Expression of extra MHC types decreases the number of clones surviving negative selection, but increases the number of positively selected clones. The net effect is that the number of clones in the functional T cell repertoire would increase if the MHC diversity within an individual were to exceed its normal value. Since MHC heterozygous individuals can present more peptides to the immune system, they are better protected against infections than MHC homozygous individuals.
Using a population genetics model, we found however that this heterozygote advantage is insufficient to explain the large degree of MHC polymorphism found in nature. Only if all MHC alleles in the population were to confer unrealistically similar fitness contributions to their hosts, could heterozygote advantage account for an MHC polymorphism of more than ten alleles.
By predicting the immunodominant peptides from various common viruses we found that different MHC alleles are expected to provide quite different levels of protection. Thus, additional selection pressures seem to be involved. Using a computer simulation model we found that frequency-dependent selection by host-pathogen coevolution provides such an additional selection pressure that can account for realistic degrees of polymorphism of the MHC.
The polymorphism of the MHC thus seems a result of host-pathogen coevolution, giving rise to a large population diversity despite the limited degree of MHC diversity within individuals.
Unable to display preview. Blood — Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med — Immunity 12 — MHC class II proteins and disease: a structural perspective. Nat Rev Immunol 6 — The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis.
Arthritis Rheum 30 — CrossRef Full Text. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis.
Nat Genet 44 —6. Molecular amino acid signatures in the MHC class II peptide-binding pocket predispose to autoimmune thyroiditis in humans and in mice. The first external domain of the nonobese diabetic mouse class II I-A beta chain is unique. Pubmed Abstract Pubmed Full Text. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus.
Nature — In APCs, the autologous peptides selected by the diabetogenic I-Ag7 molecule are unique and determined by the amino acid changes in the P9 pocket.
J Immunol — First signature of islet beta-cell-derived naturally processed peptides selected by diabetogenic class II MHC molecules. J Immunol —8. A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science — Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register. Unconventional recognition of peptides by T cells and the implications for autoimmunity. Nat Rev Immunol 12 —8. Use of eluted peptide sequence data to identify the binding characteristics of peptides to the insulin-dependent diabetes susceptibility allele HLA-DQ8 DQ 3.
Int Immunol 9 — J Biol Chem — Major histocompatibility complex class II molecules can protect from diabetes by positively selecting T cells with additional specificities. A mechanism for the major histocompatibility complex-linked resistance to autoimmunity.
T-cell tolerance by dendritic cells and macrophages as a mechanism for the major histocompatibility complex-linked resistance to autoimmune diabetes.
Diabetes 51 — Gascoigne NR, Palmer E. Signaling in thymic selection. Curr Opin Immunol 23 — Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes.
Nat Immunol 11 —4. MHC-linked protection from diabetes dissociated from clonal deletion of T cells. Science —5. Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low-affinity peptide. Nat Med 11 — Nat Immunol 2 —6. Selection of regulatory T cells in the thymus. Nat Rev Immunol 12 — Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains CD Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.
An Abd transgene prevents diabetes in nonobese diabetic mice by inducing regulatory T cells. Diabetes 47 —7. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. HLA class II molecules influence susceptibility versus protection in inflammatory diseases by determining the cytokine profile.
Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease. IL administration reveals diabetogenic T cells in genetically resistant I-Ealpha-transgenic nonobese diabetic mice: resistance to autoimmune diabetes is associated with binding of Ealpha-derived peptides to the I-A g7 molecule.
Differences in self-peptide binding between T1D-related susceptible and protective DR4 subtypes. J Autoimmun 36 — Following a diabetogenic T cell from genesis through pathogenesis. Cell 74 — Both central and peripheral tolerance mechanisms play roles in diabetes prevention in NOD-E transgenic mice. Autoimmunity 41 — Immunity 21 — Each heterozygous individual will have two MHC haplotypes, one in each chromosome one of paternal origin and the other of maternal origin.
The MHC genes are highly polymorphic; this means that there are many different alleles in the different individuals inside a population. The polymorphism is so high that in a mixed population non-endogamic there are not two individuals with exactly the same set of MHC genes and molecules, with the exception of identical twins. The polymorphic regions in each allele are located in the region for peptide contact, which is going to be displayed to the lymphocyte.
For this reason, the contact region for each allele of MHC molecule is highly variable, as the polymorphic residues of the MHC will create specific clefts in which only certain types of residues of the peptide can enter. This imposes a very specific link between the MHC molecule and the peptide, and it implies that each MHC variant will be able to bind specifically only those peptides that are able to properly enter in the cleft of the MHC molecule, which is variable for each allele.
In this way, the MHC molecules have a broad specificity, because they can bind many, but not all, types of possible peptides. The evolution of the MHC polymorphism ensures that a population will not succumb to a new pathogen or a mutated one, because at least some individuals will be able to develop an adequate immune response to win over the pathogen. The variations in the MHC molecules responsible for the polymorphism are the result of the inheritance of different MHC molecules, and they are not induced by recombination, as it is the case for the antigen receptors.
Because of the high levels of allelic diversity found within its genes, MHC has also attracted the attention of many evolutionary biologists.
0コメント