Human immune system. CH Chen

Transcription

1 Human immune system CH Chen

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3 Pathogens (such as bacteria, fungi, and viruses) INNATE IMMUNITY (all animals) Recognition of traits shared by broad ranges of pathogens, using a small set of receptors Rapid response ADAPTIVE IMMUNITY (vertebrates only) Recognition of traits specific to particular pathogens, using a vast array of receptors Slower response Barrier defenses: Skin Mucous membranes Secretions Internal defenses: Phagocytic cells Natural killer cells Antimicrobial proteins Inflammatory response Humoral response: Antibodies defend against infection in body fluids. Cell-mediated response: Cytotoxic cells defend against infection in body cells.

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5 Epidermis Four cell types Melanocytes Produce melanin which protects the skin by absorbing harmful UV radiation Keratinocyes Produce keratin that forms outer protective layer of skin Discourages bacteria and other harmful environmental agents from entering body Prevents loss of water and other valuable body substances Secrete interleukin 1 Langerhans cells Function in specific immunity by presenting antigen to helper T cells Granstein cells Suppress skin-activated immune responses

6 Contains Blood vessels Dermis Nourish the skin Play role in regulating body temperature Sensory nerve endings Provide information about the external environment Several exocrine glands and hair follicles Sebaceous glands Produce sebum Oily substance that softens and waterproofs the skin Sweat glands Produce sweat which helps cool the body

7 Additional Defenses Additional protective measures guard against entry of potential pathogens through internal cavities that communicate directly with the external environment Digestive system Antimicrobial salivary enzyme Destructive acidic gastric secretions Gut-associated lymphoid tissue Harmless resident colonic secretions Genitourinary system Destructive acidic and particle-entrapping mucus secretions

8 Additional Defenses Respiratory system Alveolar macrophage activity Secretion of sticky mucus that traps debris which is swept out by ciliary action Nasal hairs filter out large inspired particles Reflex cough and sneeze mechanisms expel irritant materials from trachea and nose Tonsils and adenoids defend immunologically

9 Immunity Body s ability to resist or eliminate potentially harmful foreign materials or abnormal cells Immune system activities Defends against invading pathogens Removes worn-out cells and tissue damaged by trauma Identifies and destroys abnormal or mutant cells that have originated in the body Mounts inappropriate immune responses that lead either to allergies or to autoimmune diseases

10 Leukocytes Effectors of the immune system Five types Neutrophils Highly mobile phagocytes that engulf and destroy unwanted materials Eosinophils Secrete chemicals that fight parasites Involved in allergic reactions Basophils Release histamine and heparin Involved in allergic reactions Monocytes Transformed into macrophages (tissue-bound phagocytic specialists) Lymphocytes Β lymphocytes (β cells) Transformed into plasma cells that secrete antibodies T lymphocytes (T cells) Responsible for cell-mediated immunity

11 Immune response Innate (nonspecific) vs. Adaptive (specific)

12 Innate immune system Nonspecific Responses work immediately when body is exposed to threatening agent Nonselectively defend against foreign invaders First line of defense Rapid but limited responses Neutrophils, macrophages, several plasma proteins are important in innate defense

13 Innate Immunity Defenses include the following Inflammation Interferon Natural killer cells Complement system

14 Inflammation Nonspecific response to tissue injury Ultimate goal is to bring phagocytes and plasma proteins to invaded or injured area Isolate, destroy, or inactivate the invaders Remove debris Prepare for subsequent healing and repair

15 Inflammation Inflammatory response is similar no matter what the triggering event Defense by resident tissue macrophages Localized vasodilation Increased capillary permeability Localized edema Walling-off the inflamed area Emigration of leukocytes Leukocyte proliferation Marking of bacteria for destruction by opsonins Leukocytic destruction of bacteria

16 Bacterial invasion or tissue damage Release of histamine by mast cells Local arteriolar vasodilation Increased local capillary permeability Increased blood delivery to injured tissue Local accumulation of fluid Redness Heat Swelling Pain Increase in crucial plasma proteins, such as clotting factors, in tissue Increase in phagocytes in tissue Phagocytic secretions Defense against foreign invader; tissue repair Systemic responses, such as fever

17 Interferon Transiently inhibits multiplication of viruses in most cells Triggers the production of virus-blocking enzymes by potential host cells Released nonspecifically from any cell infected by a virus Provides general, rapid defense until more specific but slower-responding immune mechanisms can begin Enhances macrophage phagocytic activity, stimulates production of antibodies, boosts the power of killer cells Exerts anticancer effects

18 Mechanism of Action of Interferon

19 Natural killer (NK) cells Naturally occurring lymphocyte-like cells Nonspecifically destroy virus-infected cells and cancer cells Mode of action Directly lyse cell membranes upon first exposure to these cells

20 Mechanism of Killing by Killer Cells

21 Complement system Nonspecific response Primary mechanism activated by antibodies to kill foreign cells Also activated by exposure to carbohydrate chains present on surfaces of microorganisms but not on human cells Forms membrane attack complexes that punch holes in victim cells Composed of plasma proteins that are produced by the liver and circulate in inactive form

22 Complement system Cascade sequence of events C1 is activated activates C2 activates C3 activates C4 activates C5 Components C5 through C9 assemble into large, doughnut-shaped protein complex (membrane attack complex MAC) Embeds itself in surface membrane of nearby microorganisms Resulting hole makes membrane leaky Victim cell swells and bursts Means of killing microbes without killing them

23 Membrane Attack Complex

24 Complement Several proteins in complement cascade additionally augment inflammatory process by Serving as chemotaxins Acting as opsonins Promoting vasodilation and increased vascular permeability Stimulating release of histamine from mast cells Activating kinins

25 Tissue Repair Tissue repair can be perfect Cell division replaces lost cells with same kind of cells In nonregenerative tissue (nerve and muscle) Lost cells are replaced with scar tissue Drugs that suppress with inflammatory process Nonsteroidal anti-inflammatory drugs (NSAIDs) Aspirin Ibuprofen Glucocorticoids Suppress almost all aspects of inflammatory process Reduce body s ability to resist infection

26 Adaptive immunity Two classes of adaptive immunity Antibody-mediated or humoral immunity Involves production of antibodies by B lymphocyte derivatives known as plasma cells Cell-mediated immunity Involves production of activated T lymphocytes Directly attack unwanted cells

27 Origins of B and T Cells

28 Lymphoid tissues Tissues that produce, store, or process lymphocytes Include Bone marrow Lymph nodes Spleen Thymus Tonsils Adenoids Appendix Peyer s patches (GALT) Gut associated lymphatic tissue

29 Blood capillary Interstitial fluid Adenoid Tonsils Thymus Peyer s patches (small intestine) Lymphatic vessels Spleen Tissue cells Lymphatic vessel Lymphatic vessel Appendix (cecum) Lymph nodes Lymph node Masses of defensive cells

30 免疫系統器官和組織 初級淋巴器官 骨髓 胸線 次級淋巴器官 淋巴結 脾臟 黏膜層淋巴組織 表皮免疫組織

31 Antibody T cell receptor Stimulate an immune response Immune System Cells and Receptors

32 Communication Among Immune System Cells 1. Macrophage engulfs 7. Division gives invader rise to memory B cells and plasma cells 6. Activated Helper T cell stimulates division of selected B lymphocyte 2. Macrophage displays processed antigen on MHC molecule 3. Invader binds to B lymphocyte that carries antibody matching the antigen 4. Helper T Cell binds to Macrophage 5. Macrophage releases cytokines to activate Helper T cell

33 Figure Antigenpresenting cell Antigen fragment Pathogen 1 Class II MHC molecule Accessory protein Antigen receptor Helper T cell Humoral immunity Cytokines 3 B cell 2 Cytotoxic T cell Cellmediated immunity

34 Antibodies Can physically hinder antigens By neutralization, they prevent harmful chemicals from interacting with susceptible cells Can bind to foreign cells by agglutination Enhance activity of other defense systems by Activating complement system Enhancing phagocytosis Stimulating killer (K) cells

35 B cell-bound antibodies recognize antigens on a bacterial or viral invader. Circulating antibodies mark the invader for destruction.

36 B cell specific to antigen Different B cell clones Antigens Rough endoplasmic reticulum Plasma cells Memory cells Antibodies

37 B lymphocyte with antibody matching the antigen is stimulated to divide Clonal Selection of B cells Each B lymphocyte has a unique antibody on its surface

38 Primary and Secondary Immune Responses

39 Antibody concentration (arbitrary units) Figure Primary immune response to antigen A produces antibodies to A. Secondary immune response to antigen A produces antibodies to A; primary immune response to antigen B produces antibodies to B Antibodies to A Antibodies to B Exposure to antigen A Exposure to antigens A and B Time (days)

40 First exposure to a pathogen s antigens Natural exposure to virulent, antigenic pathogen Virulent portion Antigenic portion Exposure to nonvirulent, antigenic pathogen through vaccination Combat No virulence Disease Specific B cell clone Specific B cell clone No disease Plasma cells Antibodies (slow, weak primary response) Memory cells (long-term immunity) Plasma cells Subsequent exposure to same virulent pathogen Memory cells (long-term immunity) Plasma cells Plasma cells Antibodies (not needed) Antibodies (swift, strong secondary response) Combat Combat Antibodies (swift, strong secondary response) No disease

41 Active and Passive Immunity Active immunity self-generated Results from exposure to an antigen Passive immunity borrowed immunity Results from transfer of preformed antibodies Can provide immediate protection or bolster resistance Example of passive immunity is transfer of IgG antibodies from mother to fetus

42 Antibody Structure Antibody has 2 heavy chains and 2 light chains. Each chain has variable (V) and constant (C) region joined by a J region. Variable regions bind to antigen. Constant regions bind to cells or other antibodies.

43 HUMORAL IMMUNE RESPONSE Immunogenetics Chromosomes 2, 22, 14 have genes for kappa, lambda, hvy chains Variable region genes upstream from constant region genes Genetic recombination events to form variable region of hvy and lt chains: V (variable) and J (joining) segments for light chains ~ 300 V gene segments and ~5 J segments = ~ 1500 possible V, D (diversity), and J segments for hvy chains V genes, 12 D genes, and 6 J genes = <100,000 possible Association of hvy and light chain = > 1,000,000 possible

44 Structure and Expression of Light Chain Genes Somatic recombination brings one V and one J segment together RNA Processing leads to one VJC combination

45 Structure and Expression of Heavy Chain Genes 51 V 27 D 6J Somatic recombination brings one V, D and J segment together near a C segment RNA Processing leads to one VDJC combination

46 Generating Antibody Diversity Germ Line Diversity Combinatorial Joining Junctional Diversity Somatic Hypermutation Joining Light & Heavy Chains Multiple V, D, J Segments Large number of V, D, J combinations by somatic recombination Mutations produced at the junctions between gene segments by exonuclease and terminal transferase activities V genes undergo an increased mutation rate as immune cells divide throughout the response period Combining different light and heavy chains increases the number of unique antibodies formed

47 Plasma Cells Produce antibodies that can combine with a specific kind of antigen All antibodies eventually enter blood where they are known as gamma globulins or immunoglobulins Antibody (Immunoglobulin) subclasses IgM Serves as the β cell surface receptor for antigen attachment Secreted in early stages of plasma cell response IgG Most abundant immunoglobulin in blood Produced in large amounts when body is exposed to same antigen IgE Helps protect against parasitic worms Antibody mediator for common allergic responses IgA Found in secretions of digestive, respiratory, and genitourinary systems; also in milk and tears IgD Present on surface of many β cells Function is uncertain

48 HUMORAL IMMUNE RESPONSE Immunogenetics (continued) Class switching Genes for constant region of hvy chain in set order IgM, D, G 3, G 1, G 2, G 4, E, A 1, A 2 Different constant region genes deleted in response to T cell cytokines

49 How did the arrangement of antibody genes arise? Changes in gene number and organization are due to Duplication Diversification Selection

50 Levels of Duplication Individual Genes Multigene Families Gene Superfamily

51 Action of Natural Selection Natural selection acts on the genetic variability caused by mutation If the Mutation is Neutral Deleterious Advantageous The gene will be Unselected (Remain or Disappear as a result of genetic drift) Eliminated Fixed

52 Immune System Receptors Belong to the Immunoglobulin Gene Superfamily A Gene Superfamily is a large set of related genes that is divisible into smaller sets or families Genes in each family are more closely related to each other than to genes in other families Multigene families within this Superfamily Antibody Genes T cell receptor genes MHC protein genes

53 Immunoglobulin Superfamily Genes Share a Common Homology Unit

54 T Lymphocytes Two main types of T cells CD8 cells (cytotoxic, or killer T cells) Destroy host cells harboring anything foreign CD4 cells (mostly helper T cells) Modulate activities of other immune cells Secrete chemicals that amplify the activity of other immune cells Β-cell growth factor T-cell growth factor (interleukin 2) Macrophage-migration inhibition factor

55 Antibodies Macrophages secrete interleukin 1, which enhances B cell proliferation and antibody secretion Interleukin 1 Invading bacteria Macrophage Macrophages process and present bacterial antigen to B and T lymphocyte clones specific to the antigen Antibodies enhance phagocytosis by coating the bacteria and serving as opsonins B cell B cell growth factor Plasma cell Helper T cell Activated helper T cell Plasma cells secrete antibodies that bind with the antigenic bacteria Helper T cells secrete B cell growth factor that enhances B cell proliferation and antibody secretion

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57 Cytotoxic T cell Accessory protein Class I MHC molecule Infected cell 1 Antigen receptor Antigen fragment

58 Cytotoxic T cell Accessory protein Class I MHC molecule Antigen receptor Infected cell Antigen 1 fragment 2 Perforin Pore Granzymes

59 Cytotoxic T cell Released cytotoxic T cell Accessory protein Class I MHC molecule Antigen receptor Infected cell Antigen 1 fragment 2 Perforin Pore Granzymes 3 Dying infected cell

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61 Humoral (antibody-mediated) immune response Antigen (1st exposure) Engulfed by Cell-mediated immune response Key Stimulates Gives rise to Antigenpresenting cell B cell Helper T cell Cytotoxic T cell Memory helper T cells Antigen (2nd exposure) Plasma cells Memory B cells Memory cytotoxic T cells Active cytotoxic T cells Secreted antibodies Defend against extracellular pathogens Defend against intracellular pathogens and cancer

62 Cytotoxic T cell T cell receptor Foreign antigen MHC self-antigen Invaded cell

63 Key Concepts in T-cell Receptor (TCR) 1. T-cell antigen receptor (TCR) is similar to the F(ab) of Ab but only located on the surface of T cells => No secreted form => Two major types: ab TCR and gd TCR 2. TCR functions to recognize Ag peptide and then to activate T cells => Adaptive immunity 3. Ag recognition by ab TCR requires Ag presented by Major Histocompatibility Complex (MHC). => consider both Ag peptide & MHC => Cell-Cell interaction 4. The Ag-binding site region of the TCR is formed by the Va and Vb regions.

64 Structure of the TCR (αβ) Regions Short cytoplasmic tailcannot transduce activation signal Transmembrane with hydrophobic AAs Both α and β have a variable (V) and constant (C) region V region is hypervariable, determines Ag specificity

65 Similarities & Differences between T-cell Receptor (TCR) and Ab

66 Genetic basis for receptor generation Accomplished by recombination of V, D and J gene segments TCR β chain genes have V, D, and J TCR α chain genes have V and J

67 Rearrangement of the TCR α and β genes. The TCR a-gene locus contains multiple V and J segments, only several of which are shown here. Similarly, the TCR b-gene locus contains multiple V, D, and J segments. During T-cell ontogeny, the TCR genes rearrange (arrows), so that one of the Va segments pairs with the Ja segment and a Vb segment pairs with a Db and Jb segment. The two C (constant) segments in the b gene are very similar, and differential use of Cb1 and Cb2 does not contribute to TCR diversity. 2/9/04

68 TCR & Accessory Molecules Accessory Molecules -Help T cells in response to a specific Ag 1. CD3 (e, g, d ) and z chains : associates w/ TCR => intracellular signaling transduction 2. CD4/CD8: CD4 MHC-II CD8 MHC-I 3. CD28: a co-stimulatory receptor 4. Integrin: Adhesion & co-stimulation

69 TCR and CD3 complex TCR is closely associated with CD3 complex Group of 5 proteins Commonly called invariant chains of TCR Role of CD3 complex CD3 necessary for cell surface expression of TCR transduces signal after Ag interaction with TCR

70 Interactions of Accessory molecules between T cells & APCs

71 Key steps in T cell activation APC must process and present peptides to Ts Ts must receive co-stimulatory signal Accessory adhesion molecules stabilize binding of TCR and MHC Signal from cell surface is transmitted to nucleus Cytokines produced help drive cell proliferation

72 T cells require APCs to respond to a specific Ag

73 ADAPTIVE IMMUNE RESPONSE antigen presenting cells Antigen processing and presentation

74 ADAPTIVE IMMUNE RESPONSE antigen presenting cells Antigen Presenting Cells (APCs) = Dendritic cells (DCs), B cells, and Macs Dendritic cells = only APC that can initiate Ag specific response Presumably from myeloid and lineage Precursor DCs in blood; differentiate into immature DCs (idc) idc recognized antigen with TLR and other receptors; activated Pinocytosis/phagocytosis and cytokine production, now DC DCs can no longer phagocytose; go to T-cell area of lymph nodes where they present Ag to T cells Langerhan s cells are skin DC

75 Functions of different APCs

76 Dendritic cells The Most effective APCs 1. Located at common sites of entry of microbes 2. Express receptors to capture microbes. 3. Migrate preferentially to T- cell zones in LNs. 4. Mature DCs express high levels of costimulators => T-cell activation.

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78 T Cell - Mediated B Cell Activation

79 ADAPTIVE IMMUNE RESPONSE antigen presenting cells Cross-presentation of Ag to CD8 T cells.

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81 Immune System Tolerance Tolerance refers to preventing the immune system from attacking the person s own tissues Mechanisms involved in tolerance Clonal deletion Clonal anergy Receptor editing Inhibition by regulatory T cells Immunological ignorance Immune privilege

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85 Autoimmune Diseases Arise from loss of tolerance to self-antigens Examples of causes Exposure of normally inaccessible self-antigens sometimes induces an immune attack against these antigens Normal self-antigens may be modified by factors such as drugs, environmental chemicals, viruses, or genetic mutations so that they are no longer recognized and tolerated by the immune system. Exposure of the immune system to a foreign antigen structurally identical to a self-antigen May be related to pregnancy, arising from lingering fetal cells in the mother s body after the pregnancy

86 Immune Diseases Due to abnormal functioning of the immune system Two general ways Immunodeficiency diseases Too little immune response Examples severe combined immunodeficiency AIDS Inappropriate immune attacks Too much or mistargeted immune response Categories of inappropriate attacks Autoimmune responses Immune complex diseases Allergies

87 Allergy Acquisition of an inappropriate specific immune reactivity (hypersensitivity) to a normally harmless environmental substance Offending agent is known as an allergen Categories of allergic responses Immediate hypersensitivity Delayed hypersensitivity

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89 Immediate Hypersensitivity Chemical mediators Histamine Slow-reactive substance of anaphylaxis (SRS-A) Eosinophil chemotactic factor Symptoms Vary depending on site, allergen, and mediators involved Hay fever Asthma Hives

90 Comparison of Immediate and Delayed Hypersensitivity Reactions

91 Blood Groups Form of passive immunity ABO blood types are named for presence of antigens on surface of erythrocytes Type A has A antigens and anti-b antibodies Type B has B antigens and anti-a antibodies Type AB has both A and B antigens and no antibodies related to the ABO system Type O does not have A or B surface antigens and both anti-a and anti-b antibodies Transfusion reaction occurs when blood of incompatible type is given Blood type O is the universal donor Blood type AB is the universal recipient

92 Transfusion Reaction Chapter 12 The Body Defenses Human Physiology by Lauralee Sherwood 2007 Brooks/Cole-

93 Other Blood Group Systems Rh factor Rh-positive individual has Rh factor Rh-negative individual lacks Rh factor Erythroblastosis fetalis (hemolytic disease of the newborn) Occurs when Rh-negative mother develops antibodies against the erythrocytes of an Rh-positive fetus Approximately 12 other minor human erythrocyte antigen systems

94 Key Concepts in Major Histocompatibility Complex (MHC) 1. Ag presentation to TCR is mediated by Two classes of MHC molecules. - Class-I MHC => peptides from cytosolic (intracellular) proteins => CD8 T cells - Class-II MHC => peptides from extracellular (exogenous) proteins from phagocytosis => CD4 T cells 2. In humans, the MHC is also called as the HLA (Human Leukocyte Antigen). 3. MHC genes are the most polymorphic genes present in the genome and co-dominantly expressed in each individual. 4. MHC molecules express on the cellular surfaces of only in presence of Ag-peptides. Class-I => all nucleated cells Class-II => APCs (DC, Macrophages & B cells)

95 TCR-Ag w/ Histocompatibility Complex (MHC)

96 Schematic maps of human & mouse MHC loci

97 Structure of Class-I MHC molecule a1a2 domains are polymorphic and form the peptide-binding cleft. a3 domain is conserved among all MHC class-i, and folds into an Ig domain for CD8 binding.

98 Structure of MHC class I Four regions Cytoplasmic contains sites for phosphorylation and binding to cytoskeleton Transmembrane contains hydrophobic AAs Highly conserved α3 domain binds CD8 Highly polymorphic peptide binding region formed by α1 and α2

99 Structure of Class-II MHC molecule a1b1 domains are polymorphic and form the peptide-binding cleft. b2 domain is conserved among all MHC class-ii, and folds into an Ig domain for CD4 binding.

100 Polymorphic residues of MHC molecules In Class-I, polymorphic residues => the peptide-binding cleft formed by a1a2 domains In Class-II, polymorphic residues => the peptide-binding cleft formed by a1b1 domains In this case HLA-DR, polymorphism is on b1domain

101 MHC genes are highly Polymorphic

102 Expression of MHC alleles is co-dominant

103 Polymorphism & Polygeny both contribute to the MHC diversity

104 Pathogen presentation by MHCs

105 The Class II MHC pathway of Ag Presentation

106 The Class I MHC pathway of Ag Presentation

107 MHC molecules are targets for immune evasion by pathogens Without T cells there is no effective immune response Ag specific T cells are activated by peptide/mhc complexes There is therefore strong selective pressure for pathogens to mutate genes encoding antigens so that they can evade the formation of peptide/mhc complexes The MHC has two strategies to prevent evasion by pathogens More than one type of MHC molecule in each individual. Extensive differences in MHC molecules between individuals

108 Example: If MHC X was the only type of MHC molecule MHC XX Pathogen that evades MHC X Survival of individual threatened Population threatened with extinction

109 Example: If each individual could make two MHC molecules, MHC X and Y Pathogen that evades MHC X but has sequences that bind to MHC Y MHC XX MHC YY MHC XY Impact on the individual depends upon genotype Population survives

110 Example: If each individual could make two MHC molecules, MHC X and Y and the pathogen mutates Pathogen that evades MHC X but has sequences that bind to MHC Y.until it mutates to evade MHC Y MHC XX MHC YY MHC XY Survival of individual threatened Population threatened with extinction The number of types of MHC molecule can not be increased ad infinitum

111 Populations need to express variants of each type of MHC molecule Populations of microorganisms reproduce faster than humans Mutations that change MHC-binding antigens or MHC molecules can only be introduced to populations after reproduction The ability of microorganisms to mutate in order to evade MHC molecules will always outpace counter evasion measures that involve mutations in the MHC The number of types of MHC molecules are limited To counteract the superior flexibility of pathogens: Human populations possess many variants of each type of MHC molecule Variant MHC may not protect every individual from every pathogen. However, the existence of a large number of variants means that the population is prevented from extinction

112 Variant MHC molecules protect the population MHC XX XX XX R XY R YX R YY R YY X R X R Pathogen that evades MHC X and Y but binds to the variant MHC X R and MHC Y R MHC YY MHC XY From 2 MHC types and 2 variants. 10 different genotypes Y R Y R X R Y R XY MHC YY R MHC XX R Variants alleles - of each type of MHC gene encode proteins that increase the resistance of the population from rapidly mutating or newly encountered pathogens without increasing the number of types of MHC molecule

113 Molecular basis of MHC types and variants POLYGENISM Several MHC class I and class II genes encoding different types of MHC molecule with a range of peptide-binding specificities. POLYMORPHISM Variation >1% at a single genetic locus in a population of individuals MHC genes are the most polymorphic known The type and variant MHC molecules do not vary in the lifetime of the individual Diversity in MHC molecules exists at the population level This sharply contrasts diversity in T and B cell antigen receptors which are in a constant state of flux within the individual.

114 Simplified map of the HLA region DP b a DM a b LMP/TAP DQ b a b1 b3 DR b4 b5 a B C A MHC Class II Class III MHC Class I Polygeny CLASS I: 3 types HLA-A, HLA-B, HLA-C (sometimes called class Ia genes) CLASS II: 3 types HLA-DP HLA-DQ HLA-DR. 3 extra DRb genes in some individuals can allow 3 extra HLA-DR molecules Maximum of 9 types of antigen presenting molecule allow interaction with a wide range of peptides.

115 No of polymorphisms Polymorphism in MHC Class I genes Variation >1% at a single genetic locus in a population of individuals In the human population, over 1300 MHC class I alleles have been identified - some are null alleles, synonyms or differ in regions outside the coding region Class I 1318 alleles (998 in October 2003) (657 in July 2000) A B C E F G Data from September 2005

116 No of polymorphisms Polymorphism in MHC Class II genes Over 700 human MHC class II alleles have been identified - some are null alleles, synonyms or differ in regions outside the coding region Class II 733 alleles (668 in October 2003) (492 in July 2000) A B1 A1 B1 A1 B1 DR A B A B DQ DP DM DO Data from September 2005

117 No of serologicallydefined antigens Diversity of MHC Class I and II antigens Because so many MHC class I & II alleles are null, or contain synonymous mutations, the diversity of MHC molecules that can be identified by antibodies i.e. SEROLOGICALLY, is considerably fewer than that by DNA sequencing 62 Class I - ~100 antigens Class II - ~40 antigens (Figure hasn t changed since October 2003) A B C DR DQ DP Data from September 2005

118 Polymorphism in the MHC affects peptide antigen binding MHC allele A MHC allele B Changes in the pockets, walls and floor of the peptide binding cleft alter peptide MHC interactions and determine which peptides bind. S Y I P S A K I R G Y V Y Q Q L MHC allele A MHC allele B Products of different MHC alleles bind a different repertoire of peptides

119 Replacement substitutions occur at a higher frequency than silent substitution Suggests that selective pressures may operate on MHC polymorphism Evolution of pathogens to evade MHC-mediated antigen presentation 60% of individuals in south east China & Papua New Guinea express HLA-A11 HLA-A11 binds an important peptide of Epstein Barr Virus Many EBV isolates from these areas have mutated this peptide so that it can not bind to HLA-A11 MHC molecules Evolution of the MHC to eliminate pathogens In west Africa where malaria is endemic HLA-B53 is commonly associated with recovery from a potentially lethal form of malaria

120 Diversity of MHC molecules in the individual DP DQ DR b a b a b1 a B C A Polygeny HAPLOTYPE 1 DP DQ DR b a b a b1 a B C A Variant alleles polymorphism HAPLOTYPE 2 DP DQ DR b a b a b1 a B C A Additional set of variant alleles on second chromosome MHC molecules are CODOMINANTLY expressed Two of each of the six types of MHC molecule are expressed Genes in the MHC are tightly LINKED and usually inherited in a unit called an MHC HAPLOTYPE

121 Inheritance of MHC haplotypes DP-1,2 DQ-3,4 DR-5,6 B-7,8 C-9,10 A-11,12 DP-9,8 DQ-7,6 DR-5,4 B-3,2 C-1,8 A-9,10 Parents DP DQ DR DP DQ DR X DP DQ DR DP DQ DR B C B C B C B C A A A A Children DP-1,9 DQ-3,7 DR-5,5 B-7,3 C-9,1 A-11,9 DP-1,8 DQ-3,6 DR-5,4 B-7,2 C-9,8 A-11,10 DP-2,8 DQ-4,6 DR-6,4 B-8,2 C-10,8 A-12,10 DP-2,9 DQ-4,7 DR-6,5 B-8,3 C-10,10 A-12,9 DP DQ DR DP DQ DR DP DQ DR DP DQ DR DP DQ DR DP DQ DR DP DQ DR DP DQ DR B C B C B C B C B C B C B C B C A A A A A A A A

122 Errors in the inheritance of haplotypes generate polymorphism in the MHC by gene conversion and recombination A B C A B C A B C Multiple distinct but closely related MHC genes A B C During meiosis chromosomes misalign A B C Chromosomes separate after meiosis DNA is exchanged between haplotypes GENE CONVERSION A B C RECOMBINATION between haplotypes In both mechanisms the type of MHC molecule remains the same, but a new allelic variant may be generated

123 A clinically relevant application of MHC genetics: Matching of transplant donors and recipients The biology, diversity and complexity of the MHC locus and its pattern of inheritance explains: The need to match the MHC of the recipient of a graft with the donor The difficulties faced in matching unrelated donors with recipients The ~20% chance of finding a match in siblings

124 For their work leading to the discoveries of MHC (mouse) and HLA (human). - Immune recognition => The foundation of adaptive immunity - Transplantation