Medical Immunology - Fudan University

Medical Immunology Department of Immunology Yiwei Chu [email protected] 2010-7-7 Exam: 9th July (Friday) 8:30-10:30am

Inspector: Dr. Lu Qing Dr. Gao Bao 2010-7-7 Department of Immunology Yiwei Chu Wei Xu Rui He

Yunlu Lin Qing Lu Xiaowu Hong Bo Gao Haifeng Gao Define of Immunology

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

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

Innate and Adaptive Immunity Adaptive Immune Responses Adaptive Immune Responses Cellular Components Lymphocytes - B, Th, CTL, NKT Antigen-presenting cells(APCs)

- DC, Mj, B Effector cells - Activated T cells, mononuclear phagocytes Basic Immunology Recognition Ag (antigen) APC

Activation double recognition double signaling (antigen presenting cell) Effection humural immunity

cellular immunity Chapter 1 Definition of antigen Antigen (Ag) Substances that combine specifically with a B or T cells antigen-binding receptors can then induce an immune

response are called antigens. Chapter 2 Characteristics of antigen The antigen molecule generally pose two natures, that is 1 immunogenicity 2 antigenicity

1) Antigenic determinants or epitope 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. Structure of epitopes 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

) hypervarible region (HVR) (complimentarity determining re gion, CDR) : formation of the Ag binding sit e Framework regio n FR ) : maintaining the

3- dimensional configuration CDR (complimentarity determining region,) 4. Ab-dependent Cell-mediated cytotoxicity, ADCC enhance NK killing Immune Responses to Tumors

CONCEPT APCs are immunocytes that can uptake, process and present antigens to other lymphocytes. Professional APCs Dendritic Cells (DCs) Macrophages (M) B Lymphocytes

I. Dendritic Cells (DCs) Ralph.M.Steinman, 1973 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) MHC class II molecule combined with peptide

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 Cytokine actions may be local and systemic Autocrine action

Paracrine action act on cytokine-producing cell itself act on a nearby cell circulation Endocrine action act at a distance from the site of infection

Chemokines Primary lymphoid organs Secondary lymphoid organs directing migration of leukocytes

Blood Tissu e inflammation Cellular sources to inflammatory (1) inflammatory stimuli sites

(2) Constitutively produced in lymphoid organs Physiologic traffic of lymphocytes through the organs IL-2 a growth factor for antigen-stimulated T ly mphocytes responsible for T cell clonal expansion afte r antigen recognition

Natural Killer cells (NK cells) A type of cytotoxic lymphocytes The principal physiologic role 1. Defense against infections by viruses and some other intracelluar microbes 2. Rejection of tumors The mechanism of effector function

Perforin Granzyme 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

Examples of PAMPs PAMPs Source Principle innate immune response LPS Gram-negative bacteria

cell wall Macrophage activation 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 or glycolipid phgocytosis opsonization

complement activation Patterns recognition receptors (PRRs) Proteins expressed by cells of innate immune system Present on the cell surface, in endosomal vesicles, and in the cytoplasm The subsets of CD4+Th cells How they are induced, What cytokines they produce

What effector mechanisms they activate Development of Th1 and Th2 subsets Surface receptor 1) B cell antigen receotor (BCR) BCR/mIgM Membrane Ig (mIg) Mature B cell mIgM mIgD BCR-Ig/Ig complex

BCR-Iga/Igb complex 2. BCR coreceptor Help and strengthen the BCR-Ag-signaling 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

JBC 2004;279:31973 BCR-Iga/Igb coreceptor complex B cell epitope B cell activation TCR-CD3 BCR-Iga/b

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

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

B1 B2/FO B location mucosal sites spleen, LN Ig-producing way

naturally specificity poly-reactive highly specific Ag

TI Ag TD Ag Ag-inductive polysaccharide Ig class Ig M

IgG affinity low high Significance of humoral immunity eliminate extracellular bacterium and toxin eliminate extracellular virus

Antigen crosslinks mIg(BCR), generating signal 1, which leads to increased expression of class II MHC and costimulatory B7. AntigenBCR complexes are internalized by receptor-mediated endocytosis and degraded to peptides, which are bound by class II MHC and presented as peptideMHC complexes. Th cell recognizes Agclass II MHC and B7-CD28 co-stimulation on Bcell 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.

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 Memory B IgG) General Features and Mechanisms Immunologically specific Central tolerance: induced in generative lymphoid organs immature self-reactive lymphocyte

The repertoire The repertoire of mature of mature lymphocytes lymphocytes cannot recognize cannot ubiquitous recognize

or widely ubiquitousself disseminated orantigens widely disseminated self antigens T Lymphocyte Tolerance Central T Cell Tolerance Peripheral T cell Tolerance Burnet: Clonal selection hypothesis

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 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 tu mors of the same type. 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 nor mal cellular constituents whose expression is aberrant or dysregul ated in tumors 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.

Difference between Direct Recognition and Indi rect Recognition Direct Recognition 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 57 Classification of Allograft Rejection Host versus graft reaction (HV GR)

Conventional organ transplantati on Graft versus host reaction (GV HR) Bone marrow transplantation Immune cells transplantation 58 II.Graft versus host reaction

(GVHR) Conditions Enough immune competent cells in gra fts Immunocompromised host Histocompatability differences between host and graft 59 Hypersensitivity

Tissue injury caused by an immune response that is inadequately controlled or inappropriately targeted to host tissues Types of hypersensitivity reactions GELL AND COOMBS CLASSIFICATION Type I: Type II: Type III:

Immediate Cytotoxic Immune complex Type IV: cell mediated or delayed THANK YOU

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