Immunology Flashcards
Lymph Node
Cortex is B cells. Primary follicle is dormant and secondary is active
-T cells in paracortex which communcates with HEV
-Plasma cells move to medulla to secrete Ab
-Medulla also location of dendritic cells and macrophages that can enter and exit the afferent and efferent vessels
-
LN Drainage
Scrotum, anal canal below pectinate and thigh drain to superficial inguinal
-Testes and prostate to para-aortic
Spleen
- Red pulp is fenestrated cappilaries to allow macrophages to remove damaged RBC from irculatin
- White pulp has T cells in PALS and B cells in follicles interspersed
- Autosplenectomy in sickle cell, also ruptured in mono and other trauma. Can be removed in spherocytosi
- Increased risk of encapsulated bateria (SHINSKISS)
- Strep Pneumo, H Flu, Nisseria, Salmonella, GBS, Klebsiella
- If splenectomy there will be presence of howell jolley bodies that are RNA remnants, target cells
- There will also be thrombocytopenia
Thymus
- Primary lymphoid organ derived from third pouch, DiGeorge 22q11
- Cortex is double positive T cells from marrow that undergo positive selection to see if MHC works
- Medulla contains dendrritic and epithelial cells (Hassalls Corpuscles) expressing AIRE that provide self antigens and generate self tolerance
- Encapsulated organ in anterior mediastinum
- Thymoma is Myasthenia Gravis
MHC I
- Present on all nucleated cells, no RBC
- Endogenous peptides placed in a groove, loaded in RER
- A protein is TM and beta 2 microglobulin helps sustain structure
- Interacts with CD8
- Expression is increaed by IFN a and B
- Main use against viral cells
- A,B,C
MHC 2
- Two transmembrane proteins A and B
- Exogenous antigen loaded in endosome after CLIP invariant chain is lost in acid endosome
- Expressed on antigen presenting cells
- HLA DRQ
A3
Hemochormatosis
B27
Males, MHC 1
-IBD, Ankylosing spondyltitis, Reiters, Psoriatic. RA negative
DQ2 and DQ8
Celiacs
DR2
Lupus, hay fever, MS, Goodpasteurs
DR3
DMI, Graves
DR4
RA, DM1
DR5
Hashimotos, Pernicous Anemia
NK Cells
CD16 (Fc receptor mediating ADCC) and CD 56 are markers
-Target cells with atypical or reeduced MHC I, kill by perforin and granzyme inducing apoptosis
-Highly active against tumor cells
-IL-2, 12, IFN a and b are major growth factors
-
B Cells
Growth via IL-4 and 10
-Role in hyperacute, humoral acute, and chronic rejection
T Cells
-IL-2 is growth factor
T Cell maturation
Precursors from bone marrow don’t contain TCR or MHC
- Arrive in cortex with TCR (CD3) and CD8 and CD4
- Positive selection in cortex to see if TCR interacts with MHC
- Negative selection in cortex (Hassal’s corpuscles) to see if don’t recognize self proteins (AIRE)
- CD8 will lead to CTL
- CD4 can be stimulated by IL-12 to make TH1 and IL-4 to make TH2
Activation
Expression of MHC I on all nucleated cells and MHC 2 on
- Dendritic cells (Only ones that can activate Naive T cells, live in skin and traffic and activate in LN)
- B cells, Macrophages
Naive T Cell Activation
- Dendritic cells are necessary and activate CD4 and CD8 cells in the lymph nodes
- Signal one comes from TCR and MHC interacting, second signal comes from B7 (dendritic cells) and CD 28 on T cells
B Cell Activation
CD 4 cells will interact with MHC 2 presented on surface of B cells and induce activation and class swithcing
- 2nd signal comes from CD40 on B cells and CD40L on T cells which allow for production.
- If good then release IL-4 to cause Ig production
- If bad then can use Fas BADD pathway to induce apoptosis
Hyper IgM
Defect in CD40/L that results in inability to class switch and affinity maturation leading to only IgM being produced. -Most commonly X linked in CD40L
TH1
- Activated by IL-12 secreted from macrohpages
- Secretes IFN gamma which activates Macrophages
- Macrophages secrete IL-1, TNF alpha, and IL-12 to positive feedback on TH1 creating positive loop
- IL-4 and IL-10 inhibit differentiation
TH2
- Activated by IL-4
- Secrete IL-4 (Ab and isotype switching)
- IL-10: inhibit Th1
- IL-5 Eospinophil tactic (ADCC)
- IL-13: Class switching to IgE
- Inhibited by IFNgamma
CTL
Express CD8 and interact with MHC 1 on all nucleated cells
- If doesn’t recognize secrete porphorin and granzyme to acitvate Caspase 8 and apoptosis
- Also contains FAS which induces apoptosis and controls immune response
- Highly responsible for graft rejection and death of graft cells
- Also can kill neoplastic cells
T Regs
CD25 (IL-2 receptor)
- FOXP3
- Secrete IL-10 and TGF beta to tone down immune response
Ab Structure
- Light chain is kappa and lambda, rearranges second and is VJ recombination (occurs by RAGs)
- Heavy Chain is VDJ rearrangment occurs with RAGs
- TdT adds extra nucleotides when bring together to increase variability (not somatic hypermutation which occurs with AID)
- Heavy chain contains complement and macrophage binding region
- HC also contains FC receptor interaction region (Phagocytosis, ADCC)
- Fab is antigen specificity and is light and heavy (idiotype)
- Fc is isotype and only heavy
IgG
Cross placenta, abundant in serum, phagocytose opsonize
-ADCC with NK cells only
IgG4 is a cause of systemic sclerosing llnesses like Riedel’s
IgA
Secreted as a dimer at mucosal surfaces bound to PolyIg or secretory component that is picked up from epithelial cells during transcytosis
- Can be present in serum as a monomer
- Secreted in colostrum
IgM
BCR
- Secreted as a pentamer and is often low specificity
- Best at activating complement, doesn’t cross placenta
IgD
-On surface of B cells, often imature
IgE
- Secreted in resonse to IL-4
- Physiologic role is ADCC from eosinophils, but can also play a role in type 1 hyperesnstivity
- Binds to surface of basophils and mast cells and when crosslinked leads to release of hitamine and inflammatory markers
- Basophils also play a role in parasitic infections and release IL-4 and histamine
Thymus Independent
- Non protein
- LPS and capsular polysacharides
- Can induce and immune response and secretion of IgM but can’t stimulate memory
Thymus Dependent
-Protein antigens that can be expressed on MHC
Complement
- 3 pathways all lead to production of
- C3 convertase which produces C3a and C3b (B in opsin and 5 convertase and A is anaphylatoxin)
- C5 convertase (C3b and others) leads to C5a and C5b
- C5b complexes to create MAC and C5a is neutrophilotaxic and anaphylatoxin
- Anaphylatoxins activate mast cells
- C3b is necessary to clear immune complexes
PNH
- Defect in GPI anchor that anchors DAF (Generally ccurs de novo mutation in HPSC in marrow), resides on X chromosome
- Leads to decreased DAF which normally inhibits C3 convertase. This leads to MAC and lysis of RBC
C1 Esterase Deficency
- Hereditery andiodema
- INcreased activation of classical pathway leads to increase in C3a and C5a leading to swelling of face and eyes
- Do not give ACE inhibitors as Bradykinin is activated by activated mast cells
C5-C9
Recurrent Nisseria Infections
Early complement C1-C3 deficency
- Leads to decrease C3 activation.
- Decreaased C3b leads to impaired clearance of immune complexes and can predispose to lupus and type 3 hypersensitivity
- Also higher risk for recurrent severe URI and sinus infections
IL-1
- Secreted by Macs and T cells
- Pyrogen and acute phase reactants
- Increases expression of adhesion molecules (CAM on endothelium)
- Also induces chemokine secretion
IL-6
-Similiar to IL-1, pyrogen and acute phase
IL-8
- Neutrophil tactic (Bacterial products, LTB4, C5a)
- Macrophage is the major source
IL-12
Induce TH1 phenotype
Activates NK cells
TNF alpha
- Main player in septic shock, causes endpthelilal activation, dilation, and leak
- Acute phase and pyrogen
IL-2
Tophic for T cells, necessary for survival, drugs (SCID)
IL-3
-Like GM-CSF, causes growth of HPSC
IL-4
- Causes TH2 differntiation
- B cells and class switching to IgG and IgE
IL-5
- Growth and chemotaxis of eosinophiles
- Also increases IgA prodcution
IL-10
-Immunosuppressive especially on TH1
TGF-B
Immunospressive, secreted by CD25 FOXp3 Postiiv cells
IFN gamma
- Induces antiviral state
- Activats macrophages, NK cells, Neutrophils, TH1
- Increases MHC expression
- Can be used in CGD to increase intracelllar killing
IFN a and B
- Induce expression of ribonucleases that are specific for viral mRNA
- Also decreases protein synthesis and divsion of cells
- A is used in Hep C
- B is used in MS
Macrophage Surface Markers
- CD14 is TLR4 that binds LPS and activates in the absence of other signals
- MHC2 and CD7 (TH cells), CD40 (APC)
- FcG receptor and C3b
NK
- CD16-ADCC
- CD56
Superantigen Mechanism
-Crosslinks TCR and MHC2 leading to massive activation
Endotoxin
-Binds CD14 and activates macrophages independent of cpstimulation. Leads to TNF alpha secretion and can cause DIC and shock in sepsis
Ag variation
Salmonella: flagella
-Nisseria: Pillus
Borellia
Trypanasomes (Sleeping Sickness and Cruzi longterm infecions)
Vaccine Differences
Live generates cell mediated and Killed generates humoral
Type I Hypersensitivity
- IgE binds to FcR on Mast (tissue) and Basophils (Circulating)
- Leads to degranulation and release of vasoactive amines (Histamine, seretonin), IL-5, GMCSF, IL-3 etc
- Also release lipid mediators
- Hypotension shock
Type 2 Hypersensitivity
- Ab specific for target, generally cytotoxic but doesn’t have to be
- Causes specific tissue mediated effects
- Opsonization (Extravascular hemolysis)
- Complement ativation (inflammatio)
- ADCC (CD16 on NK cells)
Type 3
- Immune complexes are deposited in tissues when they fall out of blood
- Activate complement leading to neutrophil chemotaxis and tissue injury
- Lack of early complement components can predispose to lupus
Arthus Reactions
- Injection leads to very local accumulation of Ag leading to formation of local Ag Ab complexes that cause a very local edematous and necrotic lesion,
- Commonly after recieveing a vaccine or passive immunization
Serum Sickness
- Systemic form of arthus, Drugs and Hep C can cause the precitpitation of Ab complexes throughout the body leading to vasculitis, arthtritis, proteinuira, lymphadenopathy
- Drugs are the msot common cause
- Takes days to develop (5)
Type 4
- Non humoral. T cells recognize Ag and activate macrophages that cause a local response
- Contact dermatitis, PPD, MS, Transplants, Guillan Bare
- IL-2 and IFNy are the main cytokine
Blood Transfusions
Hyperkalemia from RBC lysis
- Hypocalcemia from citrate
- CMV is the most commonly transmitted infection, Hep C is also possible
Anaphylaxis
-To IgA in patients who are IgA deficiecnt
Nonhemolytic
- Immune response to MHC antigens on leukocytes
- Leads to fever, chills, etc, but there is no hemolysis
- Type 2 hypersensitivity
Hemolytic
- ABO incompatability
- Leads to severe intra and extravascular hemolysis that is type 2 HS mediated
Brutons Agammaglobulinemia
- Defect in Tyrosine kinase present on X chromosome that is necessary for B cell maturation. Leads to no mature but normal immature B cells
- No Ig will be made
- Increaed Bacterial Infections after 6 months. Opsinization is crucial for clearance
- Occurs from 6 months after birth (CVID can be acquired)
B cell Deficencies
- Have more bacterial infections than Viral/Fungal
- Especially encapsulated
- Increase risk of enteroviral infections (IgA) and giardiasis
T cell Deficencies
- Viral and Fungal infections, increase risk of sepsis
- Candida, PCP, Viral
Granulocyte Deficencies
- CGD: Aspergillus, Staph, Pseudomonas, Serretia, Nocardia
- If problem is in neutrophils can get candida dissemination
Selective IgA
- Unknown Cause, most common
- Often assymptomatic but have increased mucosal infections, also have slight increase in autoimmune risk, also false positive B-HCG
- Anaphylaxis with transfusion
- Normal cell counts and other antibodies
CVID
- Inabiltiy to mature B cells, many causes
- No mature B cells, no plasma cells, and no Ig
- Chronic bacterial infections especially encapsulated
- Commonly is acquired form muttion in HPSC
THymic APlasia
Digeorge, absent thymic shadow and endodermal structues of 3rd and 4th pouch
- Increased viral and Fungal (Candida and PCP)
- Thymic independednt antigens can still cause response
IL-12 receptor deficency
- No TH1 cells leads to incresaed risk of viral, TB, inectonis
- Disseminated TB is most common cause of death
- There will be no IFN gamme because ther are no TH1 cells
Hyper IgE (Jobs)
Defective TH1 secretion of IFN gamma leads to an increaese in TH2 response and an increase IgE
- Hallmark is increased IgE leading to atopy and dermatitis.
- Also will have impaired neutrophil cemotaxis and function leading to recurrent staph infections, failure to lose baby teeth
Chronic Mucocutaneous Candidiasis
- T Cell dysfunction
- ALso can be immunocupressants leading to dysfunction
Defect in common gamma chain of IL receptors
- Causes decrese in IL-2 R function leading to impaired immune in all fashions
- X linked recessive
- Absent thymic shadow and decresaed germinal centers
- Decreased T circles (prodcut of recombination)
- Recurrent infections with bacteria and virus, and fungal
- Tx is BM transplant
ADA deficency
- Decreased recycling of Purines. No ADA leads to increased ATP this feedback inhibits ribonucleotide reductase leading to impaired GMP and pyrimidine synthesis
- Same as SCID in gamma chain
ATM
- Defect in ATM gene that is required for DS break repaire
- Cerebellar atrophy and ataxia, Spider angioma and telangectasia, IMmune deficecny, most commonly Ab deficency
- AFP will often be elevated in early infant period
Hyper IgM
Defect in CD 40 (B cells) or CD40L (T cells, more common, xlinked) leads to inability to class switch. Increase IgM and no other Ab present
- Can’t affinity maturation
- Most commonly bacterial infections
Wiskott Aldrich Syndrome
- Impaired actin reorganization leading to inabilty to signal through TCR
- Thrombocytopenia, Eczema, Immunodeficency
- Don’t give anticoagulants/aspirin
- Patients also commonly have bloody diahrrea
LAD
- Defect in CD 18, integrin that is expressed on leukocytes
- Leads to inability to bind tightly and inability to extravassae
- Increase in number in the blood and decrease in tissues
- Skin infections without pus
- There is delayed separation of the umbilical cord
Chediak Higashi
- Defect in LYST an important protein for microtubule trafficking, can’t fiuse phagolysosomes
- Leads to intracellular granules
- Albino (Melanin granules), Neuropathy (NT vesicels), IMmunodeficecny
- Especially staph and strep, can see large granules on EM
CGD
- NADPH oxidase turns oxygen into H2O2 that is then acted on by MPO to generate OCl in oxygen dependent killing
- X linked
- Can’t kill bugs that are catalase positive (Staph Aureus, Aspergillus, Psudomonas, Nocardia, Serretia)
- NTB/Rhodamine will not turn blue
- Can give IFN gamma to increase intracellular killing, also BM transplant is currative
- If patient has same infections, but NTB test still works, the the patient may have MPO defcency
Graft Rejection
-HLA molecules are codominantly expressed, so difficult to get right match, even in same family
Hyperacute
- Preformed Ab mediates Type 2 hypersensitivity and complement mediated RBC lysis
- Vascular occlusion, ischemia, necrosis
Acute
- Days to weeks
- CTL recognize MHC as foreign and begin killing, will see a dense lymphocytic infiltrate
- Can be reversed with immunosupressants (Muromunab-3, Cyclosporin)
- Vasculitis as generally starts in the edothelium
Chronic
- Months to years
- Long term minimal killing of MHC percieved as foreign leads to endothelial injury, and progressive occluding fibrosis.
- Humoral also plays a role
- Inevitable in reality
- Commonly seen in lungs as bronchiolitis obliterans (airway obstrucion leading to obstructive pattern, decreaed FEV1)
GVHD
- When implanted lymphocytes begin attacking host cells that are immunocompromised
- Seen most commonly in bone marrow, but can also be seen in liver transplants
- Generally starts with Jaundice, HSM and liver damage as well as maculopapular rash
- May be beneicial in leukemia
Cyclosporine
- Binds Cyclophilins and inhibits caclinueirn induced NFAT activation of IL-2 and IL-2R leading to decrased T Cells Responses
- S/E: Metabolic Syndrome, Gingival Hyperplasia, Hirsuitism, nephrotoxicity
Tacrolimus
- Binds FK proteins that leads to inhibition of Calcinueirn and decrased NFKB and IL-2 signalling
- Metabolic sydrome and nephrotoxicity. No hirsuitism or gingival hyperplasia in contrast to Cyclosporine
Sirolimus
- Inhibits mTOR pathway that is the downstream signalling of IL-2 Receptor
- S/E: Hyperlipidemia, thrombocytopenia, leukopenia
Azathioprine
- Antimeatbolite, active form is 6 mercaptopurine, inhibits purine synthesis and decreases B and T cell proliferation
- Metabolized by xanthine oxidase, allourinol can make side effects worse
- S/E: Bone Marrow Supression
Muromunab-CD3
- Binds CD3 TCR and prevents activation leading to lack of proliferation and death of T cells
- Used in combo for organ transplants
- S/E: cytokine release syndrome which is where cytokines are released and cause patient to feel sick.
Aldesleukin
- IL-2 analog
- Used to stimulate T Cells in cancer
Filgrastim
-GCSF
Saragrostim
-GMCSF
Alpha interferon
-Hep B and C, Kaposi Sarcoma, Melanoma, leukemia
IFN B
MS
IFN Y
CGD
Oprevlekin
IL-11 stimulates megakaryoytes
Thrombopoetin
Stimulates megakaryoctyes
Infliximab, Adalinumab
TNF alpha
Abciximab
GP 2b3a
Traztuzumab
Her2Neu
Rituximab
CD20
Altmetizumab
CLL
Duclizumab
IL-2 Receptor
