Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy.
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 beta receptor (LTbetaR), 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 LTbetaR 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.
Wang
Jing
J
Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA.
Anders
Robert A
RA
Wu
Qiang
Q
Peng
Dacheng
D
Cho
Judy H
JH
Sun
Yonglian
Y
Karaliukas
Reda
R
Kang
Hyung-Sik
HS
Turner
Jerrold R
JR
Fu
Yang-Xin
YX
D000818:Animals; D003176:Complement C3 / Q000378:metabolism; D005759:Gastroenteritis / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology / Q000502:physiology*; D005922:Glomerulonephritis, IGA / Q000276:immunology*; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000378:metabolism; D007678:Kidney Glomerulus / Q000276:immunology; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D003176:Complement C3; D007070:Immunoglobulin A; C505697:LTBR protein, human; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; C505914:TNFSF14 protein, human; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha