HLA Flashcards
What is HLA?
Human Leukocyte Antigens
set of hoghly polymeric proteins on a cell surface
lage number of alleles (high variation between people)
Role is presentation of peptide to T cells
Many loci allows presentation of many different peptides from any given antigen
polymorphism at each locus prevents a given organism from wiping out an entire population (varibale individual response –> species survival
HLA genes give rise to which proteins?
Each person inherits an array of HLA genes, on chromosome 6p
Give rise to proteins with 2 different structures and roles:
1) Class I: to bind peptides derived from degraded intracellular proteins (viruses and intracellular bacteria)
2) Class II: to bind peptides derived from degraded extracellular proteins (and presented on APCs)
variation in structure determines which proteins are bound (different people can bind different peptides)
Which genes relate to HLA Class I, what is it’s structure and function?
Loci HLA-A, B are most important
(also C, D, E, F, G etc)
presented on all somatic cells except RBCs and some neuronal cells
present peptide to CD8 T cells (from intraccellular infections, viruses and bacteria)
single 3 domain alpha chain (contains peptide groove) and beta-2 microglobulin
Which genes relate to HLA Class II, what is it’s structure and function?
Loci HLA-DR, DP, DQ (and DM, DO etc)
expressed only on specialised APCs (upregulated by inflammatory stimuli from other cells)
presented peptide to CD4 T cells (from extracellular antigens)
2 domain chains, alpha and beta
binds longer peptides than Class I
What is the genomic structure of HLA Class I?
single chain for wach class I molecule, A, B, C
one locus on each chromosome
single gene inherited from each parent (one maternal ABC, one paternal ABC inherited)
two potential HLAs expressed by each individual
What is the genomic structure of HLA Class II?
2 chains to each Class 2 molecule- DR, DP, DQ
1 gene coding to each chain (alpha and beta)
1 gene for each chain inherited from mother and father (4 potential HLA molecules can be expressed by each individual)
CAN have only 1 DR beta gene (so may have between 2 and 4 possible HLA-DR molecules)
How can HLA type be determined for an individual?
1) Serological method
patient’s blood cells are collected (which express HLA proteins on their surface)
incubated with antisera against different HLA proteins, antisera which lyse the cell are expressed by the individual
used for HLA-A, B, C, DR
(antisera collected from multiparous women or multitransfused patients, who have developed antibodies to multiple different HLA subtypes)
2) Molecular
determine genetic HLA sequencing from isolated DNA
extract DNA
PCR up HLA alleles
detection via primers, probes or labelled primers/terminators
2 methods correlate with 2 different classifications of nomenclature, eg HLA-X# (serological type), HLA-X*xxyyz (molecular type)
How does HLA genetic variation account for differing responses to a pathogen between individuals?
there are multiple HLA alleles
each able to bind to a variety of peptides
peptides from a pathogen will likely bind to multiple proteins derived form the alleles
different degrees of response between individuals to vaccinations due to variation in expressed proteins
some HLA alleles will fail to bind to any protein from a given pathogen –> non-responder
What is MHC restriction?
T cells are selected in the thymus to respond to one’s own MHC
CTLs response is generated from the entire surface of the self MHC and the foreign peptide presented
A different MHC has a different surface structure–> CTLs are unable to kill the same antigen presented on a different/foreign MHC
What is the role of MHC restriction in transplantation?
CTLs normally do not recognise foreign MHC, however, through random changce, 1-10% of T cells WILL RECOGNISE foreign MHC
responsible for graft rejection
measured in the mixed lymphocyte reaction (MLR): T cells from a patient are mixed with irradiated cells to prevent their replication and the rate of cell division is measured and refelcts recognition by the patient’s T cells of MHC
