scholarly journals Autoimmune syndromes in major histocompatibility complex (MHC) congenic strains of nonobese diabetic (NOD) mice. The NOD MHC is dominant for insulitis and cyclophosphamide-induced diabetes.

1992 ◽  
Vol 176 (1) ◽  
pp. 67-77 ◽  
Author(s):  
L S Wicker ◽  
M C Appel ◽  
F Dotta ◽  
A Pressey ◽  
B J Miller ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Autoimmune Diabetes ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Nod Mouse ◽  
Major Histocompatibility ◽  
Nonobese Diabetic ◽  
Histocompatibility Complex ◽  
Genes Encoding ◽  
Lymphocytic Infiltrates

The development of autoimmune diabetes in the nonobese diabetic (NOD) mouse is controlled by multiple genes. At least one diabetogenic gene is linked to the major histocompatibility complex (MHC) of the NOD and is most likely represented by the two genes encoding the alpha and beta chains of the unique NOD class II molecule. Three other diabetogenic loci have recently been identified in the NOD mouse and are located on chromosomes 1, 3, and 11. In addition to the autoimmune diabetes which is caused by destruction of the insulin-producing beta cells in the pancreas, other manifestations of autoimmunity are seen in the NOD mouse. These include mononuclear cell inflammation of the submandibular and lacrimal glands, as well as the presence of circulating autoantibodies. To determine the effect of the non-MHC diabetogenic genes on the development of autoimmunity, we constructed the NOD.B10-H-2b (NOD.H-2b) strain, which possesses the non-MHC diabetogenic genes from the NOD mouse, but derives its MHC from the C57BL/10 (B10) strain. The NOD.H-2b strain does not develop insulitis, cyclophosphamide-induced diabetes, or spontaneous diabetes. It does, however, develop extensive lymphocytic infiltrates in the pancreas and the submandibular glands that are primarily composed of Thy 1.2+ T cells and B220+ B cells. In addition, autoantibodies are present in NOD.H-2b mice which recognize the "polar antigen" on the insulin-secreting rat tumor line RINm38. These observations demonstrate that the non-MHC genes in the NOD strain, in the absence of the NOD MHC, significantly contribute to the development of autoimmunity. The contribution of a single dose of the NOD MHC to autoimmunity was assessed with a (NOD x NOD.H-2b)F1 cross. Although only approximately 3% of F1 females developed spontaneous diabetes, approximately 50% of both female and male F1 mice developed insulitis, and 25% of females and 17% of males became diabetic after treatment with cyclophosphamide. These data demonstrate that the MHC-linked diabetogenic genes of the NOD mouse are dominant with decreasing levels of penetrance for the following phenotypes: insulitis greater than cyclophosphamide-induced diabetes greater than spontaneous diabetes.

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.

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 Prevention of autoimmune diabetes in non-obese diabetic mice by treatment with a class II major histocompatibility complex-blocking peptide.

1993 ◽  
Vol 177 (5) ◽  
pp. 1499-1504 ◽  
Author(s):  
U Hurtenbach ◽  
E Lier ◽  
L Adorini ◽  
Z A Nagy
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Autoimmune Disease ◽  
Antigen Presentation ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Class Ii ◽  
Marginal Effect ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

The role of antigen presentation as a possible mechanism underlying major histocompatibility complex (MHC) association of autoimmune disease has been studied in non-obese diabetic (NOD) mice. By screening for inhibition of antigen presentation to NOD T cell hybridoma, we have selected a synthetic peptide, yTYTVHAAHAYTYt (small letters denote D amino acids), that efficiently blocks antigen presentation by the NOD class II MHC molecule A alpha g7A beta g7 (Ag7) in vitro. The inhibition is MHC selective, in that it does not affect antigen presentation by the E(d) and E(k) molecules, and has only a marginal effect on presentation by the A(d) molecule. This peptide also inhibits the priming for Ag7-restricted T cell responses in vivo, and prevents the spontaneous development of diabetes in female NOD mice, when administered chronically from 3 wk of age on. Chronic treatment with a control peptide, KMKMVHAAHAKMKM, that fails to bind to Ag7 has no effect on the disease. These data indicate that antigen presentation by the Ag7 molecule plays a pivotal role in the induction of autoimmune diabetes. Furthermore, the results demonstrate that interference with antigen presentation by a class II molecule can prevent the onset of spontaneous autoimmune disease associated with the same molecule.

Association of susceptibility to spontaneous diabetes in rat with genes of major histocompatibility complex

Diabetes ◽  
1988 ◽  
Vol 37 (10) ◽  
pp. 1438-1443 ◽  
Author(s):  
E. Colle ◽  
S. J. Ono ◽  
A. Fuks ◽  
R. D. Guttmann ◽  
T. A. Seemayer
Keyword(s):  
Major Histocompatibility Complex ◽  
Spontaneous Diabetes ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

Association of Susceptibility to Spontaneous Diabetes in Rat With Genes of Major Histocompatibility Complex

Diabetes ◽  
1988 ◽  
Vol 37 (10) ◽  
pp. 1438-1443 ◽  
Author(s):  
E. Colle ◽  
S. J. Ono ◽  
A. Fuks ◽  
R. D. Guttmann ◽  
T. A. Seemayer
Keyword(s):  
Major Histocompatibility Complex ◽  
Spontaneous Diabetes ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

scholarly journals Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice.

1993 ◽  
Vol 178 (2) ◽  
pp. 589-596 ◽  
Author(s):  
T M Laufer ◽  
M G von Herrath ◽  
M J Grusby ◽  
M B Oldstone ◽  
L H Glimcher
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Islet Cells ◽  
Autoimmune Diabetes ◽  
Class Ii ◽  
Dependent Diabetes Mellitus ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease marked by hyperglycemia and mononuclear cell infiltration of insulin-producing beta islet cells. Predisposition to IDDM in humans has been linked to the class II major histocompatibility complex (MHC), and islet cells often become aberrantly class II positive during the course of the disease. We have used two recently described transgenic lines to investigate the role of class II molecules and CD4+ T cells in the onset of autoimmune insulitis. Mice that are class II deficient secondary to a targeted disruption of the A beta b gene were bred to mice carrying a transgene for the lymphocytic choriomenigitis virus (LCMV) glycoprotein (GP) targeted to the endocrine pancreas. Our results indicate that class II-deficient animals with and without the GP transgene produce a normal cytotoxic T lymphocyte response to whole LCMV. After infection with LCMV, GP-transgenic class II-deficient animals develop hyperglycemia as rapidly as their class II-positive littermates. Histologic examination of tissue sections from GP-transgenic class II-deficient animals reveals lymphocytic infiltrates of the pancreatic islets that are distinguishable from those of their class II-positive littermates only by the absence of infiltrating CD4+ T cells. These results suggest that in this model of autoimmune diabetes, CD4+ T cells and MHC class II molecules are not required for the development of disease.

Selected Contribution: Association of gender-related LMP2 inactivation with autoimmune pathogenesis

2001 ◽  
Vol 91 (6) ◽  
pp. 2804-2815 ◽  
Author(s):  
Takuma Hayashi ◽  
Denise L. Faustman
Keyword(s):  
T Cell ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Nuclear Factor Κb ◽  
Genomic Region ◽  
Nod Mouse ◽  
Mhc Molecules ◽  
Genes Encoding ◽  
Induced Apoptosis ◽  
Factor Α

Recent results in an animal model of autoimmune diabetes, the nonobese diabetic (NOD) mouse, suggest a hypothesis to explain the role of major histocompatibility complex (MHC) in autoimmunity. The genome MHC region contains immune response genes that are important for T cell education and antigen presentation by MHC molecules. Two such genes encoding the LMP2 and LMP7 proteasome subunits are located in this high-risk MHC genomic region. Proteasome containing the LMP2 subunit is essential for T cell education and proteolytically activates transcription factor nuclear factor-κB. Splenocytes of NOD mouse with marked female specificity for disease expression are defective in LMP2 expression. The spontaneous defective LMP2 expression in NOD mice, which is gender biased toward female cohorts, is restricted to select lymphoid and myeloid cells and is developmentally controlled with lowered LMP2 protein and heightened tumor necrosis factor-α-induced apoptosis. These defects are apparent only after ∼7 wk of age. These data suggest a proteasome role in autoimmune progression, and a gender developmental and lineage restriction of LMP2 expression may contribute to the diverse autoimmune characteristics preferentially observed in female NOD mice.

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