humoral immune response_٠٩٥٢٥٨.pdf

Humoral Immune Responses Omer Abd Allah Osman MSc molecular medicine IEND ,University of Khartoum  Humoral immunity is responsible for neutralizing and eliminating extracellular microbes and microbial toxins. B cell recognize and respond to many types of antigen e.g: Polys...

Humoral Immune Responses Omer Abd Allah Osman MSc molecular medicine IEND ,University of Khartoum  Humoral immunity is responsible for neutralizing and eliminating extracellular microbes and microbial toxins. B cell recognize and respond to many types of antigen e.g: Polysaccharides Lipids Proteins Nucleic acid Phases and types of humoral immune response Naïve B lymphocytes express two membrane bound Ig (antigen receptors). The activation results in: Clonal expansion Differentiation into effector plasma cells Memory cells Secreted antibodies are of the same specificity as membrane bound receptor.  During their differentiation some B cell begin to secrete antibody of different heavy chain class, this process called heavy chain class switching. Repeated exposure to protein antigen results in production of antibodies with increasing affinity for antigen, this process called (affinity maturation)  Antibody response to antigen classified as: I. T-dependent (protein antigen) II. T-independent (non protein antigen) Classification based on requirement of T cell help. T cell help involved in class switching and affinity maturation in protein antigen response. Non protein antigen needs relatively little class switching and affinity maturation.  Antibody response to first exposure is called primary immunes response. Antibody response to second exposure is called secondary immunes response.  Stimulation of B lymphocytes by antigen Humoral immune response initiated when B cell recognize antigen by its membrane bound Ig receptor without need of processing(first signal). 1st signal is provided by BCR complex. The second signal is produced during innate immune response.  Role of complement proteins in B cell activation B lymphocyte express receptors for complement protein called type 2 complement receptor (CR2, or CD21) which bind C3b. As a result of complement activation microbe will be coated by C3b. B cell specific for antigen recognize antigen by Ig receptor(1st signal) and simultaneously recognize C3b by CR2 receptor(2nd signal). Engagement of C3b and CR2 enhance antigen- dependent activation of B cell.  When B lymphocyte activated it will: Enter the cell cycle, resulting in expansion of antigen-specific clones. Begin to produce some IgM in secreted form. Prepare B cell to interact with helper T lymphocyte. The early phase of humoral immune response is induced by antigen stimulation. Multivalent antigens great the response because it cross-link many antigen receptors.  Polysaccharides and other T-independent are multivalent so they are capable for cross-link many receptors. Soluble protein antigen are not multivalent so they are incapable to cross-link many receptors on B cell for that it can stimulate weak response without co stimulators. To produce functioning response to Protein antigen, B cell should prepare to interact with helper T cell. How B cell prepare to interact with helper T cell? 1. B cell activation leads to expression of CD40 and B7 the co stimulators which provide second signal. 2. Expression of receptors for cytokine that will produced by T cell.  The function of helper T cell in humoral immune response to protein Ags To stimulate antibody response to protein antigen,B cell and T cell specific for that antigen should come together in lymphoid organ and stimulate B cell proliferation and differentiation.  Antigen presentation by B lymphocyte Antigen bound by membrane Ig(BCR) undergo: Endocytosis Delivered to intracellular endosomal vesicle Processed into peptides Bound with class II MHC Presented to helper T cell  Antigen-activated B cell express co stimulators such as B7 molecule which stimulate T cell that recognize the antigen presented by the B cell.  How helper T cell activates B lymphocytes? The process of helper T cell-mediated B lymphocytes activation is resemble that of T cell mediated-macrophage activation in CMI. CD40L on activated T cell bind CD40 on B cell.  Binding of CD40L and CD40 stimulate: I. Clonal expansion II. Synthesis and secretion of antibodies III. Increase expression of T cell cytokine receptors IV. Heavy chain class switching V. Affinity maturation  Heavy chain class(isotype) switching Membrane bound Ig of B cell is of IgM&IgD class. The best opsonizing Ig class for viruses,bacteria and protozoa is IgG1&IgG3 because they have high-affinity Fc receptors specific for γ heavy chain on phagocytic cells.  Helminthes are best eliminated by eosinophil- based CMI, this type of CMI involve coating parasite with IgE antibody. Eosinophil has high-affinity receptors for Fc potion of IgE heavy chain. Heavy chain class switching enable immune system to make different antibody isotype to different microbes.  Class switching is initiated by CD40L-mediated signal and in its absence activated B cell express only IgM and fail to switch to another isotype. Class switching in activated B cell is directed by cytokines.  The opsonizing antibodies (IgG) which bind to phagocyte Fc receptors is stimulated by INFγ which is produced by TH1 cell to activate macrophage. Switching to IgE class is stimulated by IL-4 which produced by TH2 in case of helminthic infections. IgE act with eosinophil, which activated by 1L-5 to eradicate helminthic infection.  Affinity maturation Affinity maturation is the process that leads to increased affinity of antibodies for a particular antigen. as a T-dependent humoral response progresses.  Antibody Responses to T-independent Antigen The most important TI antigens are polysaccharides, glycolipids, and nucleic acids. These antigens cannot be recognized by CD4+ helper T cells. Most TI antigens are multivalent(composed of repeated identical antigenic epitopes).  Such multivalent antigens may induce maximal cross-linking of the BCR complex leading to activation without a requirement for T cell help.  Regulation of humoral immune response Antibody feedback: It is a mechanism by which humoral immune responses are down regulated when enough antibody has been produced and soluble antibody-antigen complexes are present. B cell membrane Ig and the receptor on B cells for the Fc portions of IgG, called FcγRIIB, are clustered together by antibody-antigen complexes.  This activates an inhibitory signaling cascade through the cytoplasmic tail of FcγRIIB that terminates the activation of the B cell.  References Cellular and molecular immunology Basic immunology Lippincott's immunology