Endothelial cell-binding properties of lymphocytes infiltrated into human diabetic pancreas. Implications for pathogenesis of IDDM.
In IDDM, mononuclear cells accumulate in the islets of Langerhans and destroy insulin-producing beta-cells. To study the mechanisms that control extravasation of circulating mononuclear cells into the pancreas, we examined the phenotype of vascular endothelium of the pancreas, propagated a T-cell line from pancreatic islets at the onset of the disease and compared endothelial binding of this cell line in vitro to vascular endothelium in different body regions. The adhesion molecules expressed on the resulting T-cell line and the functional binding capacity of these cells to the endothelium of the normal and diabetic pancreas, mucosa-associated lymphatic tissues, and regional and peripheral lymph nodes were studied. We present evidence of pancreatic endothelial activation in diabetes, leading to endothelial morphology typical for HEVs and accompanying local increase in extravasation of mononuclear cells into the pancreas. Endothelial-cell binding experiments with the T-cell line showed strong adherence of the cells to the endothelium of diabetic pancreas and mucosal lymphoid tissue. The cell line was uniformly CD4-positive, TCR V beta 5.1-positive, LFA-1-positive (CD 11a/CD18), VLA-4 alpha-positive (CD 49d), and CD 44-positive but negative for L-selectin (peripheral lymph node homing receptor). The pancreatic or control cell lines showed no binding to vessels of normal pancreas, and the binding of the pancreatic cell line to the endothelium of peripheral lymph node was weak. Our results suggest that lymphocyte-endothelial cell interactions are important for the accumulation of inflammatory mononuclear cells into the pancreas and imply that lymphocytes derived from the mucosal lymphoid tissue may be involved in the pathogenesis of IDDM.
Hänninen
A
A
Department of Pediatrics and Medical Microbiology, University of Turku, Finland.
Salmi
M
M
Simell
O
O
Jalkanen
S
S
D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000473:pathology* / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D010179:Pancreas / Q000473:pathology* / Q000503:physiopathology; D010641:Phenotype; D013601:T-Lymphocytes / Q000473:pathology* / Q000502:physiology