1. 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 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 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. 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 HLA J. Noble

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

6. HLA Class I and II Molecules Have a Distinct Structure and Function BDC

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

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

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

10. Co-Stimulation T Cell APC CTLA-4 - CD28 + CD154 (CD40L) CD2CD58 CD40 B7 (+)IL-1, IL-6, TNF  IL-10 TGF  (-) TCR-MHC BDC

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

12. MHC/self-peptide CD4 MHC/V  CD4 CD4+ V  x T cell APC Activated autoreactive CD4+ TCR V  x TH1 cell TCR V  x (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 Induction of CD4+ TH1 mediated autoimmunity: A paradigm for the pathogenesis of rheumatoid arthritis, multiple sclerosis and type I diabetes L. Chess 2002

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

14. T cell activation is regulated by signals derived from the TCR /CD3/CD4 complex and the CD40L and CD28/CTLA-4 co-stimulatory molecules    CD3 MHC class II  TCR  Peptide antigen CD4+ T Cell Antigen Presenting Cell (APC) V  V  C  C  CD4 Antigen specific TCR signals CD40 CD40L signal CD28/ CTLA- 4 CD80 (B7.1)/ CD86 (B7.2) lck Co-stimulatory signals (- ) / [+] [+] L. Chess 2002

15.    V  C  C  V    p56 lck peptide CD3 CD28 CD40 LFA-3 LFA-1 ICAM-1 MHC II B7 CD40L CD4 CD45 TCR CD2 CD4+ T Cell APC/ B cell  Molecular Interactions of Helper T Cells and APC B7 CTLA-4 VLA-1 Collagen CD80/CD86 L. Chess 2002

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

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

18. Innate Immune System: Toll-like receptor activation of APC T Cell CD28B7 TCR-MHC LPS Toll Like Receptor (pattern Recognition R) IL-1,6,12 “Signal 3” Signal 2 Signal 1 Anitgen Presenting Cell (APC) BDC

19. Th1 vs. Th2 CD4 T Cells Th1 IL-12 for differentiation Cytokines: Interferon-  Interleukin-2 Intracellular Pathogens CD8 Cytotoxicity Delayed Type Hypersensitivity Macrophage ActivationTh2 IL-4 for differentiation Cytokines: Inerluekin-4 Interleukin-5 Interluekin-13 Extracellular Pathogens B Cell activation & IgE Immunoglobulin Eosinophil responses BDC

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

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