Fibronectin receptor defects in NOD mouse leucocytes: possible consequences for type 1 diabetes.
Integrins of the very late antigen (VLA) family mediate leucocyte traffic to lymphoid organs under physiological conditions and in chronic inflammatory situations such as autoimmunity. Accordingly, the current thinking is of a positive correlation between VLA expression and capability of the generation of autoimmunity. Herein we discuss recent findings on the defective expression of integrin-type fibronectin receptors alpha4beta1 (VLA-4) and alpha5beta1 (VLA-5) in the non-obese diabetic (NOD) mouse, a murine model of autoimmune insulin-dependent diabetes mellitus. As compared with normal animals, NOD thymocytes (including the CD4+CD25+ regulatory T cells) exhibit a decrease in the membrane expression of alpha5beta1, resulting in a functional impairment of fibronectin-mediated interactions, including cell migration. Interestingly, thymocytes that are trapped within the giant perivascular spaces seen in NOD thymus are consistently alpha5beta1 negative, suggesting that the progressive arrest of mature cells can be related to the alpha5beta1 defect. Peripheral T cells also exhibit decreased alpha5beta1 membrane expression and impaired fibronectin-driven migration. Additionally, we observed a defect in alpha4beta1 fibronectin receptor expression in NOD macrophages. Peritoneal, bone marrow-derived-precursor, as well as thymic macrophages of NOD mice showed an impaired upregulation of alpha4-integrin chain expression, dependent on the level of macrophage maturation. Overall these data lead to the notion that NOD leucocytes bear distinct fibronectin receptor-mediated cell migration defects, which may be involved in the pathogenesis and/or pathophysiology of the autoimmune events seen in NOD mice. Further studies will be helpful to define whether or not this concept can be applied for other autoimmune diseases.
Geutskens
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SB
Hôpital Necker CNRS UMR-8147, Université Paris V, 161 rue de Sevres, 75743 Paris Cedex 15, France.
Mendes-da-Cruz
D A
DA
Dardenne
M
M
Savino
W
W
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004195:Disease Models, Animal; D039041:Integrin alpha4beta1 / Q000276:immunology; D039081:Integrin alpha5beta1 / Q000276:immunology; D007962:Leukocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D017469:Receptors, Fibronectin / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D017469:Receptors, Fibronectin