Faulty Major Histocompatibility Complex Class II I-E Expression is Associated With Autoimmunity in Diverse Strains of Mice: Autoantibodies, Insulitis, and Sialadenitis

Abstract

Many regions and loci of the murine genome contribute to the pancreatic and salivary gland autoimmunity observed in the diabetic NOD mouse. Examination of the major histocompatibility complex region of the NOD mouse has revealed a defect in the expression of the major histocompatibility complex class II gene, I-E. To determine the isolated role of faulty I-E expression in abnormal self-recognition, we examined six commonly used inbred strains of mice on diverse genetic backgrounds that also do not express I-E, i.e., C57BL/10, SJL, ACA, DBA/1, NOD, and 129. Autoimmunity was assessed by the presence of inflammatory cell infiltrates (0,+/-,+,++, , +) within and among the pancreatic islets and salivary glands, and autoantibodies to self determinants. At 6 mo of age, inflammatory infiltrates in the pancreas (0, 3 mice; +/-, 3 mice; +, 7 mice; ++, 6 mice; , 1 mouse; +, 5 mice) and/or salivary glands (0, 0 mice; +/-, 3 mice; +, 1 mouse; ++, 4 mice; , 6 mice; +, 10 mice) were detected as well as autoantibodies in all 24 mice of all I-E- mouse strains on diverse genetic backgrounds. This indicates that defective expression of this single locus, in isolation, is sufficient for the spontaneous development of autoreactivity. In contrast, the simultaneous examination of 19 I-E+ mice on five commonly used inbred strains of mice (BALB/c, C67/KsJ, B10.BR, B10.A [2R], and B10.A [5R]) demonstrated no signs of humoral or cellular autoimmunity with target gland destruction or lymphocytic invasion. Our data suggest that many commonly used inbred strains of mice represent models of autoimmunity attributable to this single defective gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Two NOD Idd‐associated intervals contribute synergistically to the development of autoimmune exocrinopathy (Sjögren's syndrome) on a healthy murine background

“…According to the standard grading system for determining the number of foci of lymphocytes infiltrating the exocrine tissues, the C57BL/6.NOD‐ Aec1Aec2 congenic mice had focus scores reflective of those in NOD/Lt mice (Table 3). C57BL/6J mice do not typically have focal infiltration of exocrine tissues at either 12 weeks or 16 weeks of age (31).…”

“…The Idd3 allele in C57BL/6.NOD‐ Aec1Aec2 congenic mice contains additional susceptibility intervals Idd10 and Idd17 (20, 32, 34). Based on the results of a number of studies of autoimmune diabetes and experimental autoimmune encephalomyelitis, using a 0.35‐cM Idd3 susceptibility segment from chromosome 3 (33–35), it has been proposed that the IL‐2 gene is the candidate gene responsible for the influence on immune cell activation in autoimmunity in these mouse models (31, 33, 34, 36–38). The other Idd alleles of chromosome 3 ( Idd10, Idd17, Idd18 ) have been proposed to enhance the contribution of the Idd3 susceptibility interval, but are not necessary for its action in autoimmune disease (39, 40).…”

Cartilage oligomeric matrix protein induction of chronic arthritis in mice

“…Interestingly, T cell recognition of COMP is more complex, since other class II molecules (presumably, E p , which is a DR homolog in the mouse) are also involved. Presentation of antigens through the E molecule has previously been suggested to be regulatory (43, 44), although in the case of E p and COMP, this seems not to be the case. A unique property of COMP is that fragments of COMP are released into the bloodstream from cartilage, both physiologically and pathologically during the process of cartilage destruction in arthritis (45, 46).…”

Reduction of T Cell Receptor Diversity in NOD Mice Prevents Development of Type 1 Diabetes but Not Sjögren’s Syndrome

“…Despite genetic predispositions, the key component in the development of autoimmune diseases is the recognition of a particular antigen in the context of MHC Class II molecule by CD4 + T cells. The development of diabetes in NOD mice is associated with the key I-A g7 molecule (HLA-DQ8 in humans) in the absence of a functional I-E molecule [14], [15]. Co-expression of other MHC molecules with I-A g7 can prevent development of diabetes in a dominant fashion [14], [15].…”

“…The development of diabetes in NOD mice is associated with the key I-A g7 molecule (HLA-DQ8 in humans) in the absence of a functional I-E molecule [14], [15]. Co-expression of other MHC molecules with I-A g7 can prevent development of diabetes in a dominant fashion [14], [15]. Replacement of I-A g7 with other MHC molecules, like I-A b , I-A p or I-A q , does not promote the development of diabetes yet mice continue to develop autoimmune exocrinopathy and the severity of the SS and the profile of antibodies’ specificities vary between congenic mice [16].…”