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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Defective IgA transportation and polymeric nature of serum IgA. (A) Fece...
Defective IgA transportation and polymeric nature of serum IgA. (A) Feces of mice 8–10 months of age were collected, and IgA levels in the fecal extracts were determined by ELISA. Fecal IgA levels in Tg mice decreased significantly. Data are mean values ± SE from five mice per group. Student’s t test was used to compare the values between the WT and Tg groups: P < 0.05. (B) FPLC fraction profiles of IgA in sera. Gel-filtration molecular mass marker for protein was used. IgA levels in fractioned samples of sera were determined by ELISA. pIgA is predominant in sera of Tg mice compared with WT mice 6–8 months old. (C) After pIgA was purified from serum of Igha mice, it was administered i.v. to WT or Tg mice 8–10 months of age (n = 5). The level of pIgAa was tested by ELISA against IgAa. Tg recipients showed much higher levels of pIgAa.