Antibody-Cytokine- Autoimmune
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1 Antibody-Cytokine- Autoimmune Surasak Wongratanacheewin, Ph.D Dean, Graduate School, KKU Microbiology, Faculty of Medicine, KKU การอบรมหล กส ตรประกาศน ยบ ตรการข นทะเบ ยนช วว ตถ ว นท 7-11 ม นาคม 2559 ณ โรงแรมด เอมเมอร ล กร งเทพมหานคร
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3 Immunoglobulins:Structure and Function Definition: Glycoprotein molecules that are produced by plasma cells in response to an immunogen and which function as antibodies + - Amount of protein albumin globulins α 1 α 2 β γ Immune serum Ag adsorbed serum Mobility
4 Basic Immunoglobulin Structure Immunoglobulins - heterogeneous Myeloma proteins - homogeneous immunoglobulins
5 General Functions of Immunoglobulins Ag binding Can result in protection Valency Effector functions (Usually require Ag binding) Fixation of complement Binding to various cells
6 Immunoglobulin Structure Heavy & Light Chains Disulfide bonds Inter-chain Intra-chain Disulfide bond Carbohydrate C L V L C H1 C H2 C H3 V H Hinge Region
7 Immunoglobulin Structure Disulfide bond Variable & Constant Regions Carbohydrate V L & C L V H & C H C L Hinge Region V L C H1 C H2 C H3 V H Hinge Region
8 Immunoglobulin Structure Domains Disulfide bond V L & C L V H & C H1 - C H3 (or C H4 ) Carbohydrate Oligosaccharides C L V L C H1 C H2 C H3 V H Hinge Region
9 Structure of the Variable Region Hypervariable (HVR) or complimentarity determining regions (CDR) HVR3 150 Variability Index HVR1 HVR2 FR1 FR2 FR3 FR Amino acid residue Framework regions
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11 Immunoglobulin Fragments: Structure/ Function Relationships Fab Ag binding Valence = 1 Specificty determined by V H and V L Papain Fc Effector functions Fab Fc
12 Immunoglobulin Fragments: Structure/ Function Relationships Ag Binding Binding to Fc Receptors Complement Binding Site Placental Transfer
13 Immunoglobulin Fragments: Structure/ Function Relationships Fab Ag binding Fc Effector functions Pepsin F(ab ) 2 Fc Peptides F(ab ) 2
14 Human Immunoglobulin Classes IgG - Gamma (γ) heavy chains IgM - Mu (µ) heavy chains IgA - Alpha (α) heavy chains IgD - Delta (δ) heavy chains IgE - Epsilon (ε) heavy chains
15 Human Immunoglobulin Subclasses IgG Subclasses IgG1 - Gamma 1 (γ1) heavy chains IgG2 - Gamma 2 (γ2) heavy chains IgG3 - Gamma 3 (γ3) heavy chains IgG4 - Gamma 4 (γ4) heavy chains IgA subclasses IgA1 - Alpha 1 (α1) heavy chains IgA2 - Alpha 2 (α2) heavy chains
16 Human Immunoglobulin Light Chain Types Kappa (κ) Lambda (λ)
17 Human Immunoglobulin Light Chain Subtypes Lambda light chains Lambda 1 (λ1) Lambda 2 (λ2) Lambda 3 (λ3) Lambda 4 (λ4)
18 Immunoglobulins Nomenclature IgM (kappa) IgA1(lambda 2) IgG Heterogeneity
19 IgG Structure Monomer (7S) IgG1, IgG2 and IgG4 IgG3
20 IgG Structure Properties Major serum Ig Major Ig in extravascular spaces Placental transfer Does not require Ag binding (IgG2) Fixes complement (IgG4) Binds to Fc receptors (IgG2, IgG4) Phagocytes - opsonization K cells - ADCC
21 IgM Structure Pentamer (19S) Extra domain (C H4 ) J chain J Chain C:4
22 IgM Structure Properties 3rd highest serum Ig First Ig made by fetus and B cells Fixes complement
23 IgM Structure Properties 3rd highest serum Ig First Ig made by fetus and B cells Fixes complement Agglutinating Ig Binds to Fc receptors B cell surface Ig Tail Piece
24 IgA Structure Serum - monomer Secretions (siga) Dimer (11S) J chain Secretory component Secretory Piece J Chain
25 IgA Structure Properties 2nd highest serum Ig Major secretory Ig (Mucosal or Local Immunity) Tears, saliva, gastric and pulmonary secretions Does not fix complement (unless aggregated) Binds to Fc receptors on some cells
26 IgD Structure Monomer Tail piece Tail Piece
27 IgD Structure Properties 4th highest serum Ig B cell surface Ig Does not bind complement
28 IgE Structure Monomer Extra domain (C H4 ) C,4
29 IgE Structure Properties Least common serum Ig Binds to basophils and mast cells (Does not require Ag binding) Allergic reactions Parasitic infections (Helminths) Binds to Fc receptor on eosinophils Does not fix complement
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31 Monoclonal Ab for treatments THOMAS A. WALDMANN, Nature Medicine, 2003
32 What is cytokine? Cytokine are Polypeptides or glycoproteins produced in response to various antigens. Play role in innate and acquired immunity Produce from various kinds of cells such as monokine from monocytes, lymphokine from lymphocytes. Cytokine play role in chemotaxis for leukocytes is chemokine
33 Cytokine properties Based on production: Depends on Ag stimulation Short time By more than one type of cells One cytokine can stimulate or inhibit the production of other cytokines
34 Cytokine properties Based on function: Hormone like action: autocrine, paracrine, endocrine One cytokine can affect more than one types of cells Pleiotropism Different cytokines can perform some similar functions Redundancy One cytokine can influence the function(s) and/or production of other cytokines Interleukins cytokines interact between cells of the immune systems
35 Abbas et al, Cells and Molecular Immunology, 7 edition, 2012
36 Classification Based on functions, cytokines can be divided into 3 groups: I. Mediate and regulate innate immunity II. Mediateandregulate adaptiveimmunity III. Regulate hematopoiesis
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38 Cytokine in adaptive immunity Abbas et al, Cells and Molecular Immunology, 7 edition, 2012
39 Cytokine in hematopoiesis Abbas et al, Cells and Molecular Immunology, 7 edition, 2012
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41
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43 G-CSF IFN-beta
44 Autoimmune diseases Failure of immune tolerance
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46 Autoimmunity Classification Can be classified into clusters that are either organspecific or systemic
47 Causes of Autoimmunity
48 Exceptions to the Rule Simple Genetic Autoimmune Illnesses Disease Gene Mechanism APS-1 (Autoimmune polyglandular syndrome type 1) AIRE Decreased expression of selfantigens in the thymus, resulting is a defect in negative selection IPEX (Immunodysregulation, polyendocrinopathy, enteropathy, X-linked) ALPS (autoimmune lymphoproliferative syndrome ) FOXP3 FAS, FASL Decreased generation of Tregs Failure of apoptotic death of self reactive T or B cells
49 Complex Disease and Genetics There have been numerous disease associated genes or disease susceptibility genes linked to autoimmunity
50 Environment Pathogens, drugs, hormones, and toxins are just a few ways that the environment can trigger autoimmunity
51 Pathogens
52 Sex differences in autoimmunity Nature Immunology 2, (2001)
53
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