Medical Immunology

1. Medical Immunology Department of Immunology YiweiChu 储以微 ywchu@shmu.edu.cn 2010-7-7

2. Exam: 9th July (Friday) 8:30-10:30am Inspector: Dr. Lu Qing Dr. GaoBao 2010-7-7

3. Yiwei Chu Wei Xu Rui He Yunlu Lin Qing Lu Xiaowu Hong Haifeng Gao Bo Gao Department of Immunology

4. Define of Immunology IMMUNITY ---protection from disease (infectious disease) IMMUNE SYSTEM --- organ, cell, molecule and gene IMMUNE RESPNSE --- response to the foreign substances

5. Define of Immunology IMMUNE FUNCTIONS ---immune defence (infectious disease) --- immune surveillance --- immune homeostasis

6. Define of Immunology IMMUNITY ---protection from disease (infectious disease) IMMUNE SYSTEM --- organ, cell, molecule and gene IMMUNE RESPNSE --- response to the foreign substances

7. Innate and Adaptive Immunity

8. Adaptive Immune Responses

9. Cellular Components Adaptive Immune Responses • Lymphocytes - B, Th, CTL, NKT • Antigen-presenting cells(APCs) - DC, Mj, B • Effector cells- Activated T cells, mononuclear phagocytes

10. Basic Immunology Effection Recognition Activation Ag(antigen)double recognition humural immunity APC double signalingcellular immunity (antigen presenting cell)

11. Chapter 1 Definition of antigen Antigen (Ag) Substances that combine specifically with a B or T cell’s antigen-binding receptorscan then induce an immune response are calledantigens.

12. Chapter 2 Characteristics of antigen The antigen molecule generally pose two natures, that is （1）immunogenicity （2）antigenicity

13. (1) Antigenic determinants or epitopes Antigenic determinants or epitopes are the immunologically active regions of an immunogen that bind to antigen-specific membrane receptors on lymphocytes (TCR/BCR) or to secreted antibodies.

14. Structure of epitopes 1 Conformational epitope Nonsequential polypeptides or polysaccharide on the surfaceof the molecules, Native conformation, 2 liner epitope A sequentialamino acid fragment, Linear determinant, Insideof the antigen molecule

15. (3) hypervarible region (HVR) (complimentarity determining region,CDR) : formation of the Ag binding site Framework region（ FR ) : maintaining the 3- dimensional configuration

16. CDR (complimentarity determining region,)

17. 4. Ab-dependent Cell-mediated cytotoxicity, ADCC enhance NK killing

18. Immune Responses to Tumors

19. CONCEPT APCs are immunocytes that can uptake, process and present antigens to other lymphocytes.

20. Professional APCs Dendritic Cells (DCs) Macrophages (M) B Lymphocytes

21. I. Dendritic Cells (DCs) Ralph.M.Steinman, 1973

22. The invariant chain is cleaved to leave a peptide fragment, CLIP, bound to the MHC class II molecule CLIP (class II-associatedinvariant-chain peptide)

23. MHC class II molecule combined with peptide

26. What are cytokines? • Cytokines are polypeptides produced by the cells of innate and adaptive immunity in response to microbes and other antigens as a result of cellular activation. • Cytokines initiate their actions by binding to specific membrane receptors on target cells. • The cellular responses to most cytokines consist of gene activation, resulting in the expression of new functions and sometimes the proliferation of the target cells

27. Autocrineaction act on cytokine-producing cell itself Paracrine action act on a nearby cell circulation Endocrine action act at a distance from the site of infection Cytokine actions may be local and systemic

28. directing migration of leukocytes Chemokines Tissue Primary lymphoid organs Secondary lymphoid organs Blood inflammation Cellular sources to inflammatory sites • inflammatory stimuli • Constitutively produced in lymphoid organs Physiologic traffic of lymphocytes through the organs

29. IL-2 • a growth factor for antigen-stimulated T lymphocytes • responsible for T cell clonal expansion after antigen recognition

30. Natural Killer cells (NK cells) • A type of cytotoxic lymphocytes • The principal physiologic role • Defense against infections by viruses and some other intracelluar • microbes • 2. Rejection of tumors

31. The mechanism of effector function Perforin Granzyme

32. Pathogen-associated molecular patterns (PAMPs) • Small molecular motifs conserved within a class of microbes • Usually essential for survival of the microbes • Recognized by cells of innate immune system • Activate innate immune response

33. Examples of PAMPs

34. Patterns recognition receptors (PRRs) • Proteins expressed by cells of innate immune system • Present on the cell surface, in endosomal vesicles, and in the cytoplasm

35. The subsets of CD4+Th cells • How they are induced, • What cytokines they produce • What effector mechanisms they activate

36. Development of Th1 and Th2 subsets

37. Surface receptor 1) B cell antigen receotor (BCR) BCR/mIgM Membrane Ig (mIg) Mature B cell： mIgM ＋ mIgD BCR-Igα/Igβ complex

38. BCR-Iga/Igb complex

39. 2. BCR coreceptor CD19 B-specific surface marker signal transduction CD21CR2，receptor for C3d-bound Ag CD81 BCR－coreceptor ligation inducereversible palmitoylation of CD81 to stabilize the CD19/CD21/CD81 complex Help and strengthen the BCR-Ag-signaling JBC 2004;279:31973

40. BCR-Iga/Igb coreceptor complex B cell epitope B cell activation

41. TCR-CD3 BCR-Iga/b

42. Two-signal activation model for T cells activation naive co-stimulatory molecules anergy none

43. Two-signal activation model for B cells Signal 3 Signal 1 and signal 2 are not simultaneous But in two steps, signal 2 from Th cells

44. MZ B cells innate immune functions B-1cells （peritoneal cavity） marginal zone (MZ) B cells （spleen） frequent Ag encounter. Secreting essentially germline-encoded, polyreactive natural Abs, respond rapidly and vigorously to pathogens express Toll-like receptors (TLR), provide costimulation to GC B cells important link between the innate and adaptive immunity

45. B1 B2/FO B location mucosal sites spleen, LN Ig-producing way naturally Ag-inductive specificity poly-reactive highly specific Ag TI AgTD Ag （polysaccharide） Ig class Ig MIgG affinitylow high

46. Significance of humoral immunity eliminate extracellular bacterium and toxin eliminate extracellular virus

47. Antigen crosslinks mIg(BCR), generating signal 1, which leads to increased expression of class II MHC and costimulatory B7. Antigen–BCR complexes are internalized by receptor-mediated endocytosis and degraded to peptides, which are bound by class II MHC and presented as peptide–MHC complexes. Th cell recognizes Ag–class II MHC and B7-CD28 co-stimulation on B-cell membrane which activates TH cell. Th cell begins to express CD40L. Interaction of CD40 and CD40L provides signal 2. Th cell release large quantities of cytokines(IL-4) signal 3 to support the progression of the B cell replication and differentiation.

48. Early and late event in Ab response to TD antigen Early events： follicle（B）-paracortex（T）border, B activation and T-B activation Small amounts of Ab production Late events： At the germinal center Presence of Ag and Th Affinity maturation Ig class switch (IgM IgG) Memory B

49. General Features and Mechanisms • Immunologically specific • Central tolerance: induced in generative lymphoid organs immature self-reactive lymphocyte The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens The repertoire of mature lymphocytes cannot recognize ubiquitous or widely disseminated self antigens

50. T Lymphocyte Tolerance • Central T Cell Tolerance • Peripheral T cell Tolerance