Regulation Of The Immune Response By The Inositol Phosph

限制免疫反应的机制对于避免破坏性反应至关重要，这种反应可能会导致过敏和炎症反应，在更严重的情况下，会导致致命的自身免疫性疾病。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。为此，我们启动了Fc受体FcGammaRIIB(RIIB)介导的负性调控途径的研究，并确定了相关的分子SHIP。免疫复合体与RIIB结合，通过募集肌醇磷酸酶转运到膜上，导致激活信号的取消。由于骨髓增殖性综合征，缺乏SHIP会导致小鼠存活率降低，并伴有严重的脾肿大和肺内大量髓系细胞聚集。SHIP-/-小鼠的多效性表型反映了这样一个事实：SHIP不仅介导RIIB抑制信号，而且是生长因子、白介素Fc和抗原受体活性的普遍下调因子。为了更准确地了解SHIP在特定细胞中的体内功能，同时避免多效性相互作用，我们已经开始在小鼠中表征组织特异性或可诱导的SHIP突变。我们已经产生了loxP侧翼SHIP小鼠，可以与几个表达Cre重组酶的小鼠杂交。有一份手稿正在准备中，它描述了船舶在脾边缘地带形成中的重要作用。巨噬细胞特异性SHIP突变体被用于报道的实验。

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 Fc receptor FcgammaRIIB (RIIB) and identified the associating molecule SHIP. Engagement of RIIB by immune complexes results in the abolition of activation signals through the recruitment of the inositol phosphatase SHIP to the membrane. 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 not only mediates the RIIB inhibitory signal, but is also a general down-modulator of growth factor, interleukin, 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. There is a manuscript in preparation that describes the essential role of SHIP in the formation of the splenic marginal zone. Macrophage specific SHIP mutants were used for the reported experiments.