Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA.
J Immunol. 2011 Sep 1;187(5):2702-10. doi: 10.4049/jimmunol.1000967. Epub 2011 Jul 27.
The immunopathogenic mechanisms mediating inflammation in multiorgan autoimmune diseases may vary between the different target tissues. We used the K/BxN TCR transgenic mouse model to investigate the contribution of CD4(+) T cells and β(2) integrins in the pathogenesis of autoimmune arthritis and endocarditis. Depletion of CD4(+) T cells following the onset of arthritis specifically prevented the development of cardiac valve inflammation. Genetic absence of β(2) integrins had no effect on the severity of arthritis and unexpectedly increased the extent of cardiovascular pathology. The exaggerated cardiac phenotype of the β(2) integrin-deficient K/BxN mice was accompanied by immune hyperactivation and was linked to a defect in regulatory T cells. These findings are consistent with a model in which the development of arthritis in K/BxN mice relies primarily on autoantibodies, whereas endocarditis depends on an additional contribution of effector T cells. Furthermore, strategies targeting β(2) integrins for the treatment of systemic autoimmune conditions need to consider not only the role of these molecules in leukocyte recruitment to sites of inflammation, but also their impact on the regulation of immunological tolerance.
介导多器官自身免疫性疾病炎症的免疫发病机制可能在不同的靶组织之间有所不同。我们使用 K/BxN TCR 转基因小鼠模型来研究 CD4(+) T 细胞和 β(2)整合素在自身免疫性关节炎和心内膜炎发病机制中的作用。关节炎发病后 CD4(+) T 细胞的耗竭特异性地阻止了心脏瓣膜炎症的发展。β(2)整合素缺失的遗传缺陷对关节炎的严重程度没有影响，但出人意料地增加了心血管病变的程度。β(2)整合素缺陷型 K/BxN 小鼠的心脏表型过度表达伴随着免疫过度激活，并与调节性 T 细胞缺陷有关。这些发现与这样一种模型一致，即 K/BxN 小鼠的关节炎的发展主要依赖于自身抗体，而心内膜炎则依赖于效应 T 细胞的额外贡献。此外，针对β(2)整合素的治疗全身性自身免疫性疾病的策略不仅需要考虑这些分子在白细胞募集到炎症部位中的作用，还需要考虑它们对免疫耐受调节的影响。
