Early Events in Islets and Pancreatic Lymph Nodes in Autoimmune Diabetes

Aspord C, Rome S, Thivolet C. J Autoimmun. 2004;23:27-35.

A key event in the early development of autoimmune type 1 diabetes is thought to be physiological and/or cytokine-induced β-cell destruction. Gene expression profiling, a powerful tool that enables researchers to look at the simultaneous expression of a large number of genes, was used in this study to determine the processes that occur in the early stages of the development of type 1 diabetes in nonobese diabetic (NOD) mice. Gene expression profiles of islets and pancreatic lymph nodes of 4-week-old NOD mice, NOD–SCID (severe combined immunodeficiency) mice, and BALB/c mice (a nondiabetic strain) were compared. A time-course analysis was also carried out in NOD mice 2 to 25 weeks of age.

Changes in islet genes associated with dendritic cell attraction, lymphocyte homing, and apoptosis were found prior to the detection of CD3+ T cells in the islet periphery. Unlike the immunoregulatory cytokine IL-11—which was weakly expressed in NOD islets and pancreatic lymph nodes—IL-1, TYNFSF13B, and osteopontin genes were activated. Genes involved in angiogenesis were activated in the islets of NOD mice at 2 to 4 weeks of age. Several genes were specifically expressed in NOD islets, including those coding for migration molecules (integrin-β5A, CXCR-4), angiogenic factors (Eph A2, Eph A8, Ephrin B1, ARP2, VEGF-A, VEGF-B, VEGF-R3), cell activation factors (osteopontin, LT-βR, TNF-α, TGF-β3), signal transduction molecules (c-jun, c-fos), cytokines (IL-2, IL-1α, IL-1β), and apoptosis factors (A1, BAK, caspase-3, PARP, Bcl-w). In summary, this study has helped to further determine the genes involved in autoimmune type 1 diabetes and contributes to a better understanding of the islet cell microenvironment prior to β-cell destruction.