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)
2
Q
Adaptive Immunity
A
Lymphocytes
3
Q
Innate Immunity
A
Circulating and sessile (dentritic) mononuclar macrophges
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
5
Q
Class Ib HLA loci
A
Restricted tissue distribution
Limited antigen-presenting repoertoires
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
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
8
Q
MHC Chromosome location and size
A
Short arm of chromosome 6
approx 7.6 megabased (Mb)
9
Q
HLA Class III
A
region contains numerous immune function related genese which are primarily epxressed as plama proteins.
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
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.
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.
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.
14
Q
Peptide editing
A
Oligopeptides with a better match with the groove will readily replace other oligopeptides not as well matched
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
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
HLA-DR
* 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
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