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Dectin-1 & -2:
Signaling PRR: C-type lectins bind β-glucan and α-mannans, respectively; control some bacterial & fungal infections
NOD like receptor (NLR) that responds to multiple stimuli to form a multi-protein complex termed the NALP3 inflammasome which activates the IL-1β family of cytokines (powerful mediators of inflammation) (mutation causes cryopyrinopathies such as Mucle-Wells syndrome)
RIG-1 like receptors (RLRs)
RNA helicases that detect RNA derived from viruses in the cytoplasm
Inducible Nitric Acid Synthase (iNOS) Rxn
L-arginine + O2 ð L-citrulline + NO Nitric Oxide
The inflammatory cytokines
TNF-α, IL-1, IL-6
a bridge to induce active immunity” induces naive CD4+ T cells to differentiate into TH1 cells and Activates NK cells
Chemotactic Factor, used to be called IL-8, induces integrin conformational change to promote strong adhesion
Bacterial products in the bloodstream activate macrophages in the liver & spleen to produce high levels of TNF- α
Explain Neutrophil diapedesis
Selectin and ICAM on endothelial cells bind Siayl-Lewis and LFA-1 on neutrophils
Leukocyte Adherence Deficiency (LAD)
- LAD1 a mutation in the common chain of the β2 integrin family (CD 18).
- LAD2 a mutation in the sialyl-Lewis ligand for selectins
- Leukocytes do not bind adhesion molecules (ICAMs / VCAMs) on endothelial cells
- Patients have recurrent bacterial infections, impaired pus formation and impaired wound healing
Papain and Pepsin
- Papain cuts the antibody into two Fab fragments and one Fc fragment
- Pepsin cuts the antibody into a F(ab’)2 fragment and the Fc fragment dissolves
Cd79s and CD79b
Also known as Ig-alpha and Ig-beta, when membrane bound Ig crosslink, signal is started—Tyrosine Phosphorylation of ITAM and activation of transcription factors NFkB, NFAT and AP-1
What chromosomes are involved with Ig?
- Lambda light chain = 22
- Kappa light chain = 2
- Heavy chain = 14
What CD markers are involved in the B cell co-receptor complex?
- CD19, CD21 (CR2), and CD81
- C3d binds to the CD21 (CR2) (CR = complement receptor)
X-Linked hyper-IgM syndrome
- Defect in CD40/CD40L
- Elevated IgM, but no other isotypes
- No germinal centers, no tonsils
Enzyme that mediates class switching
What cytokine promotes the switch to IgE? IgA?
IL-4 promotes IgE and TGF-beta promotes IgA
What does Forward angle Light scatter measure? What does side scatter measure?
- Forward angle light scatter measures size
- Side scatter measures granularity
Natural killer cells recognize bound antibody with which receptor?
- FcyRIII, also known as CD16
- This happens during Antibody-Dependent cell mediated cytotoxicity
What is ficolin?
Lectin protein that binds N-acetylglucosamine to start the complement pathway
What do MASP1 and MASP2 bind to?
C1r and C1s respectively
Epstein-Barr virus complexes with which receptor?
What prevents complement mediated lysis?
- CD35 (CR1), MCP, DAF, and Protectin (CD59)
- Defects in these lead to paroxysmal nocturnal hemoglobinuria
Explain hereditary angioedema
Factor XII is activated (possibly due to lack of C1 inhibitor), which activates kallikrein. Bradykinin is generated which binds Bk-B2 receptor on endothelial cells leading to edema
What is the accessory molecule for the TCR?
- CD3 and zeta: Zap70 interacts with CD3 starting Signaling cascade involves protein tyrosine phosphorylation and intracellular calcium nflux resulting in activation of transcription factors
- Protein kinase C activates NF-kappaB
- Calcineurin activates NFAT
- Ras Kinase activates AP-1
What do NF-kB, NFAT, and AP-1 activate in T cells?
What are the differences in binding of alphaBeta T cells and gammaDelta T cells?
gammaDelta T cells recognize antigen directly, they do not require MHC presentation of peptide like alphaBeta T cells do, but gammaDelta T cells have a restricted repertoire
What chromosome is the MHC complex found on?
What genes encode proteosome subunits?
LMP 2 and LMP 7
What genes encode peptide transporters from cytosol to ER?
TAP 1 and TAP 2
What do the terms double positive and double negative refer to in relation to T cells?
- before cell rearranges it is double negative (CD3- CD4- CD8-)
- If cell rearrange alphabeta TCRs they become double positive, CD3+ CD4+ CD8+
- If cell rearranges gammadelta it becomes CD3+ but CD4- and CD8-
Where does T cell alphabeta selection occur?
- Positive selection in the cortex of thymus (to determine if cell becomes CD4+ or CD8+)
- Negative selection in the medulla of thymus (removes T cells that react with self)
What is Bare lymphocyte syndrome I?
- Tap-1/2 deficiency – can’t transport antigen associated peptides to the ER to combine with MHC class I
- CD8 T cell numbers are very low
- Increased susceptibility to viruses
What is the enzyme that catalyzes CLIP removal?
What is Bare lymphocyte syndrome II?
- MHC class II deficiency – CD4 cells cannot be positively selected in Thymus and few develop
- Ig levels are low due to no T cell help
- Increased susceptibility to pyogenic and opportunistic pathogens such as Pneumocystis jiroveci
What do superantigens bind? What response is triggered?
- MHC II and TCR Vbeta regions of CD 4 T cells
- IL-1, IL-2, TNF-alpha
What functions does CD28 binding to B7 have on T cells?
- h AP-1 & NFkB, stabilizes IL-2 mRNA → increased IL-2 synthesis (100X)
- Induces expression of CD25 (high affinity IL-2 receptor)
- Induces proliferation
- h Bcl-XL (anti-apoptosis) promotes cell survival
What do Cyclosporin A and FK 506 (tacrolimus) do?
inhibit IL-2 production in T cells
What do Daclizumab and Basiliximab do?
- CD 25 blocking antibodies
- If CD25 is blocked, then IL-2 only binds with moderate affinity instead of strong affinity
What does Sirolimus (rapamycin) do?
Inhibits IL-2 signaling and proliferation of T cells
What cells are Foxp3+?
TH3, Thymic CD4 T cells, and nTreg cells
What do Naïve CD4 T cells differentiate into in the presence of IFN-gamma and IL-12 and what do they produce?
- TH1 cells that express T-bet
- and produce IL-2, IFN-gamma, and LT
- During viral and bacterial infections IFN-gamma is produced by NK cells and IL-12 by macrophages
What do Naïve CD4 T cells differentiate into in the presence of TGF-Beta and what do they produce?
- Treg Cells that express FoxP3, CD4+, and CD25+
- and produce TGF-Beta and IL-10
What do Naïve CD4 T cells differentiate into in the presence of TGF-Beta and IL-6 and what do they produce?
- TH17 cells that express RORgammaT
- and produce IL-6 and IL-17
- TH17 cells are produced in the pro-inflammatory phase of a bacterial or fungal infection
- IL-17 stimulates fibroblasts to produce cytokines and chemokines to attract neutrophils
- IL-23 supports TH17 growth expansion
What do Naïve CD4 T cells differentiate into in the presence of IL-4 and what do they produce?
- TH2 cells that express GATA-3
- and produce IL-4 and IL-5
- These cells stimulate B cells
What do Naïve CD4 T cells differentiate into in the presence of IL-10?
- Tr1 if no TGF-Beta
- TH3 if also stimulate with TGF-Beta
- and they produce IL-10 and TGF-Beta
What are the hematopoietic cytokines?
SCF, IL-7, IL-3, and CSF
What are the inflammatory cytokines?
IL-1Beta, TNF-alpha, IL-6
What cytokines stimulate adaptive immunity?
IL-2, IL-4, IL-5, IL-13, IFN-gamma, LT
What are the inhibitory cytokines?
What does a defect in the common gamma chain of the IL-2 receptor result in?
Which type I cytokine receptors share a common Beta chain?
IL-3, IL-5, and GM-CSF
Which type I cytokine receptors share a common gamma chain?
IL-2, IL-4, IL-7, and IL-9
What are the type II cytokine receptors?
INF-alpha, IFN-Beta, IFN-gamma, IL-10, and IL-13
What cytokines from the TH1 and TH2 cells are antagonistic to each other?
- IL-10 from TH2 inhibits TH1
- INF-gamma from TH1 inhibits TH2
What do nTreg cell do?
Suppress T cell responses by secreting IL-10 and TGF-Beta
What difference in cell surface molecules do activated Effector vs resting T cells have?
- Resting exhibits L-selectin (for lymph node targeting)
- Active exhibits VLA-4 (alpha4Beta1 integrin) (for endothelial cell targeting on VCAM-1)
- They both exhibit LFA-1 and CD2, but activated T cells exhibit more of both
What do cytotoxic T lymphocytes secrete?
- IFN-gamma to disrupt viral replication, increase MHC, and activate macrophages
- LT-alpha to kill target cells by apoptosis
What CD is for the Fas-Fas ligand system?
How do NK cells recognize IgG coated cells?
- The FcgammaRIII (CD16) receptor
- This is known as antibody dependent cell mediated cytotoxicity
What do natural killer cells secrete?
IFN-gamma and TNF-alpha
What two cytokines inhibit TH17 cell differentiation?
- IFN-gamma (TH1) and
- IL-4 (TH2)
How do TH1 and TH2 effector cells stimulate phagocytic activity?
They secrete IL-3 and GM-CSF
What is responsible for Type 4 hypersensitivity?
What cytokine promotes eosinophils and what cell produces it?
- Produced by TH2 cells
What does IL-10 inhibit?
- MHC II expression and co-stimulation in macrophages and APC
- Production of IL-12 by macrophages and dendritic cells
What does TGF-Beta inhibit?
- T cell proliferation and differentiation
- Activation of macrophages
- respiratory burst
What happens if the Mycobacterium leprae response is dominated by TH1 cells?
- High Cell Mediated Immunity
- Normal Ig
- Controlled infection known as Tuberculoid leprosy
- (You want it to be dominated by TH1)
What happens if the Mycobacterium Leprae response is dominate by TH2 cells?
- Weak Cell Mediated Immunity
- High Ig levels (Hypergammaglobulinemia)
- High bacterial load
- Gross tissue destruction,
- Disseminated and Lethal disease known as Lepromatous leprosy
What is the homolog to CD28 that competes for binding on activated T cells?
- CTLA-4 (CD152)
- It inhibits T cell proliferation and decreases IL-2
What are the types of hypersensitivies?
- Type I: Anaphylaxis - IgE
- Type II: Cytotoxic – IgM or IgG
- Type III: Immune Complex
- Type IV: Delayed (T cell mediated)
- Increased tendency to produce immediate hypersensitivity reactions
- Imbalance between TH2 and Treg cells
- Higher eosinophil and IgE counts
What are the leukotriene receptor agonists used to treat allergic reactions?
Montelukast (Singulair) and Zafirlukast and pranlukast
Inhibits lipoxygenase to prevent allergies
What type of hypersensitivity reaction is erythroblastosis fetalis?
What are two types of Type III hypersensitivities?
- Arthus reaction and Serum sickness
- also, SLE, rheumatoid arthritis, post-strep glomerulonephritis, and farmer’s lung
What are rheumatoid factors?
Auto antibodies against the Fc portion of IgG
What binds to Integrin Alpha4:Beta7
MAdCAM-1 (mucosal associated)
What integrin hones plasma cells to mucosal tissue?
Alpha4:Beta7 (binds to MAdCAM-1)
Allergic inflammation is a shift to which TH?
TH2 with the production of IL-4 and IL-5
Explain the recognition of alloantigens, Direct vs indirect
- Direct – host T cells recognize donor MHC + Peptide on donor cells
- Indirect – Host phagocytoses peptides from donor cells and presents them on regular MHC
What is a “white graft”?
Hyperacute rejection – preexisting antibodies to alloantigens
What is acute cellular rejection?
- Occurs within a few days to weeks after transplantation
- T cell mediated – direct recognition of allo-MHC
What is acute humoral rejection?
- occurs within a few weeks after transplantation
- Due to indirect allorecognition by TH cells
- Production of allo-Ab
- Rejection vasculitis
- C4d staining shows because of C4d produced during classical complement activation
What is chronic rejection?
- Months to years after transplantation
- antibody mediated – arteriosclerosis leading to lack of blood flow
Which MHC classes are particularly polymorphic?
A and B on MHC I and DRB on MHC II
What happens with a mutation in FoxP3?
XPID or IPEX
What happens if there is defect in AIRE?
APECED (also known as APS-1)
What happens if there is a mutation in Fas or Fas-L?
Ab to kidney basement membrane – Glomerulonephritis
Ab to group A strep; cross reacts with heart muscle
Ab to acetylcholine receptor inhibits binding of ligand to receptor on muscle cells
anti TSH receptor Ab stimulates thyroid cells
What do Infliximab and Adalimumab do?
They are anti TNF-alpha mAb used to treat theumatoid arthritis and GVHD
What do Azathioprine and Mycophenolate mofetil do?
Interfere with DNA synthesis, inhibit immune responses
What do the terms Omab, Ximab, Zumab, and Umab mean?
- They are the four types of monoclonal antibodies
- Omab = fully mouse eg Muromomab (OKT3)
- Ximab = chimeric (variable region mouse, rest human) eg Rituzimab (CD20) and Basiliximab (CD25)
- Zumab = Humanized (mostly human, few mouse parts) eg Daclizumab (CD25)
- Umab = fully human eg Adalimumab (TNF-alpha)
Three causes of SCID
- defect in cytokine mediated lymphocyte maturation signaling (X-linked SCID)
- Adenosine deaminase deficiency (lymphocytes die)
- RAG deficiency