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Transcript
The Adaptive Immune Response Chapter 16 Note: In this class, antibody and immunoglobulin are synonymous The Adaptive Response is Slow to Start During childhood, billions of T cells and B cells (lymphocytes) are generated, but only a few of these can recognize a given species of pathogen When these cells recognized the particular pathogen, they begin to rapidly divide that results in a dramatic increase of pathogen-specific cells over several days - termed clonal expansion A single lymphocyte can divide in about 8 hours (3 divisions/day) In 5 days, 215 divisions occur, resulting in 32,768 cells During these first few days of infection, the pathogen can cause substantial pathology to the individual If the pathology is severe enough, it can cause the death of the individual Because of this delay, it is critical that the innate immune response immediately engage the pathogen and delay its actions long enough for the adaptive response to join the battle 16.1 Strategy of the Adaptive Immune Response All microbial components are potential antigens for the immune response Antigens are any molecules that can elicit an immune response Primary Immune Response The first exposure to an infectious agent Slow to start Often with pathology Secondary Immune Response Any additional exposures to the pathogen Very quick to respond - usually without symptoms 16.1 Strategy of the Adaptive Immune Response The Two Adaptive Immune Responses Type I immunity (formerly cell-mediated immunity) Type II immunity (formerly humoral or antibody immunity) These responses are often mutually exclusive Immunity Innate Adaptive Type I Type II 16.1 Strategy of the Adaptive Immune Response Overview of Humoral (Type II) Immunity B cells are covered with thousands of copies of a membranebound immunoglobulin, termed B cell receptor (BCR) or surface Ig (sIg) The immunoglobulin is specific for a particular molecule from a particular species of pathogen If the pathogen enters the body, then this cell will bind to it (or its products) by virtue of its BCR This results in the activation and maturation of the B cell into a plasma cell, which then begins to secrete soluble versions of its immunoglobulin These antibodies can circulate in blood and lymph for years If they bind to the antigen, they target it for destruction 16.1 Strategy of the Adaptive Immune Response Overview of Cellular (Type I) Immunity Subsets of T cells Helper T (Th) cells Secretes cytokines that mediate local immune responses Augment activities of the innate response Are the “generals” of the immune response Cytotoxic T (Tc) cells Physically interact with cells harboring a pathogen (such as a virus) and kills the cell Are the “special forces” of the immune response Regulatory T (Treg) cells Suppress inflammation as the immune response wanes 16.2 Anatomy of the Lymphoid System Lymphatic vessels contain lymph Secondary lymphoid organs are where immune cells gather to coordinate their activities Lymph nodes Spleen Peyer’s patches (large intestine) Many others Primary lymphoid organs are where immune cells develop from stem cells Bone marrow 16.3 The Nature of Antigens Antigen composition Protein Lipids linked to other macromolecules Carbohydrates linked to other macromolecules A microbe usually has tens to thousands of antigenic determinants (aka, epitopes) that can be recognized by the immune system 16.4 The Nature of Antibodies Antibodies are glycoproteins (carbohydrates and polypeptides) Structure and Properties Two arms that compose the Fab (fraction antibody) region that bind to antigenic determinants (the “business end”) Antibodies are divalent One stem (Fc - fraction crystalizable) that can bind to phagocyte receptors or complement proteins 16.4 The Nature of Each antibody is composed of Antibodies Two identical light (L) polypeptide chains Two identical heavy (H) polypeptide chains These polypeptides have intrachain and interchain disulfide bonds (covalent) that hold the chains together and maintain the antibody’s 3D shape There are 5 antibody classes based upon the H chains IgG IgM IgE IgA The class of the antibody dictates its biological functions 16.4 The Nature of Antibodies The variable regions of H and L chains dictate binding to the antigen The constant regions of H and L chains determine the 3D structure and the biological activities of the antibody 16.4 The Nature of Antibodies Protective Outcomes of Antigen-Antibody (Ag:Ab) Binding Antibodies bind to antigens with noncovalent interactions Early in the adaptive response, antibody affinity is weak, while late in the response it is very strong Effects of antibody binding to antigen Neutralization - blocks the biologically-relevant portion of an antigen, rendering it inactive Immobilization and preventing adherence Agglutination and precipitation Opsinization facilitates phagocytosis Complement system activation Antibody-dependent cell cytotoxicity (ADCC) 16.4 The Nature of Antibodies • Immunoglobulin classes • IgM •IgG • First secreted antibody • •High affinity Exists as a pentamer (valency of 10) •Several subclasses Efficient at complement •Some are efficient complement fixation fixers Primary antibody against LPS •Others mediate ADCC Low affinity, but high avidity •Some cross the placenta and are in breast milk (colostrum) • Avidity is the collective strength of interaction • • • •Most common Ab in serum 16.4 The Nature of Antibodies Immunoglobulin classes IgA Most abundant Ab Exists as monomers (blood/tissues) and dimers (secreted) Breast milk The J chain holds two IgA Ab together to form the dimer and provides protection from digestive enzymes •IgD •Usually expressed as BCR •No known functional role •IgE •Only small amounts are produced •Efficient at inducing degranulation of granulocytes •May be protective against helminths •Associated with allergies 16.5 Clonal Selection and Expansion of Lymphocytes Clonal selection theory states that antigens select T and B cells for expansion The presence of antigen stimulates the naive T and B lymphocytes into mitosis and differentiation that leads to a large pool of antigen-specific effector lymphocytes As the infection is cleared, antigen becomes limiting and most of the responding lymphocytes die (99% or more) The remaining lymphocytes serve as memory cells, poised to engage the pathogen should it recur 16.6 B Lymphocytes and the Antibody Response Antigens recognized by B cells T-independent (do not require T cell help) Non-proteinaceous (e.g., LPS) Cannot class-switch from IgM to others Do not induce durable immunity T-dependent (requires T cell help) Proteins Class switching to IgG, IgA, IgE Usually provide long-term immunity B cell activation to protein antigen A B cell has thousands of identical BCR molecules protruding from its surface These BCR have identical specificity (clonotypic) because they have the exact same amino acid sequences If a protein antigen is bound by these BCR, it is internalized The internalized antigen is fragmented into peptides of 10-15 amino acids The peptides are assembled on MHC class II proteins, which are then presented on the B cell surface A helper T cell that recognizes the peptide engages the B cell to activate it by: Releasing cytokines (noncognate signals) Cognate (physical) interactions with the B cell The B cell begins secreting antibodies (which are soluble versions of the BCR) 16.6 B Lymphocytes and the Antibody Characteristics of the primary B Response cell response Class-switching to other isotypes Affinity maturation by programmed mutation of antibody variable genes Most mutations result lower or no change in affinity of BCR Some result in higher affinity BCR and these out compete B cells with lower affinity Generation of memory B cells These three events require T 16.6 B Lymphocytes and the Antibody Response Characteristics of the secondary B cell response The memory cells, which can number in the tens of thousands, are capable of rapid response to recurrent infections They do not have to undergo class-switching They do not have to undergo affinity maturation They undergo clonal expansion again This occurs so rapidly, symptoms of illness are rare 16.6 B Lymphocytes and the Antibody Response The response to T-independent antigens Reliant upon repetitive motifs of the antigen on the surface of the microbe Results in cross-linking multiple BCR This causes B cell activation and secretion of soluble antibody (IgM only) 16.7 T Lymphocytes: Antigen Recognition and Response General characteristics of T cells Possess a clonotypic T cell receptor (TCR) The TCR is virtually identical to one Fab antibody arm Recognize antigenic peptide fragments of microbial proteins The peptide fragments must be bound to a major histocompatibility complex (MHC) molecule MHC class I molecules are for presenting peptide antigens from intracellular microbes (i.e., infected cell) and target those cells for destruction by Tc cells MHC class II molecules are for presenting peptide antigens from extracellular microbes (i.e., NOT infected cell) and presenting those peptides to Th cells, which secrete cytokines that mediate the local immune response 16.7 T Lymphocytes: Antigen Recognition and Response The MHC I pathway targets a cell for destruction Intracellular pathogens use cellular ribosomes to synthesize their proteins Some of these proteins are fragmented and inserted into the lumen of the ER MHC I proteins bind to the peptides and then are displayed on the cell’s surface CD8+ Tc cells recognize these microbial peptides and kill the cell Puncturing holes in the membrane with perforin Inducing a death signal that causes DNA fragmentation The MHC II pathway is for activating Th cells that secrete cytokines to mediate immune responses during infections Only professional antigen presenting cells (APC), such as macrophages, dendritic cells, and B cells, participate in this pathway They capture extracellular antigens and internalize them B cells use their BCR Macrophages use phagocytosis Dendritic cells use pinocytosis The antigens are fragmented into peptides phagolysosomes that possess MHC II proteins, which bind to the peptides The MHC II:peptide complex is displayed on the cell surface CD4+ Th cells recognize the peptide and respond by making cytokines 16.7 T Lymphocytes: Antigen Recognition and Response Subsets of CD4+ Th cells Th1 cells secrete inflammatory cytokines Th2 cells secrete cytokines that augment B cell responses Treg (regulatory) cells secrete antiinflammatory cytokines The responding subset can determine susceptibility or resistance to a pathogen