Affiliation:
1. Department of Pediatrics, Vanderbilt Children’s Hospital, Vanderbilt University, Nashville, Tennessee
2. Harrison Department of Surgical Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Abstract
Although it is well established that B-cells are required for the development of diabetes in the nonobese diabetic (NOD) mouse, the nature of their role remains unknown. Herein, we investigate the hypothesis that B-cells in this autoimmune background actively disrupt the tolerant state of those T-cells with which they interact. We demonstrate that NOD B-cells express elevated levels of crucial molecules involved in antigen presentation (including CD21/35, major histocompatibility complex class II, and CD40), alterations that invite the possibility of inappropriate T-cell activation. However, when chimeric animals are generated in which all B-cells are NOD-derived, a tolerant state is maintained. These data demonstrate that although B-cells are required for the development of autoimmunity, they are not sufficient to disrupt established tolerance. Moreover, non-B-cell antigen-presenting cells may be the critical actors in the establishment of the tolerant state; this function may be absent in NOD mice as they are characterized by deficient professional antigen-presenting cell function.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
Reference49 articles.
1. Charre S, Rosmalen JG, Pelegri C, Alves V, Leenen PJ, Drexhage HA, Homo-Delarche F: Abnormalities in dendritic cell and macrophage accumulation in the pancreas of nonobese diabetic (NOD) mice during the early neonatal period. Histol Histopathol 17:393–401,2002
2. Alleva DG, Johnson EB, Wilson J, Beller DI, Conlon PJ: SJL and NOD macrophages are uniquely characterized by genetically programmed, elevated expression of the IL-12(p40) gene, suggesting a conserved pathway for the induction of organ-specific autoimmunity. J Leukoc Biol 69:440–448,2001
3. Rosmalen JG, Homo-Delarche F, Durant S, Kap M, Leenen PJ, Drexhage HA: Islet abnormalities associated with an early influx of dendritic cells and macrophages in NOD and NODscid mice. Lab Invest 80:769–777,2000
4. Piganelli JD, Martin T, Haskins K: Splenic macrophages from the NOD mouse are defective in the ability to present antigen. Diabetes 47:1212–1218,1998
5. Serreze DV: Autoimmune diabetes results from genetic defects manifest by antigen presenting cells. FASEB J 7:1092–1096,1993
Cited by
7 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献