Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy
Jing Wang, … , Jerrold R. Turner, Yang-Xin Fu
Jing Wang, … , Jerrold R. Turner, Yang-Xin Fu
Published March 15, 2004
Citation Information: J Clin Invest. 2004;113(6):826-835. https://doi.org/10.1172/JCI20096.
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Article Autoimmunity

Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy

Abstract

Whether and how T cells contribute to the pathogenesis of immunoglobulin A nephropathy (IgAN) has not been well defined. Here, we explore a murine model that spontaneously develops T cell–mediated intestinal inflammation accompanied by pathological features similar to those of human IgAN. Intestinal inflammation mediated by LIGHT, a ligand for lymphotoxin β receptor (LTβR), not only stimulates IgA overproduction in the gut but also results in defective IgA transportation into the gut lumen, causing a dramatic increase in serum polymeric IgA. Engagement of LTβR by LIGHT is essential for both intestinal inflammation and hyperserum IgA syndrome in our LIGHT transgenic model. Impressively, the majority of patients with inflammatory bowel disease showed increased IgA-producing cells in the gut, elevated serum IgA levels, and severe hematuria, a hallmark of IgAN. These observations indicate the critical contributions of dysregulated LIGHT expression and intestinal inflammation to the pathogenesis of IgAN.

Authors

Jing Wang, Robert A. Anders, Qiang Wu, Dacheng Peng, Judy H. Cho, Yonglian Sun, Reda Karaliukas, Hyung-Sik Kang, Jerrold R. Turner, Yang-Xin Fu

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Elevated serum IgA and IgA deposition in the kidneys of Tg mice. (A) Ser...
Elevated serum IgA and IgA deposition in the kidneys of Tg mice. (A) Sera were collected from WT and Tg mice at the age of 6–8 months (right) or 7 weeks (left) and were subjected to IgA ELISA. Right, the level of serum IgA was dramatically enhanced in aged Tg mice (n = 10). Left, the level of serum IgA was increased up to tenfold in Tg mice (n = 4 per group). (B) Sera were collected from WT and Tg mice 6–8 months of age and were subjected to IgG1 and IgG2a ELISA (n = 5). Open circles, WT; filled circles, Tg. (C) LIGHT Tg mice were crossed with LTβR–/– mice. Sera were collected from LTβR–/– and Tg/LTβR–/– mice 6–8 months of age and IgA levels were determined by ELISA (n = 5). Hyperserum IgA was absent in Tg/LTβR–/– mice compared with Tg mice. (D) Anti-DNA antibody was examined in WT and Tg mice (n = 5 per group). Anti-DNA IgG and anti-DNA IgA were both increased in aged Tg mice (6–8 months old), while there was no increase in young Tg mice (7 weeks old).