Lecture 2 - Types Of Immunity (1) PDF

The Immune System Types Of Immunity Immune System functional system rather than organ system  Hematopoetic  Vasculature  Lymphatic Fig 21.1 Innate vs. Adaptive Immune System – Introduction Innate: structural defenses; responds to nonspecif...

The Immune System Types Of Immunity Immune System functional system rather than organ system  Hematopoetic  Vasculature  Lymphatic Fig 21.1 Innate vs. Adaptive Immune System – Introduction Innate: structural defenses; responds to nonspecific foreign substances  Firstline: external surface epithelium & membranes  Second line: inflammatory processes – antimicrobial proteins, phagocytes, etc. Fig 21.1 Innate vs. Adaptive Immune System – Introduction Adaptive: responds to specific foreign substances Has the ability to “remember” antigens Fig 21.1 Innate & adaptive mechanisms work together Antigens Antigens, defined broadly, are molecules that have the ability to initiate adaptive immune responses  e.g. components of pathogenic organisms the term immunogen is more correct in this context. Antigens are not just components of foreign substances, such as pathogens. A large variety of ‘self’ molecules can serve as antigens as well, provoking autoimmune responses that can be highly damaging, and even lethal. Antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large Y-shape protein produced by plasma cells that is used by the immune system to identify and neutralize antigens. Immune Responses to Pathogens Pathogens, however come in many different forms, with various modes of transmission and reproductive cycles, so the immune system has different ways of responding to each of them. The exterior defenses of the body present an effective barrier to most organisms. Once inside the body, type of immune response which will be induced is determined by:  the site of the infection  the nature of the pathogen  and most importantly whether the pathogen is: an intracellular pathogen (i.e. invades the host cells to divide and reproduce); or an extracellular pathogen (i.e. does not invade the host cells). Innate, Surface Defenses Innate, Surface Defenses Skin  physical barrier to microbes  Keratin resistant to most bacterial enzymes & toxins  secretions are acidic pH 3-5 Mucosa  physical barrier & produces a variety of protective chemicals Gastric mucosa  very acidic & produces proteolytic enzymes Saliva & lacrimal fluid contain lysozyme Mucous  traps bacteria & moves them away from epithelial surface Innate, Internal Defenses Based on recognition of surface carbohydrates (glycocalyx)  Glycocalyx is recognized as “self” or “non-self” Figure 3.3 Innate, Internal Defenses Phagocytes  Macrophages: derived from monocytes Free Macrophages: roam through tissues Fixed Macrophages: Kupffer cells (liver) & microglia (brain) Ingest cellular debris, foreign material, bacteria, fungi  Neutrophils: ingest pathogens  Eosinophils: weakly phagocytic of pathogens. Attack parasites (degranulation)  Mast Cells: phagocytic of various bacteria Innate, Internal Defenses Phagocytic mechanisms:  Adherence: cell binds to invader Aided by opsonization (a chemical process that enhances binding via complement & antibodies)  Ingestion: formation of phagolysosomes Respiratory Bursts: merge phagosome with lysosome & flood phagolysosome with free radicals (macrophage) Defensins: proteins that crystallize out of solution & pierce pathogen membranes (neutrophils) Enzymes digest pathogen Innate, Internal Defenses Natural Killer Cells:  Small population of large granular lymphocytes  Non specific for “non-self”  Not phagocytic: attack is by release of perforins that perforate the target cell plasma membrane. Shortly after perforation the target nucleus disintegrates.  Release chemicals that enhance the inflammatory response Innate, Internal Defenses: Inflammation tissue response to injury Triggered by injury – trauma, heat, chemical irritation, infection, etc. Beneficial effects  Preventsspread of injury  Disposes of cellular debris & pathogens  Promotes repair Innate, Internal Defenses: Inflammation cardinal signs of inflammation  Redness  Heat  Swelling  Pain  (functional impairment Rigor) Innate, Internal Defenses: Inflammatory Response Leukocytosis: leukocytosis inducing factors released by injured cells promote rapid release of WBCs from marrow Margination: increased vascular permeability causes decreased fluid in vessels; blood flow slows & neutrophils are able to move to vessel margins. Here endothelial markers (CAMs) allow neutrophils to cling to vessel walls (pavementing). Innate, Internal Defenses: Inflammatory Response Diapedesis: neutrophils migrate through capillary walls Chemotaxis – inflammatory chemicals attract neutrophils to move up the chemical concentration gradient (neutrophils respond first) As the process continues, monocytes diapedes into the area & become macrophages. With chronic inflammation, macrophages predominate Inflammatory Response: Phagocytic Mobilization Figure 21.4 Innate, Internal Defenses: Inflammatory Response Macrophages clean up cellular debris & pathogens If pathogens were associated with the injury, activation of the complement cascade occurs & elements of adaptive immunity join the process Innate, Internal Defenses Complement – a group of plasma proteins (20) that are activated in the presence of foreign substances Complement activation enhances & amplifies inflammation Bacteria & some other cell types are lysed by complement activation Complement activation enhances both innate & adaptive defenses ADAPTIVE DEFENSES ADAPTIVE DEFENSES  Innate & adaptive mechanisms work together in a cohesive fashion Adaptive Defenses: Characteristics Specificity: directed at specific targets Systemic: not restricted to initial site of infection / invasion Memory: after initial exposure & activation, a more rapid & more vigorous response is made to subsequent exposures to pathogens  (secondary response) Adaptive, Humoral Response Humoral response (clonal selection) B-cells: Antigen challenge to naïve immunocompetent B-cell Antigen binds to B-cell receptors & form cross- links between receptors Cross linked antigen-receptor complex undergoes endocytosis B-cell presents antigen to T-cell T cell prompt the B-cell to mature & form antibody Humoral Immunity Active humoral immunity:  B-cellsencounter & respond to antigen to produce an antibody Passive humoral immunity:  Introduced “non-native” antibody Active Humoral Immunity Naturally acquired: natural exposure to antigen (i.e. infection) Artificially acquired: vaccines; dead/attenuated or fragmented pathogen injected to elicit an immune response  Bestow immunity without disease; primary response  Booster shots (secondary response); intensify response  Shortcomings – adverse reactions & the immunity is less durable (poor memory) & has less cell mediated component Passive Humoral Immunity Natural: maternal antibody crosses the placental barrier conferring temporary immunity to the baby (degrades after a few months) Artificial: antibodies harvested from an outside source given by injection protect from immediate threat but no memory is formed (antitoxins, antivenins , gamma globulin, etc.) Antibodies A.K.A Immunoglobulins & gamma globulins Structure  variable  hypervariable  constant Figure 21.13a Antibody Classes Antibody Classes: IgM, IgG, IgA, IgD, IgE (Ig = immunoglobulin) Antibody Targets & Functions Immune complex formation = antigen-antibody binding. All the following events are initiated by antigen-antibody binding. Complement fixation: Neutralization: Agglutination: Precipitation: Inflammation & phagocytosis prompted by debris Types of Acquired Immunity Figure 21.11 Adaptive, Cellular Response Lymphocytes  T-cells  B-cells Antigen Presenting Cells (APCs) Cell Mediated: MHC MHC occurs as two classes  MHC I on virtually all tissue cells  MHC II only on PM some immune system cells Interacts with two major types of T cells  CD8 - Cytotoxic  CD4 – Helper T cells Cell Mediated: MHC display properties Figure 21.16a MHC I on virtually all tissue cells  Display only proteins produced inside the cell  Endogenous antigens = foreign proteins produced by the cell (viral / cancer)  Stimulate the CD8* cell population form cytotoxic T-cells (Killer T, TC) *formerly T8 cells Cell Mediated: MHC display properties Figure 21.16b MHC II found only on PM of B-cells, some T-cells & APCs  Display proteins derived from a phagocytized target  Exogenous antigen: foreign protein from outside the cell – presented to PM surface  Stimulates the CD4* cell population form Helper T-cells (T ) H *formerly T4 cells Helper T cells Helper T cells are arguably the most important cells in adaptive immunity, as they are required for almost all adaptive immune responses. They help activate B cells to secrete antibodies and macrophages to destroy ingested microbes, and they also help activate cytotoxic T cells to kill infected target cells. Helper T cells themselves, however, can only function when activated to become effector cells. They are activated on the surface of antigen-presenting cells, which mature during the innate immune responses triggered by an infection. The innate responses also dictate what kind of effector cell a helper T cell will develop into and thereby determine the nature of the adaptive immune response elicited. Helper T cells When a an antigen-presenting cell activates a naïve helper T cell in a peripheral lymphoid tissue, the T cell can differentiate into either a TH1 or TH2 effector helper cell. These two types of functionally distinct subclasses of effector helper T cells. TH1 cell  will mainly defend the animal against intracellular pathogens.  will activate macrophages to kill phagocytized microbes and activate cytotoxic T cells to kill infected cells. TH2 cell  will mainly defend the animal against extracellular pathogens.  will stimulate B cells to make antibodies T-cell roles: Cytotoxic T-cells Cytotoxic T-cells (TC, Killer T): directly attack & kill cells with specific antigen Cytotoxic T-cell Activated TC cells are co- stimulated by TH cells TC mechanism Target  TC binds to cell & releases perforin cell & granzymes  In the presence of Ca2+ perforin forms pores in target cell PM  Granzymes enter through pores & degrade cellular contents  TC then detaches & moves on  Macrophages clean up Antigen Presenting Cells (APCs) Antigen Presenting Cells (APCs) APCs ingest foreign material, then present antigenic fragments on their cell surface where they are recognized by T-cells  T-cells: respond to antigen only if it is displayed on plasma membrane. APCs: Macrophages & B lymphocytes Interactions between APCs & lymphocytes & lymphocyte-lymphocyte interactions are critical to immune response Major Types of T Cells Figure 21.14 Antigen Presentation - MHC Class I Figure 21.16 Antigen Presentation - MHC Class II Figure 21.17a T-cell roles: Humoral Immunity Activated TH cells interact with B-cells displaying antigen & produce cytokines that prompt the B-cell to mature & form antibody Figure 21.18 T-cell roles: Cell Mediated Immunity TH cells also produce cytokines that promote TC cells TH cells recruit other WBCs & amplify innate defenses (inflammatory) Subpopulations of TH cells specialize in specific sets of activations Figure 21.18 Cell Mediated: T-cell roles Helper T-cells (TH) stimulate B-cells & other T-cells to proliferate Figure 21.18 Cell Mediated: T-cell roles Other T-cells  *Regulatory T-cells (TReg): release inhibitory cytokines that suppress B-cell & T-cell activity Help to prevent autoimmune events *formerly Suppressor T (TS)  Gamma Delta T-cells (Tgd): live in the intestine. Function in surveillance & are triggered much like NK cells Summary of the Primary Immune Response Figure 21.19 Immunologic Disorders Primary immunodeficiency disorders (see Box 4-3)  Mostly these are inherited single-gene disorders that present in infancy in early childhood with the exception of common variable immunodeficiency which usually occurs in adults.  They are sometimes classified according to which component is faulty (T cells, B cells, phagocytic cells or complement) or according to individual clinical syndromes.  The overall incidence of symptomatic primary immunodeficiency is estimated to be 1/10,000.  About 80% of patients are less than 20 years old when diagnosed, because the majority of cases are inherited or congenital. 70% occur in males due to X-linked inheritance in many syndromes.  B-cell defects account for 50% of primary immunodeficiency.  T-cell defects account for 30%, phagocytic deficiencies 18% and complement deficiencies 2%. Immunologic Disorders Secondary immunodeficiency disorders (See Box 4-4)  Secondary immunodeficiencies, also known as acquired immunodeficiencies, can result from various immunosuppressive agents, for example: pathogens malnutrition aging medications (e.g. chemotherapy, disease-modifying antirheumatic drugs, immunosuppressive drugs after organ transplants, glucocorticoids).  For medications, the term immunosuppression generally refers to both beneficial and potential adverse effects of decreasing the function of the immune system.