Alpha4beta7 integrin/MAdCAM-1 adhesion pathway is crucial for B cell migration into pancreatic lymph nodes in nonobese diabetic mice.
Although B cells are crucial antigen-presenting cells in the initiation of T cell autoimmunity to islet beta cell autoantigens in type 1 diabetes (T1D), adhesion molecules that control migration of B cells into pancreatic lymph nodes (PanLN) in the nonobese diabetic (NOD) mouse model of human T1D have not been defined. In this study, we found that B cells from PanLN of 3-4-week-old female NOD mice expressed high levels of alpha(4) integrin and LFA-1 and intermediate levels of beta(7) integrin; half of B cells were L-selectin(high). In short-term in vivo lymphocyte migration assays, B cells migrated from the bloodstream into PanLN more efficiently than into peripheral LNs. Moreover, antibodies to mucosal addressin cell adhesion molecule 1 (MAdCAM-1) and alpha(4)beta(7) integrin inhibited >90% of B cell migration into PanLN. In contrast, antibodies to peripheral node addressin, L-selectin or LFA-1 partially inhibited B cell migration into PanLN. Furthermore, one intraperitoneal injection of anti-MAdCAM-1 antibody into 3-week-old NOD mice significantly inhibited entry of B cells into PanLN for at least 2 weeks. Taken together, these results indicate that the alpha(4)beta(7) integrin/MAdCAM-1 adhesion pathway plays a predominant role in migration of B cells into PanLN in NOD mice. Thus, specific blockage of alpha(4)beta(7) integrin/MAdCAM-1 adhesion pathway-mediated B cell migration may be a potential treatment for T1D.
Xu
Baohui
B
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5176, USA. xubaohui@gmail.com
Cook
Rachel E
RE
Michie
Sara A
SA
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D006801:Humans; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009088:Mucoproteins; D010179:Pancreas / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
D019138:Antibodies, Blocking; D015815:Cell Adhesion Molecules; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; C071777:integrin alpha4beta7