Microbiology Lecture 23-24 Adaptive Immunity PDF

ADAPTIVE IMMUNITY Christopher Weiss, PhD Senior Scientist MRIGlobal – Infectious Diseases Surveillance & Diagnostics [email protected] Lectures 23-24  Overview of Specific (Adaptive) Immunity Three major functions:...

ADAPTIVE IMMUNITY Christopher Weiss, PhD Senior Scientist MRIGlobal – Infectious Diseases Surveillance & Diagnostics [email protected] Lectures 23-24  Overview of Specific (Adaptive) Immunity Three major functions: Recognize non-self. Respond to non-self. Effector response—eliminates or renders foreign material harmless. Memory cells “remember” the foreign material—upon second encounter with same pathogen, the immune system mounts a faster and more intense response. Remember non-self. 2 ©2020 McGraw-Hill Education  Four Characteristics of Adaptive Immunity Discrimination between self and non-self. Usually responds selectively to non-self, producing specific responses against the stimulus. Specificity. Can be directed against one specific pathogen or foreign substance among trillions. Diversity. Generates enormous diversity of cellular receptors and antibodies. Memory. Response to a second exposure to a pathogen is so fast that there is usually no noticeable illness. 3 ©2020 McGraw-Hill Education Types of Adaptive Immunity—Humoral vs. Cellular Humoral immunity. Also called antibody-mediated immunity. Based on antibody activity. Cellular immunity. Also called cell-mediated immunity. Based on action of specific kinds of T lymphocytes. 4 ©2020 McGraw-Hill Education Finding the Right Targets  Antigens Self and non-self substances that elicit an immune response. Most are large, complex molecules. Antigenic determinant sites (epitopes). Site on antigen that reacts with specific antibody. Valence is number of epitopes on an antigen. Antibody affinity. Strength with which antibody binds to its antigen at a given antigen-binding site. Avidity of antibody. Overall ability to bind antigen at all antigen-binding sites. 6 ©2020 McGraw-Hill Education  Haptens Small organic molecules. Not antigenic but may become antigenic when bound to larger carrier molecule. For example, penicillin. Can initiate a severe allergic immune reaction. Access the text alternative for these images 7 ©2020 McGraw-Hill Education  Types of Specific Immunity Naturally acquired active immunity. Type of specific immunity a host develops after exposure to foreign substance. Naturally acquired passive immunity. Transfer of antibodies, For example, mother to fetus across placenta, mother to infant in breast milk. Artificially acquired active immunity (vaccination). Intentional exposure to a foreign material. Artificially acquired passive immunity. Preformed antibodies or lymphocytes produced by one host are introduced into another host. 8 ©2020 McGraw-Hill Education  Acquisition of Immunity Access the text alternative for these images 9 ©2020 McGraw-Hill Education (a) ©Paul Bradbury/Getty Images; (b) ©JGI/Blend Images LLC; (c) ©Phil Nealey/Getty Images; (d) ©Miodrag Gajic/Getty Images  Recognition of Foreignness Immune system must recognize foreign antigens as non-self AND recognize host cells as self. This allows for selective destruction of invading pathogens without destruction of host tissues. Involves the major histocompatibility complex. 10 ©2020 McGraw-Hill Education  Major Histocompatibility Complex (MHC) Collection of genes that code for self/non-self recognition potential of a vertebrate. In humans, located on chromosome 6 and called human leukocyte antigen (HLA) complex. Three classes of MHC molecules. Class I molecules found on all types of nucleated cells—important for organ transplantation. Class II molecules found only on cells that can process and present antigens to T lymphocytes—macrophages, dendritic cells, and B cells present antigen in this way. Class III molecules include secreted proteins not required for self/non- self recognition; include various secreted proteins. 11 ©2020 McGraw-Hill Education  Diagrams of MHC Molecules Access the text alternative for these images 12 ©2020 McGraw-Hill Education  Class I and Class II Bind to Antigens in the Cell Endogenous antigen processing. Class I binds to antigen peptides that originate in the cytoplasm and present antigen to CD8+ T cells. Exogenous antigen processing. Class II binds to antigen fragments that come from outside the cell and present to CD4+ T-helper cells. Access the text alternative for these images 13 ©2020 McGraw-Hill Education Cellular Adaptive Immunity  T-Cell Development 1 Multiple subsets of T cells work together to initiate, orchestrate, and carry out an adaptive immune response. Originate from common lymphoid progenitor (CLP) cells from bone marrow that mature in thymus. Thymic selection: Determines what kind of T cell any given immature cell will become; defined by structure of the T-cell receptor (TCR) and then by the structure of the T-cell coreceptor. Determines coreceptor specificity. T-cell coreceptors are members of the family of cluster of differentiation (CD) molecules. 15 ©2020 McGraw-Hill Education  Development and Function of B and T Lymphocytes Access the text alternative for these images 16 ©2020 McGraw-Hill Education  T-Cell Receptors (TCRs) Reside in the plasma membrane surface. Recognize and bind fragments of antigens. Antigen fragments must be presented by antigen- presenting cells (APCs) on the ends of MHC molecules. Access the text alternative for these images 17 ©2020 McGraw-Hill Education  T-Cell Activation Requires binding a specific antigen. Occurs through antigen presentation bridging MHC class II on the APC to the T-cell receptor (immune synapse). Initiates signaling cascade involving other membrane-bound proteins and intracellular messengers. Second signal required for lymphocyte proliferation, differentiation, and expression of specific cytokine genes. Access the text alternative for these images 18 ©2020 McGraw-Hill Education  Types of T Cells Mature T cells are naïve until activated by antigen presentation. Once activated, they proliferate into effector cells and memory cells. Effector cells carry out specific functions to protect host against foreign antigen. Three types: T-helper (TH) and T regulatory cells, cytotoxic T lymphocytes (CTL). Access the text alternative for these images 19 ©2020 McGraw-Hill Education  T-Helper Cells—Overall Traits Also known as CD4+ T cells. Activated by antigen presentation with class II MHC. Most important types of T-helper cells: TH0—mature, naïve T cells; not yet activated. TH1—help activate macrophages. TH2—help B cells produce antibodies. TH17—assist in antibacterial responses. Treg—help control lymphocyte responses. 20 ©2020 McGraw-Hill Education  Cytotoxic T Lymphocytes Are CD8+ T cells that have been activated by antigen presented on MHC-I molecules of dendritic cells. Once activated, these CTLs can kill host cells that have been infected by intracellular pathogens, such as a virus, are presenting cancer neoantigens, or have the same antigen-MHC-I combination that originally activated the CTL. After binding target, CTL kills target cell via the perforin pathway and an apoptotic (programmed cell death) pathway. 21 ©2020 McGraw-Hill Education  T-Cell Development 2 Access the text alternative for these images 22 ©2020 McGraw-Hill Education Humoral Adaptive Immunity  B-Cell Biology B cells must be activated by a specific antigen. Cells then replicate and differentiate into plasma cells which secrete antibodies. B cells have immunoglobulin receptors (called B-cell receptors (BCRs)) for the specific antigen that will activate that particular B cell. Interaction with that antigen is communicated to the nucleus via a signal transduction pathway similar to that described for T cells. Access the text alternative for these images 24 ©2020 McGraw-Hill Education  Two Mechanisms for Antigen-Specific B-Cell Activation T-cell-dependent B-cell activation. Involves interaction with T cells. T-cell-independent B-cell activation. T-independent antigens trigger B-cells to produce antibodies without T-cell cooperation. Polymeric antigens with large number of identical epitopes (For example, bacterial lipopolysaccharides). Antibodies produced have a low affinity for antigen. No memory B cells formed. 25 ©2020 McGraw-Hill Education  T-Dependent Antigen Activation Like T cells, require two signals. Antigen-BCR specific interaction. Activated T-helper 2 binds B- cell presented antigen and secretes B-cell growth factors. B cell differentiates into plasma cell and memory cell. Access the text alternative for these images 26 ©2020 McGraw-Hill Education  Antibodies Antibody. Immunoglobulin (Ig). Glycoprotein made by activated B cells (plasma cells). Serves as antigen receptor (BCR) on B-cell surface. Found in blood serum, tissue fluids, and mucosal surfaces of vertebrate animals. An antibody can recognize and bind antigen that caused its production. 27 ©2020 McGraw-Hill Education  Immunoglobulin Structure All immunoglobulin molecules have the same basic structure. Four polypeptide chains—two identical heavy chains and two identical light chains; heavy/light chains connected by disulfide bonds. Both chains contain two different regions—constant (C) regions (CL and CH); variable (V) regions (VL and VH). Four chains arranged in flexible Y form with hinge region. Stalk of Y is the crystallizable fragment (Fc)—composed of only constant region. Top of Y is two antigen-binding fragments (Fab)—composed of both constant and variable regions. Access the text alternative for these images 28 ©2020 McGraw-Hill Education  Immunoglobulin Function Fab binds antigen specifically. Marks antigen for immunological attack. Activates nonspecific defense mechanisms that can destroy antigen (For example, opsonization for enhanced phagocytosis). Fc mediates binding to: Host tissue. Receptors on various immune cells. First component of complement system. 29 ©2020 McGraw-Hill Education  Immunoglobulin Classes—IgG and IgD IgG. 80% of serum immunoglobulin. Opsonization, neutralization, activates complement. Only Ig that can cross the placenta for natural passive immunity to neonate. IgD. Part of the B-cell receptor complex. Signals B cells to start antibody production. 30 ©2020 McGraw-Hill Education  Immunoglobulin Classes—IgM and IgA IgM. Pentamer arranged in pinwheel. First Ig in all immune responses. Agglutination, activates complement. IgA, secretory IgA (sIgA). Monomers and dimers. Secreted across mucosal surfaces. Tears, saliva, MALT. Immune exclusion. 31 ©2020 McGraw-Hill Education  Immunoglobulin Classes—IgE IgE. Lowest Ig serum level, elevated in parasitic infection and allergic reactions. Mast cells bind Fc portion, activated to degranulate vasoactive granules when Fab portion binds allergens. Access the text alternative for these images 32 ©2020 McGraw-Hill Education  Antibody Kinetics Antibody synthesis and secretion can be evaluated as a function of time. Primary antibody response. Relatively slow antibody response when an antigen is encountered for the first time. Secondary antibody response. Occurs upon subsequent exposure to the same antigen. Rapid, efficient, prevents illness. Demonstrates ability of the adaptive immune system to “remember” a pathogen; the basis for vaccination. 33 ©2020 McGraw-Hill Education  Primary Antibody Response Several days to weeks lag or latent period after initial exposure to antigen. No antigen-specific antibody detectable in blood. After B-cell differentiation into plasma cells, antibody is secreted. Antibody titer is measure of serum antibody concentration. IgM appears first, followed by IgG. 34 ©2020 McGraw-Hill Education  Antibody Production and Kinetics Access the text alternative for these images 35 ©2020 McGraw-Hill Education  Secondary Antibody Response Upon secondary exposure to same antigen, B cells mount a heightened, memory response. Characterized as having: Shorter lag. More rapid log phase. Longer persistence. Higher titer. Production of antibodies with a higher affinity for the antigen. 36 ©2020 McGraw-Hill Education  Diversity of Antibodies Four mechanisms contribute to generation of antibody diversity: Rearrangement of antibody gene segments (combinatorial joining); genes are split or interrupted into many gene segments. Generation of different codons during antibody gene splicing. Different codons are created in a process called splice site variability. Somatic mutation. 37 ©2020 McGraw-Hill Education  Combinatorial Joining Segments clustered separately on same chromosomes. Exons that code for constant regions (C). Exons that code for variable regions (V). Joining (J) regions between V and C regions. Exons for constant region are joined (spliced together) to one segment of the variable region. RAG-1 and RAG-2 are recombination enzymes. Join one V gene segment with one J segment; all other V and J regions are cut out of the DNA and are lost to the cell. Creates many different combinations of V and J regions. 38 ©2020 McGraw-Hill Education  Light Chain In B-cell development: One V is joined with one J region. Many possible combinations formed. VJ joined with C (constant) exon after transcription. Access the text alternative for these images 39 ©2020 McGraw-Hill Education  Heavy Chain V and J regions are joined to third coding region called D (diversity) sequences. Antibody class switch. VDJ region is joined with a new constant region that encodes a different class of antibody, usually IgG or IgA. Region containing initial IgM C region is deleted, along with other intervening sequences. This is what causes antibody class switching 40 ©2020 McGraw-Hill Education  Heavy Chain Antibody Gene Recombination Access the text alternative for these images 41 ©2020 McGraw-Hill Education  Antibody Diversity Splice site variability. VJ joining can produce polypeptides with different amino acid sequences. Somatic hypermutation. V region “hotspots” are susceptible to high rate of somatic mutation. Produce antibodies with different epitope recognition. 42 ©2020 McGraw-Hill Education  Clonal Selection Theory Body forms large, diverse B lymphocyte pool that can bind to large range of antigenic epitopes. Self-reactive cells are eliminated at an early stage of development (clonal deletion). Encounter with antigen stimulates only those B cells that recognize and bind antigen. Stimulated B cells proliferate to form a clonal population (all have same antigen specificity). 43 ©2020 McGraw-Hill Education  Lymphocyte Clonal Expansion Access the text alternative for these images 44 ©2020 McGraw-Hill Education  Action of Antibodies Bind antigens with great specificity. Essential for the protection of animal from microbes and their products, and cancer cells. Antibody coats foreign invading material. Marks it for recognition by components of the innate and adaptive immune systems. Neutralization, opsonization, and immune complex formation. 45 ©2020 McGraw-Hill Education  Consequences of Antigen-Antibody Binding Access the text alternative for these images 46 ©2020 McGraw-Hill Education  Toxin Neutralization Inactivation of toxins resulting from interaction between toxin and specific antitoxin antibodies. Complexing toxin with antibodies. Can prevent the toxin from attaching to host cells. Can prevent toxin from entering host cells. Can result in ingestion by phagocytes. 47 ©2020 McGraw-Hill Education  Viral Neutralization IgG, IgM, and IgA antibodies can bind to some extracellular viruses and inactivate them. Fixation of complement component C3b, from classical complement pathway, helps in the neutralization process. Viral infection is prevented because neutralization of viruses prevents them from binding and entering target cells. 48 ©2020 McGraw-Hill Education  Opsonization Microorganisms or other foreign particles become coated with antibodies and/or complement. Opsonizing antibodies bind Fc receptors on surface of dendritic cells, macrophages, and neutrophils, creating bridge between phagocyte and antigen. 49 ©2020 McGraw-Hill Education  Immune Complex Formation Antigens and antibodies can cross-link, producing immune complexes. Precipitation (precipitin) reaction occurs when antigens are soluble molecules and the immune complex settles out of solution. Agglutination reaction occurs when cells or particles are cross- linked. The immune complex formed is more readily phagocytosed than are free antigens. Immune complexes can harm the host. Is the basis for many immunological assays. 50 ©2020 McGraw-Hill Education  Immune Tolerance Preventing activation against “self” antigens  Acquired Immune Tolerance How do we “know” to respond to foreign but not self antigens? Three proposed mechanisms: Negative selection (deletion) of self-reactive lymphocytes; called central tolerance if performed in bone marrow or thymus. Induction of anergy (peripheral tolerance); limits activity of self-reactive lymphocytes released from the bone marrow or thymus. Inhibition of the immune response by the action of Treg cells. 52 ©2020 McGraw-Hill Education  Immune Disorders Hypersensitivities – Overreactions to benign stimuli Autoimmune diseases – Self reactive responses Transplantation (tissue) rejection – Reaction to benign non-self markers on donor tissue Immunodeficiencies – Dysregulation (loss of function) of one or more aspect of immune response Congenital Acquired 53 ©2020 McGraw-Hill Education  Hypersensitivities Exaggerated immune response upon second or subsequent contact with antigen. Causes tissue damage. Reactions classified as immediate or delayed. Gell–Coombs classification into four different types of hypersensitivity: I, II, III, and IV. 54 ©2020 McGraw-Hill Education  Type I Hypersensitivity Allergy. One kind of type I hypersensitivity. Allergen. Antigen that causes allergic reaction. Occurs immediately following second contact with allergen. Involves production and action of IgE and mast cells. Basophils or eosinophils may be involved as well. 55 ©2020 McGraw-Hill Education Type I Hypersensitivity—Allergic Response Access the text alternative for these images 56 ©2020 McGraw-Hill Education  Anaphylaxis Release of physiological mediators in response to allergen cause. Smooth muscle contraction. Vasodilation. Increased vascular permeability. Mucus secretion. Can be systemic or localized. 57 ©2020 McGraw-Hill Education  Systemic Anaphylaxis Results from massive release of mast cell mediators in a short time. Usually results in respiratory impairment, decreased blood pressure, and circulatory shock. Can cause death within a few minutes. 58 ©2020 McGraw-Hill Education  Localized Anaphylaxis An atopic (“out of place”) reaction. Symptoms depend on route by which allergen enters body. Hay fever. Upper respiratory tract. Hives—raised (wheal) and reddened (flare) lesions. Skin. 59 ©2020 McGraw-Hill Education  Type II Hypersensitivity Cytolytic or cytotoxic reaction. Results in destruction of host cells. Involves IgG and IgM antibodies. Directed against cell-surface or tissue antigens. Stimulate complement pathway. 60 ©2020 McGraw-Hill Education  Examples—Type II Hypersensitivities Blood transfusion reaction in which donated blood cells are attacked by recipient’s antibodies. Erythroblastosis fetalis. Mother can be passively immunized with anti-Rh factor antibodies or RhoGam to control this disease which is potentially fatal for newborn. Access the text alternative for these images 61 ©2020 McGraw-Hill Education  Type III Hypersensitivity Involves overproduction of immune complexes. Usually removed by dendritic cells and macrophages. If accumulate, leads to hypersensitivity reaction. Resulting inflammation causes tissue damage. For example, vasculitis, glomerulonephritis, and arthritis. 62 ©2020 McGraw-Hill Education  Example Diagram of a Type III Hypersensitivity Access the text alternative for these images 63 ©2020 McGraw-Hill Education  Type IV Hypersensitivity Involves delayed, cell-mediated immune reactions. Important factor is time required for T cells to reach and accumulate near antigens. TH and CTL cells can elicit type IV reactions. For example, tuberculin hypersensitivity and allergic contact dermatitis. Access the text alternative for these images 64 ©2020 McGraw-Hill Education  Autoimmunity Presence of serum antibodies that react with self antigens (autoantibodies). Benign. Natural consequence of aging, inducible by infectious agents or drugs. Typically reversible when triggering agent is removed. 65 ©2020 McGraw-Hill Education  Autoimmune Diseases Results from activation of self-reactive T and B cells. Leads to chronic tissue damage. Can be fatal. Examples (see table 33.3). Rheumatoid arthritis. Insulin-dependent diabetes mellitus. 66 ©2020 McGraw-Hill Education  Transplant (Organ) Rejection Types of transplants: Allograft—transplants between genetically different individuals within a species. Xenograft—donor and recipient are different species. Two mechanisms of host-versus-graft disease: Foreign MHC molecules on transplanted tissue (graft) recognized as non-self, resulting in activation of cytotoxic T cells; response results in destruction of graft. TH cells react to graft by releasing cytokines which stimulate destruction of graft by macrophages. 67 ©2020 McGraw-Hill Education  Graft-Versus-Host Disease Can occur in bone marrow transplant recipients. Immunocompetent cells in donor tissue attack host. Disease controlled by treating donor with immunosuppressive drugs. Access the text alternative for these images 68 ©2020 McGraw-Hill Education  Immunodeficiencies Failure to recognize and/or respond to foreign antigens. Primary (congenital) immunodeficiencies. Result from genetic disorder. Acquired immunodeficiencies. Result from infection by immunosuppressive microbes (For example, HIV). 69 ©2020 McGraw-Hill Education  Take Home Message Adaptive immune responses require detection of non-self Cell types of the adaptive immune system produce cell- mediated and humoral defenses Cell-mediated defenses can either kill infected cells directly, or modulate other aspects of the immune response to tune the activity against the invading organism Humoral immunity arises from B cell recognition of antigens in the context of helper signals Antibodies undergo maturation in B cells to increase affinity and avidity and switch classes Immune disorders can arise from a dysregulation of many aspects of immune function 70 ©2020 McGraw-Hill Education