Immunology ✔ Flashcards
how does vaccination work?
Exposure to a pathogen/antigens stimulates an acquired immune response. –> Immunologic memory is developed by stimulation of T and B lymphocytes specific for the epitopes on this pathogen. –>
Some of these cells become long living memory cells, capable of responding to the viable pathogen upon encounter.
what is the natural & normal development of effector lymphocytes?
primary lymphoid organs make some naïve lymphocytes which wait for an antigen to be presented by an APC. This leads to clonal expansion of the lymphocytes, and some are remembered as effector lymphocytes
what is an antigen presenting cell?
a cell that can present peptides to T lymphocytes to initiate an acquired immune response
what types of cells are antigen presenting cells?
macrophages
B lymphocyte
Langerhans cells
Dendritic cells
how do CD4 T cells work for immunity?
an antigen is presented by an APC to a CD4 T cell. This activates the CD4 T cells which produces cytokines. In the meantime, the CD4 T cells undergo clonal expansion… “helper T cells”
This expansion requires the cytokines and a specific antigen
what are helper T cells?
CD4 T cells. Because they ‘help’ other lymphocytes
how does the immune system work to provide protection with CD8 T cells?
an antigen is presented by APC to a CD8 T cell. The CD8 cell is then activated which releases cytokines and causes clonal expansion. At this point T helper cells (CD4) provide help to CD8 cells with cytokine GF. Some of these CD8 cells are then kept in reactive memory and some effectors kill the virus infected cells
what is the role of T helper cells with relation to CD8 T cells?
they help to illicit the clonal expansion and cytokine release with the provision of cytokine growth factor
what are the two types of activated CD8 T cells that provide immune protection?
- effectors: kill virus infected cells
- reactive memory cells: remember if the antigen presents again in future
how do B cells work in providing immunity?
specific antigen will activate an immediate cytokine response and the cytokines work with T -helper cells (CD4) to activate B cells for expansion and isotype switching. The effector cells of B cells are plasma cells that produce antibodies. Some B cells remain memory cells
what types of cells have remaining memory cells that will recognize if this same antigen comes up again?
- B cells
- CD8 T cells
which types of cytokines create a cell-mediated immune response?
Th1, type 1 cytokines: IL-2, IFN-gamma, TNF
which types of cytokines create a humoral response?
Th2, type 2 cytokines: IL4, IL5, IL6
what is the target for infectivity-neutralizing antibodies in influenza?
hemagglutinin is the receptor binding and membrane fusion glycoprotein of influenza virus
what is the main cell involved in TB immune response?
T- cell mediated
what antibody mediates primary immune response?
IgM
what antibody mediates secondary immune response?
IgG but some IgM is still present
what is the difference between immediate and memory immunity?
- memory immunity is more rapid and more aggressive because the memory cells have higher affinity to antigen and are more activated
- different pattern of expression of cell surface proteins
- memory t-cells are maintained for a long time without antigen by continual low level proliferation in response to cytokines
which cytokines are involved in memory cells proliferation without antigen?
IL2
IL7
IL15
what are the two subsets of memory T cells?
1) central memory T cells (TCM)
2) effector memory T cells (TEM)
the difference is the presence of CCR7 on endothelial cells and CD62L presence
what is the difference between central memory T cells and effector memory T cells in action?
central memory: migrate efficiently to peripheral LNs. Produce IL-2, no IFN, no perforin
effector memory: found in other sites from LNs (eg liver, lungs); little IL-2 but high IFN/perforin
what are the three phases of T cell immune response?
1) expansion
2) contraction
3) memory
what are the main parts to vaccine components?
1) live, attenuated
2) inactivated/component
3) adjuvant
what are some examples of live and attenuated vaccines?
yellow fever MMR typhoid TB (BCG) Polio
what are the advantages of live vaccines?
- Establishes infection,
- Often confers lifelong immunity after one dose (no boosters).
- Activates all phases of immune system. Can get humoral IgG and local IgA.
- Raises immune response to all protective antigens.
- More durable immunity; more cross-reactive.
what are the disadvantages of live vaccines?
- Possible reversion to virulence (recombination, mutation).
- Storage problems (cold chain)
- Safety issues
- Problem in immunodeficiency
what are some examples of inactivated vaccines?
- influenza
- cholera
- polio
- hepatitis A
- rabies
- DTaP
what are some advantages of inactivated vaccines?
- No mutation or reversion
- Can be used with immuno-deficient patients
- Can lead to elimination of wild type virus from the community
- Storage easier
- Lower cost
what are some disadvantages of inactivated vaccines?
- some components have poor immunogenicity
- may need multiple injections
- may require adjuvants
what is an adjuvant and give an example?
Adjuvant increases the immune response without altering its specificity.
A depot adjuvant acts by slowing the release of antigen. e.g. Alum
what is the method of action of DNA vaccines?
- a plasmid containing the gene of choice that will confer immunity to the pathogenic bits
- inserted into muscle cell (several copies)
- no replication of the plasmid
- expression of gene at cell surface so immune response generated
why don’t vaccinations work effectively in the elderly?
- immune senescence (inc. frequency of terminally differentiated effector memory T cells already exist with reduced production of recent thymic emigrants that are ‘naïve T-cells’
- nutrition (insufficient energy/vitamins & minerals)
what defines atopy?
production of specific IgE responses to common environmental antigens - a marker of sensitization ONLY and not disease
what type of hypersensitivity is in allergic disease?
type I
what is the difference between atopy and allergic disease?
atopy - sensitized
allergic disease - type I hypersensitivity reaction to allergens
what is the age of onset of most food allergies?
infancy
what is the age of onset for hayfever/asthma?
childhood
what sorts of allergies onset as adults?
- drug allergy
- bee allergy
- oral allergy syndrome
what are the clinical features of IgE allergic responses?
- Occurs within minutes or up to 2 hours after exposure
- symptoms: angioedema, urticaria, pruritus, rhinitis conjunctivitis, wheeze, diarrhoea vomiting and anaphylaxis.
- > 2 organ systems are usually involved.
how do we investigate allergic disease?
- skin prick tests
- Lab measurement of IgE
- component-resolve diagnostics
- challenge test
what is the ‘gold standard’ for diagnosing allergies?
- skin prick tests
- if positive, local wheal/flare response to allergen (>2mm)
what is a RAST test?
- specific IgE test
- Measure IgE in serum directed against a specific allergen (peanut, cat dander, egg etc)
- used to confirm dx of allergy, check prognosis
what are the indications for RAST testing?
- patients who can’t stop antihistamines (for skin prick)
- dermatographism
- extensive eczema
- history of anaphylaxis
- borderline skin prick test results
what is component resolved diagnostics for allergens?
- detect individual allergens within a protein against which the immune system makes IgE antibodies (eg peanut contains at least 5 major allergens)
- can allow the clinician to predict whether a patient will experience sx
how would we check if someone is having an acute allergic reaction?
- mast cell tryptase test
- product of mast cell granules which means when mast cells degranulate in allergic reaction the levels of serum tryptase increase
- peak at 1-2 hours; return to baseline by 6-12 hours
what is the gold standard test for food allergy diagnosis?
challenge tests (inc. volume of food are ingested in order to interpret which level leads to symptoms). Done under close medical supervision.
what defines anaphylaxis?
severe systemic allergic reaction involving respiratory difficulty and hypotension; usually involves skin or N&V
what are the 3 criteria required to diagnose anaphylaxis?
1) sudden onset/rapid progression symptoms
2) life threatening ABC issues
3) skin & mucosal changes
what are the mechanisms of anaphylaxis (+ examples)?
- IgE mediated mast degranulation (eg peanuts, penicillin, bee venom, latex)
- non IgE mediated mast cell degranulation (eg NSAIDs, IV contrast, opioids)
if we want to do a serum tryptase level to check for real anaphylaxis, when do we check?
-1 hour
-3 hour
-24 hours
Rise in tryptase is proportional to hypotension
what is the emergency management of anaphylaxis?
- IM adrenaline 500 mcg
- oxygen & fluids
- hydrocortisone 100mg IV
- (if skin rash) chlorpeniramine 10mg IV
- Follow up with referral to allergy clinic to investigate cause
- Give epipen
what are the appropriate investigations for food allergies?
- a positive SPT is useful to confirm but a negative skin prick test (SPT) excludes IgE mediated allergy
- the Gold standard for diagnosis of food allergy is a double blind oral food challenge.
what cells are involved in an innate immune response?
- phagocytes: macrophages & neutrophils
- NK cells
- dendritic (APC) cells
- complement
what cells are involved in adaptive immunity?
- CD4
- B cells
- CD8
what are causes of secondary immunodeficiency?
1) infection - HIV, measles, mycobacterium
2) biochemical - malnutrition, mineral deficiencies, renal impairment
3) malignancy - myeloma, leukemia, lymphoma
4) drugs - steroids, cytotoxic
how does the skin work as a constitutive barrier to infection?
1) tightly packed keratinized cells
2) physiological - low pH, low O2
3) sebaceous glands ( + lysozymes, ammonia…)
how do mucosal surfaces work as barrier to infection?
1) mucous as physical barrier and IgA secretion
2) cilia
3) commensal bacteria
what cells and soluble components are in the innate immune system?
cells: neutrophils, eosinophils, basophils, dendritic cells, NK cells, monocytes, macrophages
components: complement, APP (CRP/ESR), cytokines, chemokines
how do cells of the innate immune system recognize antigens at site of infection?
PRR: pattern recognition receptors like TLR which recognize pathogen-associated molecular patterns (PAMPs) generic motifs
how does the innate immune system combat infection?
- chemokines/cytokines
- PRR to activate and go to active CD8 T cells/ B cells
- phagocytic capacity for pathogens
how do Neutrophils, Eosinophils and Basophils/Mast cells work in the immune system?
- produced in bone marrow
- migrate rapidly to site of injury
- release enzymes, histamines, lipid mediators of inflammation from degranulation
where are monocytes & macrophages made? what do they do?
monocytes are produced in bone marrow and differentiate into macrophages in the tissues of the body. They are APCs to T cells.
list the macrophages for the following organs: Liver Kidney Bone Spleen Lung Neural Skin
Liver - Kupffer Kidney - Mesangial Bone - osteoclast Spleen - sinusoidal lining cell Lung - alveolar macrophage Neural - microglia Skin - Langerhans
what sort of infections are contracted when someone is phagocyte deficient?
- recurrent skin/mouth infections (Staph aureus, Candida, Aspergillus)
- mycobacterial infection
what is the condition where stem cells fail to differentiate along myeloid lineage and produce neutrophils?
“reticular dysgenesis”
- AR inheritance
- severe SCID
- mutation in mitochondrial energy metabolism enzyme AK2
what is reticular dysgenesis?
autosomal recessive severe SCID
- failure to produce neutrophils
what is Kostmann syndrome?
AR severe congenital neutropenia (a specific failure of neutrophil maturation)
*due to mutation in HAX1 associated protein
what is the syndrome where someone fails to mature neutrophils?
Kostmann syndrome - AR
or cyclic neutropenia - AD
what is cyclic neutropenia?
an AD inherited episodic neutropenia every 4-6 weeks. Due to mutation in neutrophil ELA2
what is leukocyte adhesion deficiency?
- a deficiency of CD18
- usually expressed on neutrophils, binds to ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/transmigration
- -> In Leukocyte adhesion deficiency the neutrophils lack these adhesion molecules and fail to exit from the bloodstream
how does leukocyte adhesion deficiency present?
characterized by
very high neutrophil counts in blood
absence of pus formation
what happens if somebody has a defect in complement production or antibody production?
decreased efficiency of opsonisation –> affects phagocyte function
what is chronic granulomatous disease?
- failure of oxidative killing mechanisms
- inability to generate oxygen free radicals
- impaired killing of intracellular micro-organisms
- excessive inflammation
- persistent neutrophil/macrophage accumulation
- granuloma formation
how does chronic granulomatous disease present?
- lymphadenopathy
- hepatosplenomegaly
how do we investigate chronic granulomatous disease?
- nitroblue tetrazolium (NBT) test
- dihydrohodamine (DHR) flow cytometry test
what is the important of IL12 and IFN?
IL12, IL12R, IFNg or IFNg R deficiency may cause susceptibility to mycobacterial infections
what conditions come from a failure of neutrophil differentiation? (3)
- reticular dysgenesis
- severe congenital neutropenia (Kostmann’s)
- cyclic neutropenia
what condition arises from failure to express leukocyte adhesion markers?
leukocyte adhesion deficiency
what part of innate immune system fails of there is an antibody or complement deficiency?
failure of opsonisation
what disease is characterized by a failure of oxidative killing?
chronic granulomatous disease
spot diagnosis: recurrent infections with high neutrophil count, no abscess formation
a) IFN gamma receptor def.
b) Leukocyte adhesion def.
c) Chronic Granulomatous Disease
d) Kostmann’s syndrome
b) leukocyte adhesion deficiency
spot diagnosis: recurrent infections with hepatosplenomegaly, abnormal DHR test
a) IFN gamma receptor def.
b) Leukocyte adhesion def.
c) Chronic Granulomatous Disease
d) Kostmann’s syndrome
c) chronic granulomatous disease
spot diagnosis: recurrent infections with no neutrophils on FBC
a) IFN gamma receptor def.
b) Leukocyte adhesion def.
c) Chronic Granulomatous Disease
d) Kostmann’s syndrome
Kostmann’s syndrome
spot diagnosis: infection with atypical mycobacteriums, normal FBC
a) IFN gamma receptor def.
b) Leukocyte adhesion def.
c) Chronic Granulomatous Disease
d) Kostmann’s syndrome
a) IFN gamma receptor deficiency
how do natural killer cells work in the immune system?
- have two receptors: one is inhibitory and one is activating
- a normal cell matches on both receptors –> no lysis
- a target cell does not match on the inhibitory receptor –> cytotoxicity, cytokine secretion, lysis
what sort of infections do we get if we have natural killer cell deficiencies?
viral infections - HSV, HPV, VZV, EBV, CMV
what is the treatment for NK cell deficiencies?
- prophylactic antiviral drugs
- cytokines to stimulate function
what are the two classifications of NK cell deficiencies?
- functional
- classical (absence of them)
what do dendritic cells do in the immune system? (NB- list multiple things!)
- Express receptors for cytokines and chemokines - to detect inflammation
- release cytokines
- Express PRRs – to detect pathogens
- Express Fc receptors for Ig - to detect immune complexes
- Capable of phagocytosis
- mature following phagocytosis by migrating, upregulating HLA, expressing costimulatory molecules
- Present processed antigen to T cells in lymph nodes to prime the adaptive immune response
what is complement?
> 20 tightly regulated proteins produced by the liver and present in the circulation as inactive molecules. If activated, enzymatically activate other proteins in biological cascade for amplified response
what are the 3 pathways of complement activation?
-classical (via C1, C2, C4)
-MBL (via C4, C2)
-alternative
All finish in final common pathway via C3 –> C5-C9 –> Membrane Attack Complex (MAC)
what other roles do complement fragments play in the immune response?
- increase vascular permeability
- increase cell trafficking to site of inflammation
- solubilize and clear immune complexes
- opsonisation of pathogens (phagocytosis)
- activate phagocytes
- promote mast cell/basophil degranulation
- punch holes in bacterial membranes
how does the classical pathway activate complement?
- formation of Ab-Ag immune complexes
- change in Ab shape –> binding site for complement C1
- binding of C1 –> activates C4/C2 –> activate C3 –> activates cascade
what’s the disadvantage of the classical pathway of complement activation?
dependent upon activation of acquired immune response
what happens if somebody has a defect in the early classical complement activation pathway?
- immune complexes fail to activate complement pathway
- increased infection susceptibility
- associated with SLE from deposition of immune complexes
how does the MBL system work to activate complement?
MBL: mannose binding lectin
- activated by direct binding of MBL to antigen surface carbohydrates
- directly stimulates classical pathway
- NOT dependent on acquired immune response
how does the alternative pathway work to activate complement pathway?
- bacterial cell wall fails to inactivate C3b (eg LPS on gram negative or teichoic acid of gram positive)
- so still activates C3 and goes through complement pathway
- NOT dependent on acquired immune response
what happens if somebody has a defect in the alternative complement pathway?
- inability to mobilize complement rapidly in response to bacterial infections
- recurrent infections with encapsulated bacteria (bacterial cell wall is able to inactivate C3b)
since all 3 pathways activate C3 in the complement pathway activation, what happens if there is a defect and C3 cannot be activated?
- severe susceptibility to bacterial infections
- increased risk of development of connective tissue disease
since all 3 pathways activate C3 and follow the common pathway at the end, what happens if there is a defect and the common final pathway cannot be activated?
- inability to make MAC
- inability to use complement to lyse encapsulated bacteria
- specific hole in immune system: N. meningitis, Strep. pneumonia, H. influenza
what are some secondary potential causes of complement deficiency?
- active lupus
- nephritic factors
how do we investigate a possible complement deficiency?
- C3
- C4
- CH50 (classical)
- AP50 (alternative)
spot diagnosis: membranoproliferative nephritis and bacterial infections
a) C9 deficiency
b) C3 deficiency with presence of nephritic factor
c) MBL pathway deficiency
d) C1Q deficiency
b) C3 deficiency with presence of nephritic factor
spot diagnosis: spot diagnosis: severe childhood onset SLE, normal levels of C3 & C4
a) C9 deficiency
b) C3 deficiency with presence of nephritic factor
c) MBL pathway deficiency
d) C1Q deficiency
C1Q deficiency (problems with classical pathway activation)
spot diagnosis: meningococcus meningitis with family history of sibling dying of same condition as child
a) C9 deficiency
b) C3 deficiency with presence of nephritic factor
c) MBL pathway deficiency
d) C1Q deficiency
C9 deficiency (problems with common pathway --> MAC)
spot diagnosis: recurrent infections when receiving chemotherapy but previously well
a) C9 deficiency
b) C3 deficiency with presence of nephritic factor
c) MBL pathway deficiency
d) C1Q deficiency
MBL deficiency
what are cytokines (and list some examples)?
-small protein messengers of immunomodulatory function
-autocrine or paracrine dependent action
Examples: IL2, IL6, IL10, IL12, TNF, TGF
what are chemokines (and examples)?
-chemotactic chemokines are chemoattractants for the direct recruitment/homing of leukocytes in an inflammatory response
Examples: CCL19, CCL21, IL8, MIP1 alpha/beta
what type of hypersensitivity is in contact dermatitis?
type IV
symptoms occur 24-48 hours after exposure… itchy & rash. Not responsive to anti histamines.
when might we see rouleaux formation?
multiple myeloma
how does HIV work?
it is a retrovirus that replicates inside cells using an enzyme called Reverse Transcriptase (RT) to convert RNA into DNA which can be integrated into host cell’s genes. Prefers CD4+ T helper cells as host targets.
what is the organization of the HIV virus?
- Icosahedral (20-faced tr).
- Slow developing disease
- Genome is diploid, (+)ssRNA
- 9 genes (e.g. env, gag, pol) (tat, rev, nef) (vif, vpr, vpu) encoding: 15 Proteins.
why does the immune system fail to protect against HIV infection?
- the CD4+ T helper cells are the target of the virus. *Progressive decline in CD4 T-cell function & numbers
- HIV-1 can also be trapped by FDC when enters the lymph node
how does the HIV virus enter the cell?
- CD4 molecule/Ag is the receptor for HIV-1
- use co-receptor molecules in addition to enter the target cells
eg. chemokine receptor on surface of activated T- helper CD4+ cells
what cells are lost in HIV infection?
selective loss of CD4+ T cells.
HIV infection interferes also at several key points of CD8 T cell activation. List some (there are 5)
1) CD4+ T helper cells from activating APC
2) CD4+ T cells from activating naïve B cells
3) APCs from activating memory B cells
4) APCs from activating naïve B cells
5) CD4+ from activating effector CD8+ T cells
in what 3 ways are CD4 cells targeted by the HIV virus?
- activated infected T cells die
- infected T cells anergised by virus (T cell memory lost; cannot prime naïve CD8 cells)
- infected APCs are killed by virus
what is the life cycle of the HIV virus?
1) attachment/entry
2) reverse transcription, DNA synthesis
3) integration
4) viral transcription
5) viral protein synthesis
6) assembly of virus & release of virus
7) maturation
where do antiretroviral drugs work? ( 4 points)
1) attachment - attachment inhibitors or fusion inhibitors
2) reverse transcription inhibitors
3) integrase inhibitors
4) viral protease inhibitor so viral protein can’t be cleaved
what is the progression of HIV infection?
- HIV causes CD4 T-cell count to drop
- Low CD4 T-cell count relates to risk of disease
- HIV causes AIDS (CD4 T-cell count <200 cells/ul)
what are the 3 patterns of HIV disease progression that might occur?
1) typical progressors - takes 8-10 years without treatment to turn into AIDS (85%)
2) rapid progressors - takes <3 years without treatment to turn into AIDS (10%)
3) long-term non progressors - no change to AIDS even after 10-15 years (<5%)
how do we detect the presence of HIV?
First, HIV antibody ELISA - screening
Then, HIV antibody western blot - confirms
We measure viral load with PCR. We can measure CD4 T cell counts with flow cytometry.
what is HAART?
-combination of 3+ drugs (two drug backbone + one or more binding agents)
can be: nucleoside reverse transcriptase inhibitors’ nucleotide RTI; integrase inhibitors; attachment or fusion inhibitors; protease inhibitors
when do we initiate treatment?
*All symptomatic patients
*All CD4 <200 cells/ml
(START: CD4 200-350 cells/ml )
Choices: 2NRTIs + NNRTI or boosted PI
what are the components of the adaptive immune system?
a) B lymphocytes - B cells, antibodies, plasma cells
b) T lymphocytes - CD4 T cells and CD8 T cells
c) soluble components - cytokines/chemokines
what are the key characteristics of cells of the adaptive immune system?
- wide repertoire of antigen receptors
- exquisite specificity
- clonal expansion
- immunological memory
what are the primary lymphoid organs involved in the acquired immune system?
- bone marrow: both T and B lymphocytes, site of B cell maturation
- thymus: site of T cell maturation
how do T lymphocytes mature?
- bone marrow: stem cells –> lymphoid progenitors –> pre T-cells –> thymus - export of mature T lymphocytes to periphery following positive/negative selection
- arise from hematopoetic stem cells, exported as immature cells to the thymus where they undergo selection. Mature T lymphocytes will then enter the circulation, and reside in secondary lymphoid organs
what HLA/peptide complex do T cell receptors recognize?
CD8 Tcell - HLA class I CD4 T cell - HLA class II
how does T cell selection in the thymus work?
- T cells with low affinity for HLA –> not selected to avoid inadequate reactivity
- T cells with intermediate affinity for the HLA molecules –> positive selection (about 10% of original cells) –> if for HLA I then CD8+ cells and if HLA II then CD4+ cells
- T cells with high affinity for HLA –> negatively/not selected to avoid any auto reactivity
list some CD4+ T cell subsets (5)
1) Th1 - help CD8 T cells (helper T cells), macrophages
2) Th17 - help neutrophil recruitment, enhance autoantibodies
3) Treg - IL10/TGF beta expressing CD25+
4) TFh - follicular helper T cells
5) Th2 - helper T cells
what is the difference between CD4 T cells and CD8 T cells….
- CD8 T cells are specialized cytotoxic cells & can kill cells directly (perforin and granzymes). Recognizes HLA Class I
- CD4 T cells recognize HLA class II. Help B cell and CD8 T cells.
- both secrete cyotkines
what is the process of B lymphocyte maturation?
bone marrow: stem cells –> lymphoid progenitors -> pro B cells –> pre B cells
Then they move to the peripheral blood where pre B cells become IgM B cells. A subset further matures into antibody secreting B cells- can be IgA, IgE, IgG, or IgM. Plasma cells come from IgM or IgG B cells.
how is central tolerance determined in B lymphocytes?
- no recognition of self in bone marrow –> survive
* recognition of self in bone marrow –> negative selection to avoid autoreactivity
what happens to B cells when they first encounter an antigen?
Either
a) IgM response and stay IgM secreting plasma cell
OR
b) Germinal Center reaction in lymph nodes (dependent on CD4 T cells) –> B cell proliferation and somatic hypermutation into IgA, IgG, IgE secreting plasma cell. Some stay as memory cells for future antigen presentation.
How do CD4 T cells get into this? Dendritic/APC cells prime CD4+ T cells which then help the B cells.
what are immunoglobulins?
- soluble proteins made up of 2 heavy & 2 light chains
- heavy chain –> determines antibody class
- effector function: constant region of heavy chain (Fc)
- antigen recognition: antigen binding regions (Fab) of both heavy/light chains
- remove pathogens via complement, phagocytes, or NK cells (Fc mediated)
which antibodies are of highest affinity in B cell memory response to antigen?
IgG> IgM
how would T cell deficiency present clinically?
- viral infections (eg CMV)
- fungal infection
- bacterial infection (Tb)
- early malignancy
how would B cell deficiency present clinically?
- bacterial infections (staph/strep)
- toxins
- enterovirus
what is the commonest form of SCID?
- x-linked SCID
- mutation of gamma chain of IL2 receptor on chromosome Xq13.1
- shows as very low/absent T cell numbers, normal or increased B cell numbers, poorly developed thymus tissue
what is DiGeorge syndrome?
- deletion at 22q11.2
- sporadic, rather than inherited
- Presents: high forehead, low set ears, cleft palate, small mouth/jaw, esophageal atresia, complex congenital heart disease
- Bloods - dec. Calcium, T cell lymphopenia, normal B cell numbers
what is bare lymphocyte syndrome?
- Defect in 1+ regulatory protein involved in HLA II expression
- absent expression of MHC Class II molecules –> deficiency of CD4+ T cells but normal number of CD8+ cells and B cells
- no IgG or IgA antibody
what is the clinical phenotype of bare lymphocyte syndrome?
- unwell by 3 months (after mom’s placenta crossing antibodies run out)
- infections
- failure to thrive
how might we investigate if we suspect someone has T cell deficiency?
- total WBC count
- Lymphocyte subsets
- serum Ig
- protein electrophoresis (IgG is surrogate marker for CD4 T cell function)
- HIV test
what immunodeficiencies involve T cells? (There are 5)
- SCID
- DiGeorge
- Bare lymphocyte syndrome
- IL12 receptor deficiency
- IFN gamma deficiency
spot diagnosis: Severe recurrent infections from 3 months,CD4 and CD8 T cells absent, B cell present but immature phenotype, some IgM present, IgA and IgG absent. Normal facial features and cardiac echocardiogram
a) bare lymphocyte syndrome type II
b) X linked SCID
c) DiGeorge syndrome
d) IFN gamma receptor def.
b) X linked SCID
spot diagnosis: Young adult with chronic infection with Mycobacterium marinum
a) bare lymphocyte syndrome type II
b) X linked SCID
c) DiGeorge syndrome
d) IFN gamma receptor def.
d) IFN gamma receptor def.
spot diagnosis: Recurrent infections in childhood, abnormal facial features, congenital heart disease, normal B cells, low T cells, normal IgM, borderline low IgA and IgG
a) bare lymphocyte syndrome type II
b) X linked SCID
c) DiGeorge syndrome
d) IFN gamma receptor def.
c) DiGeorge syndrome
spot diagnosis: 6 month baby with two recent serious bacterial infections. T cells present – but only CD8+ population. B cells present. IgM present but IgG absent
a) bare lymphocyte syndrome type II
b) X linked SCID
c) DiGeorge syndrome
d) IFN gamma receptor def.
b) bare lymphocyte syndrome type II
what is Bruton’s x-linked hypogammaglobulinemia?
- abnormal B cell tyrosine kinase (TK) gene = diagnostic
- pre B cells cannot develop to mature B cells –> no circulating Ig from 3 months old
- recurrent infections during childhood
what is hyper IgM syndrome?
- B cell maturation defect
- X linked
- mutation in CD40 ligand gene ( T cell defect - so cannot ‘help’ B cells)
- Clinical phenotype - boys, first few years of life, recurrent bacterial infections, failure to thrive
- Bloods: elevated serum IgM and undetectable other Ig; normal number of B cells & T cells; no germinal center development within LNs/spleen
what happens in common variable immune deficiency?
- Presents with low IgG, IgA, IgE from failure of differentiation of B lymphocytes
- recurrent bacterial infections
- heterogenous group of disorders from many different genetic defects
how does common variable immune deficiency develop?
- marked reduction in IgG, low IgA or IgM (definitive)
- poor/absent response to immunization
- recurrent bacterial infections (often pulmonary or GI)
- autoimmune diseases
- malignancy
how would we investigate B cell deficiencies?
-total white cell count
-lymphocyte subsets
-serum immunoglobulins, protein electrophoresis
-functional tests
NB: same as investigation of T cell deficiencies
what immunodeficiency can exist involving B cells?
- SCID
- X linked Bruton’s hypogammaglobulinemia
- X linked hyperIgM syndrome
- common variable immunodeficiency
- IgA specific deficiency
spot diagnosis: adult with bronchiectasis, recurrent sinusitis, development of atypical SLE
a) IgA deficiency
b) common variable immunodeficiency
c) bruton’s x linked hypogammaglobulinemia
d) x linked hyper IgM syndrome
b) common variable immunodeficiency
spot diagnosis: Recurrent bacterial infections in a child, episode of pneumocystis pneumonia, T and B cells present, high IgM, absent IgA and IgG
a) IgA deficiency
b) common variable immunodeficiency
c) bruton’s x linked hypogammaglobulinemia
d) x linked hyper IgM syndrome
d) x linked hyper IgM syndrome
spot diagnosis: 1 year old boy. Recurrent bacterial infections. CD4 and CD8 T cells present. B cells absent, IgG, IgA, IgM absent
a) IgA deficiency
b) common variable immunodeficiency
c) bruton’s x linked hypogammaglobulinemia
d) x linked hyper IgM syndrome
c) bruton’s x-linked hypogammaglobulinemia
spot diagnosis: Recurrent respiratory tract infections, absent IgA, normal IgM and IgG
a) IgA deficiency
b) common variable immunodeficiency
c) bruton’s x linked hypogammaglobulinemia
d) x linked hyper IgM syndrome
IgA deficiency
what is the indication for bone marrow transplant?
- life threatening primary immunodeficiency (leukocyte adhesion defects; SCID)
what is the indication for antibody replacement therapy?
-primary antibody deficiency
(X linked Bruton’s, X linked hyper IgM syndrome, common variable immune deficiency)
-secondary Ab deficiencies (CLL, multiple myeloma)
when is interferon alpha used?
Hep B
Hep C
Kaposi’s sarcoma (HHV8)
when is interferon gamma?
chronic granulomatous disease
what is Ipilimumab and when is it indicated?
indicated: advanced melanoma
action: antibody for CTLA4
what are Pembrolizumab and Nivolumab and when are they indicated?
indicated: metastatic melanoma
action: antibody for PD-1
how is x-linked hyper IgM syndrome treated?
human normal immunoglobulin
how do corticosteroids work?
*Breaks down phospholipids to form arachidonic acid which is converted to eicosanoids by COX
- inhibit phospholipase A2 –> Blocks arachidonic acid and prostaglandin formation –> reduces inflammation
- decreased traffic of phagocytes to inflamed tissue & decreased phagocytosis
how does cyclophosphamide work and when is it indicated?
MoA: alkylates guanine base of DNA, damages DNA and prevents cell replication.
indicated: anti-cancer; vasculitis with severe end-organ involvement
what are the side effects of cyclophosphamide?
- toxic to proliferating cells
- hemorrhagic cystitis
- infection
- bladder cancer
how does azathioprine work and when is it indicated?
MoA: metabolized to 6-mercaptopurine which blocks de novo purine synthesis and inhibits T cell activation
indicated: translplants, auto-immune or inflammatory disease
how does mycophenolate work and when is it indicated?
MoA: blocks de novo nucleotide synthesis
indicated: in transplantation, alternative to azathioprine
what do we worry about if we give someone mycophenolate?
- Particular risk of herpes virus reactivation
* Progressive multifocal leukoencephalopathy (JC virus)
what is plasmapheresis?
patient’s own blood is taken out of the body, plasma treated to remove immunoglobulins, reinfused into body
under what circumstances might we use plasmapheresis?
- Antibody-mediated disease
eg. Goodpastures, acute myasthenia gravis, vascular rejection
how do cyclosporine & tacrolimus work?
- inhibit cell signaling by inhibiting cytokine transcription
- prevent effector functions
what side effect do we worry about with cyclophosphamide?
infertility
what side effect do we worry about with prednisolone?
osteoporosis
what side effect do we worry about with azathioprine?
neutropenia
what side effect do we worry about with cyclosporine?
hypertension
what does Abatacept target?
CTLA4-Ig
reduces T cell activation
what does Rituximab target?
anti CD20
depletes B cells
what does Natalizumab target?
anti-alpha4 integrin
what do infliximab and adalimumab target?
anti-TNFalpha
what does denosumab target?
anti-RANK ligand
what side effect do we worry about when giving denosumab?
Avascular necrosis of jaw
in severe psoriasis what immunosuppressive medications can be used?
inhibition of IL 12/23, TNF alpha, IL17A
in severe rheumatoid arthritis what immunosuppressive medications can we use?
inhibition of IL6, TNF alpha, depletion of B cells
in severe osteoporosis, what immunosuppressive medications can we use?
denosumab - inhibition of RANK ligand
which vaccines CANNOT be used in immunosuppressed patients?
Measles
Polio
BCG
Yellow Fever
what infections & malignancies would immunosuppressed patients be more likely to get?
- TB
- Hep B/ Hep C
- HIV-CMV
- JC virus (can cause PML)
- EBV lymphoma
- HPV skin cancers
- Melanoma
what are the 3 phases of immune response to a graft which is rejected?
Phase 1: recognition of foreign antigens
Phase 2: activation of antigen specific lymphocytes
Phase 3: effector phase, graft rejection
what is HLA?
HLA - human leukocyte antigens. Cell surface proteins coded for by MHC (major histocompatibility complex).
Presentation of foreign antigens on HLA molecules to T cells is central to T cell activation
what are the HLA classes?
HLA Class I (A,B,C)– expressed on all cells
HLA Class II (DR, DQ, DP) – expressed on antigen-presenting cells but also can be upregulated on other cells under stress
how do APCs present the antigen?
-phagocyte/APC eats the bacteria –> the antigen goes to the surface of phagocyte –> phagocyte presents antigen to CD4+ T helper cell –> activates CD4+ T helper cell –> activates acquired immune response
how can allogenic transplants be recognized in the recipient’s body as a foreign antigen?
-direct presentation: acute rejection; the allogenic APC activates the recipient’s CD8 or CD4 T cells and starts the process
or
-indirect presentation: chronic rejection; the recipient APC activates the recipient CD4 T cells but with allogenic peptides from transplant. This leads to a delayed type IV hypersensitivity
what does ‘perforin’ released from cytotoxic CD8 T cells do?
punches holes in target cell/bacteria/antigen
what does ‘granzyme B’ released from cytotoxic CD8 T cells do?
release of toxins to kill target
what does ‘Fas-ligand’ released from cytotoxic CD8 T cells do?
causes apoptotic cell death
what happens in phase 3 (‘effector phase’) of t-cell mediated graft rejection?
- graft infiltration by CD4 + cells
- cytotoxic CD8 T cells release toxins to kill target, punch holes in it, lead to apoptotic cell death
- macrophages release cytokines, chemokines, phagocytose allogenic graft
what are the presenting symptoms of acute T-cell mediated rejection of allogenic transplant?
- deteriorating graft function
(e. g. in liver transplant - coagulopathy, rise in LFTs) - pain/tender graft
- fever
what are the 3 phases of an antibody-mediated allogenic graft rejection?
Phase 1: exposure to foreign antigen
Phase 2: proliferation/maturation of B cells with Ab production
Phase 3: effector; Abs bind to graft endothelium and lyse it, other parts of acquired immunity step in (eg opsonization, phagocytosis, lysis…)
how do we work to prevent graft rejection?
- HLA/Ab matching
- screen for any anti-HLA Abs
- immunosuppress recipient
what drugs can be used to specifically help prevent GvHD in hematopoietic SCT?
Methotrexate
Cyclosporine
how does GvHD present?
- skin rash
- N&V
- abdominal pain
- diarrhea/bloody
- jaundice
how do we treat GvHD?
- supportive
- corticosteroids (immune suppress)
what’s the difference in pathology between auto-inflammatory and auto-immune conditions?
auto-inflammatory: innate immune response
auto-immune: adaptive immune response
(Can also have ‘mixed pattern’ disease which has a bit of both playing in)
-both tend to be polygenic, monogenic causes are v rare
what are some examples of auto-inflammatory (as opposed to auto-immune) disease?
Crohn’s, UC, Giant cell arteritis, Takayasu’s arteritis
what are some examples of auto-immune (as opposed to auto-inflammatory) disease?
Rheumatoid Arthritis, Pernicious anemia, Grave’s, SLE, PBC, pANCA vasculitis, Goodpasture’s, myasthenia gravis
what is the pathophysiology behind a monogenic auto-inflammatory disease?
Mutations in a gene encoding a protein involved in a pathway associated with innate immune cell function
(commonly abnormal signaling via cytokine pathways)
list some examples of monogenic auto-inflammatory disease
-Familial mediterrranean fever
-Muckle Wells syndrome
(Think of periodic fevers)
how do monogenic auto-inflammatory diseases cause problems?
- the inflammasome complex
- toxins/urate/pathogens will activate cryopyrin (where the pyrin molecule puts negative feedback on this) to activate the apoptosis associated protein ASC –> procaspase 1 –> IL-1, NFkB, Apoptosis
what causes familial Mediterranean fever?
-AR condition due to mutation in MEFV gene
which encodes pyrin
-we call it Mediterranean because seen in Sephardic jews, Armenians, turks
-this mutated pyrin fails to regulate cryopyrin (that activates neutrophils in the inflammasome complex)
-neutrophils constantly active
how does familial Mediterranean fever present?
- periodic fevers lasting 2-3 days
- abdominal pain (peritonitis)
- chest pain (pleurisy)
- arthritis
- long term risk of amyloidosis
- chronic renal failure
how do we treat familial Mediterranean fever?
Colchicine 500ug bd - binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion
how do monogenic auto-immune diseases develop?
Mutation in a gene encoding a protein involved in a pathway associated with adaptive immune cell function –> leads to abnormality in tolerance
what is the pathogenesis of IPEX (X linked immune dysregulation)?
. Single gene mutation involving FOXp3 resulting in abnormality of T reg cells
what is the pathogenesis of ALPS (autoimmune lymphoproliferative disorder)?
Mutation within the Fas pathway (leading to defect in lymphocyte apoptosis) associated with lymphocytosis, lymphomas and auto-immune cytopenias
what is the pathogenesis of familial Mediterranean fever?
Single gene mutation involving MEFV and affecting the inflammasome complex, resulting in recurrent episodes of serositis
which gene is mutated in a large proportion of patients with Crohn’s disease?
NOD2
CARD15
Ankylosing Spondylitis is an example of a ‘mixed pattern’ disease for autoimmune and autoinflammatory conditions. What makes it mixed pattern?
Abnormalities affecting both innate and adaptive immune system resulting
in increased tendency to ‘inflammation’
Enhanced inflammation occurs at specific sites where there are high tensile forces (sites of insertions of ligaments or tendons)
what is the pathophysiology of Crohn’s disease?
Polygenic auto-inflammatory disease. ~30% patients have a mutation of NOD2/CARD15 which may affect response of myeloid cells to bacteria.
what is the pathophysiology of ankylosing spondylitis?
Mixed pattern auto-inflammatory / auto-immune disease with >90% heritability that results in inflammation typically involving the sacro-iliac joints and responds to TNF alpha antagonists
what is the pathophysiology of giant cell arteritis?
Polygenic auto-inflammatory disease resulting in a large vessel vasculitis and requiring immediate treatment with high dose corticosteroids
how do polygenic auto-immune diseases develop?
genetic polymorphisms –> loss of tolerance –> auto-antibody formed and auto-reactive T cells –> disease
what HLA genotype is associated with Goodpasture’s disease?
HLA - DR15
what HLA genotype is associated with Graves disease and SLE?
HLA-DR3
what HLA genotype is associated with Type I DM?
HLA DR3/DR4
what HLA genotype is associated with Rheumatoid arthritis?
HLA-DR4
what are some diseases that HLA-DR3 predisposes you to?
- Graves
- SLE
- Type I DM
what are some diseases that HLA DR4 predisposes you to?
- Rheumatoid Arthritis
- Type I DM
what is the Gel & Coombs classification?
the 4 types of hypersensitivity that can occur in the body - old system
what are the 4 types of hypersensitivity classified by Gel & Coombs?
Type I: immediate, IgE mediated (ie anaphylaxis)
Type II: Ab reacts with cellular Ag
Type III: Ab reacts with soluble antigen - form immune complex
Type IV: delayed type, T- cell mediated (eg contact dermatitis)
describe the type I hypersensitivity reaction:
-IgE mediated
-Rapid allergic reaction
where IgE binds to allergen and to Fc receptors on mast cells and basophils –> Cell degranulation
- Release of inflammatory mediators (Histamine, prostaglandins, cytokines, leukotrienes)
-Increased vascular permeability
-Smooth muscle contraction
describe the type II hypersensitivity reaction:
- Auto-antibody binds to cell associated auto-antigen (eg TSH receptor sets off antibodies in Graves)
- -> antibody dependent destruction (NK cells, phagocytosis, complement activation)
- examples: Auto-immune hemolytic anemia, Goodpasture’s, Grave’s
describe the type III hypersensitivity reaction:
- antibody binds to a SOLUBLE antigen to form a circulating immune complex –> cytokines/chemokines, inflamed and damaged vessels, macrophages/neutrohils
- it is this complex that distinguishes it from type II
- examples: SLE (where antigen is DNA), Rheumatoid Arthritis (where antigen is Fc IgG)
what type of hypersensitivity reaction is occurring in:
a) hemolytic anemia (AI)
b) Eczema
c) Graves
d) Nickel Allergy
e) Peanut Allergy
f) SLE
g) Rheumatoid Arthritis
h) Type I DM
a) type II
b) type I
c) type II
d) type IV
e) type I
f) type III
g) type III/IV
h) type IV
describe type IV cell mediated disease:
-T cell mediated
-HLA class I molecules present antigen (self peptide) to CD8 T cells –> cytolytic granule release from cytotoxic CD8 T cell –> cell lysis, inflammation, tissue damage
AND/OR
-HLA class II molecules present self-antigen to CD4 helper T cells –> primed CD4 T cell –> macrophage, inflammation, damage
which Gel & Coombs hypersensitivity reaction is most commonly involved in autoimmune disease?
-type I
sometimes type III or IV
what type of hypersensitivity is involved in Hashimoto’s thyroiditis?
- anti TPO Abs
- Type II and Type IV
which antibodies are involved in type I DM?
- anti-islet cell Abs
- anti insulin Abs
- anti GAD Abs
- Anti IA2 Abs
what is the complication of uncontrolled pernicious anemia?
- no absorption of vitamin B12 (no IF)
- -> subacute combined dengeration of the cord; peripheral/optic neuropathy
which antibodies are found in rheumatoid arthritis?
-anti CCP:
Antibodies to cyclic citrullinated peptide
Bind to peptides in which arginine has been converted to citrulline by peptidylarginine deiminase (PAD)
-anti RF: antibody directed against the common Fc region of human IgG
why is rheumatoid arthritis associated with type II and type III hypersensitivity responses?
Type II response: antibody binding to CCP (anti-CCP)
Type III: immune complex formation with RF, anti-CCP; deposits
what antibodies do you want to test for when suspecting SLE?
- ANA Abs
- dsDNA Abs
- ENAs (Ro, La, Sm, RNP)
- Anti phospholipid Abs
what antibodies are characteristically seen in Sjogren’s syndrome?
- ANA Abs
- Anti Ro
- Anti La
what antibodies are seen in diffuse cutaneous systemic sclerosis? (think of CREST)
- ANA Abs
- Scl70 Abs
- RNA Polymerase Abs
- Fibrillarin Abs
what antibodies are seen in anti-phospholipid syndrome?
- anti cardiolipin ab
- lupus anti coagulant
what is the pentad of CREST syndrome (limited cutaneous systemic sclerosis) ?
- calcinosis
- Raynaud’s
- esophageal dysmotility
- sclerodactyly
- telangiectasia
- primary pulmonary HTN
- skin does not involve beyond forearms
what is the difference between limited and diffuse cutaneous systemic sclerosis?
- Skin involvement - progresses beyond forearms in diffuse cutaneous systemic sclerosis*
- same CREST features
- diffuse is more extensive: skin, GI, kidney crisis
what ANA Abs are seen in limited CREST?
(ANAs)
Anti-centromere Antibodies
what are the antibody differences between diffuse and limited CREST syndrome (cutaneous systemic sclerosis)?
Diffuse: nucleolar pattern to ANAs; Scl 70; RNA poly; fibrillarin
Limited: anti-centromere Abs
what is the difference between dermatomyositis and polymositis?
In dermatomyositis the cellular infiltrate is around the blod vessels so there is pervascular infiltration of CD4 T cells and B cells.
In polymyositis CD8 cytotoxic T cells surround the HLA class I expressing muscle fibres, and they induce muscle cell necrosis via the actions of perform and granzyme granules
what pathophysiology happens in dermatomyositis?
- within muscle
- perivascular CD4 T cells, B cells
- immune complex mediated vasculitis
- Type III
what pathophysiology happens in polymyositis?
- within muscle
- CD8 T cells (HLA class I) around myofibres
- kill myofibres via perforin/granzymes
- Type IV response
what antibodies will be positive in dermatomyositis?
- ANA +
- Jo 1
- Anti Mi2
what antibodies will be positive in polymyositis?
- ANA+
- Anti SRP Abs
- Anti Mi2 (possible)
spot diagnosis: dsDNA Ab +, ANA Abs +
SLE
spot diagnosis: ANA Abs +, Anti Ro +, Anti La +, Anti Sm +, Anti RNP
SLE or Sjogren’s
spot diagnosis: ANA Abs +, Scl70+
Diffuse cutaneous systemic sclerosis (CREST)
spot diagnosis: ANA Abs +, centromere Abs
Limited CREST
spot diagnosis: ANA Abs +, Anti Jo1+
dermatomyositis > polymyositis
what is ANA?
A. Screening test for a connective tissue disease
B. May be positive in SLE or in Sjogren’s syndrome but not usually in systemic sclerosis
C. Sometimes positive in patients with idopathic inflammatory myopathy particularly if they have interstitial lung disease
A. screening test
what is Anti-Ro?
A. Screening test for a connective tissue disease
B. May be positive in SLE or in Sjogren’s syndrome but not usually in systemic sclerosis
C. Sometimes positive in patients with idopathic inflammatory myopathy particularly if they have interstitial lung disease
b. may be positive in SLE or Sjogren’s but not systemic sclerosis
what is Anti-Jo-1?
A. Screening test for a connective tissue disease
B. May be positive in SLE or in Sjogren’s syndrome but not usually in systemic sclerosis
C. Sometimes positive in patients with idopathic inflammatory myopathy particularly if they have interstitial lung disease
C. sometimes positive in patients with idiopathic inflammatory myopathy
what are the 3 ANCA associated small vessel vasculitidies?
- microscopic polyangitis
- granulomatosis with polyangitiis (Wegener’s)
- eosinophilic granulomatosis with polyangitis (Churg-Strauss)
what are the two main immune complex associated small vessel vasculitidies?
- anti GBM disease (Goodpasture’s)
- IgA disease
what are ANCA antibodies and how do they cause vasculitis?
Antibodies specific for antigens located in primary granules in neutrophils –>
Inflammation leads to expression of these on neutrophil cell surface –>
Antibody engagement with cell surface antigens –> type II hypersensitivity
what is the difference between cANCA and pANCA?
cANCA: cytoplasmic fluorescence associated with antibodies to proteinase 3 enzyme
pANCA: perinuclear staining associated with antibodies to myeloperoxidase
what small vessel vasculitis is cANCA associated?
granulomatous polyangiitis with renal involvement
Wegener’s
what small vessel vasculitis is pANCA associated?
- eosinophilic granulomatosis with polyangitis (Churg-Strauss)
- microscopic polyangitis
where do you see tear drop cells, hypochromia, poikilocytosis on blood film?
iron deficiency anemia
when do we see target cells on blood film?
IDA
Liver disease
Hypospenism
Thalassemia
what HLA genotype is seen in 90% of Coeliac’s disease?
HLA DQ2
what antibodies are found in Coeliac’s disease?
anti-TTG
anti-endomysial
what gut abnormalities can cause increased epithelial lymphocytes?
- coeliac’s
- derm. herpetiformis
- cows milk protein sensitivity
- IgA deficiency
- tropical sprue
- post infective malabsorption
- drugs
- lymphoma
what gut abnormalities can cause villous atrophy?
- celiac’s
- giardiasis
- tropical sprue
- radiation/chemo
- crohn’s
- bacterial overgrowth
- GvHD
- nutritional deficiencies
- common variable immunodeficiency (no plasma cells)
when do we see Gottron’s papules?
dermatomyositis
what do we see in sarcoidosis in
a) skin
b) Eyes
c) Parotids
d) Lungs
e) Liver
Skin: Lupus pernio, erythema nodosum
Eyes: Uveitis, keratoconjunctivitis
Parotids: Bilateral enlargement
Lungs: BHL, fibrosis, lymphocytosis (CD4+ in BAL)
Liver: Hepatitis, cholestasis & cirrhosis
what changes histopathologically do we see in sarcoidosis?
Non-necrotizing granulomas: histiocytes (epithelioid cells), multinucleated giant cells of Langhans (peripheral nuclei) and lymphocytes.
what presents in Kawasaki’s disease?
- Fever
- Erythema of palms & soles, desquamation
- Conjunctivitis
- Lymphadenopathy
- Coronary arteries may be affected (MI)
what happens in polyarteritis nodosa?
A necrotising arteritis with rampant Polymorphs, lymphocytes, eosinophils. It heals by fibrosis.
More often affecting renal and mesenteric arteries
Nodular appearance on angiography (small aneurysms)
what antibody is involved in Granulomatosis with polyangiitis?
C-ANCA (cytoplasmic ANCA) directed against proteinase 3
what antibody is involved in Churg-Strauss
(Eosinophilic Granulomatosis with polyangiitis)?
P-ANCA (perinuclear ANCA) directed against myeloperoxidase
