Valter Hillörn
Autoimmune diabetes; cellular and molecular aspects on the pathogenesis of diabetes in the NOD mouse and in humansABSTRACT
Academic DissertationValter Hillörn, Dpt of Internal Medicine. Umeå University, 901 87 Umeå
Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease controlled by multiple genes and influenced by environmental factors. In the non-obese diabetic (NOD) mouse model, diabetes was strong resemblance to human IDDM develops as a result of T-lymphocyte-mediated destruction of the pancreatic beta cells.
Transplantation of Langerhans´ islets of different origins into embryo aggregation (EA) chimeras between NOD and non-diabetic mouse strains was used to evaluate the contribution of NOD antigens in the autoreactive process. In this experimental design, NOD specific beta-cell antigen(s) appeared not to be required for insulitis and diabetes development. Moreover, by showing that suppression of the neonatal B cell development in the NOD mouse prevents development of insulitis and diabetes, we propose a role for B cells/Ig early in the pathogenesis of NOD mouse diabetes.
Exceeding our studies to human IDDM, we addressed the issue of aberrations in the B cell reportoire. Findings of abnormalaties in VH-gene utilization suggested a defect in the V-gene directed cellular selection occurring between resting, immunocompetent B cells and naturally activated plasma cells in the diabetic patients.
Next, nucleotide sequence analyzes of VH6-D-JG rearrangements obtained from peripheral blood lymphocytes (PBLs) showed "fetal/neonatal" characteristics and an increased frequency of B cells with mutataed VH genes, suggesting a defect in the negative selection of B lymphocytes.
Dysregulation of the apoptosis machinery in the NOD mouse has been proposed to constitute a pathogenesis factor in NOD mouse diabetes. By in vitro exposure of PBLs to gamma irradiation, we detected a relative resistance to adoptosis induction which was most evident in lymphocytes from diabetic patients with concomitant autoimmune thyroid disease. This observation is consistent with previous report of a common susceptibility locus in the NOD mouse and in human IDDM mapping to a genetic region which encodes molecules with functional properties including apoptosis regulation.
Key words autoimmune diabetes, IgVH genes, NOD mouse, apoptosis
ISSN 0346-6612 ISBN 91-7191-327-0
