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The Immune System

Innate Antimicrobial Peptides Phagocytes (Macrophages, PMNs, Monocytes, DCs) Alternative Complement System. Acquired (Adaptive) -B Lymphocytes Antibody -T Lymphocytes Cytotoxicity “Help” Antibody Cytokine Secretion. The Immune System. BDC. 2 light chains (  or  )

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The Immune System

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  1. Innate Antimicrobial Peptides Phagocytes (Macrophages, PMNs, Monocytes, DCs) Alternative Complement System Acquired (Adaptive)-B Lymphocytes Antibody-T Lymphocytes Cytotoxicity “Help” Antibody Cytokine Secretion The Immune System BDC

  2. 2 light chains ( or ) 2 heavy chains (5 isotypes: IgG, 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 V V VH VH g e e d C C z CH1 z CH1 VL VL CL CL CH2 CH2 Iga/Igb Iga/Igb fyn lck Zap 70 CH3 CH3 Blk, Fyn or Lyn B and T Lymphocyte Antigen Receptors BDC

  3. XPID: X-linked polyendocrinopathy, immune dysfunction and diarrhea • XLAAD: “Autoimmunity Allergic Dysreg” • Scurfin gene (Foxp3/JM2) • Immunopathogenesis: Th2 Cytokines, abnormal activation (Il-4,5,13)-Scurfy+Nude: No Autoimmunity-CD4+ into Nude: Disease-Bone Marrow into irradiated: No Disease-Require Antigen Stimulation for Disease-Mixed Chimera: No Disease BDC

  4. J. Noble HLA Human Leukocyte Antigen human MHC cell-surface proteins important in self vs. nonself distinction present peptide antigens to T cells CLASS II: DR,DQ,DP CLASS I: A,B,C

  5. Class III Class II(1.1 Mb) Class I (2.2Mb) (0.7Mb) DP DQ DR B C A Telomere Centromere Frequent Recombination Class I-like genes and pseudogenes Complement and Cytokines Recombination is Rare Recombination is Rare The Human Leukocyte Antigen Complex (6p21.31) BDC

  6. Binds 13-25mers • Expressed on APCs, • Macs, B cells, activated • T cells • Presents Vesicular • Proteins to CD4+ T cells • Binds 8-10mers • Expressed on most • Nucleated cells • Presents Cytosolic • Proteins to CD8+ T cells a2 a1 b1 a1 b2 a3 a2 b2 Class I Class II HLA Class I and II Molecules Have a Distinct Structure and Function BDC

  7. Cis and Trans- Class II Dimerization DQA1 DQB1 cis 05010201 Maternal Paternal DQA1*0501/DQB1*0201 cis 0301 0302 trans DQA1*0301/DQB1*0302 DQA1*0301/DQB1*0201 DQA1*0501/DQB1*0302 BDC

  8. DQB1*0402  -chain Leu56 -chain Asp57 BDC BDC

  9. HLA-Peptide: TCR NH3+ 2 Helix α1 Helix TCR alpha CDR1 CDR3 CDR2 CDR2 CDR3 TCR beta CDR1 BDC COO-

  10. (-) Co-Stimulation IL-10 TGF CTLA-4 - B7 CD28 + CD154 T Cell CD40 APC (CD40L) CD2 CD58 TCR-MHC (+)IL-1, IL-6, TNF BDC

  11. The 2-Signal Model of Lymphocyte Activation Absence of Signal 2 APC T Cell TCR MHC Tolerance Clonal Anergy or Deletion Signal 1 + Signal 2 CD28 B7 APC T Cell TCR MHC cytokines Activation BDC

  12. Induction of CD4+ TH1 mediated autoimmunity: A paradigm for the pathogenesis of rheumatoid arthritis, multiple sclerosis and type I diabetes (1) expansion of CD4+, autoreactive TH1 cells specific for autoantigens (2) migration and infiltration of these self reactive CD4+ TH1 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 CD4+ T cells MHC/self-peptide CD4 CD4 MHC/Vb TCR Vbx TCR Vbx APC CD4+ Vbx T cell Activated autoreactive CD4+ TCR Vbx TH1 cell L. Chess 2002

  13. The Control of Activated CD4+ T Cells by Regulatory T cells NKT cells/ CD4+CD25+ cells CD4+CD25- cells Apoptosis (- ) TH1 CD4+ cells IL-12/ IFN-g peptide/APC (- ) IL-10 IFN-g IL-4 (- ) Activated CD4 T cells Resting CD4 T cells (- ) TH2 CD4+ cells Regulatory immunity CD4/CD8 interactions CD8 or CD4 suppressor effector CD8 or CD4 suppressor precursor L. Chess 2002

  14. CD4+T Cell Antigen specific TCR signals Co-stimulatory signals (- ) / [+] lck CD3 z z d e g h h C a C b a,bTCR CD28/ CTLA-4 V V a b CD40L Peptide antigen MHC class II CD4 CD40 signal CD80 (B7.1)/ CD86 (B7.2) [+] Antigen Presenting Cell (APC) T cell activation is regulated by signals derived from the TCR /CD3/CD4 complex and the CD40L and CD28/CTLA-4 co-stimulatory molecules L. Chess 2002

  15. Molecular Interactions of Helper T Cells and APC CD4+ T Cell CTLA-4 CD28 CD3 p56 lck CD2 z z g d e h h CD40L TCR C C LFA-1 a b CD45 VLA-1 V b V a peptide B7 LFA-3 B7 CD4 MHC II ICAM-1 Collagen APC/ B cell CD40 CD80/CD86 L. Chess 2002

  16. T cell activation induces expression of functional T cell surface molecules Induction and activation of B cells APCs Activated CD4+ T cell Late Activated CD4+ T cell MHC/peptide CD40L TCR TCR TCR CD25 Resting CD4+ T cell (-) APC (+) VLA-1 Qa-1/Vb Collagen TCR (anti-Qa-1/Vb) Migration of sites of inflammation Activated CD8+ T cell Regulatory CD8+ T cell Down-regulation of Activated CD4+ T Cells L. Chess 2002

  17. Immunopathophysiology of Diabetes Dendritic cell/ APC Activated TH1 CD4+ T Cell CD2 CD4+ Cell (TH0 ) IL-12 DR3, DR4,,DQ8/insulin peptide CD40L a,b, TCR IFN-g CD40 IL-4 Macrophage/dendritic cell CD4+ Cell (TH2 ) Fc R FasL perforin CD40L CD8+ CTL IL-1, TNF, LT, NO, PGE-2 IL-4 CD40L ?anti-insulin, GAD ab anti-Mog B Cell b cell death b islet cells ?Antibody mediated injury L. Chess 2002

  18. Innate Immune System: Toll-like receptor activation of APC CD28 B7 LPS Signal 2 IL-1,6,12 “Signal 3” Toll Like Receptor (pattern Recognition R) Signal 1 TCR-MHC T Cell Anitgen Presenting Cell (APC) BDC

  19. Th1 IL-12 for differentiation Cytokines:Interferon-Interleukin-2 Intracellular Pathogens CD8 Cytotoxicity Delayed Type Hypersensitivity Macrophage Activation Th2 IL-4 for differentiation Cytokines:Inerluekin-4Interleukin-5Interluekin-13 Extracellular Pathogens B Cell activation & IgEImmunoglobulin Eosinophil responses Th1 vs. Th2 CD4 T Cells BDC

  20. Tr: T Regulatory CellsReview: Roncarolo Curr Opinion Immunol 2000 BDC

  21. “Tetramer” for T Cell Analysis DQ PEPTIDE Avidin DQ DQ DQ BDC

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