Section 6: Human Leukocyte Antigen Flashcards
major histocompatibility complex (MHC)
-unlike B-cells, T-cells recognize antigen only in the form of a short peptide chain bound to MHC molecule
-this means for a pathogen to elicit a T-cell response its proteins must be degraded into peptides
- this occurs inside cells (ANTIGEN PROCESSING) and then loaded onto MHC molecule for (ANTIGEN PRESENTING)
MHC I
-1 transmembrane heavy chain- alpha (3 domains)
-1 small protein- B2 microglobulin
MHC II
- 2 transmembrane heavy chain- alpha and beta (each with two domains)
promiscuous binding specificity
-MHC molecules bind a variety of peptides which is called…
-MHC I bind 8-10 mer peptide long
-MHCII bind 13-25 mer peptide long
MHC genetics
-MHC molecules and other proteins involved in Ag processing/presenting are encoded in a cluster of genes on chromosome 6 also called the major histocompatibility complex
-the genes that code for MHC I and II are highly polymorphic in the human population
-they do not undergo recombination
Human leukocyte
-when discussing MHC molecules and genes in the human population it is referred to as human leukocyte antigen (HLA)
MHC I = HLA class I
MHC II = HLA class II
isotypes
different forms of HLA
ex: HLA I and HLA II
alleles
different forms of a given gene
-you inherit one paternal allele and one maternal for most genes in your body
allotypes
-different forms of a given gene with their differing protein products
Highly polymorphic
-many many alleles
Polymorphic
-many alleles
Oligomorphic
few alleles
Monomorphic
-one allele
What are the 6 human MHC class I isotypes
(HLA-A, B, C, E, F, G)
- HLA-A, B, C are highly polymorphic and they function to present
Ag to CD8 T-cells and NK cells
- HLA-E, G are oligomorphic and form ligands for NK cells
- HLA-F is monomorphic and remains intracellular (unknown)
What are the 5 human MHC class II isotypes?
(HLA-DM, DO, DP,
DQ, DR)
-HLA-DP, DQ, DR are highly polymorphic and present Ag to CD4 T cells
- HLA-DM, DO are responsible for loading peptides onto DP, DQ,
DR
HLA Diversity
-HLA genes are located on the short arm of chromosome 6 which is divided into three regions
-there is no gene for β2-microglobulin this gene is found on chromosome 15
-an individual may carry multiple alleles for each HLA chain
- Since HLA molecules are dimers, a HLA-DRA (alpha chain) can combine with any of the DRB1, B3, B4, B5 beta chains to form slightly different HLA-DR receptors
HLA Nomenclature
-For HLA type II isotypes the genes that encode the α and β chains respectively are called A and B respectively
ex: HLA-DQA, HLA-DQB
-when there is more than one gene (alleles) coding a particular chain, a number series is added to identify the gene
ex:HLA-DQA1 , HLA-DQA2
haplotype
-an individuals specific combination of HLA genes is called this
HLA Polymorphism
-HLA genes are highly polymorphic and HLA proteins can differ by 1-50 amino acid substitutions
-these polymorphism are concentrated at sites of peptide and T-cell receptor binding
-mutations between HLA isoforms can vary greatly, a few amino acids are conserved between some isoforms
anchor residues
-this is what the amino acid residues are called, they are important for binding the peptide
MHC restriction
-the fact a given T-cell receptor will recognize its peptide antigen only when it is bound to a particular form of MHC molecule
-your response to an infectious disease is extremely governed by your MHC molecules
Selection for diversity
-the frequency of nonsynonymous mutation (coding for a different amino acid) in HLA genes is much greater than what would be expected by chance
-this diversity is due to strong selective pressures caused by pathogens
It appears natural selection has driven the highly polymorphic nature of HLA and the general HETEROZYGOSITY present in most individuals
-Grey circles represent the total number of antigenic peptides derived from a pathogen
-Yellow circles represent the subpopulation of peptides that can be presented
-Heterozygotes for HLA haplotypes can potentially respond to a larger number of peptides
Balancing selection
all these selective processes on HLA genes work to maintain a variety of isoforms in the population
- we are constantly getting affected or challenged by some infectious disease (before medicine) populations would be periodically infected, so homogenous offspring for HLA would be selected against
-this selection restricts some forms of HLA and enriches it for the heterozygosity
-this happens all the time
direction selection
- a strong selective process that favors a specific HLA allele
- this favors a specific type of combination of alleles, so now we got rid of homozygous, and now people without a certain HLA
-this has to do with major epidemics
interallelic conversion and gene conversion
-result in the production of new HLA and alleles by swapping gene segments from different alleles or genes (homologous recombination)’
-because pathogens adapt to the HLA of their host, there is a preference for new HLA alleles, to which the pathogen has not been exposed
-these happen more when you are first developing and maternal and paternal genes are recombining in your chromosomes
HLA and HIV
-the current pandemic of HIV provides a unique opportunity to study the effects of HLA polymorphisms on an infectious disease
-certain allotypes of HLA genes are associated with disease progression
-Even with specific HLA alleles conferring disease progression… HLA heterozygosity still affects progression
slow progression HLA allotypes
HLA-B14, B27, B57, C8, C14
rapid progression HLA allotypes
HLA-A29, B22, B35, C16, DR11
organ transplant
-during T-cell development any cells that respond strongly to self-peptide presented by MHC are eliminated
autologous
-an individuals particular self-MHC isoforms are described as this
allogenic
other isoforms are described as this
Alloreactive T-cells
-In a given population of T-cells there are between 1-10% of cells capable of reacting to peptide bound to allogenic MHC
-are the main players in organ transplant rejection
-this is why individuals are HLA typed before a transplant to try and minimize the alloreactive response
-the more similar the HLA alleles the lower the risk of rejection
Direct alloantigen
-donor DCs present alloantigens to T-cells in host lymph node
indirect alloantigen
- Host DCs present alloantigens to T-cells in host lymph node
alloantibody
-happens naturally in pregnant women where the mother produces these
-the fetus is protected from these alloantibodies
-can cause major complications in organ transplants which is almost untreatable
interallelic conversion
-mom and dad genes cross over a make a new gene,
-this one is in between alleles of the same gene
gene conversion
-within an individual, as it recombines, so now have two HLA molecules that might have an area of homologous that can cross over and create a new allele
-this one is a completely different gene
