Early and quantal (by litter) expression of insulin autoantibodies in the nonobese diabetic mice predict early diabetes onset.
Aiming to study the early stages of type 1 diabetes phenotype, before insulitis appears, we measured insulin autoantibodies (IAA) between 3 and 5 wk of age in the NOD mouse (early-IAA (E-IAA)). We report that IAA are found as early as at 3 wk of age, at weaning, and their expression is a quantal phenotype. Maternal autoantibody status influences this early phenotype, because animals of litters issued from IAA-positive ante partum mothers develop E-IAA with a significantly higher incidence than animals issued from IAA-negative mothers. These E-IAA represent synthesized rather than transplacental autoantibodies, as evidenced by higher levels in many offspring compared with maternal IAA, and negative as well as positive offspring in the same litters and it correlates with early diabetes onset, defining the first autoimmune window in diabetes pathogenesis. Therefore, autoimmune processes leading to type 1 diabetes initiate early in life, are influenced by maternal autoantibody status, and can be revealed by the presence of IAA. Our data suggest that the mechanisms responsible for the breakdown of self-tolerance are subjected not only to genetic predisposition, but also to the physiological status of the mother. Pathological progression to autoimmunity is marked by the presence of immunological windows relating early steps with final disease onset.
Melanitou
Evie
E
Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, CO 80262, USA. eviemel@pasteur.fr
Devendra
Devasenan
D
Liu
Edwin
E
Miao
Dongmei
D
Eisenbarth
George S
GS
D017668:Age of Onset; D000818:Animals; D000831:Animals, Newborn / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis*; D015415:Biomarkers / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D007330:Insulin Antibodies / Q000096:biosynthesis*; D008297:Male; D008431:Maternal-Fetal Exchange / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D010641:Phenotype; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011237:Predictive Value of Tests; D011247:Pregnancy
D001323:Autoantibodies; D015415:Biomarkers; D007330:Insulin Antibodies