Adaptive and Humoral Immunity Lecture Notes PDF

Microbiolog y Adaptive and Humoral Immunity Professor Name : Dr. Zeinab Abdel Khalek Professor title at MSA: Head of department LECTURE OUTLINE Humoral immunity Antibodies: their structures and function LECTURE ILOs Understand humoral immunity Understand the difference bet...

Microbiolog y Adaptive and Humoral Immunity Professor Name : Dr. Zeinab Abdel Khalek Professor title at MSA: Head of department LECTURE OUTLINE Humoral immunity Antibodies: their structures and function LECTURE ILOs Understand humoral immunity Understand the difference between immunoglobulins Understand Ab different fuctions Adaptive and Humoral Immunity Humoral immunity B cells markers  B-cell receptors are able to directly bind to epitopes on an antigen. T-independent (TI) antigens are usually large carbohydrate and lipid molecules with multiple, repeating subunits. B lymphocytes mount an antibody response to T-independent antigens without the requirement of interaction with effectors T4 lymphocytes. Activation of B Lymphocytes by T- Independent Antigens Antigens found outside cells of the body are called exogenous antigens. Examples include bacteria, free viruses, yeasts, protozoa, and toxins. Epitopes of these exogenous antigens bind to B-cell receptors and enter B lymphocytes through endocytosis. After lysosomes fuse with the phagosome, protein antigens are degraded by proteases into a series of peptides. These peptides eventually bind to grooves in MHC-II molecules and are transported to the surface of the B lymphocyte. Types of adaptive immunity: Extracellular pathogens RESPONDING EFFECTOR FUNCTIONS MICROBE LYMPHOCYTES MECHANISMS B Y Y Block Y Y Y invasion, Y infection and Th eliminate Y pathogens. Neutralise Extra cellular B lymphocytes Secreted toxins pathogen helped by T antibody helper cells T helper cells are activated by antigens presented by MHC class II molecules Immunoglobulins Schematic representation of some proteins of the immunoglobulin (Ig)superfamily All members of the superfamily are involved in the cellular ability to recognize other cells or foreign particles. They share a basic structural similarity in the so-called Ig domain (shown shaded in blue), indicating that the genes encoding these proteins evolved from a common ancestral gene involved in cell-to-cell recognition.  Cell surface antigen receptor on B cells Allows B cells to sense their antigenic environment Connects extracellular space with intracellular signalling machinery Secreted antibody Neutralisation - Agglutination Arming/recruiting effector cells Complement fixation - ADCC The basic unit is composed of two identical light (L) chains and two identical heavy (H) chains, which are held together by disulfide bonds to form a flexible Y shape. Each chain is composed of a variable (V).region and a constant (C) region Variable (V) and constant (C) domains within the light (L) and heavy (H) chains of an antibody, or immunoglobulin, molecule. The folded shapes of the domains are maintained by disulfide bonds (−S−S−). CH3 CH2 CH3 CH1 CH2 CH3 VH1 CH1 CH2 CH3 VH1 CH1 VL CH2 CH3 VH1 CH1 VL CL CH2 CH3 VH1 CH1 VL CL CH2 CH3  VH1 CH1 CL VL CH2 Elbow Hinge CH3 Hypervariable COMPLEMENTARITY DETERMINING REGIONS (CDRs) are located on loops at the end of the Fv regions Hypervariable regions  C1q binding motif is located on the Cg2 domain Carbohydrate is essential for complement activation Subtly different hinge regions between subclasses accounts for differing abilities to activate complement  IgM facts and figures Heavy chain: m - Mu Half-life: 5 to 10 days % of Ig in serum: 10 Serum level (mgml-1): 0.25 - 3.1 Complement activation: ++++ by classical pathway Interactions with cells: Phagocytes via C3b receptors Epithelial cells via polymeric Ig receptor Transplacental transfer: No Affinity for antigen: Monomeric IgM - low affinity - valency of 2 Pentameric IgM - high avidity - valency of 10  IgD facts and figures Heavy chain: d - Delta Half-life: 2 to 8 days % of Ig in serum: 0.2 Serum level (mgml-1): 0.03 - 0.4 Complement activation: No Interactions with cells: T cells via lectin like IgD receptor Transplacental transfer: No IgD is co-expressed with IgM on B cells due to differential RNA splicing Level of expression exceeds IgM on naïve B cells IgD plasma cells are found in the nasal mucosa - however the function of IgD in host defence is unknown  IgA dimerisation and secretion IgA is the major isotype of antibody secreted at mucosal surfaces Exists in serum as a monomer, but more usually as a J chain-linked dimer. S S S S C J C C C C ss C S S S S IgA exists in two subclasses IgA1 is mostly found in serum and made by bone marrow B cells IgA2 is mostly found in mucosal secretions, colostrum and milk and is made by B cells located in the mucosae  Secretory IgA and transcytosis ‘Stalk’ of the pIgR is degraded to release IgA containing part of the pIgR - the secretory SS SS C ss C component C C S C J C S S S SS SS SS SS C ss C C ss C C C C C J C C S S S C J C S S S S S IgA and pIgR are transported Epithelial CJC SS SS to the apical C C CssC cell surface in S S S S vesicles pIgR & IgA are Polymeric Ig receptors S S C J C C C S S internalised are expressed on the basolateral surface of C ss C SS SS epithelial cells to capture IgA produced B B cells located in the submucosa in the mucosa produce dimeric IgA  IgA facts and figures Heavy chains: a1 or a2 - Alpha 1 or 2 Half-life: IgA1 5 - 7 days IgA2 4 - 6 days Serum levels (mgml-1): IgA1 1.4 - 4.2 IgA2 0.2 - 0.5 % of Ig in serum: IgA1 11 - 14 IgA2 1 - 4 Complement activation: IgA1 - by alternative and lectin pathway IgA2 - No Interactions with cells: Epithelial cells by pIgR Phagocytes by IgA receptor Transplacental transfer: No IgA is inefficient at causing inflammation and elicits protection by excluding, binding, cross-linking microorganisms and facilitating phagocytosis  IgE facts and figures Heavy chain: e - Epsilon Half-life: 1 - 5 days Serum level (mgml-1): 0.0001 - 0.0002 % of Ig in serum: 0.004 Complement activation: No Interactions with cells: Via high affinity IgE receptors expressed by mast cells, eosinophils, basophils and Langerhans cells Via low affinity IgE receptor on B cells and monocytes Transplacental transfer: No IgE appears late in evolution in accordance with its role in protecting against parasite infections  IgG facts and figures Heavy chains: g 1 g 2 g3 g4 - Gamma 1 - 4 Half-life: IgG1 21 - 24 days IgG2 21 - 24 days IgG3 7 - 8 days IgG4 21 - 24 days Serum level (mgml-1): IgG1 5 - 12 IgG2 2-6 IgG3 0.5 - 1 IgG4 0.2 - 1 % of Ig in serum: IgG1 45 - 53 IgG2 11 - 15 IgG3 3-6 IgG4 1-4 Complement activation: IgG1 +++ IgG2 + IgG3 ++++ IgG4 No Interactions with cells: All subclasses via IgG receptors on macrophages and phagocytes Transplacental transfer: IgG1 ++ IgG2 + IgG3 ++ IgG4 ++  Comparison between primary and secondary antibody response Primary response Secondary response Induction (lag) Long (7-10 days). Short (few hours to few period: days). Antibody level: Low High (10 times greater). Duration: Short (antibodies decline Long (months). rapidly). Ig class: Predominantly IgM. Predominantly IgG. Memory cells: Absent. Present. Effector Mechanisms vs. Extracellular Pathogens & Toxins NEUTRALISATION Toxin ` Bacterium Y ` Y ` ` Y ` ` Toxin release ` Adhesion to host cells blocked blocked Y ` Prevents Prevents invasion toxicity NEUTRALISING ANTIBODIES  Monoclonal antibodies Monoclonal antibodies (McAb) come from clones of B cells that produce a single antibody of known specificity. In essence, they can be deployed to find a single targeted substance, such as an antigen found only on a cancer cell, and make it possible to pinpoint the cell and destroy it. In addition to cancer therapies, MAbs are also used in diagnostic tests for everything from pregnancy, to AIDS, to drug screening. Further, the antibodies can be used to lessen the problem of organ rejection in transplant patients and to treat viral diseases that are traditionally considered “untreatable.”  Monoclonal antibodies (continue) Monoclonal antibodies are currently utilized in many diagnostic procedures, including: measuring protein and drug levels in serum typing tissue and blood identifying infectious agents identifying clusters of differentiation for the classification and follow-up therapy of leukemias and lymphomas identifying tumor antigens and auto-antibodies identifying the specific cells involved in the immune response identifying and quantifying hormones  Monoclonal antibodies (continue) Therapeutic uses of McAb: Antitumour therapy Immunosuppressive in graft rejection ( Anti CD3 McAb) Treatment of drug toxicity, e.g. digitalis Passive immunotherapy in some viral diseases. Prevention of RH incompatibility by using McAb anti-RH. Complement Physiologically Active Split Products Membrane attacking complex (MAC) Cytolysis  Regulation of the complement system Activation of complement components tends to occurs spontaneously - especially by alternative pathway- which leads to destruction of cells to which they bind, therefore a serious of complement-regulatory proteins function to protect the body , e. g. C1 inhibitor that bind to activated C1 preventing further activation of C4 & C2 Deficiency of such regulatory proteins results in extensive Activation of complement components that leads to sever inflammation and widespread cell death.