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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Dominant IgA deposition and abnormal UA in Tg mice. (A) Immunofluorescen...
Dominant IgA deposition and abnormal UA in Tg mice. (A) Immunofluorescence staining of kidney sections of WT (left) and Tg (right) mice 6–8 months of age. Distinct IgA, C3, IgM, and IgG deposition were observed in aged Tg mice. Representative data are shown (n = 3). Magnification, ×630. (B) Urine samples were subjected to strip UA. The incidence and severity of proteinuria (n = 10) and hematuria (n = 10) were higher in aged Tg mice (filled symbols) than in WT mice (open symbols). (C) EM analysis of Tg glomeruli, showing mesangial deposition of immunoglobulin. (D and E) WT normal glomerulus (D) (H&E; magnification, ×400) and Tg glomerulus with significant mesangial expansion with acellular eosinophilic material (E) (H&E; magnification, ×400). (F–H) WT normal glomerulus (F) (PAS; magnification, ×400), and Tg glomerulus (G and H) with diffuse (G) and focal (H, right half of glomerulus) deposition of PAS-stainable material in the glomerular matrix. (I and J) WT tubulointerstium with no significant inflammatory cellular infiltrate (I), and Tg tubulointerstium with patchy collections of inflammatory cellular infiltrates (J) (H&E; magnification, ×200). (K) Semiquantitative assessment of the degree and severity of glomerular lesions in WT and Tg mice (n = 4 mice per group).