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Explain the binding of LPS to TLRs and its downstream effects.
LPS binds to LPS-BP and binds to CD14, BP dissociates, CD14-LPS binds to TLR4 and its accessory protein MR2, the cytoplasmic TIR domain of the TLR recruits MyD88 which activates signaling molecule TRAF6 which activate NF-kb
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Name the ligands and sources for TLR2.
- LP (bact)
- Peptidoglycans (G+ bact)
- LPS (lepto)
- Zymosan (fungi)
- GPI anchor (trypanosomes)
- Lipoarabinomanan (mycobact)
- Phosphatidyl dimanoside (mycobact)
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Name the ligands and sources for TLR3.
DS DNA (viruses)
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Name the ligands and sources for TLR4
- LPS (G- bact)
- HSF00 (Chlamydia)
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Name the ligands and sources for TLR5
Flagellin (bact)
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Name the ligands and sources for TLR6
CpG DNA (bact, protozoa)
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What does abTCR recognize?
Peptides displayed on MHC
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Describe the structure of the TCR complex.
5 parts: TCRa and b + 2z and 3 CD3 � g, d, e
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What does the gdTCR recognize?
Peptides lipids and small molecules not associated with MHC.
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What do Tcells need for activation?
- 2 signals:
- 1) TCR binds to MHC bound Ag along with accessory mol (ex. CD4 � MHCII, CD8 � MHCI)
- 2) Co-stim molecules � CD80 or 86 (B7-1 and 2) on APC to CD28 on Tcell
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What happens if co-stimulation of Tcell (via CD28-CD80/86) does not occur?
Apoptosis
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What cytokines do TH1 and TH2 secrete? What are there functions
- TH1: IL2 and IFNg � fxn: delayed hypersensitivity, mac activation, IFNg stim prod of opsonizing/complement fixing abi
- TH2: IL4, IL5 and IL13 � fxn synthesis of other classes of abi � IgE esp and activation of eos
- NOTE: CD8 T cells are cytotoxic but can secrete TH1 type cytokines
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Describe the structure of the BCR complex:
Heavy and light chains of Ig plus CD79a-b heterodimer (NB for signal transduction)
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List other molecules NB for B-cell function:
FC, CD21 (complement receptor 2), CD40
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How do Tcells help Bcell activation?
CD4 T cells express CD40L � binds to CD40 on Bcell ? secrete IgG, IgA, IgE
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How are macrophages activated?
IFNg by CD4 Tcells
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Macs phagocytize microbes opsonized by which molecules?
IgG or C3b
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Name the two types of DCs and some of their features.
- Interdigitating: epithelia, interstium of tissues, have lots of MHCII and co-stim mol B7-1 and 2 (so activate T cells) and receptors for same chemokines as na�ve T cells so move with them
- Follicular: germ centers of LN, spleen, Fc for IgG and C3b receptors so trap opsonized Ag then present to B cells and pick best ones!
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What is the difference between NK cells and NK-T cells?
The latter have TCR as well as NK receptors, NK cells have no TCR or surface Ig
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Name some of the NK markers.
CD56, CD16 (Fc for IgG)
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Describe the activating and inhibiting effects on NK cells.
- NK cells have activating receptors: ex. NKG2D � recognize stress induced proteins, viral proteins etc.
- Also have inhibiting receptors ex. KIR, CD94-NKG2A,B - bind to self MHC I on normal cells to inhibit
- If cells viral inf or mal transformed then decrease MHCI and incr. expr of activating receptors ? killing
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What cytokines do NK cells produce?
IFNg (activate macs and promotes diff of TH1 cells), TNF and GM-CSF
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What cytokines regulate NK cells?
IL2 and IL15 stim prol, IL12 activates killing and secretion of IFNg
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Which cytokines mediate innate immunity?
Innate: IL1, TNF, IL6 (IL12 and IFNg � both innate and adaptive)
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Which cytokines protect against viral infection?
IFNs
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Which cytokines regulate lymph growth, activation and differentiation?
IL2 (T cell GF), IL4 (TH2), IL12 (TH1), IL15 (NK), TGFb, IL10 � latter 2 downregulate immune response
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Which cytokines activate inflammatory cells?
IFNg (mac), IL5 (eos), TNF and lymphotoxin (neuts and endo)
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Which cytokines affect leuk movement (ie. chemokines)?
C-C (made by T cells) or C-X-C (made by macs and endo)
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Which cytokines stimulate hematopoiesis?
G and GM-CSF, c-kit, CD117 � more� not listed
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Describe differences between MHCI and II.
- MHC I present on all cells, present endogenous proteins ex. viral antigens, cytosolic proteins are processed in proteosomes, transported to ER, binds to MHCI, transported and presented at surface to CD8 T cell � Ag binds to TCR
- MHC II only on APCs (macs, DC, some Bcells), present exogenous proteins to CD4 T cells, proteins are first processed in lysosomes or endosomes � note: can be induced on fibroblast and endo cells by IFNg
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Describe Type I (immediate) hypersensitivity reaction.
- Ex. Anaphylaxis, allergies, atopy
- Ag presented by DC to TH2 cell
- TH2 secretes: IL4 (prol of TH2, activate na�ve B to IgE prod), IL5 (activates eos) and IL13 (? IgE, mucus)
- TH2 and epi produce chemokines to attract more TH2
- Mast cells and basos have Fc receptors for IgE, after X-inking of IgE, mast cells release granule contents
- with mediators
- Primary mediators: histamine (sm mm contraction, incr. vas perm, incr gland secretion of nasal, bronch and gastric glands), enzymes � acid hydrolases and neutral proteases, heparin and chondroitin sulfate (package and store other mediators).
- Secondary mediators:
- Lipid mediatiors: LT and PG via action of PLA2 on mast cell membranes (aa pathways), LTC4/D4 � sm mm cont and vasoactive, chemotactic for neuts, eos, monos, PGD2 � bronchospasm, PAF (triggered by PLA2 � plt ag, histamine release, bronchospasm, vas perm, vasodil, chemotactic for eos and neuts
- Cytokines: mast cells release: TNF, IL1, IL3, IL4, IL5, IL6, GM-CSF, MIP 1a and 1b (both chemokines)
- Epis can produce IL6, IL8 and GM-CSF
- Eos survival incr. by IL5, IL3 and GM-CSF (TH2 and MCs)
- Eos can also produce PAF and LTC4
- NOTE: Reaction can also be stim by C5a, C3a, IL8 (from macs), drugs (codein/morphine), mellitin (bee toxin), physical stimuli
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What mediators result in vasodilation?
Histamine, PAF
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What mediators result in increase vascular permeability?
- PAF
- LT C4, D4, E4
- Neutral proteases
- PG D2
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What mediators result in smooth mm contraction?
- LT C4, D4, E4
- Histamine
- PGs
- PAF
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What mediators result in cellular infiltration?
- Cytokines
- LT B4
- Eos and neut chemotactic factors
- PAF
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Describe Type II (Abi-mediated) hypersensitivity.
- ex. IMHA, transfusion rxn, NI, drug rxn
- 3 different mechanisms:
- 1. Opsonization, complement and FC mediated phagocytosis
- IgG or M dep on membrane � complement activation � C3b and C4b bind cell surface and macs phag d/t complement receptors on surface, macs also have FC receptors so can phag cells opsonized by IgG
- complement fixation also leads to killing with MAC
- This can also occur via NK cell, mono, neut or eos (ADCC) � usually IgG
- 2. Complement and FC receptor mediated inflammation
- Abi deposited on BM and ECM � activate complement C5a (some 4a, 3a) � recruit neuts and monos which bind to abi via FC receptors � activate and release mediators � damage to tissues
- 3. Antibody mediated cellular dysfunction: abi bind to cell-surface receptors interfering with fxn ex. myasthenia gravis or pemphigus vulgaris (abi vs epi jxns � vesicle formation)
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Describe type III (immune complex mediated) hypersensitivity.
- ex. SLE, glomerulonephritis, serum sickness, arthus reaction � rxns can be generalized or localized
- Ag combines with Abi in circulation � deposit in vessel walls
- See in three phases: 1. formation of complex in circulation, 2. deposition in tisues 3. inflammation
- Most pathogenic complexes are: small with excess Ag � phagocytized less readily
- Inflammation is caused by: 1. activation of complement and/or 2. activation of neuts/macs via FC rec
- Complement activation results in recruitment of PMN and monos (C5a) and release of anaphylaxatoxins (C3a and 5a) � increase vascu perm
- When leuk get there they are activated via C3b and Fc receptors � proinflam mediators � PGs, vasodilator peptides, chemotactics, lysosomal enz, ROS
- Complexes also ag plts and activate FXII
- IgG and IgM fix complement and IgG binds Fc
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Name disease examples of type III
- SLE, vs DNA, nucleoproteins --- nephritis, arthritis, vasculitis
- Blue eye, vs canine adenovirus --- ant uveitis
- EIA vs viral antigen --- anemia, Tpenia
- Arthus rxn vs foreign proteins --- cutaneous vasculitis
- COPD vs fungal spores, dust ---- bronchiolitis
- Aleutian mink dz ---- viral ag --- glomerulonephritis
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Describe type IV (delayed) hypersensitivity.
- ex. DM, MS, RA, TB, contact derm, Johne�s dz, allograft rejection, equine recurrent uveitis
- Initiated by Ag activated T lymphs � delayed type rxn by CD4
- APC presents Ag on MHCII to na�ve CD4 cell � differentiated to Th1 cell --- secretes IFNg
- Macs/APC secrete IL12 NB for diff into Th1 cell � induce IFNg prod by the Th1 cell
- IFNg that is secreted activates macs � more effective killing, more MHCII, PDGF prod (fibroblast prolif, collagen syn), secreteTNF, IL1 and chemokines and more IL12 (amplifies)
- IL2 also secreted by Th1 � autocrine to incr T cell prol and paracrine
- TNF and lymphotoxin � effects on endo cells: prostacycline (incr bld flow), exp of P and E selectins � attach passing lymphs and monos and induces secretion of IL8 � extravasation of lymphs and monos to rxn
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Describe T cell mediated cytotoxicity.
- Sensitized CD8 cells via perforins and granzymes within preformed vescicles in the CTL, perforins perforate membrane and granzymes initiate apoptosis
- Also express FASL which binds FAS and mediates Apoptosis
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Name and describe the three mechanisms of peripheral tolerance.
- 1. Anergy � T cell activation needs 2 signals including the costim signal � self tissue cells have no costim mol
- 2. Suppression by Treg � CD4 cells express CD25 � mech ? but involves IL10 and TGFb, need transcription factor Foxp3 for Treg cell dev and fxn
- 3. Clonal deletion by activation induced cell death � some T cell express FasL, thought that self T cell keep getting stimulated till they die by Fas ligand induced apoptosis or possibly by expressing BIM (pro-apoptotic molecule)
- NOTE: if self-reactive T cells are stim by exposure to an infectiou agent � they can then prol and get autoimmunity.
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What is amyloid?
Proteinaceous substance made up of non-branching fibrils with cross beta pleated sheet conformation � 95% is fibril proteins the rest is P component and other glycoproteins
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Name 3 forms of amyloid.
- AL � from plasma cells, Ig light chains � associated with B monoclonal dz
- AA � non- Ig produced in liver � fibrils derived from SAA, circulated in association with HDL3 lipoproteins
- A? - Alzheimers
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List and describe the types of amyloidosis.
- 1ry: associated with monoclonal gammopathies � ex. MM
- 2ry: associated with chronic inflammation � SAA synthesized in response to IL6 and IL1
- Hereditary: heterogenous group of dzs
- Endocrine amyloid: medullary carcinoma of thyroid, islet tumors of pancreas, pheo, carcinomas of stomach --- amyloid derived from polypeptide hormones or unique proteins produced by the tumor
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