* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Slide 1
Survey
Document related concepts
Immunocontraception wikipedia , lookup
Duffy antigen system wikipedia , lookup
Lymphopoiesis wikipedia , lookup
DNA vaccination wikipedia , lookup
Complement system wikipedia , lookup
Immune system wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Innate immune system wikipedia , lookup
Molecular mimicry wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Adaptive immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Transcript
Immunology Part II: Adaptive Immunity Lecture #18 Bio3124 1 Overview of Specific (Adaptive) Immunity three major functions recognize nonself Discriminates btw self and nonself, antigenic determinants respond to nonself: specific, diverse (>1011 antigens) effector response eliminates or renders foreign material harmless anamnestic response upon second encounter with same pathogen immune system mounts a faster and more intense response remember non-self: memory cells 2 Antigens and Haptens Antigens: elicit immune response Epitopes: antigenic determinant sites on antigens to which antibody binds; Whole cells, large and complex molecules Proteins-> linear vs conformational Valence number of epitopes on an antigen determines number of antibodies to bind antigen Haptens small organic molecules antigenic when bound to larger carrier molecule e.g., penicillin binds serum proteins among allergic patients 3 Types of specific immunity (adaptive) humoral immunity also called antibody-mediated immunity based on antibody activity and B-cells cellular immunity also called cell-mediated immunity (CMI) based on action of specific kinds of T lymphocytes 4 Cell Mediated Adaptive Immune Response (CMI) 5 Recognition of Foreignness distinguishing between self and non-self allows for selective destruction of invading pathogens without destruction of host tissues MHC molecules: APCs present foreign antigens to T cells T-cells mediate launching either cell mediated immune response (CMI) or humoral response (antibody) MHC-I: presents antigens of endogenous origin eg. viral infection; all nucleated cells MHC-II: antigens of exogenous origin eg bacteria/toxins entering APC; include macrophages, dendritic cells, B-cells 6 MHC-I and MHC-II MHC-I: α-chain: 45 kD, α1, α2 and α3 domains β2 microglobulin: 12 kD, associated with α3 α1 and α2: antigen binding pocket MHC-II α-chain and β-chain Form large antigen binding pocket for peptide presentation by APCs 7 Antigen processing and presentation MHC-I: Bind foreign peptides originating in cytoplasm (endogenous antigens) eg. viral proteins Viral proteins breakdown to peptides pumped into ER via LMP and TAP α and β chains synthesis on ER α and β join together in ER lumen and pick up viral antigenic peptides Pass through golgi → cell surface → antigen presentation LMP: low molecular mass polypeptide component of proteosome TAP: transporter of antigen peptides 8 Antigen processing and presentation MHC-II: Bind foreign peptides originating outside cytoplasm (exogenous antigens) eg. bacteria Enter APCs via endocytosis Breakdown in endosomes by proteolytic degradation In the ER: MHC-II α and β chains synthesis Associated with invariant chain, fits in Ag binding cleft temporarily, all MHC-II Pass through Golgi, invariant chain degraded Endocytic vesicles fuse with golgi vesicles Fitting antigenic determinant picked up by MHC-II Carried and presented on cell surface 9 T- Cell Biology major players in cell-mediated immune response have major role in B-cell activation produce regulatory cytokines; Cytotoxic function recognize and bind antigens using specific TCR Specific binding to antigen presented by antigen-presenting cells (APCs) using MHC-I or MHC-II CD3 complex activation & signaling and proliferation, cytokine production T-cell receptor (TCR) 10 Types of T-cells 1. T-helper (TH) cells (CD4+ T Cells) TH0 undifferentiated precursors of TH1 and TH2 cells carry CD4+ that is MHC-II co-receptor activated by antigens presented on MHC-II TH1 cells produce specific set of cytokines (IL-2, TNFs, IFN) involved in cellular immunity responsible for CTLs and macrophage activation TH2 produce cytokines (IL4, 5, 6, 10, 13) involved in humoral immunity (B-cell activation) defend against helminth parasites 2. Cytotoxic T Lymphocytes (CTLs) CD8+ T cells that have been activated by antigen presented on MHC-1 molecules of nucleated cells 11 MHC-I and Cell Mediated Immune Response On the scene: virus infected nucleated cells MHC-I: viral antigen presented on MHC-I CTL response: activated by binding to antigen presented on MHC-I Differentiate Targets:other infected cells Kill target cells by perforin and granzyme Inducing apoptosis 12 MHC-II and Cell Mediated Immune Response CTL response via MHC-II Can also be activated through TH1 helper T-cells and MHC-II TH1 activation: two signals required 1st signal: TH1 binds by CD4 to antigen presented by MHC-II on infected APC 2nd signal: B7 and CD28 interaction Triggers IL-2, IFN and TNF production Activate Naïve cytotoxic T cells attacks other infected cells presenting same Ag on MHC-I Cytolysis or apoptosis ensues Helper memory cells produced APC is not targeted 13 Humoral Adaptive Immune Response 14 B-Cell Biology immunologic roles proliferate and differentiate into plasma cells Produce antibodies and memory cells act as APC BCR: B-cell receptor (monomeric IgM) accompanied by Igα and Igβ BCR binds to its specific antigen Capping: BCR clustering through Igα and Igβ Signaling to nucleus -> DNA recombination differentiate into plasma cells -> secrete antibodies Capping 15 B-cell Ag specificity & clonal selection theory Billions of different B cells Antibodies attached to membrane Each cell binds different antigens Clonal Selection Cells that bind antigen replicate Differentiate to plasma cells Secrete antibodies Some differentiate to memory cells Second antigen exposure Memory cells replicate, differentiate 16 B-Cell Activation needs antigen binding (triggering) leads to proliferation and differentiation into plasma cells cytokines produced by helper T cells can act on B cells and assist in growth and differentiation typically antigen-specific two mechanisms for antigen-specific activation T- dependent T- independent 17 T dependent B-Cell Activation Triggered by bacteria, hapten-carrier, proteins requires two signals antigen-BCR interaction T cell cytokines Three cells involved: macrophages T-helper cells B-cells specific for antigen Mechanism: Naïve TH0 cells bind Ag/MHC-II on APC Activated to TH2 cells TH2 cells bind B-cells displaying same Ag/MHC-II Produce cytokines IL4,5,6 B-cells proliferate and differentiate antibody producing plasma cells Form memory cells 18 T-independent B cell activation T-independent antigens polymeric antigens with large number of identical epitopes (e.g., bacterial lipopolysaccharides) mediate capping and activation less effective than T-dependent B cell activation antibodies produced have a low affinity for antigen no memory B cells formed 19 Antibodies immunoglobulins (Ig) glycoprotein made by activated B cells (plasma cells) serve 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 20 Immunoglobulin Structure same basic structure four polypeptide chains two identical heavy chains two identical light chains heavy and light chains connected to each other by disulfide bonds both chains contain two different regions Constant (C) regions (CL and CH) Variable (V) regions (VL and VH) Isotypes: IgM, IgG, IgA, IgD, IgE 21 Immunoglobulin Function Fab binds antigen marks antigen for immunological attack activates nonspecific defense mechanisms that can destroy antigen e.g., opsonization Fc mediates binding to: host tissue various cells of immune system first component of complement system 22 Effector and anamnestic response Effector response: first exposure, IgM or IgD followed by isotype switch to IgG Memory cells stored Anamnestic response Some IgM Lots of IgG Rapid intensive response 23 Consequences of Antigen-Antibody Binding 24 Classical Complement activation Antibodies coat antigenic particles FC portions stick out Fc bound by C1 complex C1 cleaves C4, C2 C4b2a is a convertase (C3 convertase) C3 C3a and C3b C3bC5 form C5 convertase Cleaves C5 to C5b and C5a C5b recruits C6, 7, 8 and C9 Form membrane attack complex Cytoplasmic leakage-> cell dies C3 convertase C5 convertase 25 Classical Complement activation 26 Resistance to Viral Infections antibodies neutralize viruses antibodies enhance phagocytosis of viruses by opsonization interferons cause death of infected cells NK cells stimulated by interferons and antibodies Cytotoxic T lymphocytes (CTLs) destroy virusinfected cells 27 Resistance to Bacterial Infections Opsonization: certain antibodies and complement proteins act as opsonins IgM and IgG agglutinate bacteria Classical complement activation: antibodies trigger formation of membrane attack complex certain complement proteins attract phagocytic cells antitoxin antibodies neutralize bacterial exotoxins cytokines attract and stimulate macrophages cytokines stimulate T cells and increase population of cells involved in cell-mediated response 28 Summary Animation: CMI and Humoral responses 29