Robbins Ch 6 Immunity

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

• LP (bact)
• Peptidoglycans (G+ bact)
• LPS (lepto)
• Zymosan (fungi)
• GPI anchor (trypanosomes)
• Lipoarabinomanan (mycobact)
• Phosphatidyl dimanoside (mycobact)

DS DNA (viruses)

• LPS (G- bact)
• HSF00 (Chlamydia)

Flagellin (bact)

CpG DNA (bact, protozoa)

Peptides displayed on MHC

5 parts: TCRa and b + 2z and 3 CD3 � g, d, e

Peptides lipids and small molecules not associated with MHC.

• 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

Apoptosis

• 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

Heavy and light chains of Ig plus CD79a-b heterodimer (NB for signal transduction)

FC, CD21 (complement receptor 2), CD40

CD4 T cells express CD40L � binds to CD40 on Bcell ? secrete IgG, IgA, IgE

IFNg by CD4 Tcells

IgG or C3b

• 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!

The latter have TCR as well as NK receptors, NK cells have no TCR or surface Ig

CD56, CD16 (Fc for IgG)

• 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

IFNg (activate macs and promotes diff of TH1 cells), TNF and GM-CSF

IL2 and IL15 stim prol, IL12 activates killing and secretion of IFNg

Innate: IL1, TNF, IL6 (IL12 and IFNg � both innate and adaptive)

IFNs

IL2 (T cell GF), IL4 (TH2), IL12 (TH1), IL15 (NK), TGFb, IL10 � latter 2 downregulate immune response

IFNg (mac), IL5 (eos), TNF and lymphotoxin (neuts and endo)

C-C (made by T cells) or C-X-C (made by macs and endo)

G and GM-CSF, c-kit, CD117 � more� not listed

• 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

• 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

Histamine, PAF

• PAF
• LT C4, D4, E4
• Neutral proteases
• PG D2

• LT C4, D4, E4
• Histamine
• PGs
• PAF

• Cytokines
• LT B4
• Eos and neut chemotactic factors
• PAF

• 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)

• 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

• 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

• 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

• 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

• 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.

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

• 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

• 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