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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IBD patients show upregulated serum IgA levels and enhanced incidence of...
IBD patients show upregulated serum IgA levels and enhanced incidence of abnormal UAs. (A) Comparison of serum IgA in patents with ulcerative colitis (w/UC; n = 10) or Crohn disease (w/CD; n = 24) and unaffected control subjects (Unaffected; n = 9) by ELISA illustrates the increase in serum IgA in IBD patients (left panel). Avg, average. Higher serum IgA levels correlate with a positive UA in IBD patients (right panel: UC, n = 9; CD, n = 17). UA+, trace to 4+. (B) Macroscopic and microscopic UAs show the remarkable increase in hematuria in IBD patients (UC) compared with unselected patients (Control) or normal individuals (Normal) at the same hospital. (C) Immunohistochemical staining demonstrates increased IgA+ PCs in the intestine of active IBD patients (Active IBD), while the quiescent IBD patients (Quiescent IBD) or control patients show much less positive staining for IgA (n = 3 per group). Severe intestinal inflammation was observed in active IBD patients but not in quiescent or control patients (n = 3; H&E). Magnification, ×200. (D) PCs and IgA-PCs in LP were counted using a microscope. The numbers of PCs and IgA-PCs in active IBD patients were dramatically increased compared with those of controls. Cells in ten high-power fields (hpf’s) were counted for each control or patient, and three controls or patients were analyzed. (E) Anti-DNA IgG and IgA antibodies were tested in controls (n = 5) and patients (n = 6). Data are means ± SE of OD values.