scholarly journals A Mechanism for the Major Histocompatibility Complex–linked Resistance to Autoimmunity

1997 ◽  
Vol 186 (7) ◽  
pp. 1059-1075 ◽  
Author(s):  
Dennis Schmidt ◽  
Joan Verdaguer ◽  
Nuzhat Averill ◽  
Pere Santamaria
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Pancreatic Beta Cell ◽  
Nod Mice ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Nonobese Diabetic ◽  
Histocompatibility Complex ◽  
Nonobese Diabetic Mice ◽  
Mhc Class Ii Genes

Certain major histocompatibility complex (MHC) class II haplotypes encode elements providing either susceptibility or dominant resistance to the development of spontaneous autoimmune diseases via mechanisms that remain undefined. Here we show that a pancreatic beta cell–reactive, I-Ag7–restricted, transgenic TCR that is highly diabetogenic in nonobese diabetic mice (H-2g7) undergoes thymocyte negative selection in diabetes-resistant H-2g7/b, H-2g7/k, H-2g7/q, and H-2g7/nb1 NOD mice by engaging antidiabetogenic MHC class II molecules on thymic bone marrow–derived cells, independently of endogenous superantigens. Thymocyte deletion is complete in the presence of I-Ab, I-Ak + I-Ek or I-Anb1 + I-Enb1 molecules, partial in the presence of I-Aq or I-Ak molecules alone, and absent in the presence of I-As molecules. Mice that delete the transgenic TCR develop variable degrees of insulitis that correlate with the extent of thymocyte deletion, but are invariably resistant to diabetes development. These results provide an explanation as to how protective MHC class II genes carried on one haplotype can override the genetic susceptibility to an autoimmune disease provided by allelic MHC class II genes carried on a second haplotype.

scholarly journals Analysis of the Role of  Variation of Major Histocompatibility Complex Class II Expression on Nonobese Diabetic (NOD) Peripheral T Cell Response

1998 ◽  
Vol 188 (12) ◽  
pp. 2267-2275 ◽  
Author(s):  
William M. Ridgway ◽  
Hiroaki Ito ◽  
Marcella Fassò ◽  
Chen Yu ◽  
C. Garrison Fathman
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Transgenic Mice ◽  
Mhc Class Ii ◽  
Nod Mice ◽  
Class Ii ◽  
Nonobese Diabetic ◽  
Histocompatibility Complex

The current paradigm of major histocompatibility complex (MHC) and disease association suggests that efficient binding of autoantigens by disease-associated MHC molecules leads to a T cell–mediated immune response and resultant autoimmune sequelae. The data presented below offer a different model for this association of MHC with autoimmune diabetes. We used several mouse lines expressing different levels of I-Ag7 and I-Ak on the nonobese diabetic (NOD) background to evaluate the role of MHC class II in the previously described NOD T cell autoproliferation. The ratio of I-Ag7 to I-Ak expression correlated with the peripheral T cell autoproliferative phenotype in the mice studied. T cells from the NOD, [NOD × NOD.I-Anull]F1, and NOD I-Ak transgenic mice demonstrated autoproliferative responses (after priming with self-peptides), whereas the NOD.H2h4 (containing I-Ak) congenic and [NOD × NOD.H2h4 congenic]F1 mice did not. Analysis of CD4+ NOD I-Ak transgenic primed lymph node cells showed that autoreactive CD4+ T cells in the NOD I-Ak transgenic mice were restricted exclusively by I-Ag7. Considered in the context of the avidity theory of T cell activation and selection, the reported poor peptide binding capacity of NOD I-Ag7 suggested a new hypothesis to explain the effects of MHC class II expression on the peripheral autoimmune repertoire in NOD mice. This new explanation suggests that the association of MHC with diabetes results from “altered” thymic selection in which high affinity self-reactive (potentially autoreactive) T cells escape negative selection. This model offers an explanation for the requirement of homozygous MHC class II expression in NOD mice (and in humans) in susceptibility to insulin-dependent diabetes mellitus.

scholarly journals Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease.

1993 ◽  
Vol 178 (5) ◽  
pp. 1675-1680 ◽  
Author(s):  
H Deng ◽  
R Apple ◽  
M Clare-Salzler ◽  
S Trembleau ◽  
D Mathis ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Class Ii ◽  
Dependent Diabetes Mellitus ◽  
Protective Effects ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

How peptide-major histocompatibility complex (MHC) class II complexes are naturally generated is still unknown, but accumulating evidence suggests that unfolding proteins or long peptides can become bound to class II molecules at the dominant determinant before proteolytic cleavage. We have compared the immunogenicity of hen egg-white lysozyme (HEL) in nonobese diabetic (NOD), (NOD x BALB/c)F1, and E(d) alpha transgenic NOD mice. We find that a response to the subdominant ANOD-restricted determinant disappears upon introduction of an E(d) molecule, and is restored when scission of HEL separates this determinant from its adjoining, competitively dominant, E(d)-restricted determinant. This suggests that the E(d) molecule binds and protects its dominant determinant on a long peptide while captured neighboring determinants are lost during proteolysis. These results provide clear evidence for "determinant capture" as a mechanism of determinant selection during antigen processing and a possible explanation for MHC-protective effects in insulin-dependent diabetes mellitus.

scholarly journals Within-trio tests provide little support for post-copulatory selection on major histocompatibility complex haplotypes in a free-living population

2021 ◽  
Vol 288 (1945) ◽  
pp. 20202862
Author(s):  
W. Huang ◽  
J. M. Pemberton
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Ovis Aries ◽  
Transmission Ratio Distortion ◽  
Transmission Ratio ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Ratio Distortion ◽  
Mhc Class Ii Genes

Sexual selection has been proposed as a force that could help maintain the diversity of major histocompatibility complex (MHC) genes in vertebrates. Potential selective mechanisms can be divided into pre-copulatory and post-copulatory, and in both cases, the evidence for occurrence is mixed, especially in natural populations. In this study, we used a large number of parent-offspring trios that were diplotyped for MHC class II genes in a wild population of Soay sheep ( Ovis aries ) to examine whether there was within-trio post-copulatory selection on MHC class II genes at both the haplotype and diplotype levels. We found there was transmission ratio distortion of one of the eight MHC class II haplotypes (E) which was transmitted less than expected by fathers, and transmission ratio distortion of another haplotype (A) which was transmitted more than expected by chance to male offspring. However, in both cases, these deviations were not significant after correction for multiple tests. In addition, we did not find any evidence of post-copulatory selection at the diplotype level. These results imply that, given known parents, there is no strong post-copulatory selection on MHC class II genes in this population.

scholarly journals Developmental extinction of major histocompatibility complex class II gene expression in plasmocytes is mediated by silencing of the transactivator gene CIITA.

1994 ◽  
Vol 180 (4) ◽  
pp. 1329-1336 ◽  
Author(s):  
P Silacci ◽  
A Mottet ◽  
V Steimle ◽  
W Reith ◽  
B Mach
Keyword(s):  
Gene Expression ◽  
Major Histocompatibility Complex ◽  
B Lymphocytes ◽  
Mhc Class Ii ◽  
Plasma Cells ◽  
Terminal Differentiation ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class Ii Genes

Constitutive major histocompatibility complex (MHC) class II gene expression is tightly restricted to antigen presenting cells and is under developmental control. Cells of the B cell lineage acquire the capacity to express MHC class II genes early during ontogeny and lose this property during terminal differentiation into plasma cells. Cell fusion experiments have suggested that the extinction of MHC class II expression in plasma cells is due to a dominant repression, but the underlying mechanisms are not understood. CIITA was recently identified as an MHC class II transactivator that is essential for MHC class II expression in B lymphocytes. We show here that inactivation of MHC class II genes in plasmocytes is associated with silencing of the CIITA gene. Moreover, experimentally induced expression of CIITA in plasmocytes leads to reexpression of MHC class II molecules to the same level as that observed on B lymphocytes. We therefore conclude that the loss of MHC class II expression observed upon terminal differentiation of B lymphocytes into plasmocytes results from silencing of the transactivator gene CIITA.

scholarly journals Resistance alleles at two non-major histocompatibility complex-linked insulin-dependent diabetes loci on chromosome 3, Idd3 and Idd10, protect nonobese diabetic mice from diabetes.

1994 ◽  
Vol 180 (5) ◽  
pp. 1705-1713 ◽  
Author(s):  
L S Wicker ◽  
J A Todd ◽  
J B Prins ◽  
P L Podolin ◽  
R J Renjilian ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Nod Mice ◽  
Insulin Dependent Diabetes ◽  
Chromosome 3 ◽  
Major Histocompatibility ◽  
Congenic Strains ◽  
Nonobese Diabetic ◽  
Histocompatibility Complex ◽  
Insulin Dependent ◽  
Nonobese Diabetic Mice

Development of diabetes in NOD mice is polygenic and dependent on both major histocompatibility complex (MHC)-linked and non-MHC-linked insulin-dependent diabetes (Idd) genes. In (F1 x NOD) backcross analyses using the B10.H-2g7 or B6.PL-Thy1a strains as the outcross partner, we previously identified several non-MHC Idd loci, including two located on chromosome 3 (Idd3 and Idd10). In the current study, we report that protection from diabetes is observed in NOD congenic strains having B6.PL-Thy1a- or B10-derived alleles at Idd3 or Idd10. It is important to note that only partial protection is provided by two doses of the resistance allele at either Idd3 or Idd10. However, nearly complete protection from diabetes is achieved when resistance alleles are expressed at both loci. Development of these congenic strains has allowed Idd3 to be localized between Glut2 and D3Mit6, close to the Il2 locus.

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