Immune Mechanisms Flashcards
What is hapten-carrier effect?
Small-molecule antigen requires a larger carrier to stimulate adaptive response. This process is achieved with hapten-specific B cells and carrier-specific T cells.
- basis of conjugated vaccines
What are the common superantigens (4) and related diseases?
1,2. SEB and SEC from Staph aureus food poisoning
- TSST from staph aureus for toxic shock synd
- SPE-C from strep pyogenes for toxic shock synd
Which type of T cell recognizes lipid antigens and what molecule is involved? (2)
- NK T cells recognize lipid antigens and CD1 molecules are involved
- gamma delta T cells
what antigens are T cell dependent and which are T cell independent?
Dependent - protein Ag
Independent - polysaccharide, nucleic acid, lipids
Where do superantigens bind?
Vbeta region of TCRs that are outside of the peptide-binding groove on the MHC molecule
what is the name of molecules in vaccine that enhance the immune response?
Adjuvants
what is the difference between an antigen and immunogen?
- Ag = recognized by immune system
- immunogen = stimulates an immune response
what do epitopes bind to?
Ab or T cell receptor
what is an acute multi-organ inflammatory syndrome that can happen in response to infections or immune therapies
cytokine release syndrome
what are the chief cytokines in cytokine release syndrome (3)
IL- 6, IL -10, TNF alpha
what is potential complication of (CAR)-T therapy
cytokine release syndrome
What vaccination have purely polysaccharide Ag (2)
23-valent pneumococcal vaccine, typhoid vaccine
what is the binding site for CD8 on the MHC class I molecule
alpha 3
what chain makes up the peptide binding cleft in MHC class I molecules
alpha 1 and 2
MHC class I molecule presents which type of Ag and where does the Ag-MHC class I loading happen?
presents both intracellular antigens (ex viral Ag in cytoplasm) and extracellular Ag (via cross presentation).
- the loading site is endoplasmic reticulum (ER)
in which chromosomal region are the TAP proteins located?
MHC class II locus, which is involved in peptide processing for MHC class I.
MHC class II molecule presents which type of Ag? where does Ag-MHC class II loading happen?
presents extracellular Ag (ex Ag from phagocytosed bacteria)
- loading site is phagolysosome
which cytokines are important for Tregs? (2)
IL-10 and TGF beta
Where does Pepsin cleave and what is the result?
Ig below the hinge region at multiple sites and produces a single F(ab)2
what is RF
Ab against the Fc portion of IgG
which Ig class has the highest plasma concentration? Highest total body concentration?
IgG and IgA
what is secretory immunity?
small quantities of IgG and IgM are secreted into the gut lumen and bind to microbes and toxins to neutralize them
which cytokines primarily activate NKFB
IL1, TNF and IL-17 families
what are Th2 cytokines? (6)
IL- 4, 5, 9, 13, 25, 31
which cytokine is involved in IgA class switch?
TGF beta
which cytokine inhibits class switching to IgE and IgG4?
IFN gamma
what is the function of IL- 6 (4)
pro-inflammatory cytokine, stimulates synthesis of acute-phase protein by hepatocytes, stimulates production of neutrophils, and stimulates growth of B lymphocytes
what molecules belong to the Ig superfamily (10)
TCR, MHC molecules, CD4, CD8, CD19, B7-1, B7-2, Fc receptors, KIR and VCAM-1
what is the role of the FcRn receptor? (4)
FcRn receptor binds to IgG and allows it to be endocytosed.
- protects IgG from lysosomal degradation and recycles it to the cell surface, accounting for the long half-life of IgG in humans
- also the mechanism by which IgG is transported across the placenta and fetal intestine.
- IgG3 has the shortest half-life because it poorly binds to FcRn
mutation in SAP causes which disease?
X linked lymphoproliferative syndrome (XLP)
immunosuppressant cyclosporine binds to which molecule in T cell signaling pathway?
cyclosporine binds to cyclophilin, also called immunophilin. The drug-protein complex inhibits calcineurin and therefore inhibits NFAT translocation to the nucleus
what CD molecules are in the BCR coreceptor?
CD19, CD21, and CD81
which chemokine receptor is associated with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome?
CXCR4
which integrin molecule is important for gut homing by binding to MAdCAM?
alpha4beta7
which receptors are associated with CCL5 (RANTES)
CCR 1, 3, 5
what is another name for CCL 17? what receptor is it associated with?
TARC; CCR4
what ligand does Rhinovirus bind to?
ICAM-1
which chemokine receptor is required for HIV entry to CD4 T cells?
CCR 5
what is the defect in LAD-2?
PMNs cannot express carbohydrate ligands for E and P selectins
upon first exposure to a medication, when might a patient develop symptoms of serum sickness?
7-12 days
which component is shared by IL-4 and IL-13 receptors?
IL-4alpha which is targeted by dupilumab
what is the result of IFN gamma receptor deficiency?
susceptibility to Mycobacterium tuberculosis and other intracellular bacteria
what interleukin is excessively produced in cryopyrinopathies?
IL-1 beta
what is the function of LRBA?
Recycles/maintains intracellular stores of CTLA4, which can stop T cell activation
which complement deficiency is X linked?
properdin
what two molecules inhibit MAC formation?
CD59 and S protein
which complement receptor is implicated in PNH (paroxysmal nocturnal hemoglobinuria)?
CD55 and CD59
what is the main source of Factor D?
adipose tissue
anti-C1q antibody is found in which disease process?
HUVS (hypocomplementemic urticarial vasculitis)
contact activation pathway is initiated by which factor?
Factor XII
bradykinin acts on what receptor on endothelial cells?
B2 receptor
what are the primary immunoglobulins involved with type II hypersensitivity
IgG and IgM
IgG and IgM activate which complement pathway?
classical pathway
what is the binding site for CD4 on the MHC class II molecule?
beta2
which chain makes up the peptide binding cleft in MHC class II molecules?`
alpha1 and beta1
where is HLA-G located?
fetal derived placental cells
what is the role of HLA-DM?
removes CLIP, allowing antigenic peptides to load into MHC class II binding cleft
mutations in which transcription factors can lead to MHC class II deficiency? (4)
MHC2TA, RFX5, FRXAP, FRAXANK
what are the possible outcomes of central T cell tolerance?
apoptosis (negative selection) – strong binding affinity
- Treg dev – intermediate binding affinity
what cells in the thymus express AIRE
medullary thymic epithelial cells (MTECs)
what are the possible outcomes of central B cell tolerance?
apoptosis (negative selection)
receptor editing
anergy
what are the mechanisms of peripheral T cell tolerance? (3)
apoptosis
suppression by Treg cells
anergy
what are the mechanisms of peripheral B cell tolerance? (2)
apoptosis, anergy
what has the greatest binding affinity for C1q? (4)
IgM > IgG3 > IgG1> IgG2
C3 nephritic factor is associated with which diseases? (2)
type II membranoproliferative glomerulonephritis and partial lipodystrophy
patients with C2 deficiency are at risk for which infections (2)
strep pneumo and Hib
what enzymes degrade bradykinin? (2)
ACE, DPP-4
how are serum sickness and arthus reaction similar and different?
both are type III hypersensitivity rxn, but serum sickness is systemic and arthus reaction is local
what receptor is involved with the inflammasome?
NLR family receptors
which TLR does not signal through MyD88
TLR3
which TLR can signal through both MyD88 dependent and independent pathways?
TLR4
which TLRs are present in the intracellular compartment?
TLR 3,7,8,9
how do PAMPs differ from DAMPs?
PAMPs- conserved microbial sequences
DAMPs - endogenous molecule from damaged or dying cells
which TLR binds lipopolysaccharide (LPS) on gram negative bacteria?
TLR4
unmethylated CpG motifs bind to which TLR?
TLR 9
what gene defects increase susceptibility to recurrent herpes encephalitis? (6)
TLR3, UNC93B, TRAF3, TRIF, TBK1, IRF3
name the cytosolic pattern recognition receptors (3)
NLRs, include NOD and NLRP family
RLRs, include RIG-1, MDA-5
CDS, include AIM2 and STING
Dectin-1 mutation leads to what disease?
chronic mucocutaneous candidiasis
name the preformed mediators stored in mast cells (6)
histamine, tryptase, acid hydrolases, cathepsin G, carboxypeptidase, +/- chymase
name the preformed mediators stored in eosinophils (5)
MBP, ECP, eosinophil peroxidase, lysosomal hydrolase, lysophospholipase
disease causing immune complexes are formed under what conditions?
moderate antigen excess
AGEP (Acute generalized exanthematous pustulosis) is what subtype of type IV hypersensitivity?
type IVd
what somatic recombination process introduces the greatest diversity in immune receptors and which enzyme is important in this process?
junctional diveristy; TdT enzyme is important in this process
C3 convertase in classical and alternative pathway
C4b2a for classical.
C3bBb for alternative
C5 convertase in classical and alternative pathway
C4b2a3b
C3bBb3b
which complements are chemoattractants? (4)
C2b, C3a, C4a, C5a
which complement is anaphylotoxin?
C5a
order of binding affinity of C1q (4)
IgM > IgG3 > IgG1 > IgG2
- IgG4 cannot bind C1q
name two things that inhibit formation of MAC
S protein and CD59
what is a superantigen?
antigens that activate a large number of polyclonal T cells by directly binding to Vbeta domain of TCR and the external surface of MHC II molecule (outside of peptide binding cleft)
- leads to massive cytokine release
name four superantigens
- Staph enterotoxin B
- staph enterotoxin C
- toxic shock syndrome toxin (staph. aureus)
- strep pyrogenic exotoxins
name three main cytokines involved in cytokine storm
IL6
TNF alpha
IL 10
Describe immune cells involved, surface molecule involved, B cell response and vaccines for protein antigen
Describe immune cells involved, B cell response and vaccines for polysaccharide antigen
Describe immune cells involved, and surface molecule involved for lipid antigen
amino acid epitopes are recognized by what type of cell?
T cells
- linear determinants of amino acids only
- length limited by MHC binding cleft
are conjugated vaccines T cell dependent or independent? (3 vaccines)
T cell-independent antigens linked to a carrier protein, that can trigger a T cell DEPENDENT response and memory
- 13 valent s.pneumo
- Hib
- meningococcal
MHC molecules are located on which chr? (2)
chr 6 (expressed co-dominantly)
- beta microglobulin for MHC class I is on chr 15
describe domains of MHC class I molecule and its location
- three alpha chains and one beta microglobulin
- located on nucleated cells
describe domains of MHC class II molecule and its location
- two alpha chains and two beta chains
- located on APCs, thymic epithelia, and activated T cells
what does MHC restriction mean
- can only present peptides to T cells
- does NOT present lipids, nucleic acids, and polysaccharides
which cytokines induce expression of MHC class I?
IFN alpha, beta and gamma
which cytokines induce expression of MHC class II?
IFN gamma
class III region on chr 6 also encodes for? (3)
- complements - Factor B, C4 and C2
- heat shock proteins
- cytokines - TNF alpha and lymphotoxin alpha and beta
describe antigen processing and MHC class I presentation
- newly made MHC class I remains in ER by interacting with chaperone proteins
- cytoplasmic proteins are degraded by proteasome
- antigenic peptides are transported into ER by TAP proteins (both TAP1 and 2 subunits must be present)
- tapasin brings TAP and MHC molecule close together
- antigenic peptides are loaded onto the new MHC I
- transported to cell surface
describe antigen processing and MHC class II presentation
- extracellular antigen is endocytosed –> into phagosomes
- fuse with lysosome –> phagolysosome (protease called cathepsin degrade peptides)
- new MHC II is transported to phagolysosome from ER
- invariant chain that occupied the binding cleft is degraded by proteases –> leaves CLIP behind
- HLA-DM removes CLIP and allows antigenic peptide to be loaded
- transported to cell surface
what is cross presentaion?
the ability of APCs (mostly DC) to present extracellular antigens with MHC class I molecules to CD8 T cells
- extracellular antigens are usually presented on MHC class II
MHC class I deficiency (bare lymphocyte synd) (5)
- mutation in gene encoding for TAP or tapasin
- AR
- bacterial sinopulm infections, necrotizing granulomatous skin lesions, necrobiosis lipoidica
- CD8 lymphopenia
- tx with abx, aggressive pulm toilet and chest PT
MHC class II deficiency (bare lymphocyte synd) (6)
- mutation in MHC2TA, RFX5, FRXAP, FRXANK
- AR
- viral, bacterial, fungal and/or protozoal infections
- infections usually start in the first year of life
- CD4 lymphopenia, absent germinal centers, hypogamm
- tx: HSCT, IVIG, abx
what happens when a developing T cell reacts to self-antigen in the thymus? (2)
negative selection (strong binding affinity and high concentration) –> apoptosis
intermediary binding –> Treg cell
what is AIRE gene?
- expressed by medullary thymic epithelial cells (MTECs)
- promote expression of non-thymic tissue antigens
mutation in AIRE gene leads to (3)
autoimmune polyglandular syndrome (aka APECED)
- lymphocytes are not deleted or tolerized to endocrine self-antigens during selection in the thymus
- therefore, endocrine organs (parathyroid, adrenal and pancreatic cells) are attacked by autoreactive T cells and autoantibodies
name three outcomes when B cell reacts to self antigen in the bone marrow
- receptor editing
- apoptosis (negative selection)
- anergy
describe receptor editing process (4)
- reactivation of RAG1/2
- new kappa light chain is given (always first, then lambda)
- if still unsuccessful, a lambda light chain is used
- if still fail, apoptosis
T cell peripheral tolerance outcomes (3)
apoptosis, suppression by Tregs, anergy
B cell peripheral tolerance outcomes (2)
apoptosis or anergy
- receptor editing only in central organ.
surface markers for Tregs (3)
CD3, CD25 (IL2R alpha), FoxP3 (forkhead box P3)
cytokines that are essential in survival of Tregs (2)
IL2 and TGF beta
tolerance or regulation is maintained by which two cytokines?
IL10 (target MO and DC) and TGF beta (inhibits lymphocytes and MO)
Apoptosis intrinsic pathway
T cell stimulation without costim by self antigens –> activate Bim (pro-apoptotic member of Bcl-2 family)
- Bim binds to Bax and Bak (pro-apoptotic effector proteins)
- insert into mitochondrial membrane –> inc permeability and cell death
(also known as mitochondrial pathway)
apoptosis extrinsic pathway
- FasL (CD95L, on T cells) is upregulated on repeatedly activated T cells
- FasL can interact with Fas on a cell with self-antigen
- lead to either deletion of the cell or the T cell.
- via caspase system
Steps of peripheral B cell tolerance (3)
chronic antigen recognition downregulates CXCR5 –> inhibits B cell homing and interaction with T cells –> cell death
what is a dominant negative mutation?
when a mutation, when expressed, leads to product that interferes with the activity of wild-type allele.
what does histone acetylation do?
opens the chromatin to allow transcription
what does DNA methylation do?
typically represses gene expression
earliest B cell stage that produces Ig
pre-B cell stage
what is the most variable part of an Ig
CDR3
de-glycosylated IgG cannot ___ (2)
- cannot bind Fcgamma Rs and C1q effectively
- therefore, unable to trigger antibody-dependent cell-mediated cytotoxicity and complement activation
decreased glycosylation is associated with which autoinflammatory diseases? (4)
- RA, SLE, Crohn’s and TB
what is a rheumatoid factor?
its is an Ab against Fc portion of IgG.
usually in the form of IgM, but can be in any form
definition of affinity (3)
- strength of binding between a single antigen epitope and Ig.
- indicated by Kd.
- lower Kd = higher affinity
Ig isotype that has the highest affinity
IgE
difference between somatic hypermutation and class switch recombination
- somatic hypermutation –> changes in V, not C regions.
- class switch –> changes C, not V regions. does NOT change Ag specificity
what is junctional diversity?
random (nontemplated) addition/removal of nucleotide sequences at junctions between V,D, and J regions –> extensive somatic variability in immune receptors
what are the CD markers for different FcgammaRs?
FcgRI - CD64
FcgRII - CD32
FcgRIII - CD16
what is the CD marker for FceRII?
CD23
isotype switching to IgA is stimulated by which cytokines (2)
TGFb and IL-5
which T cells are not HLA restricted?
gamma delta T cells
most important cytokine produced during T cell activation
IL-2 (binds to CD25/IL-2Ra to give T cell survival signal and proliferation)
which disease cannot form immunological synapse?
Wiskott Aldrich syndrome, due to its defective actin cytoskeleton -> cannot polymerize T cells
Full activation of T cells require?
prolonged interaction between T cells and APC via LFA1 on T cell and ICAM on APC, as part of the immune synapse
ZAP 70 deficiency
SCID with no CD8+Tcells or T cell function, but with normal B and NK cells (T-B+. NK+)
function of NFAT
encodes for cytokines IL-2,4, TNF
- Tacrolimus blocks T cell cytokine gene transcription
function of NFKB
essential for cytokine synthesis and plays an important role in lymphocyte dev, neoplasms, and formation of secondary lymphoid organs
what is part of a BCR complex?
surface Ig and Iga and Igb chains
what is part a B cell co-receptor complex? (3)
Cd21 (CR2) - Cd19 - Cd81.
- C3b bound to Ag –> binds to CD21 –> brings complex near BCR –> CD19 has an ITAM that is phosphylated, which recruites Lyn to enhance phosphorylation of Iga/Igb
inhibitory receptors on NK, T and B cells (1 each)
- NK cell: KIRs
- T cell: CD28 family (CTLA-4/CD152, PD-1)
- B cell: FcgRIIb (also on DCs and MOs)
which cytokine receptors contain a common gamma chain? (6)
IL -2,4,7,9,15,21
which cytokine receptors share a common beta chain? (3)
IL-3, IL-5, GM-CSF
what happens when TNF-RI receptor is bound?
apoptosis via caspase 8
GoF mutation of NALP leads to? (3)
uncontrolled IL-1 production and autoinflammatory syndromes
- IL-1b is cleaved by caspase 1, which is activated by NALP.
- IL-1Ra is a competitive inhibitor of IL-1 (Anakinra)
IRAK-4 deficiency leads to
susceptibility to pyogenic infections, esp Strep pneumo
patients with IL-12Rb1 mutations are susceptible to which infections?
intracellular bacteria, notably Salmonella and atypical mycobacteria
which JAK/STAT pathway is activated by IL2?
JAK3-STAT5
which cytokine and transcription factor promotes differentiation of naive CD4 T cells to the Th1 subset?
IFN gamma - STAT1 - Tbet
IL-4 uses which STAT?
STAT6
which JAK/STAT pathway does IL-5 use?
JAK2-STAT3
what is Castleman’s disease? (8)
hyperproduction of IL-6
- angiofollicular lymph node hyperplasia
- fever, microcytic anemia, lymphadenopathy, hypoalbuminemia, elevated CRP and normal bone marrow iron
Hot T-Bone stEAk mnemonic
IL-1: fever (Hot)
IL-2: stimulates T cells
IL-3: stimulates Bone marrow
IL-4: stimulates IgE
IL-5: stimulates IgA
chemokines or receptors associated with HIV/AIDS (5)
CCR5, CCL3L1, CXCR4, CCR2, CXCL12
cell adhesion molecule pair involved in lymphocyte homing to LN
CCL19/21 - CCR7
cell adhesion molecule pair involved in pro Th2 response
CCL17/22 - CCR4
receptor for CCL5 (RANTES)
CCR 1,3,5
receptor for CCL11 (eotaxin)
CCR3
receptor for CCL17 (TARC)
CCR4
receptor for CXCL8 (IL-8)
CXCR1,2
CD marker, location, ligand, and function of P selectin
- C62P
- on Platelets, and Weibel-Palade bodies of endothelium
- lingand:PGSL and sLex
- Function: bind PMNs, T cells and monocytes
CD marker, location, ligand, and function of E selectin
- CD62E, ELAM
- on endothelium
- ligand: ESL-1, CD15, PGSL, sLex
- function: homing of T cells to peripheral sites of inflammation
CD marker, location, ligand, and function of L selectin
- Cd62L, LAM-1
- on lymphocytes and leukocytes
- ligand: GLYCAM-1, MADCAM-1, Cd34, and sLex
- function: homing to lymph node HEV (GLYCAM-1) and PMN rolling (MADCAM)
TLRs that are on cell membrane (5)
TLR 1,2,4,5,6
which cytokine is necessary for Th1 differentiation?
IL-12
Name associated condition with CXCL4
Heparin-induced thrombocytopenia
-CXCL4 = platelet factor 4 (PF4)
name associated chemokines with asthma/allergies (5)
CCL2,5,7,11, CXCL8
name implicated chemokines for HIV
- CCR5: homozygotes - no infection. heterozygote - slow progression of the infection
- CXCR4: T trophic
- CCL3L1: low level –> higher HIV acquisition, viral load, worse disease
steps of the alternative complement pathway
steps of classical complement pathway
steps of MBL complement pathway
which proteins inhibit MAC formation?
S protein and Cd59
what is CR4 a marker of?
dendritic cells
what does CR2 (CD21) do?
- binds to C3d (not C3b) and provides a second signal for B cell activation by Ag
- trap Ab-Ag complexes within germinal centers
what does CR1 bind to and what is its function?
- binds to C3b, C4b
- dissociates C3 convertase
- phagocytose C3b and C4b coated particles
what does CR3 bind to and what is its function?
- alternative names = Mac-1, Cd11b/CD18
- ICAM-1
- phagocytosis, leukocyte adhesion to endothelial cells
what does CR4 bind to and what is its function?
- alternative names = gp150/95, CD11c/CD18
- binds to iC3b
- phagocytosis
what does CD46 (MCP) bind to and what is its function?
- binds to C3b, C4b
- is a cofactor with Factor I to inactivate C3b and C4b
- associated with atypical HUS
what does CD55 (DAF) bind to and what is its function? (3)
- binds to C3b, C4b
- prevents formation of C3 convertase
- associated with paroxysmal nocturnal hemoglobinuria
what does CD59 (protectin) bind to and what is its function?
- binds to C7, 8
- prevents C9 from binding to C5b-8
- associated with paroxysmal nocturnal hemoglobinuria
three examples of microorganisms using complement receptors for cell entry
- opsonized HIV can infect cells via CR1 (associated with enhanced viral replication and sustained HIV infection)
- EBV can bind CR2 to facilitate cell entry
- M. TB uses CR3
deficient complements when CH50 is absent, but AH50 is ok
C1q, C1r, C1s, C2, C4
deficient complements when CH50 is ok, but AH50 is absent (3)
Factor B, D, properdin
deficient complements when both CH50 and AH50 are absent
C3,5,6,7,8,9
deficient complements when both CH50 and AH50 are absent and C3 is absent also.
Factor H, I
pemphigus vulgaris is which type of hypersensitivity reaction and what is MOA?
- type II
- anti-desmoglein 1/3 Ab mediated destruction of keratinocyte junctions
Goodpasture syndrome is which type of hypersensitivity reaction and what is MOA?
anti-basement membrane Ab mediated complement and phagocyte activation
- type II
Myasthenia Gravis is which type of hypersensitivity reaction and what is MOA?
anti-acetylcholine receptor Ab that inhibits receptor function and downregulates receptor
- type II
what is Arthus reaction
- type III hypersensitivity reaction
- production of local edema, PMN migration, hemorrhage and necrosis at the site of injection
- due to local vasculitis caused by immune complex deposition
- peak at 4-10h
what kind of cells/cytokines are involved in type IVa hypersensitivity reaction? and what are the associated diseases? (3/2)
- Cd4+ Th1 cells (IFNg, TNFa, IL2)
- MO, NK cells
- contact derm, TB
what kind of cells/cytokines are involved in type IVb hypersensitivity reaction? and what are the associated diseases? (3/2)
- CD4+ Th2 cells (IL4,5,13)
- eos, B cells
- DRESS, morbilliform drug rash
what kind of cells/cytokines are involved in type IVc hypersensitivity reaction? and what are the associated diseases?
- Cd8+ T cells (perforin, granzyme)
- Cd4+ T cells
- psoriasis, drug induced hepatitis
what kind of cells/cytokines are involved in type IVd hypersensitivity reaction? and what are the associated diseases?
- T cells , PMNs
- contact derm, AGEP (Acute generalized exanthematous pustulosis)
which cytokines does caspase 1 cleave to make them active? (2)
IL-1b and IL-18
GoF mutation in NLRP3 leads to?
cryopyrin-associated periodic syndrome (CAPS)
which signaling pathways does MyD88 activate? (3)
- NFkB and AP-1
- involved in all TLRs, EXCEPT TLR3
what kind of signaling pathway does TLR3 activate?
- uses adaptor protein TRIF/TRAF and activates IRF3,7 –> type I IFN
which TLR can use both MyD88 and TRIF?
TLR 4 (on the cell membrane)
PRRs associated with HSV1 encephalitis
UNC93B, TLR3
Transcription factor defects associated with recurrent pyogenic infections like strep or staph
MyD88, IRAK4
PRRs associated with canonical incisors, ectodermal dysplasia, and recurrent bacterial infections
NEMO or Ikk
PRRs associated with Crohn’s or Blau’s syndrome
NOD2
PRRs associated with chronic mucocutaneous candidiasis (2)
Dectin 1, CARD9
PRRs associated with pulmonary immune deficiency with infectious and mycobacterial susceptibilities
NEMO
pathway for PI3K (4)
- PIP2 becomes PIP3 by PI3K
- PIP3 activates PDK1
- Akt is then activated
- leads to cell survival
MAP kinase pathway with Grb2-SOS (3)
- Lyk - ZAP70- LAT
- Grb2-SOS –> Ras.GTP
- transcription of c-Fos
MAP kinase pathway with Vav (5)
- Lyk - ZAP70-LAT
- Vav activates Rac.GTP
- JNK activated
- c-Jun is phosphorylated
- later combines with c-Fos to become AP-1 transcription factor
PLCg - IP3 pathway (7)
- Lck-ZAP70-LAT
- Itk (BTK in B cells) - PLCg
- PIP2 hydrolyzed to IP3 by PLCg
- IP3 - STIM senses lack of Ca in ER
- brings extracellular Ca to the cytoplasm
- activates Ca-calmodulin
- calcineurin activated –> NFAT
PLCg - DAG pathway (5)
- Lck-ZAP70-LAT
- Itk (BTK in B cells) - PLCg
- PIP2 hydrolyzed to DAG by PLCg
- activates protein kinase C (PKC)
- NFkB
Which important cytokine is involved in the proliferation and function of natural killer cells and T- regulatory lymphocytes?
IL-2
homing pattern of Th1 (4)
- CXCR3, CCR5 = tissues
- E and P selectin ligands
homing pattern of Th2 (3)
CCR3,4,8 = mucosa
homing pattern of Th17 (2)
CCR6-CCL20 produced by tissue cells and macrophages
IFN gamma inhibits (2)
Th2 and Th17 differentiation
IL-4 inhibits (1)
Th1 differentiation
IL-21 promotes _ and inhibits __
promotes Th17
inhibits Th1 and Th2
development of Th1 subset (
Th1 cytokines (3)
- IFN gamma
- TNF (Activates neutrophils, inflammation)
- IL-10 (inhibitory) - negative feedback
functions of IFN gamma (4)
- activate MO
- activate IgG class switch
- polarization toward Th1
- increased expression of TAP, proteasome, HLA-DM, MHC molecules, B7 and amplification of T cell response
transcription factors involved in CD8 T cell development (2)
Tbet and eomesodermin
what is the role of cathepsin B in CTL mediated killing?
protects CTLs from their own perforin when it is released
what are the two CTL-mediated killing pathways?
- via cytotoxic proteins like perforin and granzyme
- via Fas- FasL
Which complement receptor is exploited by HIV?
CR1
Which complement receptor binds to EBV?
CR2
MOA of UNC93B1
- helps with endosomal TLR signaling. (TLR 3, 7,8,9)
What is the biochemical function of NADPH oxidase?
Convert molecular oxygen to superoxide
Which cytokine is a major growth factor for dendritic cells?
FLT3LG
what is ICOS?
ICOS is a T cell receptor required for the development of Tfh
classical vs alternative MO pathway
- classical: pro-inflammatory. kill microbes and clear apoptotic cells
- alternative: tissue repair and fibrosis
In regards to donor selection, which is the most favorable donor selection?
matched sibling donor from bone marrow
The gold standard and most commonly used graft source for HSCT
- gold standard = bone marrow
- most commonly used = peripheral blood stem cells
PFAPA tx (3)
- steroids
- anakinra
- tonsillectomy
FMF - genetic cause and tx (2)
- MEFV
- colchicine ppx (decrease risk of amyloidosis)
TRAPS - genetics and tx (4)
- TNFRSF1A (AD)
- steroids
- anakinra
- etanercept
Mevalonate kinase deficiency (hyperIgD syndrome) - genetics and tx (3)
- MVK
- steroids
- anakinra
CAPS - genetics and tx (4)
- CIAS1 (AD)
- anakinra (IL-1 blockade)
- rilonacept (IL-1 blockade)
- canakinumab (IL-1 blockade)
PAPA - genetics and tx (4)
- PSTPIP1 (AD)
- anakinra (IL-1 blockade)
- rilonacept (IL-1 blockade)
- canakinumab (IL-1 blockade)
DIRA- genetics and tx (4)
- IL1RN
- anakinra (IL-1 blockade)
- rilonacept (IL-1 blockade)
- canakinumab (IL-1 blockade)
PLAID - genetics and tx (4)
- PLCg2 (AD)
- avoidance of triggers
- antihistamines
- +/- IGRT
PFAPA presentation (5)
- regularly recurring fever q3-8 weeks
- lasts for 3-6 days
- asx between attacks
- normal growth and dev
- exclusion of cyclic neutropenia
FMF presentation (6)
- recurrent fever at variable frequency
- lasts 12h to 3 days
- sterile peritonitis (abd pain)
- pleuritis
- arthritis
- erysipelas-like rash
side effects of colchicine (3)
- GI distress (pain and bleeding)
- bone marrow suppression
Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) presentation (9)
- usually adult onset
- fever can last weeks
- myalgia
- periorbital swelling
- conjunctivitis
- HA
- and pain
- pleuritis with effusion
- deep, caudally migrating erythematous inflammation
Mevalonate Kinase Deficiency presentation (8)
- MVK - involved in cholesterol and steroid synthesis
- present in infancy
- fever lasts 3-7 days
- painful lymphadenopathy
- aphthous ulcers
- arthritis/arthralgia
- erythematous macules or urticaria-like lesions
- amyloidosis is rare
3 diseases that are part of Cryopyrin- Associated periodic syndrome (CAPS)
- CINCA (most severe)
- Muckle Wells syndrome
- FCAS (least)
does FCAS have postive or negative ice cube test?
negative ice cube test but positive evaporative cooling test
symptom not present in FCAS but present in CINCA or Muckle-Wells
sensorineural hearing loss
symptoms present in CINCA but not in Muckle-Wells or FCAS (4)
- bony overgrowth
- dysmorphism
- developmental delay
- leptomeningeal inflammation
pyogenic Sterile Arthritis, Pyoderma Gangrenosum and Acne Syndrome (PAPA) presentation (3)
- mutation in CD2 binding protein 1, aka PSTPIP1
- early in life with arthritis
- skin issues in teens
Deficiency of Interleukin-1 Receptor Antagonist (DIRA) presentation (8)
- due to uninhibited activity of IL-1
- skin and bone disease
- neonatal multifocal osteomyelitis
- rib widening
- periosteal elevation
- diffuse osteopenia and osteolytic lesions
- pustulosis with neutrophilic predominance
- ABSENT fever
PLCg2 associated Ab deficiency and Immune Dysregulation (PLAID) pathophysiology (4)
- AD
- cold urticaria, Ab deficiency, susceptibility to infections/autoimmunity
- diminished signaling at physiologic temp (Ab def)
- enhanced signaling at subphysiologic temp (cold urticaria)
diseases that have negative ice cube but positive evaporative test (2)
Familial cold-induced autoinflammatory syndrome (FCAS) and PLAID
Majeed syndrome (6)
- aka chronic recurrent multifocal osteomyelitis
- mutation in LPIN2 (lipin 2)
- childhood onset of fever, bone lesions, and relapsing episodes of pain
- psoriatic-looking rash and acne
- congenital dyserythropoietic anemia
- tx is limited to NSAIDs and steroids
Blau syndrome (6)
- GOF NOD2/CARD15 mutation (AD)
- presents early in life
- triad of granulomatous polyarthritis, uveitis and pustular skin lesions
- tx with anti-IL-1 or anti-IL6
mutations in Blau syndrome vs Crohn’s disease
- Blau = GOF NOD2
- Crohn’s = LOF NOD2
Deficiency of Adenosine Deaminase 2 (DADA2) pathophysiology (6)
- mutation in CECR1
- deficiency of ADA2 leads to adenosine accumulation, neutrophil activation, M1 polarization, and inflammatory cytokine production
- deficiency of ADA1 –> T-B-NK- SCID
DADA2 presentation (7)
- fevers
- recurrent lacunar strokes (typically <5yo)
- organomegaly
- cytopenias
- hypogamm
- lived reticularis
- polyarteritis nodosa
STING-Associated Vasculopathy with Onset in Infancy (5)
- GOF in TMEM173 that encodes for STING (stimulator of interferon genes)
- typically dx in the first 8 weeks of life
- violaceous, scaly lesions that worsen, even becomes necrotic
- pulmonary complications
- tx: JAK inhibitors. steroids are not helpful
molecules that promote granuloma formation (5)
- ACE
- calcitriol (1, 25 dihydroxyvitamin D3)
- osteopontin
- TNF alpha
- IFN gamma
Lofgren’s syndrome (3)
- self limited, acute form of sarcoidosis
- triad of b/l hilar adenopathy, erythema nodosum and polyarthritis
- fever
labs for sarcoidosis (4)
- restrictive on PFT
- IFN gamma predominant cytokine pattern
- high serum ACE and vit D
- high CD4/CD8 ratio
berylliosis is seen in which pt population?
ppl who work with electronics and space industries
tissue vs kidney biopsy results of GPA
- tissue: neutrophilic microabscesses rimmed by granulomas and multinucleated giant cells
- kidney: pauci-immune glomerulonephritis
Hyperacute solid organ rejection - mediator, timing, pathophysiology (3)
- mediator: pre-existing Ab
- timing: minutes to hours
- Ab to Ag complement activation and endothelial damage, fibrosis
acute solid organ rejection - mediator, timing, pathophysiology (3)
- mediator: T cells, PMNs +/- Ab
- after 7d ~ 3months
- direct killing by CTLs, cell infiltration and endovasculitis
chronic solid organ rejection - mediator, timing, pathophysiology (3)
- mediated by T cells (usually CD4), B cells and cytokines
- months to years
- vessel smooth mm proliferation, fibrosis and occlusion
acute Ab-mediated solid organ rejection - mediator, timing, pathophysiology (3)
- mediated by alloAb and alloAg (HLA)
- days to months
- binding of alloAb to endothelial cell surface triggers local complement, endothelial injury and intravascular thrombosis
major functions of IL-2 (2)
- proliferation of Ag-stimulated T and NK cells
- maintenance of Tregs
components of TCR complex (4)
what is inactive NFkB in the canonical pathway?
IkBa/RelA/p50
what is the active NFkB in the canonical pathway?
RelA/p50
what is inactive NFkB in the non-canonical pathway?
RelB/p100
what is the active NFkB in the non-canonical pathway?
RelB/p50
steps in activating NFkB via canonical pathway (4)
- ubiquitination of NEMO activates IkkB
- activated IkkB phosphorylates IkBa and tags it for ubiquitination
- polyubiquitinated IkBa is degraded
- remaining RelA/p50 = active form of NFkB that can enter the nucleus
a4b7 binds to which surface receptor for gut homing of lymphocytes?
MADCAM-1
what is C3 nephritif
what is C3 nephritic factor? (3)
- AutoAb that stabilize C3bBb
- protects it from degradation by Factor I –> unregulated consumption of C3 and complement activation
steps in the Kallikrein contact activation pathway
- Factor XII cleaved to XIIa by contact
- XIIa cleaves HK-PK complex to kallikrein
- kallikrein cleaves HK to bradykinin
S1P1 for naive T cells in the LN (3)
- S1P1 gradient is higher in blood
- internalized if recognize Ag-MHC complex (stay in LN longer)
- reappear in effector T cells (therefore leave LN into circulation)
Which cytokines (2) can increase expression of MHC class I molecules on all types of nucleated cells?
IFN-a and b
- IFN gamma increases expression of both MHC I and II
On which human chromosome is the locus encoding the κ light-chain gene located?
Chromosome 2
- λ light-chain locus on chr. 22
what guides the rearrangement of the DNA of the genetic segments V, D and J?
Recombination Signal Sequences (RSSs)
Which enzyme is a lymphoid-specific component of the V(D)J recombinase?
RAG-1 and RAG-2
What is the defect in MHC class II deficiency?
Class II transactivator
- MHC2TA = positive transcriptional co-activator of MHC class II genes
- RFX complex binds to the promoter of the MHC class II genes
What is a transcription factor that is very important for dendritic cell development and for cross-presentation?
CXCR1
The signaling subunit of the pre-BCR is the
ITAM containing Igα and Igβ
Deficiency of the scaffold protein BLNK arrests B cell development at which stage?
Pro-B cell
(BLNK deficiency causes arrest of B cell development in the pro B cell stage since the pre-B-cell stage requires successful signaling via the pre-BCR.)
Which cells produce most of the naturally circulating IgM in the blood?
B-1 cells
(B-1 cells are innate-like cells that are mostly present in the peritoneal and pleural cavities. constitutively produce IgM without T cell help)
Pre-TCR is expressed in which stage of T cell development?
Double negative 3
α chain locus is rearranged in which stage of T cell development?
Double positive
The pre-TCR signals constitutively via which signaling molecule?
Lck
(The pre-TCR signals constitutively via the cytoplasmic protein kinase Lck. In mice deficient in Lck, T cell development is arrested before the CD4+CD8+ double positive stage and no α chain rearrangement can occur. ZAP-70, expressed early from the double negative stage, is not essential for pre-TCR signaling.)
A key initiator of cutaneous inducible innate immunity that is preformed in the cytoplasm of kertinocytes
IL-1 alpha
the most potent anaphylotoxin
C5a
