Humoral Immune Response PDF

HUMORAL IMMUNE RESPONSE by Dr. Ehab M. Fahmy Associate Professor of Medical Microbiology and Immunology Faculty of Medicine-Helwan University Objectives: - Explain clonal selection in the humoral immune response - Describe the activation of n...

HUMORAL IMMUNE RESPONSE by Dr. Ehab M. Fahmy Associate Professor of Medical Microbiology and Immunology Faculty of Medicine-Helwan University Objectives: - Explain clonal selection in the humoral immune response - Describe the activation of naïve B cells and the different types of antigens - Highlight the significance of immunoglobulin class switching - Compare and contrast primary and secondary immune responses  HUMORAL IMMUNE RESPONSE - The primary function of the humoral immune response is to eliminate extracellular pathogens, such as bacteria, and prevent the spread of intracellular pathogens, like bacteria and viruses, as they move between cells through extracellular fluids. - The response is mediated by antibodies produced by B lymphocytes and secreted by their fully differentiated plasma cells. These antibodies react specifically with the antigens that stimulated their production. Clonal selection: - During the embryonic development, a large pool of B lymphocytes are produced. - Each naïve B lymphocyte bears a single kind of receptor (BCR) which can recognize and bind to a specific antigen. - when the antigen enters the body, it selects the B lymphocyte that has the specific receptor , bind to it and stimulates its proliferation into a clone (family) of B cells. These selected B cells soon become plasma cells and secrete antibody specific for that antigen. - B lymphocytes that carry receptors for self molecules are deleted at an early stage and become absent from the pool of mature naïve B lymphocytes i.e. clonal deletion or negative selection. N.B.: The term clonal selection refers to the idea that a certain clone of B cells is selected from the pool of naïve lymphocytes. Clonal selection Steps of naïve B cell activation - Mature, naive antigen-specific B cells leave the bone marrow and migrate to peripheral lymphoid tissues, such as lymph nodes, where they encounter their specific antigens. - These antigens are recognized and bind to the B cell receptors (IgM and IgD).  To become fully activated, naïve B cell must receive two signals: 1) The first signal is triggered by the binding of an antigen to the B cell receptor (BCR). 2) The second signal, known as the co-stimulatory signal, is provided by activated helper T cells (mainly Th2). - To receive the second signal, the B cell engulfs the bound antigen, breaks it down into peptides, and presents them on its surface with class II MHC molecules. This peptide-MHC complex is recognized by antigen-specific helper T cells*, which then trigger the T cell to produce : a) CD40L, a molecule present on activated helper T cell that binds to CD40 on the B cell. b) Cytokines such as IL-4, IL-5, IL-6, and IL-10, which stimulate the B cell. N.B.: *Naïve T cell activation by B cells occurs through antigen presentation via MHC-II and co-stimulation, where CD28 on the T cell binds to B7 on the B cell). - After receiving both necessary signals, the B cell will undergoes activation , proliferation and differentiation to effector plasma cell secreting antibodies specific to the antigen. - Initially IgM is secreted, but later the B cell can switch to producing a different antibody isotype with the same antigenic specificity. - Some activated B- lymphocytes form memory cells, which are long-lived and can be rapidly activated upon re-exposure to the antigen. This explains the rapid appearance of antibody during the secondary immune response and the long lasting immunity following certain infections such as measles and poliomyelitis. - Most antigens require this form of B cell – T cell interaction to initiate an immune response and are, therefore, termed thymus-dependent (TD) antigens. Activation of B cell  Thymus independent antigens (TI): - Non- peptide antigens activate B cells directly without T cell cooperation. In such cases, B cell activation is delivered by the antigen only. - They are usually large polymers composed of repeated epitopes such as capsular polysaccharide. The repeating epitopes cross-link BCRs resulting in B-cell activation. - TI responses provide an early and specific antibody response against many important bacterial pathogens without the need for T cell activation. - Because there is no T cell help, only IgM is produced and the B cell cannot switch to production of other isotypes. In addition, memory cells are not produced.  Thymus-Dependent (TD) Antigen Thymus-Independent (TI) Antigen Requires T cell help YES NO B cells are activated via T-B cell B cells are directly activated by the B Cell Activation interaction antigen Can induce class switching to IgG, Antibody Class Switching No class switching (mainly IgM) IgA, IgE Memory B Cell Strong memory B cell response absent memory B cell response Typically non-peptide large Typically proteins e.g. bacterial Antigen polymer with repeated epitopes toxin e.g. capsular polysaccharides Immunoglobulin Class Switching (Isotype Switching): - During an immune response, plasma cells switch from producing IgM to producing IgG or other immunoglobulin classes. - Class switching occurs through DNA rearrangement and RNA splicing of the relevant gene, resulting in changes in the constant domains of the heavy chain (CH). The light chain and the variable domain of the heavy chain (VH) remain unchanged, meaning the immunoglobulin produced later (IgG, IgA, or IgE) retains the same antigen specificity as the original IgM but differs in biological characteristics. - Class switching requires interaction between CD40 on B cells and CD40L on T cells. Cytokines released by T cells determine the isotype of antibody produced e.g. IL-4enhances IgE production. TGF-β encourages cells to switch their Ig class to IgA, and then IL-5 augments IgA production by these cells. High levels of IgG secretion occur under the combined effects of IL-4, IL-5, and IL-6. Primary and Secondary Antibody Response Primary immune response - When the body encounters an antigen for the first time, the primary antibody response occurs. During this initial exposure, there is a lag or induction period of about 7-10 days where antibodies are undetectable. -This delay is due to the time needed for B cells to activate, proliferate, and differentiate into plasma cells, which begin secreting antibodies. -The primary antibody produced is mainly IgM, which peaks in concentration within 1-2 weeks before declining rapidly to undetectable levels. Secondary immune response - In contrast, the secondary antibody response happens upon re-exposure to the same antigen, ( weeks, months, or even years later). Because memory cells were generated during the primary response, the immune system reacts much faster, with antibodies detectable within hours rather than days. - IgG is the main isotype produced. It appears in much higher concentrations—about 10 times greater than in the primary response. when antigens enter the body via mucosal routes (oral or inhaled), IgA is predominantly produced, offering protection at these entry points. - These antibodies have a higher affinity for the antigen and persist for longer periods, sometimes months or even years, ensuring long-term immunity. - This response can be boosted to higher levels by further exposure to the antigen. Therefore, most vaccines are given in more than one dose (booster doses) Primary and secondary immune response  Primary Immune Response Secondary Immune Response Antigen Exposure Subsequent exposures to the same First exposure to an antigen antigen Lag/Induction Period 7-10 days A few hours to a day predominantly IgG ( sometimes IgA Main Antibody Produced Predominantly IgM or IgE ) Antibody level (peak response) Low High (10 times higher) Antibody Affinity Lower Higher Duration of Antibody Short (antibody decline rapidly) Long ( months or years) Responding B cell Naïve B cell Memory B cell Inducing agent All immunogens protein antigen only