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Chapter 5 Immunology
Chapter 5 Immunology
Chapter 5 Immunology
Chapter 5 Immunology
Chapter 5 Immunology
Chapter 5 Immunology
Chapter 5 Immunology
Chapter 5 Immunology
Chapter 5 Immunology
Chapter 5 Immunology
Chapter 5 Immunology
Chapter 5 Immunology
Chapter 5 Immunology
Chapter 5 Immunology
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Chapter 5 Immunology
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Chapter 5 Immunology
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Chapter 5 Immunology

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  • 1. Chapter 5 Antigen Recognition by T Lymphocytes
  • 2. Chapter 5
    • T-cell receptor diversity
      • -Formation of receptors
    • Antigen processing and presentation
      • -Antigen processing for T cell recognition
    • The major histocompatibility complex
      • -Polymorphism and MHC diversity
  • 3. B lymphocytes versus T lymphocytes: Similarities
    • Igs and TCR structure
      • Result of gene rearrangement.
    • Variable and diverse antigen specificity
    • Clones express single species of antigen receptor.
    • Clonal distribution of diversity in receptors produced by genetic mechanisms.
  • 4. Fab Domain structure of TCR is similar to Ig
  • 5. B lymphocytes versus T lymphocytes: Differences
    • Igs-variable binding sites (wide range of Ags.).
    • “ Ultimate” sole function to produce secreted antibodies.
    • Bind epitopes on “intact molecules”
      • Proteins, carbohydrates & lipids on surfaces of bacteria, viruses and parasites
      • Soluble toxins
    • TCR-variable binding sites (one type of Ag).
    • More diverse roles with other cells.
    • Important differences in the “type of Ags”
      • One type of antigen
      • Requires presentation by another human cell
      • Ag-presenting glycoproteins ( MHC molecules )
  • 6. Key Difference between Ig and TCR antigen recognition
    • T cells bind one type of antigen which must be presented to them on the surface of another human cell.
  • 7. Major histocompatibility complex (MHC)
    • Ag presenting molecules are glycoproteins.
    • Expressed on almost all cells.
    • Large number genetically determined variants in human population.
      • i.e. differences between individuals in the MHC molecules.
        • MHC determinants of tissue incompatibility before AP role was known.
  • 8. T-cell receptor
    • Membrane bound glycoprotein
    • Resembles a single antigen-binding arm of immunoglobulin.
    • Consists of two polypeptides the  and  chains ; one Ag-binding site .
      • “ membrane bound ”; no secreted form
      • Each chain has variable region (binds Ag) and a constant region just like Igs .
  • 9. T-cell development
    • T-cell development
      • Gene rearrangement = sequence variability in V regions (similar to B-cell)
      • No further mutation in Ag-binding site after Ag stimulation.
      • No switching of constant-region isotype.
    • TCR function - used only to recognize Ag.
    • Ig functions
      • Recognition (Fab region)
      • Effector (Fc region)
  • 10. The T-cell receptor resembles a membrane associated Fab fragment of Ig
    • 2 different polypeptide chains = TCR  and TCR 
    • Genes encoding  and  chains
      • consist of segments that must be rearranged to form a functional gene (like Ig).
    • Rearrangements occur during T cell development ; mature T cell has one functional  , one functional  - chain together they define a unique TCR.
    • An individual’s population of T-cells = many millions of different TCR , each defines a clone of T-cells with a single Ag-binding specificity.
  • 11. Organization of TCR  and  chains
    • TCR  and  chains
      • V regions and C regions.
      • Folded into discrete protein domains.
      • Each chain has an amino-terminal V domain, followed by C domain , and then a membrane-anchoring domain.
  • 12. Comparison of a.a. sequences of V domains from different clones of T-cells
    • Sequence variation in the  and  chains clustered into regions of “ hypervariability”.
    • Correspond to loops of the polypeptide farthest from the T-cell membrane.
    • Loops = Ag-binding site ; complementarity-determining regions ( CDR1,CDR2,CDR 3)
  • 13. T-cell receptor binding
    • TCRs possess single binding site for antigen.
    • Used only as “ cell-surface” receptors for Ag.
      • Never as soluble Ag-binding molecules
    • Occurs in context of two opposing cell surfaces.
    • Multiple copies of TCR bind to multiple copies of Ag:MHC complex on the opposing cell.
    • Multipoint attachment
  • 14. T-cell receptor diversity is generated by gene rearrangement
    • B-cell mechanisms:
    • Prior to Ag encounter
      • Gene rearrangement = V-region sequence
    • Post Ag encounter
      • mRNA splicing =secreted Ig
      • C-region DNA rearrangements = isotype switching
      • Somatic hypermutation = Ab of higher affinity
    • T-cell mechanisms:
    • Prior to Ag stimulation
      • Gene rearrangement = V-region
    • Post Ag stimulation
      • Genes encoding TCR remain unchanged
  • 15. T-cell receptor is used only for the recognition of Ag
    • Effector functions handled by other T-cell molecules.
    • Effector functions of B-cells = solely dependent on secreted Abs.
      • Ab’s different C-region isotypes trigger different effector functions.
  • 16. Human TCR  chain locus (Chr 14) Human TCR  -chain locus (Chr 7)
    • Organization of TCR C-region simpler than Ig:
      • only one C  gene and
      • two C  genes (no functional distinction known)
    • The  chain contains V and J segments (like Ig L-chain)
    • The  chain contains V, J, and D segments (like Ig H-chain)
  • 17. TCR rearrangement occurs during T cell development in the thymus
    • The V domain of  is encoded by V and J.
    • The V domain of  is encoded by V, D, and J.
    • TCR gene segments flanked by recombination signal sequences (RSS).
    • RAG complex and other DNA-modifying enzymes involved in the recombination process.
    • In addition to V, D, J recombination junctional diversity is also attained by insertion of additional, non-templated P and N nucleotides.
  • 18.
  • 19. Rare genetic defect in a RAG gene = Severe combined immunodeficiency disease (SCID)
    • One of the RAG genes does not work.
    • Combined = Functional B and T cells both absent.
    • SCID children die in infancy from common infections (unless they have bone marrow transplants )
    Candida albicans infection
  • 20. Missense mutations that produce RAG proteins with partial enzymatic activity = Omenn syndrome
    • Rapidly fatal immunodeficiency
      • Differs from SCID in symptoms
    Red rash on face and shoulders
  • 21.
    • TCR =  :  heterodimer
      • Alone can not leave ER
      •  :  heterodimer stable association with 4 “invariant” membrane proteins
        • CD3 complex (Chr 11, homologous CD3  , CD3  & CD3  ).
        •  chain (Chr 1).
        • TCR has short cytoplasmic tails .
    Expression of the TCR on the cell surface requires association with additional proteins
    •  = gamma
    • = delta
    • = epsilon
    •  = zeta
  • 22. Expression of the TCR on the cell surface requires association with additional proteins (cont.)
    • CD3 complex &  chain, longer sequence , transduce signals to cell’s interior after Ag recognition by TCR.
    • Lack of functional CD3  & CD3  = low TCR expression and impaired signal transduction = immunodeficiency.
  • 23. TCR complex
    • The TCR complex is composed of 8 polypeptides .
    •  chains form core.
    • the  chains interact with intracellular signaling molecules
  • 24.  And  chains form a second class of TCR expressed by a distinct population of T-cells =  :  TCR
    •  :  TCR structure similar to  :  TCR
      •  chain resembles  chain
      •  chain resemble  chain
    • A cell can express either  :  or  :  TCRs , never both.
    • Cells expressing  :  TCR are called  :  T cells and cells expressing  :  TCRs are called  :  T cells.
    • Cells expressing  :  receptors form a small subset of all T cells (only 1-5%).
    • Can be dominant T cell population in epithelial tissue.
    •  :  T-cells immune functions and Ags less well defined.
    • Not restricted to recognition of Ag associated with MHC.
  • 25. Ag presented by MHC No MHC
  • 26. The germline organization of the  and  loci resembles that of the  and  loci
    • The  gene segments are situated “within” the  -chain locus on chromosome 14.
      • Between the V  and J 
      • Rearrangement of the  -gene = deletion and inactivation of the  -chain.
    • The  chain is on chromosome 7.
    • The  and  chain loci have fewer V gene segments than the  - or  -chain loci.
      • Might produce less diverse receptors.
      • The  chain compensates by having an increase in junctional diversity (pg 72 typo. book states “  chain compensates”) .
  • 27.
    • Organization of the human T-cell receptor γ - and  -chain loci
    •  gene segments are situated within the  -chain locus on chromosome 14
  • 28. Rearrangement at the  and  loci resembles that of the  and  loci
    • Exception: during  -gene rearrangement two D segments can be incorporated into the final gene sequence.
      • = increased variability of the  chain
        • 1. Increase in the potential numbers of recombinations.
        • 2 . Extra N nucleotides can be added at the junction between the two D segments, as well as at the VD and DJ junctions.
  • 29. Antigen processing and presentation
  • 30. B cells can recognize a wide range of molecules in their native form.
  • 31.
  • 32. TCR recognize Ag as a peptide bound to MHC on human cell surface
    • Pathogen-derived protein must first be broken down (Ag processing) and displayed on the surface of cells bound to MHC (Ag presentation)
  • 33. Microorganisms that infect the human body can be broadly divided into two intracellular and extracellular
    • Microorganisms that propagate within cells.
      • Example - Viruses
    • Microorganisms that live in the extracellular spaces.
      • Most bacteria
      • Virus particles present in the EC fluid after release from infected cells.
  • 34. Two class of T cells are specialized to respond to intracellular and extracellular sources of infection
    • Circulating  :  T-cells = 2 “mutually exclusive” classes
      • Defined by CD4 glycoprotein expression
      • Defined by CD8 glycoprotein expression
        • Different functions
        • Different types of target pathogens
    • CD8 T-cells are cytotoxic and kill cells that are infected with a virus or other intracellular pathogen.
      • Prevents pathogen replication and further infection of healthy cells.
    • CD4 T-cells - help other immune cells respond to extracellular sources of infection.
  • 35. The structures of CD4 and CD8 glycoproteins
    • CD4 and CD8 molecules are called T cell co-receptors .
    Ig-like domains
  • 36. CD4 T-cells are helper T-cells
    • Two subclasses:
    • T H 2 cells stimulate B cell (plasma cells) to make antibody.
    • T H 1 cells activate macrophages to phagocytose and kill extracellular pathogens secrete cytokines & other biologically active molecules to affect the course of the immune response.
  • 37. T-cells function by making contact with other cells
  • 38. Two classes of MHC molecule present antigen to CD8 and CD4 T-cells respectively
    • MHC molecules function to ensure that the appropriate class of T cells is activated in response to a particular source of infection.
    • MHC Class I
      • Presents intracellular Ags to CD8 T-cells (ex. Virus infected cell) .
    • MHC Class II
      • Presents extracellular Ags to CD4 T-cells (ex. phagocytosed or endocytosed antigens) .
  • 39. The two classes of MHC membrane glycoprotein molecules have similar 3-D structures
    • MHC Class I = transmembrane heavy chain, or  chain noncovalently complexed to  -microglobulin .
    •  -chain has 3 extracellular domains (  1,  2 and  3) encoded by a gene in the MHC loci.
    •  -microglobulin is not coded by a gene in MHC loci.
    • Folding of  1 and  2 = peptide-binding site farthest from the cell membrane, supported by  3 and  -microglobulin.
  • 40.
    • MHC Class II consists of two transmembrane chains,  and  chain .
      • Each contributes one domain to the peptide-binding site and one Ig-like supporting domain.
      • Both  and  chains are encoded by genes in the MHC.
    The two classes of MHC membrane glycoprotein molecules have similar 3-D structures
  • 41. The similar 3-D structures of MHC I and MHC II molecules consist of two pairs of extracellular domains
    • The paired domains farthest form the membrane resemble each other and form the peptide-binding site.
    • The domains supporting the peptide-binding domains are Ig-like domains:  3 and  -microglobulin in MHC I and  2 and  2 chain in MHC II.
    • Ig-like domains of MHC class I and II are not just a support for the peptide-binding site.
    • They provide binding sites for the CD4 and CD8 co-receptors.
    • Allows the simultaneous engagement of both T-cell receptor and co-receptor by an MHC molecules .
  • 42. MHC class I binds CD8 and MHC class II binds CD4
  • 43. MHC bind a variety of peptides
    • MHC molecules have degenerate binding-capable of binding peptides of many different amino acid sequences.
    • Peptide-binding site = deep groove on the surface of the MHC molecule, a single peptide is tightly noncovalently bound.
    • Length and amino acid sequence constraints.
  • 44. MHC I molecule binding
    • MHC class I
      • Length limited because the two ends of the peptide are grasped by pockets situated at the ends of the peptide-binding groove.
        • 8, 9, 10 a.a. (slight kinking to accommodate)
        • Also may have a hydrophobic or basic residue at the carboxyl terminus complementary to pocket present in MHC I binding groove.
  • 45. MHC II molecule binding
      • MHC class II
        • Two ends of the peptide not pinned down into pockets at each end
        • Extend out at each end of the groove
        • Longer and more variable in length than peptides bound by MHC class I
        • 13-25 a.a. in length or longer
  • 46. There are 2 major compartments within cells, separated by membranes
    • Peptide Ags are bound and presented by MHC.
    • Proteins derived from “intracellular” and “extracellular” antigens are:
      • In 2 “ different” intracellular compartments.
      • Processed by 2 different intracellular pathways of degradation.
      • Bind to 2 different classes of MHC molecule.
  • 47. There are 2 major compartments within cells, separated by membranes
    • Peptide Ags are bound and presented by MHC inside the cells.
    • Proteins derived from “intracellular” and “extracellular” antigens are:
      • In 2 “ different” intracellular compartments.
      • Processed by 2 different intracellular pathways of degradation.
      • Bind to 2 different classes of MHC molecule.
    (2) Vesicular system (ER, Golgi, vesicles) is contiguous with extracellular fluid (1) Cytosol is contiguous with the nucleus through nuclear pores. Extracellular fluid
  • 48. Peptides Generated in Cytosol are Transported into the ER where they bind MHC class I molecules
    • Peptides derived from degradation of intracellular proteins or pathogens are:
      • Formed in the cytosol
      • Delivered to the ER
      • Bound by MHC class I
  • 49. Peptides presented by MHC class II molecules are generated in acidified intracellular vesicles
    • Peptides derived from degradation of extracellular proteins or pathogens are:
      • Taken up by cellular phagocytosis and endocytosis.
      • Degraded in the lysosomes and other vesicles of the endocytic pathways.
      • Bind to MHC class II molecules in these endocytic vesicles.
  • 50. The processing pathway determines which class of MHC molecule interacts with a peptide that originates from extracellular or intracellular pathogen. Intracellular pathogen Extracellular pathogen
  • 51. The processing pathway determines which class of MHC molecule interacts with a peptide that originates from extracellular or intracellular pathogen. Intracellular pathogen Extracellular pathogen
  • 52. Viral infection of human cells
    • Viruses exploit the cell’s protein synthesis machinery to synthesize viral proteins.
      • Viral proteins are found in the cytosol prior to being assembled into viral particles (peptides).
    • In response, the cell uses its normal processes of breakdown and turnover of cellular proteins.
      • To degrade some of the viral proteins into peptides.
      • Peptides are bound by MHC class I molecules.
      • Presented to cytotoxic CD8 cells.
  • 53. Formation and transport of peptides that bind to MHC class I molecules
    • Proteins in the cytosol are degraded by the proteasome protein complex
      • 28 polypeptide subunits (20-30 kDa)
    Tap-2 Tap-1
  • 54. Formation and transport of peptides that bind to MHC class I molecules
    • Ag peptides are then transported into the ER
      • By TAP (the membrane embedded transporter associated with antigen processing)
      • TAP = heterodimer
        • TAP-1 and TAP-2
        • Transport dependent on the binding and hydrolysis of ATP
        • TAP transports peptides of eight or more amino acids having hydrophobic or basic residues at the carboxy terminus
    Tap-1 Tap-2
  • 55. Newly synthesized MHC class I molecules
    • Newly synthesized MHC class I H-chains and  -microglobulin translocate to the ER.
      • Partially complete folding
      • Associate together
      • Bind peptide to complete folding
        • Chaperones = proteins that assist in correct folding of proteins and assembly of other proteins, protection until they enter their respective cellular pathways and to carry out their intended functions
  • 56. When MHC class I heavy chains enter the ER they bind a membrane protein-calnexin
    • Calnexin retains the partly folded  -chain in the ER
      • Calnexin is a Ca 2+ dependent lectin
        • Lectins are carbohydrate-binding proteins that retains many multisubunit glycoproteins (TCRs and Igs) in the ER until they fold correctly.
      • MHC class I  -chain binds  2-microglobulin and calnexin is released from the  :  -microglobulin heterodimer .
  • 57. MHC class I H-chain binds  2-microglobulin and calnexin is released from the  :  -microglobulin
    • Calreticulin and tapasin bind the TAP-1 subunit of the peptide transporter to position the partly folded  :  -microglobulin heterodimer to wait for a suitable peptide from the cytosol.
    • A peptide delivered by TAP binds to class I heavy or  -chain , forming mature MHC class I molecule.
    • The class I molecule dissociates from calreticulin, tapasin, and TAP and is exported from the ER to cell surface.
  • 58. Chaperone proteins aid the assembly and peptide loading of MHC class I molecules in the endoplasmic reticulum Golgi stacks  cell membrane
  • 59. Bare lymphocyte syndrome
    • TAP is non-functional???
    • No peptides enter ER … MHC class I does not reach surface
    • Patients have less than 1% of normal MHC class I
    • Patients have poor CD8 T cell responses to viruses and suffer chronic respiratory infections
  • 60. Peptides Presented by MHC Class II are Generated in Acidified Vesicles
    • Recall: Extracellular bacteria , extracellular virus particles and soluble protein Ags are processed by a different intracellular pathway than intracellular bacteria (cytosolic proteins) and viral proteins.
  • 61. Peptides Presented by MHC Class II are Generated in Acidified Vesicles (cont.)
    • Vesicles travel inwards from the plasma membrane , their interiors become acidified by the action of proton pumps in the vesicle membrane.
    • Vesicle membranes fuse with other vesicles ( lysosomes ) to form phagolysosomes that contain proteases and hydrolases that are activated at low pH.
    • Enzymes degrade the vesicles contents to produce peptides from proteins and glycoproteins.
  • 62. Internalization of extracellular Ags by receptor-mediated endocytosis
    • B cells also bind specific Ags via surface Ig , internalize the Ags by receptor-mediated endocytosis.
    • These antigens are similarly degraded within the vesicular system as by endocytosis mechanism.
    • Peptides within endosomes bind to MHC class II complexes and are carried to the cell surface by outgoing vesicles.
    • Take home message:
      • MHC class I pathway samples the intracellular environment
      • MHC class II pathway samples the extracellular environment
  • 63. The pathways of the MHC class I and II
  • 64. MHC Class II Molecules are Prevented from Binding Peptides in the ER by the Invariant Chain
    • Newly synthesized MHC Class II  and  chains translocated from ribosome  ER.
    •  and  chains ( vary from person) associate in ER with an “invariant” chain (identical in all persons).
      • Invariant chain blocks peptide binding site (formed by  and  chain) from binding peptides present in the ER.
      • Result is that all peptides in ER bind MHC class I molecules only.
      • Invariant chain also delivers class II molecules to endocytic vesicles (called MHC class II compartments or MIIC ).
  • 65. MHC class II compartments or MIIC (Endocytic vesicles )
    • MIIC contain proteases ( cathepsin S ) that selectively cleave invariant chain leaving a small fragment of the invariant chain to cover the MHC class II peptide-binding site
      • Class II-associated invariant-chain peptide ( CLIP fragment)
  • 66. MHC class II compartments or MIIC (Endocytic vesicles )
    • Removal of CLIP and binding of peptide the MHC class II molecule is aided by interaction HLA-DM glycoprotein.
    • HLA-DM catalyzes the release of CLIP and allows MHC class II molecule to sample other peptides until it finds one that binds strongly.
    • MHC class II molecule binds appropriate peptide and is transported to cell surface by outward going vesicles .
  • 67. The invariant chain prevents peptides from binding to a MHC class II molecule UNTIL…it reaches the site of extracellular protein breakdown
  • 68. The TCR Specifically Recognizes Both Peptide and MHC Molecules
    • TCR binds to a peptide - MHC complex .
      • TCR contacts both peptide and MHC surface
      • Each peptide-MHC complex forms unique TCR ligand.
    TCR MHC class I peptide
  • 69. The TCR Specifically Recognizes Both Peptide and MHC Molecules
    • Floor of the peptide-binding groove of both classes of MHC molecule is formed by eight strands of antiparallel  -sheet , with two antiparallel  -helices
    • Peptide lies between the  -helices and parallel to them.
  • 70. The TCR Specifically Recognizes Both Peptide and MHC Molecules
    • Peptide residues that bind to the MHC molecule are deep within the peptide-binding groove making them inaccessible to the TCR.
    • S ide chains of other peptide amino acids stick out of the binding site to bind the TCR.
    Interact with T cell Interact with MHC
  • 71. TCR-ligand:MHC molecules visualized by X-ray crystallography
    • Overall organization of the
    • TCR Ag-binding site
    • resembles that of an Ab
    TCR Ag-binding site of an Ab
  • 72. Similar interactions for peptides bound to either MHC class I or class II
    • TCR binds to MHC class I:peptide complex with long axis of its binding site oriented diagonally across the MHC class I molecule peptide-binding groove
    • TCR binds to an MHC class II:peptide complex in a similar orientation.
  • 73. The CDR3 loops of the TCR  and  chains form the central part of the binding site
    • CDR3 loops grasp the side chain of one of the amino acids in the middle of the peptide.
    • CDR1 and CDR2 loops form the periphery of the binding site and contact the  -helices of the MHC molecule.
    • CDR3 loops directly contacts peptide Ag and they are the most variable part of the T-cell receptor Ag-recognition site.
    • The  -chain CDR3 includes the joint between the V and J sequences.
    • The  -chain CDR3 includes the
      • joints between V and D,
      • the whole of the D segment and
      • the joint between D and J
  • 74. TCR does not interact symmetrically with the peptide and the helices of the MHC molecule.
    • CDR1 and CDR2 loops of the  -chain make stronger contact with the peptide:MHC complex that do the CDR1 and CDR2 loops of the  -chain TCR’s.
      •  -chain CDR1 and CDR2 are light and dark blue respectively.
      •  -chain CDR1 and CDR2 are light and dark purple respectively.
      • The  -chain CDR3 is yellow and the  -chain CDR3 is dark yellow.
      • The 8 amino acid peptide is colored yellow with the first (P1) and the last (P8) amino acids indicated .
  • 75. The TCR Specifically Recognizes Both Peptide and MHC Molecules
    • When the TCR binds to a peptide-MHC complex, it contacts both peptide and MHC surface.
    • Each peptide-MHC therefore forms unique TCR ligand.
  • 76. Most cells express MHC class I; few express MHC class II
    • MHC class I molecules are expressed on almost all nucleated cells.
    • MHC class I are most highly expressed in hematopoietic cells.
  • 77. Most cells express MHC class I; few express MHC class II
    • MHC class II molecular are normally expressed only by a subset of hematopoietic cells (antigen presenting cells) and by stromal cells in the thymus.
    • MHC class II molecules can be produced by other cell types on exposure to the cytokine interferon-  .
  • 78. The major histocompatibility complex
  • 79. Major histocompatibility complex
    • MHC molecules and other proteins involved in Ag presentation are encoded by cluster of closely linked genes called the major histocompatibility complex .
    • Large number of genetic variants for some MHC class I and class II; evolved to permit MHC molecules to bind large variety of peptide sequences.
    • Differences in MHC molecules responsible for graft rejection in organ transplantation.
  • 80. Diversity of MHC molecules in the human population is due to multigene families and genetic polymorphism
    • Unlike Ig and TCR, MHC genes are stable and do not undergo rearrangement or somatic structural change.
    • Inherited diversity is achieved in 2 ways:
      • Multiple similar gene families
        • encoding MHC class I heavy or  chains and
        • encoding MHC class II  and  chains
      • Polymorphism: existence within the population of a great many alternative forms of a MHC class I or class II gene.
      • Individuals are therefore heterozygous for MHC genes
  • 81.
    • The genetic loci that makes up the MHC is highly polymorphic, that is many different forms of the gene or alleles exist at each locus in a population. Their encoded proteins are allotypes.
    • Genes for the MHC loci lie close together and individuals inherit the alleles encoded by these closely linked loci as two sets, one from each parent – called haplotype.
    • Alleles are co-dominantly expressed.
    • Heterozygous = individual inherits different forms of a gene from each parent.
    • Homozygous = an individual inherits the same form of a gene from both parents .
  • 82. MHC class I and class II genes are linked in the MHC complex
    • Genes that encode MHC class I heavy chain and MHC class II  and  chains are closely linked.
    •  -microglobulin and invariant chain are not polymorphic.
      • located on chromosomes 15 and 5 , respectively
    • Region called the MHC complex because first identified as region containing polymorphisms underlying graft rejection.
  • 83. In humans the MHC is called the HLA complex
    • HLA = human leukocyte antigen complex
    • Antibodies used to identify human MHC molecules react with white cells (leukocytes) but not with red cells.
    • The isotypes differ in function and the extent of their polymorphism.
    6 MHC class I isotypes 5 MHC class II isotypes
  • 84. Human MHC class I and II isotypes differ in function and the extent of their polymorphism
    • Human MHC class I isotypes
      • HLA-A, HLA-B and HLA-C present peptide Ags to CD8 T cells and form ligands for NK-cell receptors
      • HLA-E and HLA-G are oligomorphic and form ligands for NK-cell receptors
      • HLA-F is intracellular and of unknown function
    • Human MHC class II isotypes
      • HLA-DP, HLA-DQ and HLA-DR present peptide Ags to CD4 T cells.
      • HLA-DM and HLA-DO are intracellular and regulate peptide loading of HLA-DP, HLA-DQ and HLA-DR.
  • 85. The polymorphism of HLA class I and class II genes
    • The number of known functional alleles in the human population for each HLA class I ( greater diversity ) and class II genes.
    • Class II, diversity contributed by  and  chains
    • Class I, H-chain = polymorphism
    • Notice no gene for  2 invariant light chain of HLA class I - (Chr 15)
  • 86. For each HLA class II isotype, the genes encoding the  and  chains are called A and B, respectively
    • Human MHCs differ in the number of DR genes.
    • The MHC on every human chromosome 6 carries one gene (DRA) for the HLA class II DR  chain but four different genes (DRB1,3,4 or 5) for the DR  chain.
    • In addition, some MHCs carry other DRB3, DRB4 or DRB5.
    • Any DR  chain can pair with the DR  chain to form a class II molecule.
  • 87.
    • The MHC class I and class II genes occupy different regions of the MHC.
    • The positions within the HLA complex of the HLA class I and II genes.
    • The class I genes are all contained in the class I region .
    • The class II genes are all contained in the class II region .
    The MHC class I and class II genes occupy different regions of the MHC on Chromosome 6
  • 88.
    • Class III region (central MHC) contains a variety of genes (not shown) involved in other immune functions.
    • HLA-DP, HLA-DQ and HLA-DR , the  and  chain genes, are close together and shown as a single yellow block .
    • HLA-DO (  and  genes, DOA and DOB) are separated by the HLA-DM (  and  genes together) genes.
    The MHC class I and class II genes occupy different regions of the MHC on Chromosome 6
  • 89. Other proteins involved in antigen processing an presentation are encoded in the MHC class II region
    • HLA complex contains more than 200 genes of which the HLA class I and II genes constitute a minority.
    • Other genes embrace a variety of functions (several important to the immune system).
    • Class II region of the MHC is almost entirely dedicated to genes involved in processing and presenting Ag to T cells.
      • Genes encoding the  and  chains of the 5 HLA class II isotypes.
      • Two polypeptides of the TAP peptide transporter.
      • Gene for tapasin.
      • Genes encoding proteasome subunits ( LMP2 and LMP7).
  • 90. Almost all of the genes in the HLA class II region are involved in Ag processing & presentation to T cells
    • Genes shown in dark gray are pseudogenes that are related to functional genes but are not expressed and unnamed genes in light gray are not involved in immune system function.
    • The class II region includes genes for the peptide transporter (TAP), proteasome components (LMP) and tapasin.
    • Notice no gene for the invariant chain gene (chromosome 5).
  • 91. Variations between MHC allotypes is concentrated in the sites that bind peptide and T-cell Receptor
    • HLA class I molecule allotype variability is clustered in specific sites within the  1 and  2 domains.
    • These sites line the peptide-binding groove, lying either in the floor of the groove where they influence peptide binding or in the  helices that form the walls, which are also involved in binding the TCR.
    • In HLA class II which is a DR molecule, variability is found only in the  1 domain because the  chain is monomorphic.
  • 92. Peptide-binding motifs and the sequence of peptides bound for some MHC isoforms
    • HLA-A and HLA-B isoforms
      • Isoform peptide-binding motif with complete aa sequence of 1 peptide presented by the isoform
      • Blank boxes in the peptide-binding motifs are position at which the identity of the aa can vary
  • 93. Peptide-binding motifs and the sequence of peptides bound for some MHC isoforms
    • HLA-DR and HLA-DQ isoforms
      • only the sequence of a self-peptid e that is bound by the isoform is shown
      • Anchor residues are in green circles
      • MHC class II peptide-binding motifs are not readily defined
  • 94. Polymorphism of MHC Classes I and II affects antigen recognition by T cells
    • Variation between MHC allotypes is concentrated in the sites that bind peptide and TCR.
    • T cells that responds to peptide presented by one MHC allotype will not respond to that peptide bound to another MHC allotype –
    • MHC restriction
  • 95. T-cell recognition of Ags is MHC restricted
    • TCR of the CD8 T cell is specific for the complex of the peptide X with the class I molecule HLA-A*0201.
    • Because of this co-recognition, which is called MHC restriction , the TCR does not recognize the same peptide when it is bound to a different class I molecule, HLA-B*5201.
    • TCR does not recognize the complex of HLA-A*0201 with a different peptide.
  • 96. Haplotype
    • The term was first used in connection with the genes of the MHC
    • With respect of a linked cluster of polymorphic genes, the “set of alleles” carried on a single chromosome
    • Every person inherits 2 haplotypes, one from each parent
  • 97. MHC polymorphism is the primary cause of alloreactions that reject transplants
    • Rejection of transplant caused by immune response in which B cells and T cells of the recipient respond to differences in structure between host and recipient MHC molecules.
    • Differences are allogeneic: the immune response they provoke is an alloreaction.
    • The different MHC molecules are alloantigens and the antibodies they provoke are alloantibodies.
  • 98. Random combination of maternal and paternal haplotypes produces millions of combinations
    • Immense diversity of HLA type means clinical transplants performed across range of HLA matches and mismatches
    • Solid organs (heart/kidney) HLA mismatch overcome by immunosuppressive drugs
    • Bone marrow transplant more sensitive to HLA mismatch; have an alloreaction of the transplanted lymphocytes against recipient’s tissue
    • This graft vs. host disease can be fatal
    • Look for match among siblings
  • 99. MHC heterozygosity delays the progression to AIDS in people infected with HIV-1
    • Seroconversion = HIV-1 infected person begins to make detectable antibodies to the virus
      • The onset of overt symptoms of AIDs occurs years after seroconversion
      • The rate of progress to AIDs decreases with the extent of HLA heterozygosity as compared for individuals who are polymorphic for all the HLA class I and II loci to homozygous for 1,2 or 3
    Heterozygous for all HLA class I and II loci homozygous for 1 locus homozygous for 2 or 3 loci

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