Immunology

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Immunoglobulin Cytokine Receptors

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3 domains of 110 aa's, joined by disulfide bonds
ex - IL-1(fever), MCSF, C-Kit

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Class 1 (hematopoietin) Cytokine Receptors

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conserved CCCC motif and WSXWS
ex - IL-2->7, 9, 11->13, 15, GMSCF,GSCF,OSM,LIF,CNTF,GH,PRL

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Class 2 (interferon) cytokine receptors

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CC-CC
IFN-a,b,gamma
IL-10

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TNF Receptors

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4 domains, C1C3C2
TNF-a,b, CD40, NGF, FAS

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Chemokine Receptors

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M-tropic - CCR5 (transmission, RANTES)
T-Tropic - CXCR4 (late infection)
CCR5(32) mutation - AIDS free disease.
IL-8,RANTES,MIP-!

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Th1 Cells

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Activated by IL-12 from macrophages, Stat-4 dependent.
Secrete- IL-2,IFN-gamma, TFN-b, GMSCF
Cell mediated immune responses (delayed type hypersensitivity)

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Th2 Cells

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Activated by IL-4 from activated t-cells, stat-6 dependent.
IL-4,5,10,13 - Humoral immune response (class switching), eosinophil and mast cell mediated immunity.

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Bacterial Septic Shock

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endotoxins stimulate overproduction of IL-1 and TNF-a
Fever, diarrhea, shock, clotting.

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Bacterial toxic shock

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sperantigens stimulate T-cells
macrophages produce high levels of IL-1 and TNF-a

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Chagra's Disease

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reduction of IL-2Ra by trypanosome cruzi.

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Lymphoid and Myeloid Cancers

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overproduction of IL-6

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Contact-mediated activation of B cell

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Bcell presents an Ag
TCR mediated inositol lipid hydrolysis - CD40L induced on Tcell - binds to CD40 of the Bcell, activates cytokine receptors.
B7/CD28 bind - induces MAP kinase -> cJUN (which binds cFos)
Cytoskeleton of Bcell rearranges (talin)-directional release of IL-4 - also needs IL-1 from macrophages.

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Proliferation cytokines

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IL-2,4,5

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Differentiation cytokines

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IgA - IL-5 or TGF-b
IgG2 - INF-gamma
IgE - IL-4 + IL-13 or IL-5
IgM - IL-4 or IL-5 or IL-2

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T-cell independent B cell activation Type 1

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antigen binds a MITOGEN receptor
(TLR-4 for LPS)
NO MEMORY RESPONSE
mostly IgM
induction of polyclonal activation - Ig's secreted are not Ag specific.
No inositol lipid hydrolysis or calcium mobilization.

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Tcell independent type 2 Ag's

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crosslinking on membrane Ig
bacterial products.
IgM and IgG3 mostly produced.
Inositol lipid hydrolysis of PIP2 -> IP3 and DAG

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Poised Tcell (CD8)

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high p70(b) for IL-2R
low p55(a) for IL-2R
small amount of IL-2 produced, not enough to stimulate itself - requires IL-2 from CD4+
IL-2 increases p55(a) increased expression of IL-2R
on TC cell -> activation

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Active Tcell (CD8)

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granules - perforins, serine esterases(granzymes),toxins.
cytotoxic cytokines - TNFb (lymphotoxin-a), IFNgamma, and a little IL-2.

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Lethal Hit

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release of perforins, Ca-dependent polymerization of pores on membrane - toxins released from Tc can enter via pores, also osmotic lysis of cell - inflammatory response b/c release of lysozymes.
Also FasL/Fas triggered apoptosis of the cell - no inflammation.

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CD40L deficiency

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hyper IgM production, not germinal centers, no memory cells formed.

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Perforin deficiency

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genetic mutation - intace CTL, reduced killing of target cells by pore formation, increase in FasL/Fas mediated apoptosis.
Familial hemophagocytic lymphohistiocytosis.

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Classical Complement
(Ab mediated)

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1)binding of Ab to AG
2)C1 binds complex (c1q and c1r2s2)
3)C4 binds and cleaved by c1r2s2
4)C4b binds membrane.
5)C2 binds cleaved by C1r2s2.
6)C4b2a - C3 convertase.
7)C3 binds, cleaved
8)C3b binds membrane via thioester bonds.
9)C4b2a3b-C5 convertase
Ca and Mg dependent

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Lectin Pathway
(MBP mediated)

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1)MSAP-MBL binds membrane
2)C4 binds and cleaved by MSAP.
3)C2 binds and cleaved by MSAP.
4)C4b2a - C3 convertase.
5)C3 binds and cleaved.
6)C3b binds membrane
7)C4b2a3b - C5 convertase.
Ca and Mg dependent

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Alternate Pathway
innate immune system

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1)spontaneous cleavage of C3 in blood (low rate)
2)C3b may bind membrane
3)Factor B binds C3b
4)Factor D binds and cleaves B
5)C3bBb-C3 convertase.
6)C3 binds and cleaved.
7)C3b binds - C3bBb3b - C5 convertase.
Mg dependent.

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Late Steps of Complement Activation

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1)C5 binds and is cleaved.
2)C6 and 7 bind and complex inserted into cell membrane.
3)stable insertion of C8
4)15 C9's polymerize around the complex - MAC

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C1-INH

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complement inhibitor, prevents binding and activation of C1 - no C1r2s2 activity, can't cleave C2 or C4.
Deficiency=HANE, overproduction of C2b.

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DAF,MCP,CR1

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prevent assembly of C3 and C5 convertase, displace C2a from C4b (classical)
Alternate - only DAF and CR1 - displace Bb from C3b.

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Factor I

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serine protease in plasma, inhibits C3 convertase by cleaving C3b-iC3b
cofactors- MCP,CR1,FactorH

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MAC inhibition

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C59 - prevents C9 polymerization
serum protein S - prevents C5b-7 complex from being integrated into membrane.

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C3a

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neutrophil activation and mobilization, anaphalatoxin (a little)
mast cell degranulation
opsonization
removal of immune complexes via RBC's

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C5a

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anaphylatoxin
chemotactic
neutrophil activation
mast cell degranulation

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Immune Complex Diseases

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C1,4,2 deficiencies

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MAC deficiency

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predisposition to Neiserria

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Deficiency in C3,D,I

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pyogenic infections

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Type 1 hypersensitivity

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IgE mediated.
1)sensitization-1st exposure to Ag - Th2 cells activated (produce IL-4,13), Bcells produce specific IgE with bind FCER1 on mast cells.
2)tigger-repeat exposure, crosslinking of IgE on mast-degranulation.

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Preformed Mediators

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Histamine, Serotonin, chemotactic factors

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Newly-Formed

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Leukotrienes, prostaglandins, thromboxanes, PAF

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Late-Phase Reactants

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eosinophils, neutrophils - second wave of inflammation.
eopsinophil chemotactic factor (IL-3,4,5,13), eosinophilic cationic factor.

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Type 2 hypersensitivity

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activation of complement
NK-ADCC of Ab-coated cell
Ab may be bound to modified self Ag, attracts NK cells.

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Type 2 hypersensitivity examples

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Transfusion Reactions
Rhesus D (mother vs. fetus)
Autoimmune diseases - hemolytic anemia, drug-induced anemia, grave's disease, myasthenia gravis.

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Type 3

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immune complex mediated.
Local immune complex activates complement (deposited on walls of vessels) - blood vessel occlusion and inflammation - damage

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Type 3 examples

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SLE,RA, farmer's lung,arthus reaction(skin test, 6hrs), serum sickness.

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Type 4

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Delayed hypersensitivity.
Ag uptake, Th1 cells induced, recruitment of tcells,phagocytes, fluid, protein - visible lesion.
Skin test - 48-72 hrs.

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Type 4 examples

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contact dermatitis - poison ivy, metal ion reactions.
Insulin dependent diabetes mellitus.
Tuebrculin rxn.
Treat with steroids.

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Molecular Mimicry examples

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Type1 diabetes - CMV, rubella
Graves - yersinia enterocolitica
MS - EBV,herpes 6, milk-protein butyrophilin.
AS- cross rxn with HLAB27 and Klebsiella.
Rheumatic carditis-Strep

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SCID

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T and B cell deficiency
Xlinked
IL-2 and Il-7 receptor defects, also adenosine deaminase, purine nucleoside phosphorylase defects.

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Di George

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developmental thymic aplasia, no parathyroids, cardiac and facial abnormalities, tetany (low ca)
thymic grafts to treat.
Susceptible to pneumocystis carinii (fungal)

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Bruton's

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X linked agammaglobulinaemia
B cell defect (tyrosine kinase deficiency)
appears at 3-6 months.

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HIV destruction of Tcells

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Direct viral effect
Syncitium formation - cells with gp120 expressed bound by normal and infected CD4 cells - complex is removed.
Destruction by cytotoxic cells - NK cells, CTL, Macrophage.

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Acute phase HIV

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low or no Ab's produced,
high viral load,
ELISA test for Ab's and Western blot for Ab's - neither 100% in early phase.

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Latent Phase HIV

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gradual decrease in CD4,
Ab vs. HIV present (anti-gp41,120 and 24)
decreased viral load
asymptomatic

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Pre AIDS

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CD4 around 400/microlitre
Lymphoadenopathy
decrease in anti-gp24
increased viral load

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AIDS

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CD4 below 200/microlitre
opportunistic infections take place.

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Dendritic cells

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langerhans-epidermis and mucosa
interstitial
interdigitating-Tcell areas of secondary lymphoid tissues and thymic medulla
Circulating - aka veiled
Follicular-not APC, in Bcell rich follicles,facilitate Bcell activation in LN

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chromosome 14

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Ig heavy chain germ line
VDJ rearrangement

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Chromosome 22,2

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lambda and kappa light chains

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RSS

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one turn and two turn.
heptamer(palindromic) and AT rich nonamer conserved, random base pairs b/w.
One turn-12, two turn-23

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Ig diversity

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1)multiple genes for V region
2)multiple VJ and VDJ combinations
3)junctional flexibility in joining (CDR3).
4)Nucleotide additions - P-additions just add complement base pairs to hairpin. N-addition-adds random nucleotides to hairpin-TdT
5)Somatic hypermutations -affinity maturation
6)Combinatorial associations of H and L.

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Pro Bcell maturation

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VLA-4:VCAM-1 and CKIT:SCF
triggers VDJ rearrangement of IgM heavy chain by kinase activity.
CKit+CD25+

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Pre B

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Lose dependency on CKit and SCF for binding IL-7 growth factor.
IgM chain rearranged, SL produced, lambda5:VpreB. Expressed on surface with M heavy chain- interacts with Igalpha/beta and signals light chain rearrangement.

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Chromosome 6

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HLA
Class I - A,B,C
Class II-DP,DQ,DR,DM(like)
b/w DM and DQ - TAP1/2 and LMP
Class3-soluble factors, cytokines, complement(4,2,factorb)TNF.

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Chromosome 17

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H-2 - mouse
Class1- K,D,L
Class2- IA,IE,M
Class3-soluble factors.

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MHC II stucture

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heterodimer, alpha and beta chains.
Alpha1 and Beta1 are highly variable, 2's are conserved.

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MHC I Structure

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alpha chain and associated B2 microglobulin (not on same chromosome - 15(human),2(mouse)
B2MG bound to highly conserved alpha3

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MHC polymorphism

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variation not random-specific localization.
no hypermutation.
Polymorphism at the amino terminal domains (a1,a2 of MHC1,a1+b1 of MHC2)

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Adhesion of Th to APC

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CD2:LFA-3
LFA-1:iCAM-1

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Ag Recognition (Tcell activation)

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TCR:MHC+Ag (low affinity-serial engagement)
Immunological synapse formation - CD2 and LFA-1 move and encircle TCR/MHC

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Activation of Tcell

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CD2:LFA-3
CD4:B2 of MHCII
CD45:CD22
CD28:B7

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Tcell signaling TCR/CD3

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TCR/CD4:MHC/Ag - juxtaposition of Lck and ITAMS of CD3
CD45:CD22-activation of tyrosine phosphatase at bottom of CD45- dephosphorylates Fyn+Lck (now active)-
phosphorylate ITAMS
phosphorylated ITAM of zeta binds ZAP-70 to zeta - activated.
ZAP-70 and Fyn phospharylate PLC-gamma1

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PLC-gamma1

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cleaves PIP2-> IP3 and DAG
IP3 binds Ca channels and releases intracellular ca stores. Icreased [ca] binds PKC to pm, activated by DAG. Also Ca/calmodulin - activates calcineurin phosphatase - dephos. of NF-ATc-PO4 ->NF-AT, binds enhancer region on gene.

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PKC

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phos. inhibition factor, release of NF-KB, binds to another enhancer region on gene.
also activates protooncogene cFOS, interacts with cJUN, forms AP1 and NF dimer on IL-2 enhancer region