Genetic Modifiers Of Autoimmune Disease In FcgammaRIIB

我们已经在FcgammaRIIB缺陷的小鼠中产生了一种新的全身性自身免疫性疾病模型，FcgammaRIIB是一种IgG结合受体，可抑制抗体产生和炎症反应。这些小鼠发展出一种类似于人类狼疮的自发性疾病，但仅限于某些遗传背景。我们的目标是确定易感性/耐药的遗传位点，负责在这个系统中的背景差异。我们对200只来自抗性品系和狼疮易感品系之间杂交的小鼠进行了分析，并确定了三个新的抗性位点。已经产生了新的小鼠品系，其中这些抗性基因座被转移到RII-/-B6背景，以允许进一步的遗传作图和最终的基因鉴定。在自身免疫易感RII-/-B6小鼠的表征中，我们观察到它们的疾病可以通过与某些修饰菌株杂交而加重或减弱。我们已经观察到RII-/- B6 Yaa小鼠的疾病增强与自身抗体特异性的变化相关。通过比较这些新的疾病模型，我们的目标是剖析自身免疫病理学的要求。这些新发现的基因可能会发现改变狼疮或其他自身免疫性疾病的潜在途径，并将作为疾病易感性，进展和严重程度的预测因子。

We have generated a new model for systemic autoimmune disease in mice deficient in FcgammaRIIB, an IgG-binding receptor that inhibits antibody production and inflammatory responses. These mice develop a spontaneous disease that resembles lupus in humans but only in certain genetic backgrounds. Our goal is to identify susceptibility/resistance genetic loci that are responsible for the background differences in this system. We have performed an analysis of 200 mice derived from the cross between a resistant strain and a lupus susceptible strain and have identified three new resistance loci. New mouse lines have been generated in which these resistance loci are transferred to the RII-/-B6 background to allow further genetic mapping and eventual gene identification. In the characterization of the autoimmune-prone RII-/-B6 mice, we have observed that they can be aggravated or attenuated in their disease by crossing to certain modifier strains. We have observed enhanced disease in RII-/- B6 Yaa mice that correlates with a change in autoantibody specificity. By comparing these new models of disease we aim to dissect the requirements for the autoimmune pathology. These newly discovered genes will possibly uncover potential routes for modifying ongoing disease in lupus or other autoimmune diseases and will serve as predictors of disease susceptibility, progression and severity.