Lecture 19 v2.pdf

BIOL371: Microbiology Lecture 19 – Adaptive immunity: highly specific host defense 1 Topics of today 1. 2. 3. 4. Principles of adaptive immunity Antibodies The Major Histocompatibility Complex T cells and their receptors Materials covered:  Chapter 27.1-27.8  Figures 27.1-27.13, 27.17, 27.19...

BIOL371: Microbiology Lecture 19 – Adaptive immunity: highly specific host defense 1 Topics of today 1. 2. 3. 4. Principles of adaptive immunity Antibodies The Major Histocompatibility Complex T cells and their receptors Materials covered:  Chapter 27.1-27.8  Figures 27.1-27.13, 27.17, 27.19-27.22  Table 27.1 2 Principles of adaptive immunity 1. Specificity, memory, selective processes, and tolerance 2. Immunogens and classes of immunity 3 Adaptive immunity  Innate immunity: broadly targeted responses triggered by common structural features on microorganisms  Adaptive immunity: directed toward specific molecular components of the microbes mediated by a special class of antigen-reactive leukocytes called lymphocytes  B lymphocytes: produce antibodies that interact and protect against extracellular antigens  Conferring antibody-mediated immunity to the host  T lymphocytes (T cells): display antigen-specific receptors on their surface that defend against intracellular pathogens, such as viruses and some bacteria  Conferring cellular immunity to the host 4 Specificity  Specificity: dependent on lymphocyte receptors interacting with individual antigen (from pathogen)  T lymphocytes (T cells) display antigen-specific receptors call T cell receptors  B lymphocytes display membrane-bound immunoglobulins on their surface 5 Memory  Memory: the first antigen exposure induces multiplication of antigen-reactive cells, resulting in multiple clones. Subsequent exposures to the same antigen result in rapid production of large quantities of antigen-reactive T cells or antibodies 6 Primary and secondary immune responses  Primary immune response: first exposure to an antigen in which antigen recognition by specific B or T lymphocytes leads to B and T cell activation, proliferation, and differentiation  Secondary immune response: subsequent exposure to the same antigen activates clones from the primary immune response to generate stronger and faster response  Vaccination with killed or weakened pathogens, or their products, is a means of conferring immunity 7 T cell selection and tolerance  Tolerance: the acquired ability to make an adaptive response to discriminate between host (self) and foreign (nonself) antigens  Failure to develop tolerance may result in reactions against self, called autoimmunity 8 T cell selection and tolerance  Tolerance: Precursor T cells travel from the bone marrow to the thymus, where they mature and are put under both positive and negative selective pressure  Positive selection – T cells that recognize MHC peptides are retained  Negative selection – T cells that pass the positive selection and strongly bind to self-antigens are selected against  Clonal deletions – more than 99 percent of T cells that enter the thymus do not survive the selection process; remaining T cells react strongly with foreign antigens 9 B cell selection and tolerance  To respond to the nearly infinite variety of environmental antigens, the immune system produces an enormous diversity of antigen-reactive B cells  Positive B cell selection occurs when the B cell receptors encounter an antigen that they recognize. Upon recognition the B cells  Proliferate, make more copies  Differentiate into antibody-producing plasma cells (many) and memory cells (few)  Negative B cell selection occurs in the bone marrow, where self-reactive B cells are deleted (clonal deletion), or silenced because they lack a T cell help signal 10 Antigens and immunogens  Antigens: substances that react with antibodies or T cell receptors  Immunogens: substances that elicit an immune response; not all antigens are immunogens  Intrinsic factors that determine immunogenicity include  Size: haptens, which are small molecules, are not immunogens but they may induce an immune response if attached to a larger carrier molecule  Complexity: complex proteins and carbohydrates are good immunogens, while molecules with simple repeating units (e.g., DNA) are poor immunogens  Physical form: insoluble molecules or aggregates are usually excellent immunogens  Extrinsic factors that determine immunogenicity include  Dose: (micrograms to a gram)  Route: (injection is more effective than oral exposure)  A large, oral dose of an immunogen may induce tolerance rather than immunity 11 Antigens and epitope for antibodies  Antibodies do not interact with an entire antigen, but only with a distinct portion of the molecule called an antigenic determinant or epitope  May include sugars, short peptides of four to six amino acids, and other organic molecules that are components of a larger immunogen  T cell receptors recognize epitope only after the antigen has been processed (partially degraded), example by antigen-presenting cells Antigens typically contain several different epitopes, each capable of reacting with a different antibody 12 Examples of active and passive immunity 13 Active and passive immunity Active immunity Passive immunity Exposure to antigen; immunity achieved by purposely administering antigen or through infection No exposure to antigen; immunity achieved by injecting antibodies or antigen-reactive T cells Specific immune response made by individual achieving immunity Specific immune response made by the donor of antibodies or T cells Activated by antigen; immune memory in effect No immune system activation; no immune memory Maintained via stimulation of memory cells (i.e., booster immunization) Cannot be maintained and decays rapidly Develops over a period of weeks Develops immediately 14 Antibodies 1. Antibody production and diversity 2. Antigen binding and the genetics of antibody diversity 15 B lymphocytes and antibodies  B lymphocyte (B cell): each B cell has ~100,000 identical antibodies on its surface called B cell receptors  The B cell receptors bind to antigen (pathogen), internalize, and digest it  The pathogen-derived peptides are affixed to Major Histocompatibility Complex II proteins and display on the surface of the B cell (antigen-presenting cell)  The antigen-presenting B cell interacts with an antigen-specific T cell, T helper cell  T helper cell secrets cytokines to activate the B cell to produce clones that differentiate into plasma cells (producing antibodies) and memory cells B cells interact with antigen and T helper (Th) cells to produce antibodies 16 Antibody function  Antibodies (or immunoglobulins, Igs): either soluble or cell surface antigen receptors  Can bind to toxins or viruses to neutralize them  Can bind to foreign cells and make them easier to engulf by phagocytes 17 Structure and function of immunoglobulin G (IgG)  Five major classes of antibodies: IgG, IgA, IgM, IgD, and IgE  Defined by differences in amino acid sequence of their heavy chain  They are different structural features, expression patterns, and functional roles  IgG is the most common antibody circulating in the body  Four polypeptide chains: two heavy and two light chains  The constant domain is identical for all IgG  The Fc stem binds receptors on phagocytes to facilitate phagocytosis  The variable domains bind antigen The two heavy and two light chains are held together covalently by disulfide bond. One heavy and one light chain interact to form an antigen-binding unit. Therefore each IgG molecule has two antigen-binding sites. Billions of different antigen-binding sites for different antigens. 18 IgM, IgA, IgE, and IgD IgM: an aggregate of five immunoglobulin molecules IgA: dimers; present in body fluids such as saliva, tears, breast milk IgE: found in serum and functions as an antibody that binds to eosinophils IgD: present in serum and has no known function 19 Primary and secondary antibody responses in serum  Primary antibody response: produces short-lived plasma cells that live for less than a week; mostly IgM  Secondary antibody responses (subsequent exposures): response quicker  Memory cells do not need T cell help  Produces 10-100 times more antibodies, mostly IgG 20 Antigen binding by immunoglobulin  Variable domains and antigen-antibody interaction  Variable domains of different antibodies are different from one another, especially in complementarity-determining regions (CDRs)  The antigen-binding site of an antibody is large enough to accommodate the binding of an epitope with both the heavy and light chain variable regions  Binding is a function of the folding pattern of the heavy and light polypeptide chain  Different antibodies bind their epitopes with different strengths, called binding affinities The three CRDs provide most of the molecular contacts with antigen 21 Mechanisms of generating antibody diversity  The immune system must be able to generate an almost unlimited antibody variation  How can this be done with limited number of genes encoding immunoglobulins in the genome?  Multiple unusual mechanisms at play:  Somatic recombination  Random heavy and light chain reassortment  Coding for joint diversity  Hypermutation 22 Gene rearrangement by somatic recombination  The gene encoding each immunoglobulin is constructed from several immunoglobulin gene segments  As each B cell matures, immunoglobulin gene segments undergo random rearrangements by recombination and deletion of intervening segments  Once one antibody rearrangement is successful, the process stops  Allelic exclusion: only the rearranged allele is expressed so that each B cell produces only one antibody 23 Reassortment and hypermutation  Reassortment of heavy and light chains  Two different light chains: kappa and lambda  The five heavy chains (five classes of immunoglobulins) can join with either the kappa or lambda light chain to form antibody  Based on the number of gene segments, gene rearrangement and reassortment can generate >3.3 million possible antibodies  Somatic hypermutation: mutation rate of B cell immunoglobulin genes is higher than other genes  Occurs only in the V regions of heavy and light chains, creating slightly altered Ig cell surface receptors with changing binding affinities for the antigen  Affinity maturation: B cells with receptors displaying higher affinity for the antigen are selected  The strengthening of antibody binding is responsible for the dramatically stronger secondary immune response 24 Imprecise VDJ joining in generating antibody diversity  The recombination of the gene segments between V-D and D-J is imprecise  Can vary by several nucleotides  Change the amino acid sequence 25 Major Histocompatibility Complex  MHC Class I proteins: found on surface of all nucleated cells  Present internal antigens to T-cytotoxic cells  Internal (cytoplasmic) antigens can originate from viral proteins or cancer proteins  If the peptide presented by MHC Class I is recognized by the T cell receptor of a Tcytotoxic cell, the antigen-containing cell is destroyed  MHC Class I proteins are the major antigen barriers for tissue transplant  MHC Class II proteins: found only on the surface of antigen-presenting cells (B lymphocytes, macrophages, and dendritic cells)  Present antigens to T-helper cells  Stimulate cytokine production and lead to antibody-mediated immunity or inflammatory responses  Based on the peptides (self or foreign) presented by MHC proteins, the immune system distinguishes cells with foreign antigens from cells with self antigens 26 Antigen presentation by MHC I proteins  Protein antigens, such as virus components manufactured within the cell, are degraded by the proteasome in the cytoplasm  The peptide fragments are transported into the endoplasmic reticulum through a pore formed by the TAP (transporter associated with antigen processing) proteins  MHC I proteins in the endoplasmic reticulum are stabilized by chaperonins until peptide fragments are bound  When peptide fragments are bound by MHC I, the complex is transported to the cell surface  The MHC I-peptide complex interacts with T cell receptors (CD8) on the surface of T-cytotoxic cells  The T-cytotoxic cell is activated by the binding events, causing it to release cytokines and cytolytic toxins and kill the target cell 27 Antigen presentation by MHC II proteins  External foreign proteins are imported into the cell and digested into peptide fragments in phagolysosomes  MHC II protein bind the foreign peptide fragments  The MHC II-peptide complex is transported to the cell surface, where it interacts with T cell receptors (CD4) on T-helper cells  The T-helper cells then release cytokines that interact with other cells to promote an immune response  Note that the antigen-presenting cell in this pathway can be either a B lymphocyte, which ingests antigen by endocytosis, or a macrophage or dendritic cell, which engulf antigens through phagocytosis 28 T cells and their receptors 1. T cell receptors: proteins, genes, and diversity 2. T cell subsets and their functions 29 T cell-mediated immunity  Antigen-presenting cells, such as the phagocytes in innate immunity, ingest, degrade, and process antigens  They then present antigens to T cells that secrete protein cytokines that activate the adaptive immune response  T-helper cells produce and release cytokine that induce inflammation  T-cytotoxic cells produce and release perforin and granzyme for target cell lysis  T cells do not interact with a foreign antigen unless it is presented in the context of an MHC  T cell receptors of a given T cell bind only to MHC molecules having foreign antigens embedded in the MHC protein 30 T cell receptor and diversity  Diversity of T cell receptors is generated by some of the same mechanisms involved in producing diversity of antibodies  Somatic recombination  Random chain reassortment  Coding for joint diversity 31 Immunoglobulin gene superfamily  Immunoglobulin gene superfamily: immunoglobulins, T cell receptors and MHC proteins  Consists of two nonidentical polypeptide chains  Constant and variable regions  Share protein domains  Similar mechanisms of generating diversity for immunoglobulins and T cell receptors 32 T-cytotoxic cells  T-cytotoxic cells, or cytotoxic T lymphocytes:  Directly kill cells that display surface foreign antigens  Contact between T-cytotoxic cell and target cell is required for cell death  On contact, granules in T cytotoxic cell migrate to contact site  Degranulation releases granzymes (causing apoptosis) and perforin (causing pores formation in target cell) 33 T-helper cells  Interactions with antigen-presenting cells drive naive CD4 T-helper cells to differentiate into one of several T–helper subsets, each producing unique combinations of cytokines that direct the immune response  T-helper-1 subset (figure) activates macrophages  Secrete cytokines  Activated macrophages kill intracellular bacteria  Play a role in inflammation and rejection of transplanted organs  T-helper-2 subset plays a crucial role in B lymphocyte activation and antibody production 34