YM WANG1, G ZHANG1, JH Zhou1, M HU2, Y WANG2, Q CAO2, G ZHENG2, GREY ST3, DC Harris2, SI Alexander1

1Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, Australia. 2Centre for Transplant and Renal Research, The University of Sydney at Westmead Hospital; 3Transplantation Immunology Group, Garvan Institute of Medical Research, Sydney, Australia.

Aim: To evaluate whether innate lymphoid cells 2 (ILC2) expansion by IL-33 exacerbates IgA prone BAFF-transgenic (BAFF-Tg) mice.

Background: B-cell activating factor (BAFF) belongs to the tumor necrosis factor (TNF) ligand family. BAFF plays a central role in the proliferation and differentiation of B cells. Excessive levels of BAFF cause abnormally high antibody production, including IgA. IL-33 is a new member of the IL-1 superfamily of cytokines, which is a crucial activator of ILC2s in innate immunity and allergic inflammation.

Methods: 12-16 week old BAFF-Tg mice were injected with IL-33 (0.5ug per mouse) daily for five days. Histology and IgA expression in kidneys and spleens were evaluated at 6 weeks after IL-33 injection. B cells were measured in PBMC and spleens; ILC2 cells were evaluated from kidneys and gut. Kidney function and damage was assessed by urine protein and serum creatinine.

Results: IL-33-treated BAFF-Tg mice showed significantly higher levels of proteinuria and serum creatinine compared to untreated BAFF-Tg (p<0.05). There was significantly more glomerulosclerosis, tubular damage and interstitial infiltrates in the IL-33-treated group (p<0.01). There was an increased level of CD19 B cells in spleen, but unchanged ILC2 cell numbers in kidney and gut. Furthermore, there was increased IgA expression in glomeruli of IL-33-treated BAFF-Tg mice compared with non-treated BAFF-Tg mice.

Conclusions: IL-33 exacerbates renal injury in BAFF-Tg mice with development of IgA glomerulonephritis possibly through enhanced IgA production. This suggests a potential role for IL-33 and possibly ILC2s in the pathogenesis of IgA glomerulonephritis.

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