What is MHC Haplotypes, their immune responsiveness and disease susceptibility

1. MHC: Haplotypes,
Immune Responsiveness,
Disease Susceptibility
Subject:Immunology
-Akshay More(147909)

2. Topics for Discussion
A) MHC : Haplotypes-
• Inheritance of Haplotypes
I. Inheritance of H-2
II. Inheritance of HLA
B) MHC & Immune Responsiveness.
C) MHC & Disease susceptibility.

3. A) MHC Haplotypes:
• The MHC loci are polymorphic:-
Many alternative forms of the gene, or alleles, exist at
each locus.
• The MHC loci are closely linked.-
The recombination frequency within the H-2 complex
is only 0.5%.
• Most individuals inherit the alleles as two sets, one from
each parent.
Each set of alleles is referred to as a ‘haplotype’.
• The MHC alleles are codominantly expressed;
that is, both maternal and paternal gene products are expressed
in the same cells.

4. NOMENCLATURE:
• Haplotypes are identified by individual specificities (e.g., A1, B7,
Cw4, DP5, DQ10, DR8).
• Specificities which are defined by genomic analysis (PCR), are named
with a letter for the locus and a four digit number (e.g. A0101, B0701,
C0401, etc.)
*HLA haplotype frequencies differ among different human populations.
1) Frequent Caucasian haplotypes are:
–A*0101-Cw*0701-B*0801-DRB1*0301-DRB3*0101 DQB1*0201.
–A*0301-Cw*0702-B*0702-DRB1*1501-DRB5*0101-DQB1*0602.
2) Frequent haplotypes in African Americans:
–A*3001-Cw*1701-B*4201-DRB1*0302-DRB3*0101-DQB1*0402.
–A*0301-Cw*0401-B*5301-DRB1*0804-DQB1*0301.
•New haplotypes are developed by recombination events

5. Detailed Genomic Map of Mouse and Human MHC
(Source- Kuby Immunology, 5th Edition)

6. Inheritance of Haplotypes
I) Inheritance of H-2
(Source- Kuby Immunology, 5th Edition)

7. (Source- Kuby Immunology, 5th Edition)

8. II) Inheritance of HLA
Source :https://www.seattlecca.org/client/documents/The-Science-behind-HLA-Typing.pdf

9. B) MHC and Immune Responsiveness:
• B. Benacerraf et. al – First to show that the ability of an animal to
mount Immune response is determined by its MHC Haplotype.
• H. McDevitt et al – ‘the control of immune responsiveness to class II
MHC genes.’
• Two theories have been proposed to account for the variability in
immune responsiveness observed among different haplotypes-
a) Determinant selection model:
- Different class II MHC molecules differ in their ability to bind
processed antigen.
- MHC polymorphism within species will generate a diversity of
binding specificities, so different patterns of responsiveness to
antigens.
b) Holes in the repertoire model:
- TCR that recognize foreign antigen closely resembling self antigens
may be eliminated during thymic processing.(Holes in the repertoire)

10. - T cell response to an antigen involves a trimolecular complex.
- Thus, absence of MHC or TCR, could result absence of immune
responsiveness.

11. B) MHC and Disease Susceptibility:
- Some HLA alleles occur at a much higher frequency in those suffering
from certain diseases than general population.
- Diseases associated with particular MHC alleles# autoimmune
diseases, disorders of complement system, different allergies etc.
- The association between HLA alleles and a given disease may be
quantified by determining the frequency of HLA alleles expressed by
individuals having diseases n comparing these data with frequency of
same alleles in the general population.
- It is not like that expression of allele has caused the disease.
e.g. in ankylosing spondylitis , close linkage of TNFα & TNFβ gene with
the HLA-B locus, these cytokines may involved in destruction of
cartilage.
- Reduction of MHC polymorphism in species may predispose that
species to infectious disease. e.g., Cheetahs, Florida panthers._ loss of
MHC diversity due to limited breeding stock.

12. Source- Kuby Immunology, 5th Edition

13. References:
1) MHC (MAJOR HISTOCOMPATIBILITY COMPLEX), Shridhar Rao PN, www.
microrao.com/mhc.pdf
2) https://www.dls.ym.edu.twimm03302006.pdf
3) https://www.seattlecca.org/client/documents/The-Science-behind-HLA-
Typing.pdf
4) Kuby Immunology, 5th Edition.