The critical role of LIGHT in promoting intestinal inflammation and Crohn's disease.
Crohn's disease (CD) is a type of inflammatory bowel disease associated with increased Th1 cytokines and unique pathological features. However, its pathogenesis has not been fully understood. Previous studies showed that homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for HVEM on T cells (LIGHT) transgenic (Tg) mice develop autoimmunity including intestinal inflammation with a variable time course. In this study, we establish an experimental model for CD by adoptive transfer of Tg mesenteric lymph node cells into RAG(-/-) mice. The recipients of Tg lymphocytes rapidly develop a disease strikingly similar to the key pathologic features and cytokine characterization observed in CD. We demonstrate that, as a costimulatory molecule, LIGHT preferentially drives Th1 responses. LIGHT-mediated intestinal disease is dependent on both of its identified signaling receptors, lymphotoxin beta receptor and herpes virus entry mediator, because LIGHT Tg mesenteric lymph node cells do not cause intestinal inflammation when transferred into the lymphotoxin beta receptor-deficient mice, and herpes virus entry mediator on donor T cells is required for the full development of disease. Furthermore, we demonstrated that up-regulation of LIGHT is associated with active CD. These data establish a new mouse model resembling CD and suggest that up-regulation of LIGHT may be an important mediator of CD pathogenesis.
Wang
Jing
J
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Anders
Robert A
RA
Wang
Yang
Y
Turner
Jerrold R
JR
Abraham
Clara
C
Pfeffer
Klaus
K
Fu
Yang-Xin
YX
D019264:Adoptive Transfer; D000818:Animals; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D016130:Immunophenotyping; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008198:Lymph Nodes / Q000166:cytology / Q000637:transplantation; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D016207:Cytokines; C505697:LTBR protein, human; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; C506028:TNFRSF14 protein, human; C505914:TNFSF14 protein, human; C506029:Tnfrsf14 protein, mouse; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha