what does Factor I do?
Inactivates C3b and C4b
Deficiency = low levels of C3 due to unregulated activation of alternative pathway
- recurrent bacterial infections in kids and implicated in HUS
In the complement cascade, what does Factor I do?
Inactivates C3b and C4b
Deficiency = low levels of C3 due to unregulated activation of alternative pathway
- recurrent bacterial infections in kids and implicated in HUS
What does the CD79 protein do?
The CD79a protein together with the related CD79b protein, forms a dimer associated with membrane-bound immunoglobulin in B-cells, thus forming the B-cell antigen receptor (BCR). This occurs in a similar manner to the association of CD3 with the T-cell receptor, and enables the cell to respond to the presence of antigens on its surface.
It is associated with agammaglobulinemia.
What does the CD79 protein do?
The CD79a protein together with the related CD79b protein, forms a dimer associated with membrane-bound immunoglobulin in B-cells, thus forming the B-cell antigen receptor (BCR). This occurs in a similar manner to the association of CD3 with the T-cell receptor, and enables the cell to respond to the presence of antigens on its surface.
It is associated with agammaglobulinemia.
What is CD3?
This is the T-Cell receptor!
What is CD3?
This is the T-Cell receptor!
Three main points of membranoproliferative (mesangiocapillary) GN
- Glomerular hypercellularity and basement membrane deposition on top of deposits ‘tram tracking - nephrotic, low complement, poor prog.
- Main Hep-C associated nephropathy (type 1), also: hep B, SLE, chronic infection - circulating immune complexse activate complement
- Type 2 ‘dense deposit disease’ due to C3 nephritic factor stabilising C3bBb convertase –> excessive complement
Three main points of membranoproliferative (mesangiocapillary) GN
- Glomerular hypercellularity and basement membrane deposition on top of deposits ‘tram tracking - nephrotic, low complement, poor prog.
- Main Hep-C associated nephropathy (type 1), also: hep B, SLE, chronic infection - circulating immune complexse activate complement
- Type 2 ‘dense deposit disease’ due to C3 nephritic factor stabilising C3bBb convertase –> excessive complement
What are the anti-TNF-a drugs?
Four monoclonal antibodies (MAbs) (infliximab, adalimumab, golimumab, and certolizumab pegol)
One recombinant TNF-α decoy receptor, etanercept, have been developed to inhibit TNF-α signaling.
What are the anti-TNF-a drugs?
Four monoclonal antibodies (MAbs) (infliximab, adalimumab, golimumab, and certolizumab pegol)
One recombinant TNF-α decoy receptor, etanercept, have been developed to inhibit TNF-α signaling.
What is a thymus independent antigen?
Antigens lacking a peptide component; cannot be presented by MHC to T cells (e.g., lipopolysaccharide from cell envelope of gram-negative bacteria and polysaccharide capsular antigen). Stimulate release of antibodies and do not result in immunologic memory.
What is a thymus independent antigen?
Antigens lacking a peptide component; cannot be presented by MHC to T cells (e.g., lipopolysaccharide from cell envelope of gram-negative bacteria and polysaccharide capsular antigen). Stimulate release of antibodies and do not result in immunologic memory.
What is a thymus dependent antigen?
Antigens containing a protein component (e.g., diphtheria vaccine). Class switching and immunologic memory occur as a result of direct contact of B cells with Th cells (CD40-CD40 ligand interaction).
What is a thymus dependent antigen?
Antigens containing a protein component (e.g., diphtheria vaccine). Class switching and immunologic memory occur as a result of direct contact of B cells with Th cells (CD40-CD40 ligand interaction).
Which two inhibitors prevent spontaneous activation of the complement cascade on self-cells?
Decay-accelerating factor (DAF) and Cl esterase inhibitor help prevent complement activation on self cells (e.g., RBC).
Which two inhibitors prevent spontaneous activation of the complement cascade on self-cells?
Decay-accelerating factor (DAF) and Cl esterase inhibitor help prevent complement activation on self cells (e.g., RBC).
What does IL-1-5 do?
“Hot T-Bone stEAk”:
IL-l: fever (hot).
IL-2: stimulates T cells.
IL-3: stimulates Bone marrow.
IL-4: stimulates IgE production.
IL-5: stimulates IgA production.
What does IL-1-5 do?
“Hot T-Bone stEAk”:
IL-l: fever (hot).
IL-2: stimulates T cells.
IL-3: stimulates Bone marrow.
IL-4: stimulates IgE production.
IL-5: stimulates IgA production.
What does IL-8 do?
“Clean up on aisle 8.” Neutrophils are recruited by IL-8 to clear infections.
What does IL-8 do?
“Clean up on aisle 8.” Neutrophils are recruited by IL-8 to clear infections.
What does IL-12 do?
Induces differentiation of T cells into Th1 cells.
Activates NK cells. Also secreted by B cells.
naturally produced by dendritic cells,[1] macrophages and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation.
What does IL-12 do?
Induces differentiation of T cells into Th1 cells.
Activates NK cells. Also secreted by B cells.
naturally produced by dendritic cells,[1] macrophages and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation.
Which cytokines do macrophages secrete?
IL-1, 6, 8, 12 and TNF-A
Which cytokines do macrophages secrete?
IL-1, 6, 8, 12 and TNF-A
Which two cytokines do all T-cells release and what do they do?
IL2 and IL3
IL2 - stimulates growh of helper, cytotoxic and reg t- cells.
IL-3 - supports growth and differentiation of BM stem cells - like GM-CSF
Which two cytokines do all T-cells release and what do they do?
IL2 and IL3
IL2 - stimulates growh of helper, cytotoxic and reg t- cells.
IL-3 - supports growth and differentiation of BM stem cells - like GM-CSF
What cytokine does Th-1 cells release and what does it do?
IFN-gamma
Activates macrophages and Th1 cells.
Suppresses Th2 cells. Has antiviral and antitumor properties.
What cytokine does Th-1 cells release and what does it do?
IFN-gamma
Activates macrophages and Th1 cells.
Suppresses Th2 cells. Has antiviral and antitumor properties.
What cytokines do Th2 cells release?
IL-4 - Induces differentiation into Th2 cells. Promotes growth of B cells. Enhances class switching to IgE and IgG.
IL-5 - Promotes differentiation of B cells. Enhances class switching to IgA. Stimulates the growth and differentiation of eosinophils.
IL-10 - Modulates inflammatory response. Inhibits actions of activated T cells and Th1. Also secreted by regulatory T cells. TGF-b has similar actions to IL-10, because it is involved in inhibiting inflammation.
What cytokines do Th2 cells release?
IL-4 - Induces differentiation into Th2 cells. Promotes growth of B cells. Enhances class switching to IgE and IgG.
IL-5 - Promotes differentiation of B cells. Enhances class switching to IgA. Stimulates the growth and differentiation of eosinophils.
IL-10 - Modulates inflammatory response. Inhibits actions of activated T cells and Th1. Also secreted by regulatory T cells. TGF-b has similar actions to IL-10, because it is involved in inhibiting inflammation.
What is the mechanism of interferons?
Interferons (a, b, y) are proteins that place uninfected cells in an antiviral state. Interferons induce the production of a ribonuclease that inhibits viral protein synthesis by degrading viral mRNA (but not host mRNA).
Interferes with viruses:
- a- and B-interferons inhibit viral protein synthesis.
- y-interferons increase MHC I and II expression and antigen presentation in all cells.
- Activates NK cells to kill virus-infected cells.
What is the mechanism of interferons?
Interferons (a, b, y) are proteins that place uninfected cells in an antiviral state. Interferons induce the production of a ribonuclease that inhibits viral protein synthesis by degrading viral mRNA (but not host mRNA).
Interferes with viruses:
- a- and B-interferons inhibit viral protein synthesis.
- y-interferons increase MHC I and II expression and antigen presentation in all cells.
- Activates NK cells to kill virus-infected cells.
What are the cell-surface receptors for T-cells?
TCR (binds antigcn-MI-IC complex)
CD3 (associated with TCR for signal transduction)
CD28 (binds B7 on APC)
T-helper: CD4, CD40 ligand
Cytotoxic: CD8
What are the cell-surface receptors for T-cells?
TCR (binds antigcn-MI-IC complex)
CD3 (associated with TCR for signal transduction)
CD28 (binds B7 on APC)
T-helper: CD4, CD40 ligand
Cytotoxic: CD8
What are the cell-surface receptors for B-cells?
Ig (binds antigen)
CD19, CD20, CD21 (receptor for EBV ), CD40 MHC II, B7
You can drink Beer at the Bar when you’re 21: B cells, Epstein-Barr virus; CD-21.
What are the cell-surface receptors for B-cells?
Ig (binds antigen)
CD19, CD20, CD21 (receptor for EBV ), CD40 MHC II, B7
You can drink Beer at the Bar when you’re 21: B cells, Epstein-Barr virus; CD-21.
What are the cell surface receptors for macrophages?
CD14, CD40
MHC II, B7
Fe and C3b receptors (enhanced phagocytosis)
What are the cell surface receptors for macrophages?
CD14, CD40
MHC II, B7
Fe and C3b receptors (enhanced phagocytosis)
What are the cell surface proteins of NK cells?
CD16 (binds Fc of lgG), CD56 (unique marker
for NK)
What are the cell surface proteins of NK cells?
CD16 (binds Fc of lgG), CD56 (unique marker
for NK)
What is anergy?
Self-reactive T cells become nonreactive without costimulatory molecule. B cells also become anergic, but tolerance is less complete than in T cells.
What is anergy?
Self-reactive T cells become nonreactive without costimulatory molecule. B cells also become anergic, but tolerance is less complete than in T cells.
What is the effect of bacterial toxins on the immune system?
Superantigens (S. pyogenes and S. aureus)-cross-link the B region of the T-cell receptor to the MHC class II on APCs. Can activate any T cell, leading to massive release of cytokines.
Endotoxins/lipopolysaccharide (gram-negative bacteria)-directly stimulate macrophages by binding to endotoxin receptor CD14; Th cells are not involved.
What is the effect of bacterial toxins on the immune system?
Superantigens (S. pyogenes and S. aureus)-cross-link the B region of the T-cell receptor to the MHC class II on APCs. Can activate any T cell, leading to massive release of cytokines.
Endotoxins/lipopolysaccharide (gram-negative bacteria)-directly stimulate macrophages by binding to endotoxin receptor CD14; Th cells are not involved.
What are the features of passive immunity?
Receiving preformed antibodies
Rapid
Short span of antibodies (half-life= 3 weeks)
IgA in breast milk, antitoxin, humanized
monoclonal antibody
After exposure to Tetanus toxin, Botulinum toxin, HBV, or Rabies virus, patients are given preformed antibodies (passive)-“To Be Healed Rapidly”
What are the features of passive immunity?
Receiving preformed antibodies
Rapid
Short span of antibodies (half-life= 3 weeks)
IgA in breast milk, antitoxin, humanized
monoclonal antibody
After exposure to Tetanus toxin, Botulinum toxin, HBV, or Rabies virus, patients are given preformed antibodies (passive)-“To Be Healed Rapidly”
What are the features of active immunity?
Exposure to foreign antigens
Slow
Long-lasting protection (memory)
Natural infection, vaccines, toxoid
Combined passive and active immunizations can be given in case of hepatitis B or rabies exposure.
What are the features of active immunity?
Exposure to foreign antigens
Slow
Long-lasting protection (memory)
Natural infection, vaccines, toxoid
Combined passive and active immunizations can be given in case of hepatitis B or rabies exposure.
Name the live attenuated vaccines, their mechanism, and their pros and cons
Measles, mumps, polio (Sabin), rubella, varicella, yellow fever.
Microorganism loses its pathogenicity but retains capacity for transient growth within inoculated host. Mainly induces a cellular response.
Pro: induces strong, often life-long immunity.
Con: may revert to virulent form.
Name the live attenuated vaccines, their mechanism, and their pros and cons
Measles, mumps, polio (Sabin), rubella, varicella, yellow fever.
Microorganism loses its pathogenicity but retains capacity for transient growth within inoculated host. Mainly induces a cellular response.
Pro: induces strong, often life-long immunity.
Con: may revert to virulent form.
Name the killed vaccines, their mechanism, and their pros and cons
Cholera, hepatitis A, polio (Salk), rabies.
Pathogen is inactivated by heat or chemicals; maintaining epitope structure on surface antigens is important for immune response. Humoral immunity induced.
Pro: stable and safer than live vaccines.
Con: weaker immune response; booster shots usually required.
Name the killed vaccines, their mechanism, and their pros and cons
Cholera, hepatitis A, polio (Salk), rabies.
Pathogen is inactivated by heat or chemicals; maintaining epitope structure on surface antigens is important for immune response. Humoral immunity induced.
Pro: stable and safer than live vaccines.
Con: weaker immune response; booster shots usually required.
What is the associated disorder for:
Anti-dsDNA, anti-Smith
Antihistone
Anticentromere
SLE
Drug induced lupus
Scleroderma (CREST syndrome)
What is the associated disorder for:
Anti-dsDNA, anti-Smith
Antihistone
Anticentromere
SLE
Drug induced lupus
Scleroderma (CREST syndrome)
What is the associated disorder for:
Anti-Scl-70 (anti-DNA topoisomerase I)
Antimitochondrial
lgA antiendomysial, lgA anti-tissue transglutaminase
Scleroderma (diffuse)
Primary biliary cirrhosis
Celiac
What is the associated disorder for:
Anti-Scl-70 (anti-DNA topoisomerase I)
Antimitochondrial
lgA antiendomysial, lgA anti-tissue transglutaminase
Scleroderma (diffuse)
Primary biliary cirrhosis
Celiac
What are the associated disorders for:
Anti-basement membrane
Anti-desmoglein
Antimicrosomal, antithyroglobulin
Goodpastures
Pemphigus vulgaris
Hashimoto’s thyroiditis
What are the associated disorders for:
Anti-basement membrane
Anti-desmoglein
Antimicrosomal, antithyroglobulin
Goodpastures
Pemphigus vulgaris
Hashimoto’s thyroiditis
What are the associated disorders:
Anti-Jo-1, anti-SRP, anti-Mi-2
Anti-SSA (anti-Ro)
Anti-SSB (anti-La)
Polymyositis, dermatomyositis
Sjogrens
What are the associated disorders:
Anti-Jo-1, anti-SRP, anti-Mi-2
Anti-SSA (anti-Ro)
Anti-SSB (anti-La)
Polymyositis, dermatomyositis
Sjogrens
What are the associated disorders?
Anti-Ul RNP (ribonucleoprotein)
Anti-smooth muscle
Anti-glutamate decarboxylase
MCTD
Autoimmune hepatitis
Type 1 DM
What are the associated disorders?
Anti-Ul RNP (ribonucleoprotein)
Anti-smooth muscle
Anti-glutamate decarboxylase
MCTD
Autoimmune hepatitis
Type 1 DM
What are the associated disorders?
c-ANCA (PR3-ANCA)
p-ANCA (MPO-ANCA)
Wegeners
Microscopic polyangiitis, Churg Strauss
What are the associated disorders?
c-ANCA (PR3-ANCA)
p-ANCA (MPO-ANCA)
Wegeners
Microscopic polyangiitis, Churg Strauss
What are the contraindications to the flu vaccine?
Fluvax vaccine must not be used in children under 5 years.
Anaphylactic hypersensitivity to previous influenza vaccination or to eggs, neomycin, polymyxin B sulfate (antibiotic) or any of the constituents or trace residues of this vaccine.
Immunisation must be postponed in people who have febrile illness or acute infection.
What are the contraindications to the flu vaccine?
Fluvax vaccine must not be used in children under 5 years.
Anaphylactic hypersensitivity to previous influenza vaccination or to eggs, neomycin, polymyxin B sulfate (antibiotic) or any of the constituents or trace residues of this vaccine.
Immunisation must be postponed in people who have febrile illness or acute infection.
What is the pharmacology of the flu vaccine?
Fluvax vaccine has been shown to induce antibodies to the viral surface glycoproteins, haemagglutinin and neuraminidase. These antibodies are important in the prevention of natural infection.
Seroprotection is generally obtained within 2 to 3 weeks. The duration of post vaccination immunity to homologous strains or to strains closely related to the vaccine strains varies, but is usually 6 to 12 months.
What is the pharmacology of the flu vaccine?
Fluvax vaccine has been shown to induce antibodies to the viral surface glycoproteins, haemagglutinin and neuraminidase. These antibodies are important in the prevention of natural infection.
Seroprotection is generally obtained within 2 to 3 weeks. The duration of post vaccination immunity to homologous strains or to strains closely related to the vaccine strains varies, but is usually 6 to 12 months.
3 clinical features of dermatitis herpetiformis
Itchy papules and vesicles
Elbows, knees, buttocks
Diarrhoea and fatigue
3 clinical features of dermatitis herpetiformis
Itchy papules and vesicles
Elbows, knees, buttocks
Diarrhoea and fatigue
Diagnosis of dermatitis herpertiformis (3 facts)
Skin biopsy with direct immunofluorescence: IgA deposits in the dermal papillae
Serum IgA antibodies
Stop gluten free diet six weeks early
Diagnosis of dermatitis herpertiformis (3 facts)
Skin biopsy with direct immunofluorescence: IgA deposits in the dermal papillae
Serum IgA antibodies
Stop gluten free diet six weeks early
Treatment of dermatitis herpetiformis
Dapsone - response is practically diagnostic
Gluten-free diet
Treatment of dermatitis herpetiformis
Dapsone - response is practically diagnostic
Gluten-free diet
3 main facts about dermatitis herpetiformis
Itchy vesicles of elbows, knees, buttocks
Dx by direct immunofluroescence ( perilesional bx)
Known as GLUTEN rash - assoc c/ coeliac disease/gluten intolerance
3 main facts about dermatitis herpetiformis
Itchy vesicles of elbows, knees, buttocks
Dx by direct immunofluroescence ( perilesional bx)
Known as GLUTEN rash - assoc c/ coeliac disease/gluten intolerance
Which vaccines contain egg?
The following vaccines may contain residual egg protein
- Seasonal influenza vaccine (s)
- Pandemic influenza vaccine(s) (e.g. H1N1, bird or swine flu vaccines)
- Yellow Fever vaccine (important for travellers and those living in an endemic area)
- Q fever vaccine (important in occupational setting)
The amount of residual egg protein in Yellow fever and Q fever vaccines is generally higher than that present in se asonal influenza and H1N1 vaccines.
Egg allergic patients in whom Yellow fever or Q
fever vaccines are indicated should be referred to an allergy/immunology specialist for assessment.
Which vaccines contain egg?
The following vaccines may contain residual egg protein
- Seasonal influenza vaccine (s)
- Pandemic influenza vaccine(s) (e.g. H1N1, bird or swine flu vaccines)
- Yellow Fever vaccine (important for travellers and those living in an endemic area)
- Q fever vaccine (important in occupational setting)
The amount of residual egg protein in Yellow fever and Q fever vaccines is generally higher than that present in se asonal influenza and H1N1 vaccines.
Egg allergic patients in whom Yellow fever or Q
fever vaccines are indicated should be referred to an allergy/immunology specialist for assessment.
What is the significance of a positive parietal cell antibody but negative intrinsic factor antibody?
If parietal cell antibody is positive but intrinsic factor antibody is negative-
Gastric Parietal cell antibody is associated with >90% of patients with Autoimmune
Gastritis, the end result of which may be Pernicious Anemia (PA). In 20-30% of patients, relatives of patients with PA, autoimmune thyroiditis and a small percentage of healthy persons may be positive and run an increased long term risk of pernicious anemia.
A negative Intrinsic Factor antibody result does not exclude the diagnosis of PA as only 60% of patients with PA will have this antibody.
- See more at: http://www.allergy.org.au/health-professionals/papers/consensus-on-anti-intrinsic-factor-antibody-testing#sthash.i4fwedvM.dpuf
What is the significance of a positive parietal cell antibody but negative intrinsic factor antibody?
If parietal cell antibody is positive but intrinsic factor antibody is negative-
Gastric Parietal cell antibody is associated with >90% of patients with Autoimmune
Gastritis, the end result of which may be Pernicious Anemia (PA). In 20-30% of patients, relatives of patients with PA, autoimmune thyroiditis and a small percentage of healthy persons may be positive and run an increased long term risk of pernicious anemia.
A negative Intrinsic Factor antibody result does not exclude the diagnosis of PA as only 60% of patients with PA will have this antibody.
- See more at: http://www.allergy.org.au/health-professionals/papers/consensus-on-anti-intrinsic-factor-antibody-testing#sthash.i4fwedvM.dpuf
What is the significance of a negative parietal cell antibody but positive intrinsic factor antibody?
Immunological evidence of Pernicious Anemia (if the patient has low Hb
macrocytosis and low B12 levels)
or (if only low B12)
The clinical significance of these results is uncertain in the absence of anaemia or
macrocytosis. Suggest repeating in 6 mths with serum gastrin, full blood count and
fasting B12.
What is the significance of a negative parietal cell antibody but positive intrinsic factor antibody?
Immunological evidence of Pernicious Anemia (if the patient has low Hb
macrocytosis and low B12 levels)
or (if only low B12)
The clinical significance of these results is uncertain in the absence of anaemia or
macrocytosis. Suggest repeating in 6 mths with serum gastrin, full blood count and
fasting B12.
Name the commonly implicated drugs in IgE reactions, mast cell degranulation, urticaria due to effect on metabolic pathways, and type 3 immune complex formation
Type I IgE-mediated reactions (e.g., β-lactams, other antibiotics, antimicrobials such as sulfonamides and trimethoprim, neuro- muscular blockers, pyrazolones);
Direct mast cell degranulation (e.g., opioids, contrast media, vancomycin, quinine, pentamidine, atropine)
Drugs that promote or exacerbate urticaria due to their pharmacological effects on metabolic pathways (angiotensin-converting enzyme [ACE] inhibitors, e.g., captopril, enalopril, lisinopril; NSAIDs, e.g., aspirin, indomethacin, ibuprofen);
Drugs involved in type III immune complex formation as in serum sickness (e.g., amoxicillin, cefaclor, ciprofloxacin, monoclonal antibodies); excipients, preservatives, coloring agents, antioxidants (e.g., benzoic acid, sulfites, tartrazine, butylated hydroxytoluene).
Note that evidence for adverse effects, including the induction of urticaria, is often lacking for implicated agents in the latter group
Name the commonly implicated drugs in IgE reactions, mast cell degranulation, urticaria due to effect on metabolic pathways, and type 3 immune complex formation
Type I IgE-mediated reactions (e.g., β-lactams, other antibiotics, antimicrobials such as sulfonamides and trimethoprim, neuro- muscular blockers, pyrazolones);
Direct mast cell degranulation (e.g., opioids, contrast media, vancomycin, quinine, pentamidine, atropine)
Drugs that promote or exacerbate urticaria due to their pharmacological effects on metabolic pathways (angiotensin-converting enzyme [ACE] inhibitors, e.g., captopril, enalopril, lisinopril; NSAIDs, e.g., aspirin, indomethacin, ibuprofen);
Drugs involved in type III immune complex formation as in serum sickness (e.g., amoxicillin, cefaclor, ciprofloxacin, monoclonal antibodies); excipients, preservatives, coloring agents, antioxidants (e.g., benzoic acid, sulfites, tartrazine, butylated hydroxytoluene).
Note that evidence for adverse effects, including the induction of urticaria, is often lacking for implicated agents in the latter group
What is a type I hypersensitivity reaction?
Anaphylaxis (e.g., bee sting, some food/drug allergies)
Allergic and atopic disorders (e.g., rhinitis, hay
fever, eczema, hives, asthma)
IgE binds to mast cells or basophils –> degranulation
Immediate and atopic <30m
What is a type I hypersensitivity reaction?
Anaphylaxis (e.g., bee sting, some food/drug allergies)
Allergic and atopic disorders (e.g., rhinitis, hay
fever, eczema, hives, asthma)
IgE binds to mast cells or basophils –> degranulation
Immediate and atopic <30m
What is a type 2 hypersensitivity reaction?
Antigen causes formation of IgM and IgG antibodies that bind target cell, when combined with complement, destroys target cell. Disease tends to be specific to tissue or site where antigen is found
Transfusion rxn, Rh Incompatibility
Autoimmune hemolytic anemia (AIHA) Pernicious anemia
Idiopathic thrombocytopenic purpura Erythroblastosis fetalis
Acute hemolytic transfusion reactions Rheumatic fever
Goodpasture’s syndrome
Bullous pemphigoid
Pemphigus vulgaris
What is a type 2 hypersensitivity reaction?
Antigen causes formation of IgM and IgG antibodies that bind target cell, when combined with complement, destroys target cell. Disease tends to be specific to tissue or site where antigen is found
Transfusion rxn, Rh Incompatibility
Autoimmune hemolytic anemia (AIHA) Pernicious anemia
Idiopathic thrombocytopenic purpura Erythroblastosis fetalis
Acute hemolytic transfusion reactions Rheumatic fever
Goodpasture’s syndrome
Bullous pemphigoid
Pemphigus vulgaris
What is a type 3 hypersensitivity reaction?
Antibodies and antigens form complexes. Can be associated with vasculitis and systemic manifestations
SLE
Polyarteritis nodosa Poststreptococcal glomerulonephritis
Serum sickness
Arthus reaction (e.g., swelling and inflammation
following tetanus vaccine)
What is a type 3 hypersensitivity reaction?
Antibodies and antigens form complexes. Can be associated with vasculitis and systemic manifestations
SLE
Polyarteritis nodosa Poststreptococcal glomerulonephritis
Serum sickness
Arthus reaction (e.g., swelling and inflammation
following tetanus vaccine)
What is a type IV hypersensitivity reaction?
Antigens cause formation of T-cells that kill target cells (24-48 hours). Response is delayed and does not involve antibodies (vs. types I, II, and III)
Multiple sclerosis
Guillain-Barre syndrome Graft-versus-host disease
PPD (test forM. tuberculosis)
Contact dermatitis (e.g., poison ivy, nickel
allergy)
What is a type IV hypersensitivity reaction?
Antigens cause formation of T-cells that kill target cells (24-48 hours). Response is delayed and does not involve antibodies (vs. types I, II, and III)
Multiple sclerosis
Guillain-Barre syndrome Graft-versus-host disease
PPD (test forM. tuberculosis)
Contact dermatitis (e.g., poison ivy, nickel
allergy)
What is a type V hypersensitivity reaction?
This is an additional type that is sometimes (often in the UK) used as a distinction from Type 2. IgM or IgG, complement.
Instead of binding to cell surface components, the antibodies recognise and bind to the cell surface receptors, which either prevents the intended ligand binding with the receptor or mimics the effects of the ligand, thus impairing cell signaling.
Some clinical examples:
Graves’ disease
Myasthenia gravis
The use of Type 5 is rare. These conditions are more frequently classified as Type 2, though sometimes they are specifically segregated into their own subcategory of Type 2.
What is a type V hypersensitivity reaction?
This is an additional type that is sometimes (often in the UK) used as a distinction from Type 2. IgM or IgG, complement.
Instead of binding to cell surface components, the antibodies recognise and bind to the cell surface receptors, which either prevents the intended ligand binding with the receptor or mimics the effects of the ligand, thus impairing cell signaling.
Some clinical examples:
Graves’ disease
Myasthenia gravis
The use of Type 5 is rare. These conditions are more frequently classified as Type 2, though sometimes they are specifically segregated into their own subcategory of Type 2.
What type of hypersensitivity raction is a febrile nonhemolytic transfusion reaction, and what kind is an acute hemolytic transfusion reaction?
Febrile non-hemolytic:
Type II hypersensitivity reaction. Host antibodies against donor HLA antigens and leukocytes.
Acute hemolytic:
Type II hypersensitivity reaction. Intravascular hemolysis (ABO blood group incompatibility)
or extravascular hemolysis (host antibody reaction against foreign antigen on donor RBCs).
What type of hypersensitivity raction is a febrile nonhemolytic transfusion reaction, and what kind is an acute hemolytic transfusion reaction?
Febrile non-hemolytic:
Type II hypersensitivity reaction. Host antibodies against donor HLA antigens and leukocytes.
Acute hemolytic:
Type II hypersensitivity reaction. Intravascular hemolysis (ABO blood group incompatibility)
or extravascular hemolysis (host antibody reaction against foreign antigen on donor RBCs).
What is a respiratory burst?
Respiratory burst (sometimes called oxidative burst) is the rapid release of reactive oxygen species (superoxide radical and hydrogen peroxide) from different types of cells.
Usually it denotes the release of these chemicals from immune cells, e.g., neutrophils and monocytes, as they come into contact with different bacteria or fungi. They are also released from the ovum of higher animals after the ovum has been fertilized.
NADPH oxidase, an enzyme family in the vasculature (in particular, in vascular disease), produces superoxide, which spontaneously recombines with other molecules to produce reactive free radicals.
To combat infections, immune cells use NADPH oxidase to reduce O2 to oxygen free radical and then H2O2. Neutrophils and monocytes utilize myeloperoxidase to further combine H2O2 with Cl- to produce hypochlorite, which plays a role in destroying bacteria. Absence of NADPH oxidase will prevent the formation of reactive oxygen species and will result in chronic granulomatous disease.
What is a respiratory burst?
Respiratory burst (sometimes called oxidative burst) is the rapid release of reactive oxygen species (superoxide radical and hydrogen peroxide) from different types of cells.
Usually it denotes the release of these chemicals from immune cells, e.g., neutrophils and monocytes, as they come into contact with different bacteria or fungi. They are also released from the ovum of higher animals after the ovum has been fertilized.
NADPH oxidase, an enzyme family in the vasculature (in particular, in vascular disease), produces superoxide, which spontaneously recombines with other molecules to produce reactive free radicals.
To combat infections, immune cells use NADPH oxidase to reduce O2 to oxygen free radical and then H2O2. Neutrophils and monocytes utilize myeloperoxidase to further combine H2O2 with Cl- to produce hypochlorite, which plays a role in destroying bacteria. Absence of NADPH oxidase will prevent the formation of reactive oxygen species and will result in chronic granulomatous disease.
What is proteinase 3?
- lives in neutrophils
- function unknown
- implicated in Wegeners in conjunction with C-anca
What is proteinase 3?
- lives in neutrophils
- function unknown
- implicated in Wegeners in conjunction with C-anca
What is myeloperoxidase?
Lives in neutrophils
P-anca
Produces cytotoxic acids in the respiratory burst
What is myeloperoxidase?
Lives in neutrophils
P-anca
Produces cytotoxic acids in the respiratory burst
What is lactoferrin?
Mucosal defense (saliva, human milk, tears)
Innate antimicrobial activity
Particularly for infants (highly expressed in colostrum and breast milk)
What is lactoferrin?
Mucosal defense (saliva, human milk, tears)
Innate antimicrobial activity
Particularly for infants (highly expressed in colostrum and breast milk)
What is Cathepsin G?
Lives in neutrophils, assists phagocytosis
What is Cathepsin G?
Lives in neutrophils, assists phagocytosis
What is lysozyme?
Innate immunity
Goes for bacterial cell walls
Saliva, tears, mucus, breast milk
What is lysozyme?
Innate immunity
Goes for bacterial cell walls
Saliva, tears, mucus, breast milk
What is the role of lactoferrin in cystic fibrosis?
The human lung and saliva contain a wide range of antimicrobial compound including lactoperoxidase system, producing hypothiocyanite and lactoferrin, with hypothiocyanite missing in cystic fibrosis patients.[55] Lactoferrin, a component of innate immunity, prevents bacterial biofilm development.[56][57] The loss of microbicidal activity and increased formation of biofilm due to decreased lactoferrin activity is observed in patients with cystic fibrosis.[58] These findings demonstrate the important role of lactoferrin in human host defense and especially in lung.[59]
Lactoferrin with hypothiocyanite has been granted orphan drug status by the EMEA[60] and the FDA
What is the role of lactoferrin in cystic fibrosis?
The human lung and saliva contain a wide range of antimicrobial compound including lactoperoxidase system, producing hypothiocyanite and lactoferrin, with hypothiocyanite missing in cystic fibrosis patients.[55] Lactoferrin, a component of innate immunity, prevents bacterial biofilm development.[56][57] The loss of microbicidal activity and increased formation of biofilm due to decreased lactoferrin activity is observed in patients with cystic fibrosis.[58] These findings demonstrate the important role of lactoferrin in human host defense and especially in lung.[59]
Lactoferrin with hypothiocyanite has been granted orphan drug status by the EMEA[60] and the FDA
What does interferon-gamma do?
Activates macrophages and Th1 cells.
Suppresses Th2 cells. Has antiviral and antitumor properties.
What does interferon-gamma do?
Activates macrophages and Th1 cells.
Suppresses Th2 cells. Has antiviral and antitumor properties.
What does cell-mediated immunity mean?
Cell-mediated immunity is an immune response that does not involve antibodies, but rather involves the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.
Cellular immunity protects the body by:
activating antigen-specific cytotoxic T-lymphocytes that are able to induce apoptosis in body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens;
activating macrophages and natural killer cells, enabling them to destroy pathogens; and
stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.
What does cell-mediated immunity mean?
Cell-mediated immunity is an immune response that does not involve antibodies, but rather involves the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.
Cellular immunity protects the body by:
activating antigen-specific cytotoxic T-lymphocytes that are able to induce apoptosis in body cells displaying epitopes of foreign antigen on their surface, such as virus-infected cells, cells with intracellular bacteria, and cancer cells displaying tumor antigens;
activating macrophages and natural killer cells, enabling them to destroy pathogens; and
stimulating cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.
What is the clinical picture of an IgE mediated reaction?
While many reactions are labelled as ‘allergic’, true IgE-mediated immediate hypersensitivity is characterised by the development of the following conditions, usually within one hour of drug administration:
Urticaria;
Angioedema;
Bronchospasm: or
Anaphylaxis (with objectively demonstrated hypotension, hypoxia or tryptase elevation).
What is the clinical picture of an IgE mediated reaction?
While many reactions are labelled as ‘allergic’, true IgE-mediated immediate hypersensitivity is characterised by the development of the following conditions, usually within one hour of drug administration:
Urticaria;
Angioedema;
Bronchospasm: or
Anaphylaxis (with objectively demonstrated hypotension, hypoxia or tryptase elevation).
What is the definition of latex allergy?
As with other types of immediate type hypersensitivity, the diagnosis of latex allergy requires both a history of symptoms on exposure to latex and the demonstration of latex-specific IgE (either by skin prick or in-vitro tests). Either criteria alone is insufficient to diagnose latex allergy.
What is the definition of latex allergy?
As with other types of immediate type hypersensitivity, the diagnosis of latex allergy requires both a history of symptoms on exposure to latex and the demonstration of latex-specific IgE (either by skin prick or in-vitro tests). Either criteria alone is insufficient to diagnose latex allergy.
What are the symptoms of latex allergy?
Related to IgE-mediated mast cell release of inflammatory mediators. Initial symptoms include irritation on contact with itching, redness and swelling. Typically, these symptoms occur within minutes on skin contact with latex gloves, or other rubber products. As exposure and sensitivity increases, the severity of symptoms increases and may include contact urticaria and spread to adjacent areas of skin,
Airborne exposure, particularly to aerosolised latex allergen laden cornstarch from powdered latex gloves may lead to nasal, ocular and respiratory symptoms.
There is an association between latex allergy and allergy to a variety of fruits, including banana, avocado, potato, tomato, chestnut and kiwi fruit, probably because latex protein allergens are structurally homologous with other plant proteins.
What are the symptoms of latex allergy?
Related to IgE-mediated mast cell release of inflammatory mediators. Initial symptoms include irritation on contact with itching, redness and swelling. Typically, these symptoms occur within minutes on skin contact with latex gloves, or other rubber products. As exposure and sensitivity increases, the severity of symptoms increases and may include contact urticaria and spread to adjacent areas of skin,
Airborne exposure, particularly to aerosolised latex allergen laden cornstarch from powdered latex gloves may lead to nasal, ocular and respiratory symptoms.
There is an association between latex allergy and allergy to a variety of fruits, including banana, avocado, potato, tomato, chestnut and kiwi fruit, probably because latex protein allergens are structurally homologous with other plant proteins.
How do you diagnose latex allergy?
Although the history alone may be strongly suggestive, diagnosis requires confirmatory testing. Worldwide, skin prick testing is the most common method used to diagnose latex allergy. A commercial extract is available for skin prick testing, but is not registered by the Therapeutic Goods Administration
How do you diagnose latex allergy?
Although the history alone may be strongly suggestive, diagnosis requires confirmatory testing. Worldwide, skin prick testing is the most common method used to diagnose latex allergy. A commercial extract is available for skin prick testing, but is not registered by the Therapeutic Goods Administration
What do T-reg cells express?
What do they do?
CD4, CD25, and Foxp3 (CD4+CD25+ regulatory T cells).
T regulatory cells are a component of the immune system that suppress immune responses of other cells. This is an important “self-check” built into the immune system to prevent excessive reactions.
What do T-reg cells express?
What do they do?
CD4, CD25, and Foxp3 (CD4+CD25+ regulatory T cells).
T regulatory cells are a component of the immune system that suppress immune responses of other cells. This is an important “self-check” built into the immune system to prevent excessive reactions.
3 points about IgA deficiency
Most common primary immunodeficiency
Sinusitis, otitis, bronchitis - more encapsulated bacteria
May have high titers of IgA antibody - be very careful with blood or plasma transfusions as
3 points about IgA deficiency
Most common primary immunodeficiency
Sinusitis, otitis, bronchitis - more encapsulated bacteria
May have high titers of IgA antibody - be very careful with blood or plasma transfusions as
3 points about CVID
Defect in terminal differentiation of B cells, with absent plasma cells and deficient synthesis of secreted antibody.
Pyogenic infections - frequent sinopulmonary infections secondary to humoral immune deficiency.
Confirmation by evaluation of serum immuno- globulin levels and deficient functional antibody responses.
3 points about CVID
Defect in terminal differentiation of B cells, with absent plasma cells and deficient synthesis of secreted antibody.
Pyogenic infections - frequent sinopulmonary infections secondary to humoral immune deficiency.
Confirmation by evaluation of serum immuno- globulin levels and deficient functional antibody responses.
What is the general presentation of SLE?
Young women
Photosensitivity rash
Joint sx in 90%
Anaemia, leukopaenia, thrombocytopaenia
What is the general presentation of SLE?
Young women
Photosensitivity rash
Joint sx in 90%
Anaemia, leukopaenia, thrombocytopaenia
What are two main mechanisms of the clinical manifestations of SLE?
- trapping of antigen-antibody complexes in capillaries of visceral structures
- autoantibody mediated destruction of host cells (i.e. thrombocytopaenia)
What are two main mechanisms of the clinical manifestations of SLE?
- trapping of antigen-antibody complexes in capillaries of visceral structures
- autoantibody mediated destruction of host cells (i.e. thrombocytopaenia)
What are the HLA haplotype associations of SLE?
DR2
DR3
Null complement alleles
What are the HLA haplotype associations of SLE?
DR2
DR3
Null complement alleles
How do you differentiate drug induced lupus from SLE?
- No nephritis or cerebritis
- Sex ratio is nearly equal
- Hypocomplementaemia and anti-DSDNA antibodies are absent
- Clinical / lab features revert when drug is withdrawn
How do you differentiate drug induced lupus from SLE?
- No nephritis or cerebritis
- Sex ratio is nearly equal
- Hypocomplementaemia and anti-DSDNA antibodies are absent
- Clinical / lab features revert when drug is withdrawn
Which drugs have a definite association with lupus?
Chlorpromazine
Methyldopa
Hydralazine
Isoniazid
Minocycline
Procainamide
Quinidine
Which drugs have a definite association with lupus?
Chlorpromazine
Methyldopa
Hydralazine
Isoniazid
Minocycline
Procainamide
Quinidine
How does the criteria for the classification of SLE work?
Need 4 or more out of 11.
- Malar rash
- Discoid rash
- Photosensitivity
- Oral ulcers
- Arthritis
- Serositis
- Kidney disease (inc proteinuria or casts)
- Neuro disease (seizures or psychosis w/o other cause)
- Haematologic disorders (paenias)
- Immunologic abnormalities (+ LE cell prep (not done now), antibody to native DNA, or SM, or false + for syphilis)
- Positive ANA.
How does the criteria for the classification of SLE work?
Need 4 or more out of 11.
- Malar rash
- Discoid rash
- Photosensitivity
- Oral ulcers
- Arthritis
- Serositis
- Kidney disease (inc proteinuria or casts)
- Neuro disease (seizures or psychosis w/o other cause)
- Haematologic disorders (paenias)
- Immunologic abnormalities (+ LE cell prep (not done now), antibody to native DNA, or SM, or false + for syphilis)
- Positive ANA.
How do you differentiate the swanneck deformities of lupus to other kinds of inflammatory arthritis?
- reversible
- no erosive changes on XR
- subcutaneous nodules are rare
How do you differentiate the swanneck deformities of lupus to other kinds of inflammatory arthritis?
- reversible
- no erosive changes on XR
- subcutaneous nodules are rare
What are the common pulmonary manifestations of SLE?
Pleurisy
Pleural effusion
Bronchopneumonia
Pneumonitis
Restrictive lung disease (rarer)
Alveolar haemorrhage (rare and life threatening)
What are the common pulmonary manifestations of SLE?
Pleurisy
Pleural effusion
Bronchopneumonia
Pneumonitis
Restrictive lung disease (rarer)
Alveolar haemorrhage (rare and life threatening)
What are the cardiac manifestations of SLE?
Pericardium affected in the majority of patients
Heart failure from myocarditis and hypertension
Arrhythmia common
Silent atypical verrucous Libman Sacks endocarditis can cause MR.
What are the cardiac manifestations of SLE?
Pericardium affected in the majority of patients
Heart failure from myocarditis and hypertension
Arrhythmia common
Silent atypical verrucous Libman Sacks endocarditis can cause MR.
What are the important points about DsDNA and anti-smith antibodies in the dx of lupus?
Sensitive but not specific - can’t exclude the disease on the basis of a negative test.
DSDNA correlates with disease activity in some, but not anti-Sm
Complement levels are low only when disease active
What are the important points about DsDNA and anti-smith antibodies in the dx of lupus?
Sensitive but not specific - can’t exclude the disease on the basis of a negative test.
DSDNA correlates with disease activity in some, but not anti-Sm
Complement levels are low only when disease active
How do you confirm the presence of a lupus anticoagulant?
Confirmed by an abnormal Russell viper venom time (RVVT) that corrects with the addition of phospholipid but not normal plasma.
How do you confirm the presence of a lupus anticoagulant?
Confirmed by an abnormal Russell viper venom time (RVVT) that corrects with the addition of phospholipid but not normal plasma.
What Ig isotype is the most pathogenic in terms of anti-cardiolipin antibodies?
IgM
What Ig isotype is the most pathogenic in terms of anti-cardiolipin antibodies?
IgM
Which disease gives a false positive for syphilis and which test?
Anti-phospholipid syndrome
RPR is positive but specific anti-treponemal assay is negative
Which disease gives a false positive for syphilis and which test?
Anti-phospholipid syndrome
RPR is positive but specific anti-treponemal assay is negative
What are the urine findings of SLE?
Almost always in association with renal lesions
Showers of RBCs w/ or w/o casts
Proteinuria (mild to nephrotic)
Above are frequent during exacerbations
What are the urine findings of SLE?
Almost always in association with renal lesions
Showers of RBCs w/ or w/o casts
Proteinuria (mild to nephrotic)
Above are frequent during exacerbations
What is the role of hydroxychloroquine in SLE?
Rashes and joint symptoms
Reduces incidence of severe disease flares
Need annual monitoring for retinal changes
What is the role of hydroxychloroquine in SLE?
Rashes and joint symptoms
Reduces incidence of severe disease flares
Need annual monitoring for retinal changes
What is the role of danazol in SLE?
Androgenic corticosteroid
Effective for thrombocytopaenia not responsive to corticosteroids
What is the role of danazol in SLE?
Androgenic corticosteroid
Effective for thrombocytopaenia not responsive to corticosteroids
When are systemic corticosteroids generally given in SLE?
GN, haemolytic anaemia, pericarditis, myocarditis, CNS, TTP and alveolar haemorrhage
Not usually for minor arthritis, skin rash, leukopaenia or anaemia of chronic disease.
When are systemic corticosteroids generally given in SLE?
GN, haemolytic anaemia, pericarditis, myocarditis, CNS, TTP and alveolar haemorrhage
Not usually for minor arthritis, skin rash, leukopaenia or anaemia of chronic disease.
How is CNS lupus managed?
Corticosteroids however these may mimic lupus cerebritis in that they can cause psychosis - may need to reduce dose.
How is CNS lupus managed?
Corticosteroids however these may mimic lupus cerebritis in that they can cause psychosis - may need to reduce dose.
How is severe lupus nephritis treated?
Induction and maintenance
Cyclophosphamide - improves renal but not patient survival
MMF is an effective alternative
How is severe lupus nephritis treated?
Induction and maintenance
Cyclophosphamide - improves renal but not patient survival
MMF is an effective alternative
How do you protect women from premature ovarian failure when treating SLE nephritis with cyclophosphamide?
GRH analogs
How do you protect women from premature ovarian failure when treating SLE nephritis with cyclophosphamide?
GRH analogs
What is the mechanism of action of Belalimumab in SLE?
B-lymphocyte stimulator (BLyS, also referred to as BAFF and TNFSF13), a member of the tumour necrosis factor (TNF) ligand family, inhibits B-cell apoptosis and stimulates the differentiation of B-cells into immunoglobulin producing plasma cells. BLyS is overexpressed in patients with SLE. There is a strong association between SLE disease activity and plasma BLyS levels.
Belimumab is a fully human IgG1lambda monoclonal antibody that specifically binds to soluble human BLyS and inhibits its biological activity. Belimumab does not bind B-cells directly, but by binding BLyS, belimumab inhibits the survival of B-cells, including autoreactive B-cells, and reduces the differentiation of B-cells into immunoglobulin producing plasma cells.
What is the mechanism of action of Belalimumab in SLE?
B-lymphocyte stimulator (BLyS, also referred to as BAFF and TNFSF13), a member of the tumour necrosis factor (TNF) ligand family, inhibits B-cell apoptosis and stimulates the differentiation of B-cells into immunoglobulin producing plasma cells. BLyS is overexpressed in patients with SLE. There is a strong association between SLE disease activity and plasma BLyS levels.
Belimumab is a fully human IgG1lambda monoclonal antibody that specifically binds to soluble human BLyS and inhibits its biological activity. Belimumab does not bind B-cells directly, but by binding BLyS, belimumab inhibits the survival of B-cells, including autoreactive B-cells, and reduces the differentiation of B-cells into immunoglobulin producing plasma cells.
What is the indication for belalimumab in SLE?
Benlysta is indicated as add-on therapy for reducing disease activity in adult patients with active, autoantibody positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g. ANA titre greater than or equal to 1:80 and/or anti-dsDNA titre greater than or equal to 30 IU/mL) despite standard therapy.
What is the indication for belalimumab in SLE?
Benlysta is indicated as add-on therapy for reducing disease activity in adult patients with active, autoantibody positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g. ANA titre greater than or equal to 1:80 and/or anti-dsDNA titre greater than or equal to 30 IU/mL) despite standard therapy.
How should pregnant women with antiphospholipid syndrome be treated?
Assuming recurrent fetal loss - LMWH plus aspirin
How should pregnant women with antiphospholipid syndrome be treated?
Assuming recurrent fetal loss - LMWH plus aspirin
What is the mortality profile of SLE?
Early - kidney or CNS disease
Later - cardiac disease due to accelerated atherosclerosis linked to chronic inflammation - MI rate is 5x higher in persons with SLE
Need to avoid other risk factors and smoking
What is the mortality profile of SLE?
Early - kidney or CNS disease
Later - cardiac disease due to accelerated atherosclerosis linked to chronic inflammation - MI rate is 5x higher in persons with SLE
Need to avoid other risk factors and smoking
What happens to cell mediated immunity in lupus?
It is significantly impaired - worse if moderately active to severe disease
What happens to cell mediated immunity in lupus?
It is significantly impaired - worse if moderately active to severe disease
3 points about diffuse proliferative GN
- most serious form of renal SLE - a form of Type 2 Rapidly progressive (crescentic) GN
- endothelial and mesangial proliferation of entire glomerulus - immune complexes (Ig and complement) thicken capillary wall
- ‘wire loops’ on light microscopy or electron-dense subendothelial immune complexes between endothelium and BM on electron microscopy
3 points about diffuse proliferative GN
- most serious form of renal SLE - a form of Type 2 Rapidly progressive (crescentic) GN
- endothelial and mesangial proliferation of entire glomerulus - immune complexes (Ig and complement) thicken capillary wall
- ‘wire loops’ on light microscopy or electron-dense subendothelial immune complexes between endothelium and BM on electron microscopy
What are the indications for bee-venom immunotherapy?
The indications for venom immunotherapy are a history of previous anaphylaxis to a
sting and a positive allergy skin (venom-speci
fic IgE). Children with a recent history of
anaphylaxis and a positive skin test have
a 30% to 70% chance of a generalized
reaction to a subsequent sting.
Children with a history of large local reacti
ons, and those with generalised reactions
limited to cutaneous signs and symptoms
(with no respiratory or circulatory
manifestations)are at low risk of developing a more severe allergic reactions (<10%).
Venom immunotherapy is not required in these low-risk cases
What are the indications for bee-venom immunotherapy?
The indications for venom immunotherapy are a history of previous anaphylaxis to a
sting and a positive allergy skin (venom-speci
fic IgE). Children with a recent history of
anaphylaxis and a positive skin test have
a 30% to 70% chance of a generalized
reaction to a subsequent sting.
Children with a history of large local reacti
ons, and those with generalised reactions
limited to cutaneous signs and symptoms
(with no respiratory or circulatory
manifestations)are at low risk of developing a more severe allergic reactions (<10%).
Venom immunotherapy is not required in these low-risk cases
How effective is bee-venom immunotherapy?
Once maintenance dose has been reached, less than 10% for bee venom and less than 5% for wasp. Maintenance should be continued for 3-5 years.
Approx 20% of subjects will have a generalised allergic reactioin at some stage during the injections
How effective is bee-venom immunotherapy?
Once maintenance dose has been reached, less than 10% for bee venom and less than 5% for wasp. Maintenance should be continued for 3-5 years.
Approx 20% of subjects will have a generalised allergic reactioin at some stage during the injections
3 clinical findings of Pemphigus
Flaccid bullae, crusts and erosions in crops or waves
First on mucus membrane or scalp
Rubbing a finger on surface of uninvolved skin may cause easy separation of the dermis (Nikolsky sign)
3 clinical findings of Pemphigus
Flaccid bullae, crusts and erosions in crops or waves
First on mucus membrane or scalp
Rubbing a finger on surface of uninvolved skin may cause easy separation of the dermis (Nikolsky sign)
What is the autoantibody to in Pemphigus?
Intercellular adhesion molecules
What is the autoantibody to in Pemphigus?
Intercellular adhesion molecules
What is acantholysis?
Acantholysis is the loss of intercellular connections, such as desmosomes, resulting in loss of cohesion between keratinocytes,[1] seen in diseases such as pemphigus vulgaris.[2] It is absent in bullous pemphigoid, making it useful for differential diagnosis.
This histological feature is also seen in herpes simplex infections (HSV 1 and 2).
What is acantholysis?
Acantholysis is the loss of intercellular connections, such as desmosomes, resulting in loss of cohesion between keratinocytes,[1] seen in diseases such as pemphigus vulgaris.[2] It is absent in bullous pemphigoid, making it useful for differential diagnosis.
This histological feature is also seen in herpes simplex infections (HSV 1 and 2).
How is the diagnosis of pemphigus made?
- flat bullae
- positive Nikolsky sign
- gold standard: direct IF of punch bx - acantholytic cells
- serum elisa for antibodies to intercellular adhesion molecules
How is the diagnosis of pemphigus made?
- flat bullae
- positive Nikolsky sign
- gold standard: direct IF of punch bx - acantholytic cells
- serum elisa for antibodies to intercellular adhesion molecules
How do you differentiate pemphigus from other bullous diseases?
Only one to have flaccid blisters and none of the others have acantholysis on bx
How do you differentiate pemphigus from other bullous diseases?
Only one to have flaccid blisters and none of the others have acantholysis on bx
How is Pemphigus treated?
Systemic therapy ASAP
Corticosteroid plus sparing agent from the start as they take weeks to work
Azathioprine or MMF.
Ritux if refractory to diminish amount of autoantibody
IVIG if this fails plus ritux - but watch for thromboses from high dose IVIG.
How is Pemphigus treated?
Systemic therapy ASAP
Corticosteroid plus sparing agent from the start as they take weeks to work
Azathioprine or MMF.
Ritux if refractory to diminish amount of autoantibody
IVIG if this fails plus ritux - but watch for thromboses from high dose IVIG.
What is the prognosis of pemphigus?
Chronic
Infection most cause of death, usually from s.aures
1/3 remit
What is the prognosis of pemphigus?
Chronic
Infection most cause of death, usually from s.aures
1/3 remit
What are the clinical features of bullous pemphigoid?
Tense blisters in flexural areas, pruritus
Sparing of face and mucus membranes
Men over 60, into 80s
May be preceded by urticarial or oedematous lesions for months
What are the clinical features of bullous pemphigoid?
Tense blisters in flexural areas, pruritus
Sparing of face and mucus membranes
Men over 60, into 80s
May be preceded by urticarial or oedematous lesions for months
How is the diagnosis of bullous pemphigus made?
Light microscopy of bx
- subepidermal blister
Direct IF
- IgG and C3 at dermal epidermal jtn
How is the diagnosis of bullous pemphigus made?
Light microscopy of bx
- subepidermal blister
Direct IF
- IgG and C3 at dermal epidermal jtn
How is bullous pemphigus treated?
- ultrapotent topical steroids if mild
- if widespread can give systemic corticosteroids, or erythromycin, tetracycline or nicotinamide (NOT nicotinic acid or niacin!)
- dapsone works in mucous membrane pemphigoid.
- MMF if refractory
How is bullous pemphigus treated?
- ultrapotent topical steroids if mild
- if widespread can give systemic corticosteroids, or erythromycin, tetracycline or nicotinamide (NOT nicotinic acid or niacin!)
- dapsone works in mucous membrane pemphigoid.
- MMF if refractory
What is the underlying pathophysiology of bullous pemphigoid?
The bullae are formed by an immune reaction, initiated by the formation of IgG[5] autoantibodies targeting Dystonin, also called Bullous Pemphigoid Antigen 1,[6] and/or type XVII collagen, also called Bullous Pemphigoid Antigen 2,[7] which is a component of hemidesmosomes
What is the underlying pathophysiology of bullous pemphigoid?
The bullae are formed by an immune reaction, initiated by the formation of IgG[5] autoantibodies targeting Dystonin, also called Bullous Pemphigoid Antigen 1,[6] and/or type XVII collagen, also called Bullous Pemphigoid Antigen 2,[7] which is a component of hemidesmosomes
How does dapsone work in treating skin conditions?
When used for the treatment of skin conditions in which bacteria do not have a role, the mechanism or action of dapsone is not well understood. Dapsone has anti-inflammatory and immunomodulatory effects,[36] which are thought to come from the drug’s blockade of myeloperoxidase. This is thought to be its mechanism of action in treating dermatitis herpetiformis.[37]
As part of the respiratory burst that neutrophils use to kill bacteria, myeloperoxidase converts hydrogen peroxide (H2O2) into hypochlorous acid (HOCl). HOCl is the most potent oxidant generated by neutrophils, and can cause significant tissue damage during inflammation. Dapsone arrests myeloperoxidase in an inactive intermediate form, reversibly inhibiting the enzyme. This prevents accumulation of hypochlorous acid, and reduces tissue damage during inflammation
How does dapsone work in treating skin conditions?
When used for the treatment of skin conditions in which bacteria do not have a role, the mechanism or action of dapsone is not well understood. Dapsone has anti-inflammatory and immunomodulatory effects,[36] which are thought to come from the drug’s blockade of myeloperoxidase. This is thought to be its mechanism of action in treating dermatitis herpetiformis.[37]
As part of the respiratory burst that neutrophils use to kill bacteria, myeloperoxidase converts hydrogen peroxide (H2O2) into hypochlorous acid (HOCl). HOCl is the most potent oxidant generated by neutrophils, and can cause significant tissue damage during inflammation. Dapsone arrests myeloperoxidase in an inactive intermediate form, reversibly inhibiting the enzyme. This prevents accumulation of hypochlorous acid, and reduces tissue damage during inflammation
What is dapsone?
Important SEs?
Antibiotic often used for skin problems
Triggers G6PD haemolysis
General hemolysis
Methemoglobinaemia
What is dapsone?
Important SEs?
Antibiotic often used for skin problems
Triggers G6PD haemolysis
General hemolysis
Methemoglobinaemia
What is the indication for boceprevir & telaprevir?
Indicated for the treatment of chronic hepatitis C (HCV) genotype 1 infection, in a combination regimen with peginterferon alpha and ribavirin, in adult patients (18 years and older) with compensated liver disease who are previously untreated or who have failed previous therapy.
What is the indication for boceprevir & telaprevir?
Indicated for the treatment of chronic hepatitis C (HCV) genotype 1 infection, in a combination regimen with peginterferon alpha and ribavirin, in adult patients (18 years and older) with compensated liver disease who are previously untreated or who have failed previous therapy.
What are the contraindications to boceprevir and telaprevir?
-significant hypersensitivity to the active substance or any of its excipients.
Patients with autoimmune hepatitis.
Patients with hepatic decompensation [Child-Pugh score > 6 (class B and C)] (see Pharmacology).
Coadministration with medicines that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life threatening events such as orally administered midazolam, triazolam, amiodarone, cisapride, simvastatin, lovastatin, alfuzosin, doxazosin, silodosin, tamsulosin, Revatio (sildenafil) or tadalafil when used for the treatment of pulmonary arterial hypertension, and ergot derivatives (dihydroergotamine, ergotamine)
Pregnant women (ribavirin is the culprit)
What are the contraindications to boceprevir and telaprevir?
-significant hypersensitivity to the active substance or any of its excipients.
Patients with autoimmune hepatitis.
Patients with hepatic decompensation [Child-Pugh score > 6 (class B and C)] (see Pharmacology).
Coadministration with medicines that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life threatening events such as orally administered midazolam, triazolam, amiodarone, cisapride, simvastatin, lovastatin, alfuzosin, doxazosin, silodosin, tamsulosin, Revatio (sildenafil) or tadalafil when used for the treatment of pulmonary arterial hypertension, and ergot derivatives (dihydroergotamine, ergotamine)
Pregnant women (ribavirin is the culprit)
How does boceprevir and telaprevir work?
Boceprevir - inhibitor of the HCV NS3 protease
Telaprevir is an inhibitor of the HCV NS3-4A serine protease, which is essential for viral replication.
How does boceprevir and telaprevir work?
Boceprevir - inhibitor of the HCV NS3 protease
Telaprevir is an inhibitor of the HCV NS3-4A serine protease, which is essential for viral replication.
What is the evidence behind telaprevir and boceprevir?
In patients with hepatitis C genotype 1, telaprevir significantly improves the rates of sustained virological responses when added to standard treatment.
A meta-analysis comparing the two found that efficacy was comparable, but rash and pruritus were more common with telaprevir.
Anaemia is a common adverse effect of both - need to monitor every four weeks, and reduce dose of ribavirin if necessary
What is the evidence behind telaprevir and boceprevir?
In patients with hepatitis C genotype 1, telaprevir significantly improves the rates of sustained virological responses when added to standard treatment.
A meta-analysis comparing the two found that efficacy was comparable, but rash and pruritus were more common with telaprevir.
Anaemia is a common adverse effect of both - need to monitor every four weeks, and reduce dose of ribavirin if necessary
How does sofosbuvir work?
Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated by HCV NS5B and acts as a chain terminator
How does sofosbuvir work?
Sofosbuvir is a pan-genotypic inhibitor of the HCV NS5B RNA dependent RNA polymerase, which is essential for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated by HCV NS5B and acts as a chain terminator
What is the evidence behind sofosbuvir?
- previously untreated patients with genotypes 1, 4, 5 or 6.
- Response rates in genotype 3 infections were considerably lower than those in genotype 2 infections. Liver cirrhosis was also associated with lower response rates, particularly in those with genotype 3 disease - these people may need to take treatment for longer.
Sofosbuvir also provides an alternative for people who have relapsed, cannot tolerate or do not want to take interferon-containing regimens but urgently need treatment
What is the evidence behind sofosbuvir?
- previously untreated patients with genotypes 1, 4, 5 or 6.
- Response rates in genotype 3 infections were considerably lower than those in genotype 2 infections. Liver cirrhosis was also associated with lower response rates, particularly in those with genotype 3 disease - these people may need to take treatment for longer.
Sofosbuvir also provides an alternative for people who have relapsed, cannot tolerate or do not want to take interferon-containing regimens but urgently need treatment
What are the clinical features of Sjogren’s disease?
Slow and benign course usually
Xerostomia (dry mouth)
Enlarged parotids (2/3 of primary Sjogren’s)
Ocular symptoms – Schirmer’s test, corneal ulcerations
What are the clinical features of Sjogren’s disease?
Slow and benign course usually
Xerostomia (dry mouth)
Enlarged parotids (2/3 of primary Sjogren’s)
Ocular symptoms – Schirmer’s test, corneal ulcerations
What are the disease associations of secondary Sjogren’s?
RA
SLE
Scleroderma
Mixed CT disease
Primary biliary cirrhosis
Vasculitis
Chronic active hepatitis
Predominantly middle aged women
What are the disease associations of secondary Sjogren’s?
RA
SLE
Scleroderma
Mixed CT disease
Primary biliary cirrhosis
Vasculitis
Chronic active hepatitis
Predominantly middle aged women
What is the pathogenesis of Sjogrens?
Lymphocytic infiltration of exocrine glands and B lymphocyte hyper-reactivity, circulating autoantibodies
25% also have oligomonoclonal B cells, cryoprecipitable monoclonal immunoglobulins, RF activity
What is the pathogenesis of Sjogrens?
Lymphocytic infiltration of exocrine glands and B lymphocyte hyper-reactivity, circulating autoantibodies
25% also have oligomonoclonal B cells, cryoprecipitable monoclonal immunoglobulins, RF activity
What are the systemic manifestations of Sjogrens?
Arthritis/arthralgias (60%)
Raynaud’s phenomenon (40%)
Lymphadenopathy (15%)
Lung involvement (15%) – rarely clinically important
Vasculitis (10%)
Kidney involvement (10%) (interstitial nephritis or tubular dysfunction w/ or without acidosis)
Liver involvement (5%)
Lymphoma (5%)
What are the systemic manifestations of Sjogrens?
Arthritis/arthralgias (60%)
Raynaud’s phenomenon (40%)
Lymphadenopathy (15%)
Lung involvement (15%) – rarely clinically important
Vasculitis (10%)
Kidney involvement (10%) (interstitial nephritis or tubular dysfunction w/ or without acidosis)
Liver involvement (5%)
Lymphoma (5%)
What are the features of lymphoma associated with Sjogrens?
Usually later in illness, associated with persistent parotid enlargement, purpura, leukopaenia, cryoglobulinaemia, low C4. Usually low grade, extra-nodal, B cell.
What are the features of lymphoma associated with Sjogrens?
Usually later in illness, associated with persistent parotid enlargement, purpura, leukopaenia, cryoglobulinaemia, low C4. Usually low grade, extra-nodal, B cell.
What is Type 1 Renal Tubular acidosis and how do you treat it?
- failure to excrete hydrogen ions at the distal tubule
- alkaline urine and serum acidosis
- hypokalemia
- renal stones
- treat with potassium citrate, will also inhibit calcium excretion
What is Type 1 Renal Tubular acidosis and how do you treat it?
- failure to excrete hydrogen ions at the distal tubule
- alkaline urine and serum acidosis
- hypokalemia
- renal stones
- treat with potassium citrate, will also inhibit calcium excretion
What is Type 2 Renal Tubular acidosis and how do you treat it?
Failure to reabsorb HCO3 in the proximal tubule
Hypokalemia
Associated with bone demineralisation and rickets
Treat with potassium citrate
What is Type 2 Renal Tubular acidosis and how do you treat it?
Failure to reabsorb HCO3 in the proximal tubule
Hypokalemia
Associated with bone demineralisation and rickets
Treat with potassium citrate
What is Type 4 renal tubular acidosis?
Hypoaldosteronism - not renal and not acidotic!
- treated with fludrocort and loop diuretics
What is Type 4 renal tubular acidosis?
Hypoaldosteronism - not renal and not acidotic!
- treated with fludrocort and loop diuretics
How do you differentiate between the three types of renal tubular acidosis?
Potassium low in type 1 and 2, elevated in type 4
Urine pH very high in type 1 (>5.3)
High to normal in type 2 (5.3 then drops)
Low in type 4 (less than 5.3)
How do you differentiate between the three types of renal tubular acidosis?
Potassium low in type 1 and 2, elevated in type 4
Urine pH very high in type 1 (>5.3)
High to normal in type 2 (5.3 then drops)
Low in type 4 (less than 5.3)
What are the causes of Type 1 renal tubular acidosis?
Autoimminue diseases (eg Sjogren’s syndrome, SLE, thyroiditis)
Disorders which cause nephrocalcinosis (eg primary hyperparathyroidism, vitamin D intoxication) - although nephrocalcinosis can cause RTA!!
Cirrhosis
Drugs or toxins (eg amphotericin B, toluene inhalation, lithium)
Miscellaneous - other renal disorders (eg obstructive uropathy)
Hereditary (genetic)
What are the causes of Type 1 renal tubular acidosis?
Autoimminue diseases (eg Sjogren’s syndrome, SLE, thyroiditis)
Disorders which cause nephrocalcinosis (eg primary hyperparathyroidism, vitamin D intoxication) - although nephrocalcinosis can cause RTA!!
Cirrhosis
Drugs or toxins (eg amphotericin B, toluene inhalation, lithium)
Miscellaneous - other renal disorders (eg obstructive uropathy)
Hereditary (genetic)
What are the causes of type 2 renal tubular acidosis?
Fanconi’s syndrome (proximal tubular disease)
Drugs
Myeloma and amyloidosis
Vitamin-D deficiency
Heavy metals
What are the causes of type 2 renal tubular acidosis?
Fanconi’s syndrome (proximal tubular disease)
Drugs
Myeloma and amyloidosis
Vitamin-D deficiency
Heavy metals
What are the causes of type IV renal tubular acidosis?
Hypoaldosteronism
Hyporeninism
Drugs: ACEIs, NSAIDS, Amiloride, Spironolactone, Heparin
Pseudohypoaldosteronism
What are the causes of type IV renal tubular acidosis?
Hypoaldosteronism
Hyporeninism
Drugs: ACEIs, NSAIDS, Amiloride, Spironolactone, Heparin
Pseudohypoaldosteronism
What is pseudohypoaldosteronism?
Pseudohypoaldosteronism (PHA) is a condition that mimics hypoaldosteronism.[1] However, the condition is due to a failure of response to aldosterone, and levels of aldosterone are actually elevated, due to a lack of feedback inhibition.
What is pseudohypoaldosteronism?
Pseudohypoaldosteronism (PHA) is a condition that mimics hypoaldosteronism.[1] However, the condition is due to a failure of response to aldosterone, and levels of aldosterone are actually elevated, due to a lack of feedback inhibition.
What are the causes of primary aldosterone deficiency?
Primary adrenal insufficiency
Congenital adrenal hyperplasia (21 and 11β but not 17)
Aldosterone synthase deficiency
What are the causes of primary aldosterone deficiency?
Primary adrenal insufficiency
Congenital adrenal hyperplasia (21 and 11β but not 17)
Aldosterone synthase deficiency
Why do you get kidney stones in type 1 RTA?
Hypercalciuria, hyperphosphatemia, nephrolithiasis (calcium phosphate stones) and nephrocalcinosis are frequently associated with untreated type 1 RTA.
The hypercalciuria is thought to be due to 1) increased calcium phosphate release from bone as a result of bone buffering of excess acid and 2) reduction in tubular calcium reabsorption secondary to chronic acidosis.
The hypercalciuria, alkaline urine, and reduced excretion of citrate in the urine (which normally prevents calcium crystallization) promote the precipitation of calcium phosphate and stone formation. The hypocitraturia is thought to be due to the effects of acidosis and hypokalemia on proximal tubule reabsorption.
Why do you get kidney stones in type 1 RTA?
Hypercalciuria, hyperphosphatemia, nephrolithiasis (calcium phosphate stones) and nephrocalcinosis are frequently associated with untreated type 1 RTA.
The hypercalciuria is thought to be due to 1) increased calcium phosphate release from bone as a result of bone buffering of excess acid and 2) reduction in tubular calcium reabsorption secondary to chronic acidosis.
The hypercalciuria, alkaline urine, and reduced excretion of citrate in the urine (which normally prevents calcium crystallization) promote the precipitation of calcium phosphate and stone formation. The hypocitraturia is thought to be due to the effects of acidosis and hypokalemia on proximal tubule reabsorption.
Aside from the relevant antibodies, what are some common lab findings in Sjogrens?
Polyclonal hypergammaglobulinaemia
RF factor positive
ANA positive
Thyroid associated autoimmunity
Lymphoid foci in bx of accessory saliva glands
Aside from the relevant antibodies, what are some common lab findings in Sjogrens?
Polyclonal hypergammaglobulinaemia
RF factor positive
ANA positive
Thyroid associated autoimmunity
Lymphoid foci in bx of accessory saliva glands
What is the hypocomplementaemia picture for each of the following:
SLE
Membranoproliferative GN
MAC deficiency
C1 inhibitor deficiency
What must be vaccinated against?
Systemic lupus erythematosus is associated with low C3 and C4
Membranoproliferative glomerulonephritis causes low C3, but normal C4
Deficiencies of the terminal complement components are inherited in an autosomal recessive manner and cause increased susceptibility to infections by Neisseria.[5]
C1-inhibitor deficiency or hereditary angioedema will have low C4 with normal C1 and C3 levels.[6]
Vaccinations for encapsulated organisms is crucial for preventing infections in complement deficiencies.
What is the hypocomplementaemia picture for each of the following:
SLE
Membranoproliferative GN
MAC deficiency
C1 inhibitor deficiency
What must be vaccinated against?
Systemic lupus erythematosus is associated with low C3 and C4
Membranoproliferative glomerulonephritis causes low C3, but normal C4
Deficiencies of the terminal complement components are inherited in an autosomal recessive manner and cause increased susceptibility to infections by Neisseria.[5]
C1-inhibitor deficiency or hereditary angioedema will have low C4 with normal C1 and C3 levels.[6]
Vaccinations for encapsulated organisms is crucial for preventing infections in complement deficiencies.
What is the premedication protocol for IV contrast allergy?
What else should you do?
Premedication
Cetirizine 10 mg
repeat after 12 hours
Prednisolone 25 mg
Ranitidine 150 mg
This regimen is given on the day before and on the day of the procedure. It is also given on the day after the procedure if there is a history of delayed reaction.
Giving low-osmolarity non-ionic contrast media (if this is not yet routine)
What is the premedication protocol for IV contrast allergy?
What else should you do?
Premedication
Cetirizine 10 mg
repeat after 12 hours
Prednisolone 25 mg
Ranitidine 150 mg
This regimen is given on the day before and on the day of the procedure. It is also given on the day after the procedure if there is a history of delayed reaction.
Giving low-osmolarity non-ionic contrast media (if this is not yet routine)
What is the treatment protocol for anaphylaxis?
- Remove allergen and lie flat, (sit if struggling to breath
- Give IM adrenalin, 0.5ml of 1:1000 (over 50kg) or EpiPen. Repeat doses every 5 minutes as needed
- If repeat doses required, start an adrenalin infusion
- If ineffective or unavailable - adrenalin neb and consider intubation
- For persistent shock - 50ml/kg (max) N/S in first 30 min
- If in cardiogenic shock (esp if on beta blockers), glucagon 1-2mg in adults, followed by infusion
- May require further vasoconstrictors
- Persistent wheeze - bronchodilators and oral pred
- Observe for at least 4 hours - overnight if severe reaction, repeated doses of adrenaline, hx of asthma/prolonged anaphylaxis or concomitant illness, or lives away from medical care.
What is the treatment protocol for anaphylaxis?
- Remove allergen and lie flat, (sit if struggling to breath
- Give IM adrenalin, 0.5ml of 1:1000 (over 50kg) or EpiPen. Repeat doses every 5 minutes as needed
- If repeat doses required, start an adrenalin infusion
- If ineffective or unavailable - adrenalin neb and consider intubation
- For persistent shock - 50ml/kg (max) N/S in first 30 min
- If in cardiogenic shock (esp if on beta blockers), glucagon 1-2mg in adults, followed by infusion
- May require further vasoconstrictors
- Persistent wheeze - bronchodilators and oral pred
- Observe for at least 4 hours - overnight if severe reaction, repeated doses of adrenaline, hx of asthma/prolonged anaphylaxis or concomitant illness, or lives away from medical care.
What is the followup treatment for anaphylaxis?
Oral non-sedating antihistamines for itch and urticaria.
Do NOT use injectable promethazine in anaphylaxis - can worse hypotension and cause muscle necrosis
2 day course of oral pred to reduce risk of biphasic reaction
Epipen
Allergy specialist referral
What is the followup treatment for anaphylaxis?
Oral non-sedating antihistamines for itch and urticaria.
Do NOT use injectable promethazine in anaphylaxis - can worse hypotension and cause muscle necrosis
2 day course of oral pred to reduce risk of biphasic reaction
Epipen
Allergy specialist referral
What is the role of the serum tryptase assay?
The serum tryptase assay is highly specific for anaphylaxis and can be used retrospectively to confirm the diagnosis where it was unclear. However, a negative result does not exclude the diagnosis when clinical manifestations are compelling.
Secreted during anaphylaxis, rising to a peak concentration at 1-2 hours and returning to baseline by 6 hours, making it a suitable marker of mast cell degranulation during anaphylaxis in situations where the diagnosis of anaphylaxis is not clear (eg hypotension + rash during anaesthesia).
Elevated only in patients with anaphylaxis and systemic mastocytosis, and not in patients with sepsis, myocardial infarctions or other hospital controls.
What is the role of the serum tryptase assay?
The serum tryptase assay is highly specific for anaphylaxis and can be used retrospectively to confirm the diagnosis where it was unclear. However, a negative result does not exclude the diagnosis when clinical manifestations are compelling.
Secreted during anaphylaxis, rising to a peak concentration at 1-2 hours and returning to baseline by 6 hours, making it a suitable marker of mast cell degranulation during anaphylaxis in situations where the diagnosis of anaphylaxis is not clear (eg hypotension + rash during anaesthesia).
Elevated only in patients with anaphylaxis and systemic mastocytosis, and not in patients with sepsis, myocardial infarctions or other hospital controls.
What do you have to watch out for if a patient is on a beta blocker and have anaphylaxis?
Patients on beta blockers who experience anaphylaxis may have a hypertensive response to adrenaline and suboptimal clinical improvement, and may require 1 to 3mg of IV glucagon once or glucagon by continuous infusion until anaphylaxis is controlled. IV glucagon makes most people vomit and one must prepare for that when using it.
What do you have to watch out for if a patient is on a beta blocker and have anaphylaxis?
Patients on beta blockers who experience anaphylaxis may have a hypertensive response to adrenaline and suboptimal clinical improvement, and may require 1 to 3mg of IV glucagon once or glucagon by continuous infusion until anaphylaxis is controlled. IV glucagon makes most people vomit and one must prepare for that when using it.
How is adrenaline used in anaphylaxis? What do you need to consider?
Adrenaline is the first line and most important drug used in an acute allergic reaction. Antihistamines and corticosteroids are second line therapy.
Adrenaline should be administered IM, not subcutaneously. It should not be administered IV in concentrations of greater than 1:10,000, and then only in dire straits.
There is no absolute contraindication to the use of adrenaline in patients with heart disease who experience anaphylaxis.
How is adrenaline used in anaphylaxis? What do you need to consider?
Adrenaline is the first line and most important drug used in an acute allergic reaction. Antihistamines and corticosteroids are second line therapy.
Adrenaline should be administered IM, not subcutaneously. It should not be administered IV in concentrations of greater than 1:10,000, and then only in dire straits.
There is no absolute contraindication to the use of adrenaline in patients with heart disease who experience anaphylaxis.
In a patient with urticaria of unknown cause, when would you do allergy testing?
An allergic cause should be considered in patients with short-lived “episodic” symptoms. Exposure to potential allergens in the previous 12 hours should be recorded. By contrast, routine skin testing or measurement of total or allergen-specific IgE (‘RAST’ blood tests) often results in misleading or irrelevant results. - See more at: http://www.allergy.org.au/health-professionals/hp-information/asthma-and-allergy/urticaria#sthash.LTeVghsd.dpuf
In a patient with urticaria of unknown cause, when would you do allergy testing?
An allergic cause should be considered in patients with short-lived “episodic” symptoms. Exposure to potential allergens in the previous 12 hours should be recorded. By contrast, routine skin testing or measurement of total or allergen-specific IgE (‘RAST’ blood tests) often results in misleading or irrelevant results. - See more at: http://www.allergy.org.au/health-professionals/hp-information/asthma-and-allergy/urticaria#sthash.LTeVghsd.dpuf
When would you do a RAST test over a skin test?
Skin test usually first line.
Skin disease
Dermatographism
Recent antihistamine Rx
Infancy / cord blood sampling
Severe anaphylaxis in whom there is a concern that skin testing may provoke an anaphylactic reaction (foods, latex, stinging insects, antibiotics)
When would you do a RAST test over a skin test?
Skin test usually first line.
Skin disease
Dermatographism
Recent antihistamine Rx
Infancy / cord blood sampling
Severe anaphylaxis in whom there is a concern that skin testing may provoke an anaphylactic reaction (foods, latex, stinging insects, antibiotics)
What causes false positive RAST tests?
Waning of allergen-specific IgE with time following exposure (e.g. many years following a bee sting)
Unstable allergens in the RAST substrates (especially food allergens)
RAST tests to allergen “mixes” may be less sensitive than RAST tests to single allergens (e.g. “Food Mix” vs “peanut”) and skin tests
What causes false positive RAST tests?
Waning of allergen-specific IgE with time following exposure (e.g. many years following a bee sting)
Unstable allergens in the RAST substrates (especially food allergens)
RAST tests to allergen “mixes” may be less sensitive than RAST tests to single allergens (e.g. “Food Mix” vs “peanut”) and skin tests
What is the significance of a positive or negative RAST test?
A positive RAST in the absence of a consistent history indicates sensitisation, not allergy.
A negative RAST does not exclude significant allergy
What is the significance of a positive or negative RAST test?
A positive RAST in the absence of a consistent history indicates sensitisation, not allergy.
A negative RAST does not exclude significant allergy
What are the common foods that cause IgE mediated anaphylaxis?
Peanut and tree-nuts
Shellfish and fish
Milk and egg
Soybean and sesame
Peach
What are the common foods that cause IgE mediated anaphylaxis?
Peanut and tree-nuts
Shellfish and fish
Milk and egg
Soybean and sesame
Peach
Aside from food, what other things cause IgE dependent anaphylaxis?
Stinging insects
B-lactam antibiotics
NSAIDS (IgE indepdenent as well)
Biologics
Latex
Radiocontrast (Ige independent as well)
Aside from food, what other things cause IgE dependent anaphylaxis?
Stinging insects
B-lactam antibiotics
NSAIDS (IgE indepdenent as well)
Biologics
Latex
Radiocontrast (Ige independent as well)
What drugs cause immunologic anaphylaxis but are not IgE dependent?
Radiocontrast media
NSAIDS
Dextrans
Some monoclonal antibodies
Which substances cause anaphylaxis via direct mast cell activation?
Physical - exercise, cold, heat, sunlight
Alcohol
Medications ie opioids
What are the general indications for allergy skin prick testing?
Rhinitis/rhinoconjunctivitis/rhinosinusitis/allergic conjunctivitis
Asthma
Atopic dermatitis
Food reactions such as those
manifested by anaphylaxis, immediate acute urti caria, or acute flare of eczema
Suspected latex allergy
Conditions in which specific IgE is considered likely to play a pathogenic role (eg. selected cases of chronic urticaria if the history suggests an exogenous allergic cause)
;
Rarer disorders such as allergic bronchopulmonary aspergillosis, eosinophilic oesophagitisor eosinophilic gastroenteritis
When is skinprick testing NOT done?
Nonspecific rash without allergic/atopic characteristics
Chronic urticaria in the absence of allergic features on history
Food intolerance without allergic features (eg. irritable bowel syndrome)
Assessment of the effectiveness of allergen immunotherapy
Chronic fatigue without allergic features
Migraine headaches/behavioural disorders
Reactions to respiratory irritants (smoke, fumes, perfumes etc.
Screening for allergy in the absence of symptoms (e.g. family history of allergy
When would you do intradermal allergy testing?
Insect venom hypersensitivity
Immediate allergy to beta - lactam drugs, other drugs where validated protocols exist
Immediate hypersensitivity to some vaccines
Intradermal testing is recommended for
hospital or specialist use only
Intradermal testing is not indic ated for aeroallergens, and is contraindicated in routine practice for food allergy
What is the driving reason behind doing skin prick testing for allergens?
The strongest indications for skin prick testing are where there is good evidence for the effectiv eness of allergen avoidance or allergen immunotherapy.
What are the contraindications to skin prick testing?
Diffuse dermatological conditions - test must be performed on normal healthy skin
Severe dermatographism
Poor subject cooperation
Subject unable to cease antihistamines/other interfering drugs
Why are beta blockers sometimes contraindicated in skin prick testing?
Contraindicated in situations in which the risk of systemic anaphylaxis is increased. ACE inhibitors may be relatively contraindicated in the
same circumstances. These drugs may interfere with the normal compensatory mechanisms
in anaphylaxis and beta -blockers interfere with the effect of adrenaline. In general the risk of
systemic anaphylaxis from skin testing is low and the drugs need not be withheld except
where certain high-risk features exist.
What is the pathophysiology of mastocytosis?
- classed as a myeloproliferative neoplasm
- increased local concentration of soluble mast cell growth factor in cutaneous lesions stimulate mast cell proliferation as well as melanocytes (which explains pigmentation)
- impaired apoptosis due to up-regulation of BCL-2 (apoptosis preventing protein
- IL-6 elevated and correlates with disease severity
- activating mutations of C-Kit but do not explain initiation of disease
What is the epidemiology of mastocytosis?
Really rare
M=F
Whites
Most are kids, peaks again age 30-49
What is the WHO criteria for the diagnosis of systemic mast cell disease?
Major: Multifocal dense infiltrates of mast cells (>15 close to each other) observed in bone marrow biopsy specimens and/or mast cells stained for tryptase in biopsy specimens from other extracutaneous organs.
Minor
Mast cells in bone marrow, or other extracutaneous organs show abnormal (spindling) morphology (>25%) or the presence of greater than 25% atypical mast cells in bone marrow aspirates
Demonstration of c-kit point mutation on codon 816 in bone marrow, blood, or other extracutaneous organs
CD117 (c-kit receptor)–positive cells, also positive for CD2 and/or CD25
Serum tryptase values greater than 20 ng/mL
What is the role of tryptase in the dx of mastocytosis?
Total tryptase level: Tryptase is a marker of mast cell degranulation released in parallel with histamine. Total tryptase levels in plasma correlate with the density of mast cells in urticaria pigmentosa lesions in adults with systemic mastocytosis. Patients with only cutaneous mastocytosis typically have normal levels of total tryptase. Total tryptase values are recommended by the WHO as a minor criterion for use in the diagnostic evaluation of systemic mastocytosis
What will FBC and urinary histamine levels show in mastocytosis?
CBC count: In systemic mastocytosis, CBC counts may reveal anemia, thrombocytopenia, thrombocytosis, leukocytosis, and eosinophilia.
Plasma or urinary histamine level: Patients with extensive cutaneous lesions may have 24-hour urine histamine excretion at 2-3 times the normal level.
What is mastocytosis?
Mast cells and mast cell precursors CD34+
Itching, hives, anphylaxis, shock due to histamine release
Most cases are cutaneous, commonly urticaria pigmentosa
Which drugs traditionally have been known to lead to SJS/EM/TEN?
Sulfonamide antibiotics (cotrimoxazole!), (beta lactam) penicillin antibiotics, cefixime (antibiotic), barbiturates (sedatives), lamotrigine, phenytoin (e.g., Dilantin) (anticonvulsants) and trimethoprime. NSAIDS rarely but in elderly. Allopurinol.
Combining lamotrigine with sodium valproate increases the risk of SJS.
Which groups of people are more susceptible to drug induced SJS/TEN?
Slow acetylators, patients who are immunocompromised (especially those infected with HIV), and patients with brain tumors undergoing radiotherapy with concomitant antiepileptics are among those at most risk. Also SLE.
Slow acetylators are people whose liver cannot completely detoxify reactive drug metabolites. For example, patients with sulfonamide-induced toxic epidermal necrolysis have been shown to have a slow acetylator genotype that results in increased production of sulfonamide hydroxylamine via the P-450 pathway. These drug metabolites may have direct toxic effects or may act as haptens that interact with host tissues, rendering them antigenic.
When do the symptoms of SJS/TEN usually start?
Within a week of starting the medication
What drugs are implicated in pemphigus?
penicillamine, captopril, piroxicam, penicillins, rifampicin
What is the distribution of rash in a fixed drug eruption and what drugs are implicated?
solitary or few lesions
face, hands, feet or genital area
may involve lips and mouth
NSAIDs, sulfonamide antibacterials, pseudoephedrine
What is pseudoporphyria?
Pseudoporphyria (also known as “Pseudoporphyria cutanea tarda”[1]) is a bullous photosensitivity that clinically and histologically mimics porphyria cutanea tarda.[2]:524 The difference is that no abnormalities in urine or serum porphyrin is noted on laboratories. Pseudoporphyria has been reported in patients with chronic renal failure treated with hemodialysis and in those with excessive exposure to ultraviolet A (UV-A) by tanning beds, also drugs.
REALLY REALLY RARE
What is the pathophysiology of Steven Johnson Syndrome?
Antigen presentation and production of tumor necrosis factor (TNF)–alpha by the local tissue dendrocytes results in the recruitment and augmentation of T-lymphocyte proliferation and enhances the cytotoxicity of the other immune effector cells.[7] A “killer effector molecule” has been identified that may play a role in the activation of cytotoxic lymphocytes.[8] The activated CD8+ lymphocytes, in turn, can induce epidermal cell apoptosis via several mechanisms, which include the release of granzyme B and perforin
How is autoimmune hepatitis classified?
- positive ANA and SMA, elevated immunoglobulin G (classic form, responds well to low dose steroids);
- positive LKM-1 (typically female children and teenagers; disease can be severe), LKM-2 or LKM-3.positive antibodies against soluble liver antigen[3] (this group behaves like group 1)[4] (anti-SLA, anti-LP)
- no autoantibodies detected (~20%) - (of debatable validity/importance)
3 clinical features of autoimmune hepatitis
Young female
Presenting complaint may be amenorrhoea
May present with chronic disease or acute hepatitis
How is autoimmune hepatitis diagnosed?
Always requires a liver bx
Most common antibody is anti-SMA but also LKM1-3, SLA/LP, or AMA
Increased IGG level
Can overlap with PBC and PSC but NOT lupus
How do you treat autoimmune hepatitis?
Steroids +/- Aza
Remission achieveable but shorter life expectancy.
What is montelukast and what is it used for?
Leukotriene receptor antagonist (leukotrienes are inflammatory eicosanoids released from mast cells and eosinophils)
Maintenance treatment of chronic (not acute) asthma and relieve symptoms of seasonal allergies - esp allergic rhinitis
Need to watch out for mood disorders
Mechanism of action of theophylline
- competitive nonselective phosphodiesterase inhibitor,[8] which raises intracellular cAMP, activates PKA, inhibits TNF-alpha [9][10] and inhibits leukotriene [11] synthesis, and reduces inflammation and innate immunity
- nonselective adenosine receptor antagonist,[12] antagonizing A1, A2, and A3 receptors almost equally, which explains many of its cardiac effects
3 points about theophylline
- relaxes bronchial SM, positive inotrope and chronotrope, increases BP
- anti-inflammatory
- blocks adenosine which induces sleep, contracts smooth muscle and relaxes cardiac muscle
What are the adverse effects of theophylline?
Interacts with cimeditine and phenytoin (as well as CYP450 inhibitors
- narrow TD - have to do levels
- can get toxic w/ fatty meals (dose dumping
- treat toxicity with b-blockers
What are the cardiovascular complications to pregnancy?
PAH of any cause
Severe systemic ventricular dysftn (LVEF <30%, NYHA III-IV)
Prev peripartum cardiomyopathy with any residual impairment of LVF
Marfan plus aorta >45mm
Aortic dilation >50mm in aortic disease assoc w/ bicuspid aortic valve
Native severe coarctation
What is TNF-beta?
Lymphotoxin (previously known as tumor necrosis factor-beta) is a lymphokine cytokine.
It is a protein that is produced by Th1 type T-cells and induces vascular endothelial cells to change their surface adhesion molecules to allow phagocytic cells to bind to them.[1] It is also known to be required for normal development of Peyer’s patches. [2]
Lymphotoxin is homologous to Tumor Necrosis Factor beta, but secreted by T-cells. It is paracrine due to the small amounts produced. The effects are similar to TNF-alpha, but TNF-beta is also important for the development of lymphoid organs.
