Blockade but not overexpression of the junctional adhesion molecule C influences virus-induced type 1 diabetes in mice.
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. Recruitment of inflammatory cells is prerequisite to beta-cell-injury. The junctional adhesion molecule (JAM) family proteins JAM-B and JAM-C are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. Blocking of JAM-C efficiently attenuated cerulean-induced pancreatitis, rheumatoid arthritis or inflammation induced by ischemia and reperfusion in mice. In order to investigate the influence of JAM-C on trafficking and transmigration of antigen-specific, autoaggressive T-cells, we used transgenic mice that express a protein of the lymphocytic choriomeningitis virus (LCMV) as a target autoantigen in the β-cells of the islets of Langerhans under the rat insulin promoter (RIP). Such RIP-LCMV mice turn diabetic after infection with LCMV. We found that upon LCMV-infection JAM-C protein was upregulated around the islets in RIP-LCMV mice. JAM-C expression correlated with islet infiltration and functional beta-cell impairment. Blockade with a neutralizing anti-JAM-C antibody reduced the T1D incidence. However, JAM-C overexpression on endothelial cells did not accelerate diabetes in the RIP-LCMV model. In summary, our data suggest that JAM-C might be involved in the final steps of trafficking and transmigration of antigen-specific autoaggressive T-cells to the islets of Langerhans.
Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany. christen@med.uni-frankfurt.de
Selina
S
Christen
Ken
K
Coppieters
Kerstin
K
Rose
Martin
M
Holdener
Monika
M
Bayer
Josef M
JM
Pfeilschifter
Edith
E
Hintermann
Matthias G
MG
von Herrath
Michel
M
Aurrand-Lions
Beat A
BA
Imhof
Urs
U
Christen
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology / Q000821:virology; D062786:Junctional Adhesion Molecule C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000472:pathogenicity*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D001324:Autoantigens; D062786:Junctional Adhesion Molecule C