Section 6: Human Leukocyte Antigen

Question 1

major histocompatibility complex (MHC)

Answer 1

-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)

Question 2

MHC I

Answer 2

-1 transmembrane heavy chain- alpha (3 domains)
-1 small protein- B2 microglobulin

Question 3

MHC II

Answer 3

• 2 transmembrane heavy chain- alpha and beta (each with two domains)

Question 4

promiscuous binding specificity

Answer 4

-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

Question 5

MHC genetics

Answer 5

-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

Question 6

Human leukocyte

Answer 6

-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

Question 7

isotypes

Answer 7

different forms of HLA
ex: HLA I and HLA II

Question 8

alleles

Answer 8

different forms of a given gene
-you inherit one paternal allele and one maternal for most genes in your body

Question 9

allotypes

Answer 9

-different forms of a given gene with their differing protein products

Question 10

Highly polymorphic

Answer 10

-many many alleles

Question 11

Polymorphic

Answer 11

-many alleles

Question 12

Oligomorphic

Answer 12

few alleles

Question 13

Monomorphic

Answer 13

-one allele

Question 14

What are the 6 human MHC class I isotypes

Answer 14

(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)

Question 15

What are the 5 human MHC class II isotypes?

Answer 15

(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

Question 16

HLA Diversity

Answer 16

-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

Question 17

HLA Nomenclature

Answer 17

-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

Question 18

haplotype

Answer 18

-an individuals specific combination of HLA genes is called this

Question 19

HLA Polymorphism

Answer 19

-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

Question 20

anchor residues

Answer 20

-this is what the amino acid residues are called, they are important for binding the peptide

Question 21

MHC restriction

Answer 21

-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

Question 22

Selection for diversity

Answer 22

-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

Question 23

Balancing selection

Answer 23

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

Question 24

direction selection

Answer 24

• 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

Question 25

interallelic conversion and gene conversion

Answer 25

-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

Question 26

HLA and HIV

Answer 26

-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

Question 27

slow progression HLA allotypes

Answer 27

HLA-B14, B27, B57, C8, C14

Question 28

rapid progression HLA allotypes

Answer 28

HLA-A29, B22, B35, C16, DR11

Question 29

organ transplant

Answer 29

-during T-cell development any cells that respond strongly to self-peptide presented by MHC are eliminated

Question 30

autologous

Answer 30

-an individuals particular self-MHC isoforms are described as this

Question 31

allogenic

Answer 31

other isoforms are described as this

Question 32

Alloreactive T-cells

Answer 32

-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

Question 33

Direct alloantigen

Answer 33

-donor DCs present alloantigens to T-cells in host lymph node

Question 34

indirect alloantigen

Answer 34

• Host DCs present alloantigens to T-cells in host lymph node

Question 35

alloantibody

Answer 35

-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

Question 36

interallelic conversion

Answer 36

-mom and dad genes cross over a make a new gene,
-this one is in between alleles of the same gene

Question 37

gene conversion

Answer 37

-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