Week 2 Adaptive Immunity PDF

Acquired or Adap-ve Immunity § Resistance based on specific responses to eliminate a foreign substance § Can be: cellular (CMI) or humoral (HMI) T cells, B cells, or an-bodies, cytokines Copyright ©2021 F.A. Davis Company  Cells of the Adap-ve Immunity...

Acquired or Adap-ve Immunity § Resistance based on specific responses to eliminate a foreign substance § Can be: cellular (CMI) or humoral (HMI) T cells, B cells, or an-bodies, cytokines Copyright ©2021 F.A. Davis Company  Cells of the Adap-ve Immunity B lymphocytes T lymphocytes Humoral-Mediated immunity Cell-Mediated Immunity (CMI) (HMI) § Mature in the thymus § Mature in the bone § Providing help to B marrow and differen-ate cells and other into plasma cells that phagocy-c cells produce an-bodies. § Killing virally infected target cells. Copyright ©2021 F.A. Davis Company  AdapEve immunity characterized Specificity for each The ability to remember individual pathogen or a prior exposure microbial agent An increased response to that pathogen upon repeated exposure Copyright ©2021 F.A. Davis Company Types of T Cells § Helper T cells – coordinate immune responses by communica-ng with other cells § Killer T cells – Cytotoxic killer cells Natural Killer cells Copyright ©2021 F.A. Davis Company  Types of Killer Cells § At least two types of lymphocytes are killer cells — cytotoxic T cells and natural killer cells. § To aPack, "cytotoxic T cells" need to recognize a specific an-gen on foreign invader § natural killer or NK cells do not need to recognize a specific an-gen to aPack. § Both types contain granules filled with potent chemicals, and both types kill on contact. § The killer cell binds to its target, aims its weapons, and delivers a burst of lethal chemicals. Copyright ©2021 F.A. Davis Company Cytotoxic T cells § Cytotoxic T cells help rid the body of cells that have been infected by viruses as well as cells that have been transformed by cancer. § Need to recognize a specific an-gen on the foreign cell § They are also responsible for the rejec-on of -ssue and organ graTs. Copyright ©2021 F.A. Davis Company Natural Killer NK Cells § Natural Killer Cells – are armed with granules containing lethal doses of chemical; aPack cells lacking the self MHC molecule Copyright ©2021 F.A. Davis Company  Cytotoxins § Polypep-des that cause cell injury, inflamma-on, intes-nal secre-on through inhibi-on of protein synthesis Copyright ©2021 F.A. Davis Company Modes of acquiring immunity Immunity Natural Acquired resistance Passive Ac-ve Ar-ficial Natural Ar-ficial Natural Copyright ©2021 F.A. Davis Company  Passive Immunity Natural ArEficial Placental transfer of IgG An-bodies or immunoglobulins Colostral transfer of IgA Immune cells Copyright ©2021 F.A. Davis Company  An-bodies § Are immunoglobulins Glycoproteins found in the serum 82% to 96% polypep-de and 2% to 14% carbohydrate Five major classes: IgG, IgM, IgA, IgD, IgE § Are the key element of the humoral immune response Copyright ©2021 F.A. Davis Company  An-bodies (con-nued) § Appear primarily in the gamma (γ) globulin band with serum electrophoresis at pH 8.6 Copyright ©2021 F.A. Davis Company  Tetrapep-de Structure of Immunoglobulins § Basic four-chain polypep-de Two large pep-de chains = heavy (H) chains Two small pep-de chains = light (L) chains § Held together by noncovalent forces and disulfide interchain bridges Copyright ©2021 F.A. Davis Company  Heavy and Light Chains § Heavy chains Denoted by Greek lePers for each Ig class (e.g., Gamma [γ] for IgG) § Light chains — two types Kappa (κ) Lambda (λ) Have a molecular weight of ~22,000 daltons and differ by just a few amino acids Found in all five classes of Igs but only one type is present in a single molecule Copyright ©2021 F.A. Davis Company  Tetrapep-de Structure of Immunoglobulins (con-nued) § Unique variable region (amino-terminal end) allows for specific binding to a par-cular an-gen. § Three to four constant regions (carboxy-terminal end) are responsible for biological func-ons of an-body. Copyright ©2021 F.A. Davis Company  Hinge Region § Segment of H chain between the CH1 and CH2 regions § Allows for flexibility Two an-gen-binding sites can operate independently Assists in ini-a-on of complement cascade and Fc receptor binding Copyright ©2021 F.A. Davis Company  Carbohydrate Por-on of Igs § Found in all classes of immunoglobulins § Localized between the CH2 domains of the two H chains § Increases the solubility of immunoglobulin § Provides protec-on against degrada-on § Enhances func-onal ac-vity of the Fc domains Copyright ©2021 F.A. Davis Company  Treatment of Ig With Papain § Two Fab fragments One L chain plus one-half of an H chain held together by S=S Contains an-gen-binding sites § One Fc fragment The carboxy-terminal halves of two H chains held together by S=S Important in effector func-ons of Igs Copyright ©2021 F.A. Davis Company  Treatment of Ig With Pepsin § Pepsin cleaves the Ig above the set of disulfide bonds that hold the heavy chains together § F(ab’)2 created Contains two an-gen-binding sites held together Fc’ por-on in nonfunc-onal pieces Copyright ©2021 F.A. Davis Company  Isotypes, Allotypes, and Idiotypes § Amino acid sequences in immunoglobulins that are an-genic determinants § Can react with an-bodies produced by immuniza-on of heterologous species Copyright ©2021 F.A. Davis Company  Isotypes § Unique amino acid sequences common to all Igs of a given class or subclass § Iden-cal in all individuals of a species and differ between species § Located in constant regions of heavy chains and are denoted by Greek lePers for each Ig class: IgG: γ chain, IgM: μ chain, IgA: α chain, IgD: δ chain, IgE: ε chain Copyright ©2021 F.A. Davis Company  Allotypes § Minor varia-ons of amino acid sequences that are present in some individuals of the same species but not others § Located in the constant regions of the IgG subclasses, one IgA subclass, and the λ light chain Copyright ©2021 F.A. Davis Company  Idiotypes § Varia-ons in variable regions that give individual an-body molecules specificity § Located in amino terminal regions of heavy and light chains Copyright ©2021 F.A. Davis Company  IgG § Predominant immunoglobulin in humans (70%–75% of total serum immunoglobulin) § Longest half-life of any immunoglobulin (23 days) § Monomer with a molecular weight of 150,000 daltons and a sedimenta-on coefficient of 7S § Four subclasses: IgG1: 66%, IgG2: 23%, IgG3: 7%, IgG4: 4% Copyright ©2021 F.A. Davis Company  IgG Subclasses § Have slight differences in constant region amino acid sequences § Differ in number and posi-on of disulfide bridges between the γ chains § Differ in func-ons Copyright ©2021 F.A. Davis Company  Major Func-ons of IgG § Binding to complement Leads to inflamma-on and destruc-on of foreign cells IgG3 is most efficient, followed by IgG1 Copyright ©2021 F.A. Davis Company  Major Func-ons of IgG (con-nued) § Neutraliza-on of toxins and viruses § Only Ig that can cross the placenta – provides immunity to newborn § Precipita-on and agglu-na-on Copyright ©2021 F.A. Davis Company  IgM § Known as a macroglobulin Has a molecular weight of about 900,000 d Accounts for 5% to 10% of all serum immunoglobulins § Has half-life of 6 days (much shorter than that of IgG) § Can exist as: Monomer (on surface of B cells) Pentamer (found in blood) Copyright ©2021 F.A. Davis Company  IgM (con-nued) § Pentamer form Held together by a J chain, which forms disulfide bonds that link ends of adjacent monomers Has a star-like shape with 10 an-gen-binding sites Copyright ©2021 F.A. Davis Company  Func-ons of IgM § Complement fixa-on § Agglu-na-on § Neutraliza-on of bacterial toxins and viruses § Known as the primary response an-body Appears first aTer an-genic s-mula-on and in the maturing infant Synthesized only as long as an-gen remains present and may be used to diagnose acute infec-on Copyright ©2021 F.A. Davis Company  IgA § Accounts for 10% to 15% of all circula-ng immunoglobulins in serum § Serum IgA: A monomer with three constant regions and a molecular weight of 160,000 d § Two subclasses — IgA1 and IgA2 Copyright ©2021 F.A. Davis Company  Subclasses of IgA § IgA1 Acts as an an--inflammatory agent Downregulates IgG-mediated phagocytosis, chemotaxis, bactericidal ac-vity, and cytokine release § IgA2 Predominantly found in secre-ons at mucosal surfaces along the respiratory, urogenital, and intes-nal tracts Copyright ©2021 F.A. Davis Company  Secretory IgA § Synthesized mainly by plasma cells in mucosal- associated lymphoid -ssue § Released as a dimer held together by a J chain § Contains a secretory component (SC) derived from epithelial cells Copyright ©2021 F.A. Davis Company  IgA Func-ons § Secretory IgA patrols mucosal surfaces and acts as a first line of defense Neutralizes toxins produced by microorganisms Prevents bacteria from adhering to mucosal surfaces and penetra-ng farther into body § Passively transfers immunity to newborn during breaszeeding § IgA can act as an opsonin. § Aggrega-on of IgA immune complexes may trigger alterna-ve pathway of complement. Copyright ©2021 F.A. Davis Company  IgD § Extremely scarce in the serum § Less than 0.001% of total immunoglobulins § A monomer with a molecular weight of 180,000 d and an extended hinge region § More suscep-ble to proteolysis than other immunoglobulins § Has a short half-life (1 to 3 days) Copyright ©2021 F.A. Davis Company  IgD Func-ons § IgD in serum does not appear to serve a protec-ve func-on; it does not bind complement, bind to neutrophils or macrophages, or cross the placenta. § IgD is also found on the surface of immunocompetent but uns-mulated B lymphocytes: Appears second (aTer IgM) May play a role in B-cell ac-va-on Copyright ©2021 F.A. Davis Company  IgE § Normally 0.0005% of total serum immunoglobulins § A monomer with a molecular weight of 190,000 daltons and a heavy chain with four constant domains § Binding of IgE to eosinophils results in release of enzymes that destroy large an-gens like parasi-c worms that cannot be easily phagocy-zed Copyright ©2021 F.A. Davis Company  IgE Func-on: Allergic Reac-ons § Two adjacent IgE molecules on a mast cell bind a specific an-gen. § Cascade of cellular events results in degranula-on of mast cells and release of vasoac-ve amines (such as histamine and heparin). Copyright ©2021 F.A. Davis Company  Primary Versus Secondary An-body Response Copyright ©2021 F.A. Davis Company  An-body Specificity and Diversity § Based on clonal selec-on and Ig gene-cs § 1950s: Jerne and Burnet’s theory of clonal selec-on for an-body forma-on: Lymphocytes are gene-cally preprogrammed to produce one type of immunoglobulin. A specific an-gen finds the par-cular cells capable of responding to it, causing them to proliferate. Would require a large number of genes. Copyright ©2021 F.A. Davis Company  An-body Specificity and Diversity (con-nued) § 1965: Dryer and BenneP: Constant and variable por-ons of immunoglobulin chains are coded for by separate genes. § 1987: Susumu Tonegawa: Specific Ig gene segments are selected and joined together during B-cell matura-on. Copyright ©2021 F.A. Davis Company  Clonal Selec-on § Each B cell has a BCR specific for a par-cular an-gen. § When an-gen enters the body, it binds only to the B cells that possess BCRs specific for it. § Only those B cells proliferate and differen-ate into an-body-producing plasma cells. Copyright ©2021 F.A. Davis Company  Immunoglobulin Genes § Chromosomes contain building blocks from which genes can be assembled § Human immunoglobulin genes are found in three unlinked clusters: H chain genes on chromosome 14 κ chain genes on chromosome 2 λ chain genes on chromosome 22 § Rearrangement of genes is needed to produce func-onal an-body molecules. Copyright ©2021 F.A. Davis Company  Immunoglobulin Genes (con-nued_1) § More than one gene controls synthesis of a par-cular immunoglobulin H chains ‒ Variable-region genes: VH, D, and J ‒ Constant-region genes: set of C genes L chains: VL, J, and C (lack a D region) § Through random selec-on during B-cell matura-on, individual segments are joined together, commi}ng that B lymphocyte to making an-body of a single specificity. Copyright ©2021 F.A. Davis Company  Immunoglobulin Genes (con-nued_2) § Heavy-chain gene rearrangement Copyright ©2021 F.A. Davis Company  Immunoglobulin Genes (con-nued_3) § Light-chain gene rearrangement Copyright ©2021 F.A. Davis Company  Addi-onal Sources of An-body Diversity § Junc-onal diversity Joining of V, J, and D segments does not always occur at a fixed posi-on. § Different heavy chains can combine with different light chains. § Soma-c hypermuta-on Gene-c muta-ons during the course of the immune response that result in stronger binding of an-gen (affinity matura-on) § Immunoglobulin class switching Copyright ©2021 F.A. Davis Company  Monoclonal An-bodies § Used for laboratory tes-ng and therapy § Developed based on knowledge that each B cell is gene-cally preprogrammed to synthesize a very specific an-body § Derived from a hybrid cell line (“hybridoma”) generated from a single an-body-producing B cell and a myeloma cell § Technique developed in 1975 by Georges Kohler and Cesar Milstein Copyright ©2021 F.A. Davis Company  Hybridoma Produc-on § Immunize a mouse with a specific an-gen. § Harvest spleen cells. § Combine spleen cells with myeloma cells in the presence of PEG. § Select fused cells and screen for presence of desired an-body. § Grow posi-ve cells in larger quan--es. Copyright ©2021 F.A. Davis Company  Monoclonal An-bodies § Monoclonal an-body is a created clone that contains an-bodies of a defined specificity § Monoclonal an-body is produced in vitro § What is needed is a way to make "monoclonal an-bodies”: o an-bodies of a single specificity that are o manufactured by a single clone of plasma cells o that can be grown indefinitely. Found in people with Mul-ple Myeloma Copyright ©2021 F.A. Davis Company  Mul-ple Myeloma (MM) § Plasma Cell Cancer § Multiple bone lesions § Cause: Unknown, but could be radiation, obesity,… § Overproduction of a single Ig component called M Protein or paraprotein=Monoclonal gammopathies § M proteins in palsma and/or urine Copyright ©2021 F.A. Davis Company  Mul-ple Myeloma: Diagnos-c Evalua-on § Bleeding is common. § Platelet abnormali-es are present. § Electrophoresis of serum or urine reveals tall sharp peaks on a densitometer tracing; a dense localized band is seen in 75% of myeloma cases. § A monoclonal serum protein is detected in 91% of MM pa-ents. The type of an-body is IgG in most pa-ents. IgA is seen less frequently, and IgD is rarely demonstrated. Bence Jones protein in urine: monoclonal light chains in the urine of pa-ents with MM Copyright ©2021 F.A. Davis Company  Quantification of Antibodies § Provide informa-on about the func-onal immune status of an individual § IgG, IgM and IgA van be qua-fied using : 1- Radial immunodiffusion 2- Nephelometry 3- Tubidimetry Copyright ©2021 F.A. Davis Company