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Diabetes 54:69-77, 2005
© 2005 by the American Diabetes Association, Inc.

Islet-infiltrating B-Cells in Nonobese Diabetic Mice Predominantly Target Nervous System Elements

Jorge Carrillo1,2, Maria Carmen Puertas1,2, Aurora Alba1,2, Rosa Maria Ampudia1,2, Xavier Pastor1,2, Raquel Planas1,2, Nadal Riutort1,2, Nuria Alonso3, Ricardo Pujol-Borrell1,2, Pere Santamaria4, Marta Vives-Pi1,2, and Joan Verdaguer1,2

1 Laboratory of Immunobiology for Research and Diagnosis (LIRAD) & Center for Transfusion and Tissue Bank (CTBT), Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n, Badalona, Barcelona, Spain
2 Department of Cell Biology, Physiology and Immunology, Universitat Autonoma de Barcelona, Barcelona, Spain
3 Endocrinology Service, Germans Trias i Pujol University Hospital, Carretera de Canyet s/n, Badalona, Barcelona, Spain
4 Julia McFarlane Diabetes Research Centre and Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada

B-cells accumulate in pancreatic islets during the autoimmune response that precedes the onset of type 1 diabetes. However, the role and antigenic specificity of these cells remain a mystery. To elucidate the antigenic repertoire of islet-infiltrating B-cells in type 1 diabetes, we generated hybridoma cell lines of islet-infiltrating B-cells from nonobese diabetic (NOD) mice and NOD mice expressing a diabetogenic T-cell receptor (8.3-NOD). Surprisingly, characterization of the tissue specificity of the antibodies secreted by these cells revealed that a predominant fraction of these hybridomas produce antibodies specific for the pancreatic nervous system. Similar results were obtained with B-cell hybridomas derived from mild insulitic lesions of diabetes-resistant (NOD x NOR)F1 and 8.3-(NOD x NOR)F1 mice. Immunoglobulin class analyses further indicated that most islet-derived hybridomas had arisen from B-cells that had undergone immunoglobulin class switch recombination, suggesting that islet-associated B-cells are involved in active, T-helper–driven immune responses against local antigenic targets. This is the first evidence showing the existence of a predominant active B-cell response in situ against pancreatic nervous system elements in diabetogenesis. Our data are consistent with the idea that this B-cell response precedes the progression of insulitis to overt diabetes, thus strongly supporting the idea that pancreatic nervous system elements are early targets in type 1 diabetes.

Address correspondence and reprint requests to Dr. Joan Verdaguer, Servei d’Immunologia (LIRAD), Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916 Badalona, Barcelona, Spain. E-mail: jverdagu{at}ns.hugtip.scs.es


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.