Immune Regulation by the Inositol Phosphatase Ship

限制免疫反应的机制对于避免可能导致过敏和炎症反应或在更严重的情况下导致致命的自身免疫性疾病的破坏性反应至关重要。我们的目标是了解下调免疫反应，控制淋巴细胞增殖和抗体产生的机制。有了这个意图，我们开始了研究的负调控途径介导的肌醇磷酸酶SHIP。缺乏SHIP导致小鼠的生存能力降低，这是由于骨髓增殖样综合征，伴有严重的脾肿大和肺中大量骨髓细胞积聚。SHIP-/-小鼠的非常多效的表型反映了SHIP是生长因子、细胞因子、Fc和抗原受体活性的一般下调剂的事实。为了更精确地了解SHIP在特定细胞中的体内功能，同时避免多效性相互作用，我们已经开始表征小鼠中的组织特异性或诱导性SHIP突变。我们已经产生了loxP侧翼的SHIP小鼠，可以与几个Cre重组酶表达小鼠杂交。与Jeff Ravetch合作，我们已经确定了SHIP在脾边缘区形成中的重要作用，利用巨噬细胞特异性缺失SHIP的小鼠。我们现在正在表征SHIP在T淋巴细胞选择、耐受性以及肥大细胞特异性缺失SHIP的影响中的功能作用。

Mechanisms that restrict the immune response are critical to avoid damaging reactivity that can lead to allergies and inflammatory responses or, in more severe cases, to lethal autoimmune diseases. Our goal is to understand mechanisms that downregulate the immune response, control lymphocyte proliferation and antibody production. With this intention we initiated a study of the negative regulatory pathway mediated by the inositol phosphatase SHIP. Absence of SHIP results in reduced viability of the mice due to a myeloproliferative-like syndrome, with profound splenomegaly and massive myeloid cell accumulation in the lungs. The very pleiotropic phenotype of SHIP-/- mice reflects the fact that SHIP is a general down-modulator of growth factor, cytokine, Fc and antigen receptor activity. To get a more precise idea of the in vivo function of SHIP in specific cells while avoiding pleiotropic interactions, we have begun to characterize tissue-specific or inducible SHIP mutations in mice. We have generated loxP-flanked SHIP mice that can be crossed to several Cre recombinase-expressing mice. In collaboration with Jeff Ravetch we have determined the essential role of SHIP in the formation of the splenic marginal zone utilizing mice with macrophage specific deletion of SHIP. We are now characterizing the functional role of SHIP in T lymphocyte selection, tolerance as well as the effects of mast cell-specific deletion of SHIP.