Supplementary Material for: Interleukin-17RA Promotes Humoral Responses and Glomerular Injury in Experimental Rapidly Progressive Glomerulonephritis

Background/Aims: 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. Conclusion:
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.