NATURAL-HISTORY OF HUMORAL IMMUNITY TO GLUTAMIC-ACID DECARBOXYLASE INNONOBESE DIABETIC (NOD) MICE

Autoantibodies to glutamic acid decarboxylase (GAD) are present in hum ans before and after the onset of clinical insulin-dependent diabetes (IDD). The non-obese diabetic (NOD) mouse, a model of human IDD, devel ops mononuclear cell infiltration of the pancreatic islets ('insulitis ') associated particularly in females with T cell-mediated destruction of the islet beta cells. In NOD mice of both sexes we detected serum antibodies to GAD (GAD Ab) that precipitate mouse brain GAD enzymatic activity. Antibodies in NOD sera also precipitate a M(r) 65,000 protei n from Triton X-100 extracts of S-35-methionine-labelled NOD islets, i dentical in size to that precipitated by a monoclonal antibody to GAD. GAD Ab were not detected in other mouse strains. There were significa nt differences in the frequency, level and age at initial detection of GAD Ab between females of the NOD/Lt and NOD/WEHI lines, previously s hown to have a higher and lower incidence of diabetes, respectively. C omparing NOD/Lt (n=26) and NOD/WEHI (n=20) females, in which diabetes occurred in 38% and 20% by 150 days, the frequency of elevated GAD Ab was 50 vs. 80%, the mean maximum GAD Ab level 21.1 vs. 30.6% and the m ean age at which GAD Ab were first detected 94 vs. 45 days. No signifi cant differences in these parameters were observed between male mice o f either line. There was a significant negative correlation between th e level of GAD Ab and the degree of insulitis in female mice from both lines. GAD Ab were not a prerequisite for the development of diabetes . In 7 of 10 female mice the onset of diabetes was preceded by a decre ase of GAD Ab levels into the normal range. These findings indicate th at, while GAD is a target of autoimmunity in the NOD mouse, GAD Ab do not necessarily correlate with the development of diabetes. Indeed, th e difference between the two NOD lines and the inverse relationship wi th insulitis suggests that a strong humoral response to GAD may be ass ociated with a less destructive pathology, as proposed in humans 'at-r isk' for IDD.