The Immune System Innate Acquired Adaptive B Lymphocytes
The Immune System • Innate • Acquired (Adaptive) -B Lymphocytes • Antimicrobial Peptides Antibody • Phagocytes (Macrophages, PMNs, -T Lymphocytes Monocytes, DCs) Cytotoxicity • Alternative “Help” Antibody Complement System Cytokine Secretion BDC
B and T Lymphocyte Antigen Receptors VH VH V CH 1 VL VL CL CL CH 2 Ig /Ig CH 3 V g e z z e d C C Ig /Ig fyn lck Zap 70 Blk, Fyn or Lyn 2 light chains ( or ) 2 heavy chains (5 isotypes: Ig. G, M, A, D, E) 2 Binding sites (Divalent) Secreted into circulation Binds Soluble Antigen 2 Chains / (95%) or / (5%) 1 Binding site (Monovalent) Membrane Bound, Not Secreted Binds Antigen Complexed with MHC BDC
XPID: X-linked polyendocrinopathy, immune dysfunction and diarrhea • XLAAD: “Autoimmunity Allergic Dysreg” • Scurfin gene (Foxp 3/JM 2) • Immunopathogenesis: Th 2 Cytokines, abnormal activation (Il-4, 5, 13) -Scurfy+Nude: No Autoimmunity -CD 4+ into Nude: Disease -Bone Marrow into irradiated: No Disease -Require Antigen Stimulation for Disease -Mixed Chimera: No Disease BDC
J. Noble HLA Human Leukocyte Antigen human MHC cell-surface proteins important in self vs. nonself distinction present peptide antigens to T cells CLASS I: A, B, C CLASS II: DR, DQ, DP
The Human Leukocyte Antigen Complex (6 p 21. 31) Class II (1. 1 Mb) DP Class III Class I (2. 2 Mb) (0. 7 Mb) DQ DR B C A Telomere Centromere Frequent Recombination is Rare Complement and Cytokines Class I-like genes and pseudogenes Recombination is Rare BDC
HLA Class I and II Molecules Have a Distinct Structure and Function • Binds 8 -10 mers • Expressed on most Nucleated cells • Presents Cytosolic Proteins to CD 8+ T cells • Binds 13 -25 mers • Expressed on APCs, Macs, B cells, activated T cells • Presents Vesicular Proteins to CD 4+ T cells 1 2 1 1 2 3 2 2 Class II BDC
Cis and Trans- Class II Dimerization Maternal DQA 1 DQB 1 0501 0201 cis DQA 1*0501/DQB 1*0201 Paternal 0301 0302 cis trans DQA 1*0301/DQB 1*0302 DQA 1*0301/DQB 1*0201 DQA 1*0501/DQB 1*0302 BDC
DQB 1*0402 -chain Leu 56 -chain BDC Asp 57 BDC
HLA-Peptide: TCR NH 3+ 2 Helix α 1 Helix 1 R CD TCR alpha C 2 R D 3 R CD 2 R D 3 C R CD 1 R CD COO- TCR beta BDC
(-) IL-10 Co-Stimulation TGF CTLA-4 CD 28 + T Cell CD 154 B 7 CD 40 APC (CD 40 L) CD 2 CD 58 TCR-MHC (+)IL-1, IL-6, TNF BDC
The 2 -Signal Model of Lymphocyte Activation Absence of Signal 2 T Cell APC TCR MHC Tolerance Clonal Anergy or Deletion Signal 1 + Signal 2 CD 28 T Cell B 7 APC TCR MHC cytokines Activation BDC
Induction of CD 4+ TH 1 mediated autoimmunity: A paradigm for the pathogenesis of rheumatoid arthritis, multiple sclerosis and type I diabetes (1) expansion of CD 4+, autoreactive TH 1 cells specific for autoantigens MHC/self-peptide CD 4 TCR V x CD 4+ V x T cell APC CD 4 MHC/V TCR V x Activated autoreactive CD 4+ TCR V x TH 1 cell (2) migration and infiltration of these self reactive CD 4+ TH 1 cells into tissues and induction of inflammation and autoimmunity (3) induction of regulatory cells which control the growth and activation of the pathogenic autoreactive repertoire of CD 4+ T cells L. Chess
The Control of Activated CD 4+ T Cells by Regulatory T cells NKT cells/ CD 4+CD 25+ cells CD 4+CD 25 - cells Apoptosis peptide/APC (- ) TH 1 CD 4+ cells IL-12/ IFN-g (- ) IL-10 IL-4 Resting CD 4 T cells IFN-g (- ) Activated CD 4 T cells (- ) TH 2 CD 4+ cells Regulatory immunity CD 4/CD 8 interactions CD 8 or CD 4 suppressor effector precursor L. Chess
T cell activation is regulated by signals derived from the TCR /CD 3/CD 4 complex and the CD 40 L and CD 28/CTLA-4 co-stimulatory molecules CD 4+ T Cell Antigen specific TCR signals Co-stimulatory signals (- ) / [+] lck g d e CD 3 z z hh C C CD 28/ CTLA 4 V CD 40 L [+] , TCR Peptide antigen CD 40 CD 80 (B 7. 1)/ CD 86 (B 7. 2) V CD 4 MHC class II signal Antigen Presenting Cell (APC) L. Chess
Molecular Interactions of Helper T Cells and APC CD 4+ T Cell CTLA-4 CD 28 p 56 lck CD 3 CD 40 L C C V CD 2 z zh h gd e TCR V CD 45 LFA-1 VLA-1 peptide B 7 CD 80/CD 86 CD 40 MHC II LFA-3 ICAM-1 Collagen APC/ B cell L. Chess
T cell activation induces expression of functional T cell surface molecules Activated CD 4+ T cell MHC/peptid e Induction and activation of B cells APCs CD 40 L TCR APC TCR Resting CD 4+ T cell Late Activated CD 4+ T cell TCR CD 25 (+) Qa-1/V (-) VLA-1 Collagen TCR (anti-Qa-1/V ) Activated CD 8+ T cell Regulatory CD 8+ T cell Down-regulation of Activated CD 4+ T Cells Migration of sites of inflammation L. Chess
Immunopathophysiology of Diabetes Dendritic cell/ APC CD 2 CD 4+ Cell (TH 0 ) IL-12 DR 3, DR 4, , DQ 8/insulin , , TCR peptide IFN-g IL-4 CD 4+ Cell (TH 2 ) CD 40 L CD 40 Macrophage/dendritic cell Fc R Fas. L perforin CD 40 L Activated TH 1 CD 4+ T Cell CD 8+ CTL IL-1, TNF, LT, NO, PGE-2 IL-4 CD 40 L B Cell ? anti-insulin, GAD ab anti. Mog ? Antibody mediated injury cell death islet cells L. Chess
Innate Immune System: Toll-like receptor activation of APC CD 28 Signal 2 Signal 1 T Cell B 7 IL-1, 6, 12 “Signal 3” TCR-MHC LPS Toll Like Receptor (pattern Recognition R) Anitgen Presenting Cell (APC) BDC
Th 1 vs. Th 2 CD 4 T Cells Th 1 Th 2 • IL-12 for differentiation • Cytokines: Interferon- Interleukin-2 • Intracellular Pathogens • CD 8 Cytotoxicity • Delayed Type Hypersensitivity • Macrophage Activation • IL-4 for differentiation • Cytokines: Inerluekin-4 Interleukin-5 Interluekin-13 • Extracellular Pathogens • B Cell activation & Ig. E Immunoglobulin • Eosinophil responses BDC
Tr: T Regulatory Cells Review: Roncarolo Curr Opinion Immunol 2000 BDC
“Tetramer” for T Cell Analysis DQ DQ PEPTIDE DQ Avidin DQ BDC
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