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* Laboratory of Immunobiology for Research and Diagnosis and Center for Transfusion and Tissue Bank; Institut d’Investigacio Germans Trias i Pujol, Badalona, Barcelona, Spain;
Plataforma de proteomica, Facultat de Medicina, Hospital Clínic, Barcelona, Spain; and
Immunology Unit, Department of Ciencies Mediques Basiques, Faculty of Medicine, University of Lleida, Lleida, Spain
Most of our knowledge of the antigenic repertoire of autoreactive B lymphocytes in type 1 diabetes (T1D) comes from studies on the antigenic specificity of both circulating islet-reactive autoantibodies and peripheral B lymphocyte hybridomas generated from human blood or rodent spleen. In a recent study, we generated hybridoma cell lines of infiltrating B lymphocytes from different mouse strains developing insulitis, but with different degrees of susceptibility to T1D, to characterize the antigenic specificity of islet-infiltrating B lymphocytes during progression of the disease. We found that many hybridomas produced mAbs restricted to the peripheral nervous system (PNS), thus indicating an active B lymphocyte response against PNS elements in the pancreatic islet during disease development. The aim of this study was to identify the autoantigen recognized by these anti-PNS mAbs. Our results showed that peripherin is the autoantigen recognized by all anti-PNS mAbs, and, therefore, a relevant neuroendocrine autoantigen targeted by islet-infiltrating B lymphocytes. Moreover, we discovered that the immune dominant epitope of this B lymphocyte immune response is found at the C-terminal end of Per58 and Per61 isoforms. In conclusion, our study strongly suggests that peripherin is a major autoantigen targeted during T1D development and poses a new question on why peripherin-specific B lymphocytes are mainly attracted to the islet during disease.
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1 This work was supported by a grant from the Fondo de Investigaciones Sanitarias of the Spanish National Institute of Health (FIS 03/0775). M.C.P. was supported by a Severo Ochoa fellowship from the Ferrer Foundation (Barcelona, Spain). A.A. and R.P. were supported by a BEFI Predoctoral Fellowship (01/9065 and 05/0418, respectively) from the Instituto Carlos III of the Spanish National Institute of Health. R.M.A. and X.P. were supported by the Juvenile Diabetes Research Foundation 1-2002-724 Research Grant. M.V.-P. is a researcher at the Fondo de Investigaciones Sanitarias of the Spanish National Institute of Health and the Department of Health of Catalan Government. J.V. is an associate professor of the Serra-Hunter Programme from the Catalan Government.
2 Address correspondence and reprint requests to Dr. Joan Verdaguer, Unitat d’Immunologia, Departament de Ciencies Mediques Basiques, Facultat de Medicina, Universitat de Lleida, Carrer Montserrat Roig 2, 25008 Lleida, Spain. E-mail address: joan.verdaguer{at}cmb.udl.es
3 Abbreviations used in this paper: T1D, type 1 diabetes; PNS, peripheral nervous system; 2-D, two dimensional; IPG, immobilized pH gradient.
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