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Department of Immunology

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1 Department of Immunology
Medical Immunology Department of Immunology Yiwei Chu 储以微

2 Exam: 9th July (Friday) 8:30-10:30am Inspector: Dr. Lu Qing
Dr. Gao Bao

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

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 Adaptive Immune Responses
Cellular Components 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 signaling cellular 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 receptors can then induce an immune response are called antigens.

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 Inside of the antigen molecule
1 Conformational epitope Nonsequential polypeptides or polysaccharide on the surface of the molecules, Native conformation, 2 liner epitope A sequential amino acid fragment, Linear determinant, Inside of the antigen molecule

15 Comparison of epitope of T and B cell
T cell epitope B cell epitope Receptor TCR BCR MHC molecule required to display none required processed antigen character liner peptides natural polypeptide,LPS, polysaccharide, organic compound 8 ~12 amino acids (CD8+) ,12 ~17 amino acids (CD4+) 5~15 amino acids, 5~7 monosaccharide or 5~7 nucleotide size Epitope type liner conformational, liner side any on the surface

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

17 CDR (complimentarity determining region,)

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

19 Immune Responses to Tumors

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

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

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

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

24 MHC class II molecule combined with peptide



27 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

28 Cytokine actions may be local and systemic
Autocrine action Endocrine action circulation act at a distance from the site of infection Paracrine action act on a nearby cell act on cytokine-producing cell itself Most cytokines act close to where they are produced, either on cytokine-producing cell itself

29 directing migration of leukocytes Chemokines
Tissue Primary lymphoid organs Secondary lymphoid organs Blood inflammation Stimulate leukocyte movement regulate the migration of leukocytes from the blood to tissues Cellular sources to inflammatory sites inflammatory stimuli Constitutively produced in lymphoid organs Physiologic traffic of lymphocytes through the organs

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

31 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

32 The mechanism of effector function
Perforin Granzyme

33 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

34 Examples of PAMPs PAMPs Source Principle innate immune response LPS
Gram-negative bacteria Macrophage activation cell wall dsRNA Replicating viruses Type I IFN production by infected cells Unmethylated CpG DNA Bacterial DNA Macrophage activation N-formylmethionine Bacteria protein neutrophil and macrophage activation Mannose-rich glycans Microbial glycoproteins phgocytosis or glycolipid opsonization complement activation

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

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

37 Development of Th1 and Th2 subsets

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

39 BCR-Iga/Igb complex

40 2. BCR coreceptor JBC 2004;279:31973 CD19 B-specific surface marker
signal transduction CD21 CR2,receptor for C3d-bound Ag CD81 BCR-coreceptor ligation induce reversible palmitoylation of CD81 to stabilize the CD19/CD21/CD81 complex Help and strengthen the BCR-Ag-signaling JBC 2004;279:31973

41 BCR-Iga/Igb coreceptor complex
B cell epitope B cell activation

42 TCR-CD3 BCR-Iga/b

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

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

45 B-1 cells (peritoneal cavity) marginal zone (MZ) B cells (spleen)
innate immune functions B-1 cells (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

46 B1 B2/FO B location mucosal sites spleen, LN
Ig-producing way naturally Ag-inductive specificity poly-reactive highly specific Ag TI Ag TD Ag (polysaccharide) Ig class Ig M IgG affinity low high

47 Significance of humoral immunity
eliminate extracellular bacterium and toxin eliminate extracellular virus

48 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.

49 Early events: Late events: follicle(B)-paracortex(T)border,
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

50 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

51 T Lymphocyte Tolerance
Central T Cell Tolerance Peripheral T cell Tolerance

52 Burnet: Clonal selection hypothesis

53 Peripheral T cell Tolerance
Antigen recognition without adequate costimulation Use CTLA-4 to recognize costimulators on APCs Activation induced cell death (AICD) Regulatory T Lymphocytes Factors that determine the tolerogenicity of self antigens

54 Tumor Antigen Tumor-specific antigen
Antigen that are expressed on tumor cells but not on normal cells were called tumor- specific antigens; some of these antigens are unique to individual tumors, whereas others are shared among tumors of the same type.

55 Tumor Antigen Tumor-associated antigen
Tumor antigens that are also expressed on normal cells were called tumor-associated antigens; in most cases, these antigens are normal cellular constituents whose expression is aberrant or dysregulated in tumors 2 reasons, 1)only one authorized for sale in china, under the special agreement with Peiking University Medical press. 2) An exceptionally lucid guide to the latest immunology concepts. Immunology is not an easy concept to digest at first, but luckily this book explains the difficult topics quite well.

56 Evasion of Immune Responses
Class I MHC expression may be down-regulated on tumor cells so that they cannot be recognized by CTLs. Tumor lose expression of antigen that elicit immune responses. Tumors may fail to induce CTLs because most tumor cells do not express costimulators or class II MHC molecules. The products of tumor cells may suppress antitumor immune responses. Tumor antigens may induces may induce specific immunologic tolerance.

57 Difference between Direct Recognition and Indirect Recognition
Allogeneic MHC molecule Intact allogeneic MHC molecule Peptide of allogeneic MHC molecule APCs Recipient APCs are not necessary Recipient APCs Roles in rejection Acute rejection Chronic rejection Degree of rejection Vigorous Weak

58 Classification of Allograft Rejection
Host versus graft reaction (HVGR) Conventional organ transplantation Graft versus host reaction (GVHR) Bone marrow transplantation Immune cells transplantation Allograft rejection can be classfied into … abbreviation as HVGR

59 II.Graft versus host reaction (GVHR)
Conditions Enough immune competent cells in grafts Immunocompromised host Histocompatability differences between host and graft

60 Hypersensitivity Tissue injury caused by an immune response that is inadequately controlled or inappropriately targeted to host tissues

61 Types of hypersensitivity reactions
GELL AND COOMB’S CLASSIFICATION Type I: Immediate Type II: Cytotoxic Type III: Immune complex Type IV: cell mediated or delayed


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