Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy
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
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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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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Recapitulation of IBD and IgAN in RAG-1–/– mice with adoptively transfer...
Recapitulation of IBD and IgAN in RAG-1–/– mice with adoptively transferred Tg LN cells. (A–C) LN cells from WT or Tg mice 2–3 months of age were transferred into RAG-1–/– mice 6–7 weeks old (6 × 106 cells/mouse; n = 4). (A) Disease progression was monitored. More severe intestinal inflammation was seen in Tg recipients (right panel) than in WT recipients (left panel). (B) Serum IgA was measured by ELISA 4 or 5 weeks after transfer. Serum IgA in Tg recipients (black bars) was elevated compared with that of WT recipients (white bars). (C) Top, kidney sections from WT recipients (left) and Tg recipients (right) were subjected to IgA immunofluorescence staining. Magnification, ×630. Bottom, H&E staining of kidney sections from WT (left) or Tg (right) recipients shows the obliterated glomeruli and glomerular mesangial matrix deposition in Tg recipients.