title: Interleukin-17RA Promotes Humoral Responses and Glomerular Injury in Experimental Rapidly Progressive Glomerulonephritis.
abstract: OBJECTIVE
  Interleukin (IL)-17A and IL-17F are proinflammatory cytokines, which signal through a receptor complex consisting of IL-17RA and IL-17RC subunits. We sought to define the role of IL-17RA expression by leukocytes and stromal cells in nephritogenic immunity and injury in experimental glomerulonephritis.
  
  
  METHODS
  Glomerulonephritis was induced in wild-type and IL-17RA-deficient (IL-17RA-/-) mice by sheep anti-mouse glomerular basement membrane globulin. Renal injury and immune responses were assessed at day 21. Glomerulonephritis was induced in bone marrow (BM) chimeric mice, with either BM or tissue cell (TC) deficiency of IL-17RA. To assess humoral responses, WT and IL-17RA-/- mice were sensitized to sheep globulin and euthanized 10 days later.
  
  
  RESULTS
  IL-17RA-/- mice had reduced glomerular crescent formation, neutrophils and macrophages compared to wild-type mice, while nephritic BM-TC+ mice developed less glomerular segmental necrosis. IL-17RA expression was required in both BM and TC for maximal systemic interferon-γ expression. Antigen-specific humoral immune responses were impaired in the absence of IL-17RA. Compared to BM+TC+ mice, glomerular IgG and C3 deposition was reduced in BM+TC- and BM-TC+ mice, respectively. Humoral immunity was also impaired in BM- and TC-deficient chimeras. BM+TC- mice had fewer B cells expressing CXCR5, while IL-17RA-/- mice had abnormal germinal centre development after immunization, with reduced follicular B cell and follicular helper T-cell CXCR5 expression, explaining the impaired humoral immunity.
  
  
  CONCLUSIONS
  IL-17RA contributes to experimental glomerulonephritis, with IL-17RA expression on both leukocytes and stromal cells being required for the full expression of nephritogenic humoral immunity.
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Vic., Australia.
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Ghali
authors.forename: Kim M
authors.initials: KM
authors.lastname: O'Sullivan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Eggenhuizen
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005921:Glomerulonephritis / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007678:Kidney Glomerulus / Q000276:immunology / Q000293:injuries / Q000473:pathology; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053722:Receptors, Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012756:Sheep; D017154:Stromal Cells / Q000276:immunology / Q000473:pathology; D018183:Transplantation Chimera / Q000276:immunology
chemical_list: C491673:Il17ra protein, mouse; D053722:Receptors, Interleukin-17