IRAK-M deficiency promotes the development of type 1 diabetes in NOD mice.
IRAK-M deficiency promotes the development of type 1 diabetes in NOD mice.
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作者：
Tan Q;Majewska-Szczepanik M;Zhang X;Szczepanik M;Zhou Z;Wong FS;Wen L
1型糖尿病(T1 DM)是一种器官特异性自身免疫性疾病，其特征是分泌胰岛素的胰腺β细胞进行性破坏。T细胞介导的适应性反应和先天免疫过程都参与了发病过程。白介素1受体相关激酶M(IRAK-M)能有效抑制Toll样受体通路中的MyD88下游信号，而IRAK-M的缺失与自身免疫有关。我们的研究表明，IRAK-M缺陷(IRAK-M−/−)非肥胖糖尿病(NOD)小鼠表现出早期发病和快速进展的T1 DM，并伴有糖耐量减低、更严重的胰岛素炎和血清抗胰岛素自身抗体升高。机制研究表明，IRAK-M−/−小鼠的IRAK-M−/−抗原提呈细胞的激活和抗原提呈功能增强是导致疾病快速发展的原因。此外，IRAK-M−/−树突状细胞在体外诱导糖尿病T细胞的激活，并与糖尿病T细胞共转移，可在体内诱导免疫缺陷NOD小鼠快速发病T1 DM。这项研究阐明了IRAK-M对天然免疫途径的调节如何影响自身免疫性糖尿病的发展。
Type 1 diabetes mellitus (T1DM) is an organ-specific autoimmune disease characterized by progressive destruction of insulin-secreting pancreatic β-cells. Both T-cell–mediated adaptive responses as well as innate immune processes are involved in pathogenesis. Interleukin-1 receptor–associated kinase M (IRAK-M) can effectively inhibit the MyD88 downstream signals in Toll-like receptor pathways, while lack of IRAK-M is known to be associated with autoimmunity. Our study showed that IRAK-M–deficient (IRAK-M−/−) nonobese diabetic (NOD) mice displayed early onset and rapid progression of T1DM with impaired glucose tolerance, more severe insulitis, and increased serum anti-insulin autoantibodies. Mechanistic studies showed that the enhanced activation and antigen-presenting function of IRAK-M−/− antigen-presenting cells from IRAK-M−/− mice were responsible for the rapid progression of disease. Moreover, IRAK-M−/− dendritic cells induced enhanced activation of diabetogenic T cells in vitro and the rapid onset of T1DM in vivo in immunodeficient NOD mice when cotransferred with diabetogenic T cells. This study illustrates how the modulation of innate immune pathways through IRAK-M influences the development of autoimmune diabetes.
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DOI：
10.4049/jimmunol.0902828
发表时间：
2010-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hubbard LL;Ballinger MN;Thomas PE;Wilke CA;Standiford TJ;Kobayashi KS;Flavell RA;Moore BB
通讯作者：
Moore BB
影响因子：
4.9
作者：
Berglund, Martin;Melgar, Silvia;Hultgren, Olof H.
通讯作者：
Hultgren, Olof H.
DOI：
10.1038/nri3477
发表时间：
2013-08
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
--
作者：
Hatao, Fumihiko;Yamamoto, Maya;Tanamoto, Ken-ichi
通讯作者：
Tanamoto, Ken-ichi
影响因子：
3.7
作者：
Aumeunier A;Grela F;Ramadan A;Pham Van L;Bardel E;Gomez Alcala A;Jeannin P;Akira S;Bach JF;Thieblemont N
通讯作者：
Thieblemont N