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HLA > Overview > Flashcards

Overview Flashcards

1
Q

Histocompatibility not on chromosome 6

A
  • TCR alpha and delta genes - 14q
  • TCR gamma (7p)
  • TCR beta (7q)
  • Immunoglobulin heavy chain genes (IGH 14q)
  • IG light changes (kappa 2p, lambda 22q)
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2
Q

Adaptive Immunity

A

Lymphocytes

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3
Q

Innate Immunity

A

Circulating and sessile (dentritic) mononuclar macrophges

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4
Q

Class Ia HLA loci

A
  • Classical
  • HLA-A
  • HLA-B
  • HLA-C
  • Gene product consitutively expressed on the surface of all nucleated cells
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5
Q

Class Ib HLA loci

A

Restricted tissue distribution
Limited antigen-presenting repoertoires

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6
Q

Class II Proteins

A
  • HLA-DR
  • HLA-DQ
  • HLA-DP
  • primarily epxressed on surface of antigen-presenting cells
  • Inducible on other nucleated cells
  • Present external (cell environment) antigens to CED4 T Cells
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7
Q

Class I proteins

A
  • present cytosolic self-antigens to CD8 T cells.
  • dimers of highly polymorphic “heavy” or alpha chain (45kD) and a monomorphic “light” or beta chain (12kD)
  • Heavy chain genes in HLA Class 1 region
  • Light chain is beta-2 microglobulin (15q)
  • Cell surface proetins (some secretory in some alleles)
  • Structurally cimilar to Immunoglobulin
  • Built from series of structural domains from sequential exons
  • Most antigenic and nucleotide polymorphism located in NH2-terminal domain which correcspons to polypeptide binding grovve
  • Conserved extracellular domains provide structure and ligand binding sites
  • Also transmembrae regions and complex anchoring intracellular domain with carboxy terminus.
  • Except for HLA-F, are not expressened on cell surface without an oligopepetide present in the groove
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8
Q

MHC Chromosome location and size

A

Short arm of chromosome 6
approx 7.6 megabased (Mb)

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9
Q

HLA Class III

A

region contains numerous immune function related genese which are primarily epxressed as plama proteins.

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10
Q

TCR-HLA (or MHC) Complex

A
  • The complex interaction between the antigen-presenting cell (APC) and the T cell.
  • CD8 molecule on the T cells acts as a stabilizer for the MHC complex.
  • CD28 on T cell beinds ligand B7 on the APC
  • Also binding of 4-1BBL (CD137L) on the APC by 4-1BB (CD137) on the T cell
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11
Q

CD8 Positive T Cells

A
  • “cytotoxic T cells”
  • direct cell-to-cell killing of targets cells that present nonself oligopeptides in the groove of the HLA Class I molecurles
  • this allows the CD8 positive T cell to recognize cells infected by virus or transformed by malignancy.
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12
Q

HLA protein “Antigen Binding Groove”

A

specificity is mainly from two anti-parallel alpha helixes flanking the oligopeptide, and the eight-stranded beta-pleated sheet in floor of groove.

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13
Q

TAP protein complex

A
  • Transporter associated with antigen processing.
  • Moves oligopeptides, within limited size range, from the cytosol to the ER lumen
  • Selective for peptides that are 8 to 10 amino acids long.
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14
Q

Peptide editing

A

Oligopeptides with a better match with the groove will readily replace other oligopeptides not as well matched

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15
Q

Chaperones

A
  • moves newly synthesized GLA Class I molecules inserted into the inner membrane of ER.
  • includes TAP, tapasin, TAPBPR, calreticulin, ERp57, protein disulfide isomerase, calnexin
  • until beta-2 microbloubuin binds, and an oligopeptide is instereted in the antigen-binding groove
  • binding releases the chaperones
  • Final peptide usually shortened to nine amino acies by ER aminopeptidase 1 (ERAPI) or ERAP2
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16
Q

Immune Surveillance

A
  • Process of TCR of CD8 T cell encounters HLA Class I molecule presenting antigen
  • Either recognized as “self” learned in the thymus, and T-cell does nothing
  • Or the molecule is “novel” and T cell becomes activated
  • Activated T cells release cytokines that attract and recruit other T cells.
  • The T cell may release cytotoxins to diredctly kill the cell
    *
17
Q

KIRs

A
  • killer-cell immunoglobulin-like receptors
  • expressed on the surface of natural killer cells (NK) innate immunity.
  • These are lymphoid cells without the antigen restrictinos
  • Not part of MHC (located on 19q)
  • Ligands for HLA class I molecules
  • Important in recognition and destruction of virally infected cells and ancer cells
  • Alternately, KIR/HLA intereactions, especially HLA-G, supress the immune reponse to the trophoblast during pregnancy
18
Q

HLA-E

A
  • HLA 1b molecule
  • serves as inhibitor for NK cells
  • very restricted number of nonapeptides it is able to display in the groove
  • Can be upregulated in most tissues in response to inflmamation
  • primary function appears to be protecting placental trophoblost tissue from maternal NK cells.
19
Q

HLA-F

A
  • HLA 1b molecule
  • ligand for receptors on NK cells that are minimally expressed on the the surface of cells other than placental trophoblast
  • inducible by inflammation
  • HLA-F expression is not dependent on the presence of an oligopeptide in the groove!! (unlike all others)
20
Q

HLA-G

A
  • HLA 1b molecule
  • expressed primarily on placental trophoblast tissues
  • inducible in other tissues (heart tx)
  • serves the same NK-protective function (downregulation of the immune response through interactions with ILT2, ILT4, KIR2DL4 receptors) for pregnancy as HLA-E and HLA-f (and HLA-c)
  • unique in having isoforms with result from posttrascriptional alternative splicing of the mRNA
21
Q

HLA-H

A
  • former name of HFE
  • serves as regulatory protein for the transferring receptor interaction with transferring
  • mutations result in the variable form of hemochromatosis
22
Q

MICA and MICB

A
  • MHC Class 1-related chain A and B
  • highly polymorphic loci located between HLA-B and MHC Class III region.
  • 383 AA peptides that function by binding the NKG2D activating receptor expressed on all NK cells and CD8 + T cells.
  • normally epxressed on epithelial and endothelial cells and on activated CD4 + T cells and activated B cells.
  • Unlike HLA molecules, do not bind beta-2 microglobulin and do not bind polypeptides for recognition
  • normal function appears to be recognition of altered self by NK cells (neoplasia)
  • Antibodies to MIC antigens are associated with graft reject
23
Q

HLA class II

A
  • dimers composed on heavy (alpha) and light (beta) chains just like Class I molecules
  • difference in weight of these chainse is much less than class 1 and beta-2 microglobulin
  • also present antigen to T cells but are paired with CD4 positive cells
  • both alpha and beta chain genes are location in the Class II region of the human MHC
  • generally only epxressed on specialized APC and inducible on other types
  • principle APS are circulating monocytes and sessile dentritic macrophages
  • influence the proliferative response of T cells when they are exposed to self and nonself stimulating or target cells
  • unlike class I, both alpha and beta chains are poilymorphic
  • For DR, DQ, and DP, the beta chain is much more polymorphic than the alpha chain
  • therefore, the lock-and-key fit of the presented oligopeptide into the groove is located in the amino terminal sequences of the beta chain
  • sysnthesized in the ER and stablized in the lumen by invariant chain (Ii) protein in the presence of calnexin
  • this complex transported to the Golgi
  • endosomic microvesicles are budded off and merge with the phagolysosomal vauoles
  • enzymes and adidic encironment initiate lysis of the invariant chain leaving a fragment (Class II-associated invariabnt chain peptide of CLIP)
  • binding of peptides within the groove has been referred to as “promiscuous” because binding is much less restrctive than in Class I.
  • “lock and alternate keys.”
  • peptides range from 12 to 25 amino acids in lenth (contrast to 9-11 in class I)
24
Q

HLA-DM

A
  • facilitates loading of appropriately sized (length) peptides from the lysosomal complex and removeal of the CLIP
  • functions like tapasin in Class I processing
25
Q

HLA-DR

A
  • alternate beta chains avilable to combine with the alpha chain
  • HLA-DRA provides the alpha chain for beta chain HLA-DRB1
  • Maternal and paternal souce alpha chains can combine with the beta chains that are cis (on the same chromosome) or trans (on the opposite chromosome)
  • likewise, the alpha chains can combine with the protein products of the other HLA-DR beta chains if present)
  • this alternate alpha/beta combinations increase the variety of oliogopeptides that can be presented
26
Q
A

HLA (3 decks)

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