2012年11月28日 訊 /生物谷BIOON/ --近日,，Joslin糖尿病中心科學(xué)家正在研究基因在1型糖尿病發(fā)展中的作用，與維爾茨堡大學(xué)的科學(xué)家合作,，已經(jīng)揭示了與1型糖尿病等自身免疫性疾病的相關(guān)遺傳變異是如何影響自身免疫性疾病的易感性,。這一發(fā)現(xiàn)刊登在最新一期的Diabetes雜志上。
最新研究已經(jīng)確定人類基因組中與自身免疫性疾病的區(qū)域,，如1型糖尿病相關(guān)的基因區(qū)域,。研究人員設(shè)法了解與各種自身免疫性疾病相關(guān)的基因是如何最廣泛提高疾病風險的,。
這些基因之一是PTPN22，其在調(diào)控淋巴細胞（免疫細胞）功能中起重要作用,。PTPN22基因變異（或突變）與1型糖尿病和其他一些自身免疫性疾病有關(guān),。PTPN22還參與淋巴酪氨酸磷酸酶（LYP）的形成，后者是控制免疫系統(tǒng)中T和B細胞活性的關(guān)鍵蛋白,。
PTPN22突變生成具有不同分子結(jié)構(gòu)的LYP,。大多數(shù)有關(guān)PTPN22病變異的研究表明這種變體能提高LYP活動,，減少T細胞和B細胞的活性,，增加患自身免疫疾病風險。
在免疫細胞發(fā)展成熟過稱中,，免疫細胞活性的較低有助于防止自身免疫性疾病,。然而，一項研究對人類和轉(zhuǎn)基因小鼠后分析后發(fā)現(xiàn)與1型糖尿病相關(guān)的LYP變異卻是能降低LYP的活性的,。
為了幫助解決沖突的數(shù)據(jù),，科學(xué)家進用獨特的動物模型設(shè)計實驗。使用RNA干擾和慢病毒轉(zhuǎn)基因相結(jié)合的技術(shù),，科學(xué)家們可以在最廣泛的1型糖尿病小鼠模型即肥胖性糖尿病小鼠（NOD ）中控制基因的活動,。
在這項研究中，研究人員能夠輕松地打開和關(guān)閉NOD小鼠的PTPN22基因,。PTPN22被關(guān)閉的小鼠,，研究人員發(fā)現(xiàn)調(diào)節(jié)性T細胞活性增加，自身免疫性糖尿病的風險降低,。此外,，研究數(shù)據(jù)表明PTPN22是潛在治療靶點，抑制LYP或許可防止自身免疫疾病,。（生物谷：Bioon.cm）
doi:10.2337/db12-0929
PMC:
PMID:
PTPN22 Silencing in the NOD Model Indicates the Type 1 Diabetes-Associated Allele Is Not a Loss-of-Function Variant
P. Zheng, S. Kissler.
PTPN22 encodes the lymphoid tyrosine phosphatase (LYP) and is the second strongest non-HLA genetic risk factor for type 1 diabetes. The PTPN22 susceptibility allele generates an LYP variant with an arginine to tryptophan substitution at position 620 (R620W) that has been reported by several studies to impart a gain of function. However, a recent report investigating both human cells and a knockin mouse model containing the R620W homolog suggested that this variation causes faster protein degradation. Whether LYP R620W is a gain- or loss-of-function variant, therefore, remains controversial. To address this issue, we generated transgenic NOD mice (nonobese diabetic) in which Ptpn22 can be inducibly silenced by RNA interference. We found that Ptpn22 silencing in the NOD model replicated many of the phenotypes observed in C57BL/6 Ptpn22 knockout mice, including an increase in regulatory T cells. Notably, loss of Ptpn22 led to phenotypic changes in B cells opposite to those reported for the human susceptibility allele. Furthermore, Ptpn22 knockdown did not increase the risk of autoimmune diabetes but, rather, conferred protection from disease. Overall, to our knowledge, this is the first functional study of Ptpn22 within a model of type 1 diabetes, and the data do not support a loss of function for the PTPN22 disease variant.
