Lecture 10: The Adaptive/acquired Immune System

(The adaptive/acquired immune system) Lecture 10 Review: Innate Immunity: Non-specific defense ↳ first line of defense Adaptive Immunity: Specific defense · Specialized immune cells · Specific response -skin -gut microbiota ↳ second line of defense -complement -phagocytosis of microorganisms -inflammation · Self/non-self recognition · Memory generation (eg. vaccines) Specificity is based on antigen recognition ("remembering") Antigen: · foreign molecule recognized by adaptive immune cells · elicit an immune response · best immunogenic antigens are proteins, but they can be carbs or lipids Adaptive Immunity · takes time to develop (5-7 days) · highly diverse and specific · generates memory (thats why vaccines work!) · mediated by: Characteristics of Innate + Adaptive Immunity Innate: Adaptive: · immediate response · lag time response · antigen independent · not antigen specific · no memory · antigen-dependent · antigen specific · memory ↳ B lymphocytes (humoral) ↳ T lymphocytes (cell-mediated) Body fluids, blood and lymph B lymphocytes · one unsegmented nucleus · can differentiate into plasma cells that produce antibodies · produce antibodies in response to specific antigens to fight infection · produce cytokines, chemical signals that can change the behaviour of other cells · Antigen Presenting Cells (APCs) to activate other immune cells to combat infection by cellular mechanisms ↳ have MHC II on their surface Production and Maturation · in the bone marrow · antigen-independent Activation · peripheral lymphoid organs (lymph glands) · antigen-dependent Differentiation · plasma cells or Memory B cells · peripheral lymphoid organs · antigen-dependent All proliferating cells will have the same: · B cell receptor (BCR) · specificity for antigen B cell activation depends on the antigen: · Thymus dependent (TD) antigens (proteins) ↳ best version, produces memory cells · Thymus independent (TI) antigens (other molecules) React only with antigens that activated B cell Terms: · Antigen: a foreign molecule that can be recognized by adaptive immune cells and elicit an immune response · Epitope: a specific site on an antigen recognized by immune cells or antibodies · Antibody: a protein produced by B cells that recognizes a specific epitope on an antigen (also called immunoglobulins) Cytokines · soluble proteins secreted by immune cells · chemical signals that can change the behaviour of other cells · can cause B cell proliferation (clonal expansion) and "class switching" Class Switching · changing Ig produced by B cell (eg. IgM to IgG) with no loss of antigen specificity IgM is produced first! · produces different antibodies depending on the cytokine environment around plasma cells Antibody Structure Fab Region: · variable region · two antigen binding sites · different combinations on variable region leads to lots of different antigen specificity Fc Region: · constant region · recognized by other immune cells that have to receptor (binding site) Functions of Antibodies ① Opsonization → proteins/antibodies help phagocytes by flagging them ② Complement activation ③ Agglutination → regions bind different antigens and clump them together ④ Neutralization → antibodies to toxins ⑤ Antibody-dependent cell-mediated cytotoxicity → antibodies help kill cells ① Opsonization Macrophages have Fc receptors Antibodies recognize bacterial antigens and bind leaving Fc stem sticking out of cell ② Complement Activation & that bind to antibody to the Fc stem and easily phagocytose Antibodies bind to antigens on bacterium which creates immune complex Immune complex activates the classical complement pathway · C3b is produced from complement pathway and binds to cell wall Coats bacteria → opsonization → complement activation → MAC ③ Agglutination Antibodies have 2 arms so they can bind to multiple bacteria and clump them together to phagocytose at once Antibody dependent cell mediated cytotoxicity ④ Neutralization Can either stop attachment to host or ⑤ Antibody-dependent Cell-mediated Cytotoxicity Helps NK cell or T cell bind to Fc receptors block the toxin produced (eg. tetanus toxin) Serum · yellow liquid separated from coagulated blood after centrifugation and fibrin removal · rich in proteins · mostly used for laboratory testing · contains no active blood clotting proteins Plasma · yellow fluid obtained by treating blood with an anticoagulant · RBCs removed by centrifugation · sometimes used for laboratory tests · contains intact blood clotting proteins that have not been activated Immunoglobulin G (IgG) · most abundant class of antibody in serum (80%) · can be transferred from mother to unborn child via placenta ↳ immunity on child for 6 months · highly efficient to activate complement · high affinity for FC receptors on phagocytic cell membranes and can readily mediate opsonization Immunoglobulin M (IgM) · 5-10% of serum antibody · first antibody produced in a primary response · first antibody synthesized by neonates (unborn babies) · When in membrane bound form (monomeric), it forms the the BCR (B cell receptor) · Plasma cells secrete soluble IgM as a pentamer (5 molecules connected by a joining chain/J-chain) · IgM is more efficient to activate complement Immunoglobulin A (IgA) · 10-15% of antibody in serum · predominant antibody in external secretions ↳ eg. breast milk, saliva, tears, and mucous · exists as a monomer, but dimers can form held by a J-chain for easy transport across mucosal surfaces · prevents the attachment of bacteria or viruses to mucosal surfaces, thus preventing colonization · IgA secreted in breast milk protecting newborn during the first month of life Immunoglobulin E (IgE) · extremely low concentrations in serum (0.0002% ) · responsible for allergies (releases histamine) · binds Fc receptors on mast cells and eosinophils · plays an important role in neutralization of parasites Immunoglobulin D (IgD) · 0.2% of serum antibodies · expressed at the cell surface of mature B cells along with IgM · biological function not well established but may be involved in mucosal immunity? Antigen Presenting Cells MHC: Major Histocompatibility Complex (also called HLA) MHC I: endogenous (made in cell) MHC II: exogenous (not made in cell) Foreign peptide shown Virus protein made in host cell Normal host cell Foreign protein shown Virally infected host cell MHC Class I MHC Class II · presents endogenous peptides · presents exogenous peptides · found on ALL cells with nuclei (self marker) · Found only on APCs · activates CD8+ cytotoxic cells · activates CD4+ helper cells CD: Cluster of Differentiation ↳ different proteins on surface of cells used to characterize different cell types in the body CD8+ and CD4+ are the names of the receptor T lymphocytes · Cytotoxic T lymphocytes (CTDLs): CD8+ ↳ targets and directly kills virus-infected cells, tumour cells, or cells from a tissue graft (abnormal cells) · Helper T lymphocytes: CD4+ ↳ produce cytokines that support inflammation and activates other immune cells ↳ activates B cells which leads to antibody production ↳ activates T cytotoxin cells · Regulatory T lymphocytes ↳ can suppress other immune cells so they don't go crazy Development · immature T cells travel to thymus from the Activation · in peripheral lymphoid organs (lymph glands) bone marrow · in thymus "school" they learn self from non-self · MHC and antigen dependent (programmed) · dependent on self MHC molecules and antigen Tc Activation · Needs cell contact "cellular immunity" · Activated T cells produce and secrete effector molecules to destroy target cells: ↳ perforin and granzyme ↳ perforin helps granzyme enter cell and kill Differentiation · become effector cells (Th or Tc) or memory cells Tc Differentiation · Activated Tc cells undergo clonal expansion ↳ majority remain in system as killer cells ↳ small percentage become memory cells that can quickly activate after a second encounter with the same antigen and MHC I Th Differentiation Th Activation · Activated helper T cells will secrete cytokines or act as B cell helpers · Activated Th cells undergo clonal expansion T lymphocytes: Immunodeficiency · Partial immunodeficiency ↳ loss of function or numbers ↳ majority remain in system as helper cells ↳ small percentage become memory helper cells, readily activated upon a second encounter with the same antigen and MHC II ↳ patients highly prone to infections · Auto-immunity ↳ T cells unable to differentiate self from non-self ↳ hyper-immune responses (leads to cell damage) Blabbing · Severe immunodeficiency ↳ Severe Combined Immunodeficiency (SCID) ↳ fatal if untreated by bone marrow transplant · Acquired immune deficiency syndrome ↳ HIV hijacks the cells Apoptosis: programmed cell death ↳ death of cells that occurs as a normal part of development or as a targeted event ↳ does not trigger inflammation since "clean up" of apoptic bodies is done by phagocytic cells Necrosis: caused by cell injury or infection/toxins ↳ death of a cell triggered by extrinsic factors ↳ detrimental to host and accompanied by an inflammatory response