Lnk/Sh2b3 regulates initiation and severity of autoimmune insulitis and contributes to diabetes risk
Year: 2025
Type: article
Abstract: The Lnk/Sh2b3 adaptor protein functions as a regulatory molecule for cytokine signaling in lymphohematopoiesis. A missense variant of the LNK/SH2B3 gene is reportedly a risk variant common to several autoimmune diseases, including type 1 diabetes (T1D). However, roles of Lnk in T1D development remain elusive. We found that Lnk −/− mice showed increased susceptibility to diabetes following treatment with fairly low doses of streptozotocin, manifested by hyperglycemia and insulitis accompanied by accumulation of CD8 + T-cells and loss of pancreatic β cells. The high susceptibility of Lnk −/− mice to islet damage was abolished in crosses with Rag2 −/− mice lacking lymphocytes or MyD88 −/− mice carrying various defects in activation of innate immune cells. In Lnk −/− mice pancreata, dendritic cell (DC) fractions were altered and showed augmented expression of CD40 and IL-27. Treatment with anti-CD40L or anti-GM-CSF antibodies suppressed β cell damage and prevented diabetes. Thus, Lnk regulates T-cell priming and expansion via GM-CSF- and possibly IL-27-dependent activation of pancreatic DCs after islet damage.
Source: Life Science Alliance
Authors: Mari Tenno, Satoshi Takaki
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,500
Awards: G1655983448, Lnk/SH2B3 contributes to the initiation and severity of STZ-induced diabetes, G2657272791, Obesity-induced activation of cytokine-producing cells and eosinophils in adipose tissues., IL-5/好酸球/脂質代謝軸を介する新規炎症抑制機構の解明と制御, G4144329569, G5101201322, Roles of disease associated gene Lnk/Sh2b3 in inflammation., Signaling and regulation of germinal center B cell responses involved in IgE production, G6797309550, G7230084011, G7493943804, G8609412071, G8871495320
OpenAlex ID: W4414653697