Basic Immunology (Lecture 6) PDF

Microbiology and Immunology Unit BASIC IMMUNOLOGY (LECTURE-6) Innate & Adaptive Immune response (III) (B cell activation, Immunoglobulins, Complement System) Dr. Rasha Mokhtar Elnagar Associate Profes...

Microbiology and Immunology Unit BASIC IMMUNOLOGY (LECTURE-6) Innate & Adaptive Immune response (III) (B cell activation, Immunoglobulins, Complement System) Dr. Rasha Mokhtar Elnagar Associate Professor of Medical Microbiology & Immunology Consultant Microbiology & Immunology 2. B Cell Activation ( Humoral immunity) 1. T-independent activation  Activation of B cells without help from T helper cell:  Polysaccharide bind to BCR (surface IgD & IgM) on B cell surface.  Complement receptor (CD 21, CD 35).  Clinical application: Capsular polysaccharide of Haemophilus influenzae B. 2. T-dependent activation In T-cell-dependent (TD) B cell activation, B cells binds to the antigen using B cell receptors (surface IgD & IgM). The B cell present the antigen with MHC II complex to activate the CD4 T cells. CD80/86 molecule on B cells also bind with CD28 on T helper 2 cell. CD40 molecule on B cells bind with (CD40L) on T helper 2 cell. T-dependent activation Antigen presentation - T helper 2 cell produces IL-4, IL-5, IL-6 & IL13 → B cells proliferate and differentiate into B memory cells and plasma cells which produce and secrete IgM (1ry immune response). - On re-exposure memory B cells are rapidly stimulated and differentiated into plasma cell producing larger amount of IgM, IgG, IgA (2nd immune response).  Primary & Secondary Immune Response 1ry immune 2nd immune response response Ag exposure 1st time 2nd, 3rd, 4th, …. Time Ag dose High dose Low dose Ig isotype Mainly IgM IgM, IgG, IgA Onset Delayed Rapid Duration of Short Long response  Cytokines and Immune cells interaction: N IL-4, IL-5, IL-10, IL-13 IL-2, IL-12, INFγ -Macrophages - B cell, Immunoglobulin - CD8 T cytotoxic - Extracellular pathogens (humoral mediated - Intracellular pathogens (cell mediated immunity) immunity)  Control of Immune Response: - T regulatory (CD4+CD25+) cells produce IL-10 & TGF-β inhibiting over activity of B and T Lymphocytes after elimination of the Ag to prevent tissue damage.  Immunoglobulins (Ig) (Antibodies) (Ab) Types and Effector functions Immunoglobulins (Ig): Glycoproteins. Mediate the humoral or antibody-mediated immunity. Produced by Plasma cells. Immunoglobulins are produced in 2 forms:  Membrane-bound immunoglobulins (IgM & IgD): on B lymphocytes (BCR).  Secreted immunoglobulins. There are five classes of Immunoglobulins: - Three major classes ( IgG, IgM, IgA). - Two minor classes (IgD and IgE).  Basic structure of Immunoglobulin: N Four polypeptide chains bounded together by disulfide bonds form Y-shaped molecule Two identical light (L) chains: (kappa and lambda).  Antibody carry one type of light chain (either two κ light chains or two λ light chains but never one of each).  A light chain is made up of one V domain (VL) and one C domain (CL). Two identical heavy chains (H)  A heavy chain has one V domain (VH) and 3 or 4 C domains (CH1, CH 2, CH3& CH4).  Heavy chains: o IgA contain α heavy chain (alpha). o IgD contain δ heavy chain (delta). o IgE contain ε heavy chain (epsilon). o IgG contain γ heavy chain (gamma). o IgM contain μ heavy chain (mu)  The VL & VH domains form a pocket that constitutes the antigen binding site. Functions of different Immunoglobulin isotypes: 1. Block binding of microbe or toxins to cells. 2. Opsonization and phagocytosis. 3. Antibody-dependent cellular cytotoxicity (ADCC). 4. Activation of the classical pathway of complement by IgG and IgM (Classical pathway).  Serum conc. Classes Subclasses H chain (mg/ml) Secreted form Functions None μ +++ Pentamer 1. Naïve BCR IgM 2. 1ry immune response 3. Complement activation IgA IgA1 α1 ++++ Dimer Mucosal associated lymphoid IgA2 α2 tissue (MALT) (Saliva, tears, intestinal mucus, bronchial secretions, milk, prostatic fluid) IgG IgG1 γ1 Highest Monomer 1.Opsonization Cross placenta IgG2 γ2 to fetus 2.Complement activation IgG3 γ3 Cross blood 3.ADCC brain barrier IgG4 γ4 4. 2ry immune response IgE None ε Trace Monomer 1.Defense against parasites 2.Immediate hypersensitivity IgD None δ Trace None Naïve (BCR) Complement System: -Circulating and membrane-associated proteins that function in both the innate and adaptive immune response. - These proteins are synthesized in the liver, and present in an inactive form in the serum. - Components include: C1 to C9 and factors B, D & P. Complement Pathways: 1- Classical pathway (In adaptive immune system): Activated by antigen-antibody complexes (IgM & IgG). 2- Mannan-binding lectin pathway (In innate immunity): MBL are serum proteins bind to specific mannose residues on microbes and activate two MBL-activated serine proteases (MASP1 & MASP2). 3- Alternative pathway (In innate immunity): Bacterial endotoxin ‘LPS’ directly produce spontaneous breakdown of C3 (C3a & C3b).  Functions of The Complement 1. Complement-mediated lysis: the membrane attack complex (MAC) creates pores in cell membranes and induce osmotic lysis of the cells. 2. Opsonization and phagocytosis: (C3b or C4b) act as opsonins; by binding to microbes enhance their phagocytosis. 3. Mediators of inflammations and chemo-attractants to phagocytes: (C3a, C4a, C5a).  CYTOKINE USE IL-2 Renal cell cancer & metastatic Clinical uses of cytokines: melanoma IL-11 Thrombopoietin Treatment of thrombocytopenia G-CSF GM-CSF Bone marrow recovery from inhibition Erythropoietin Anemia with renal failure Link: https://next.amboss.com/us/article/4p03pS?q=Recombinant %20cytokines#Y9be3335096ffb8d89be9e23943255ced SDL: Therapeutic use of: Interferon alpha (IFN-α) Interferon beta (IFN-β) Interferon gamma (IFN-γ)  Study Questions 1- The classical complement pathway is initiated by: A. Stimulation of killer activation receptors on NK cells B. Secretion of interferons by virally infected host cells C. The formation of antigen - antibody complex D. Mannose residues on certain microbes 2- The alternative complement pathway is initiated by: A. MBL bind to mannose residues on microbes B. Stimulation of killer activation receptors on NK cells C. The formation of antibody-antigen complexes D. Lipopolysaccarides (LPS) of Gram negative bacteria Reference: Lippincott® Illustrated Reviews: Immunology, 3rd Edition