INTERLEUKIN-33 EXPANSION OF ILC2 IN B CELL ACTIVATING FACTOR (BAFF) TRANSGENIC MICE EXACERBATES IGA GLOMERULONEPHRITIS

Y WANG 1, K SHAW 1, G ZHANG 1, E CHUNG 1, M HU 2, Q CAO 2,  Y WANG 2, G ZHENG 2, S WALTERS 3, D HARRIS 3, S GREY 3, S ALEXANDER 1

1Centre For Kidney Research, The Children’s Hospital At Westmead, University of Sydney, NSW 2145, Australia, , , 2Centre for Transplantation and Renal Research, University of Sydney at Westmead Millennium Institute. Westmead, NSW 2145 Australia., , , 3Transplantation Immunology Group, Garvan Institute of Medical Research, Sydney, Australia

Aim: To assess the role of IL-33 in the development of IgA glomerulonephritis in B-cell activating factor-transgenic (BAFF-Tg) mice.

Background:BAFF belongs to the tumor necrosis factor (TNF) ligand family and plays a central role in the proliferation and differentiation of B cells. Excessive levels of BAFF cause abnormally high antibody production, including IgA. Interleukin-33 (IL-33) is a crucial activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation.

Methods: BAFF-Tg mice were treated with IL-33 to evaluate whether ILC2 expansion by IL-33 exacerbates disease in BAFF-Tg mice. To further confirm the role of ILC2s, Rag1-/- (Rag) mice were treated with IL-33, with a control group treated with IL-33 plus anti-CD90.2 to deplete ILC2s. The Rag splenocytes were then adoptively transferred into BAFF-Tg mice.

Results: There was increased IgA and C3 expression in glomeruli, and significantly higher levels of proteinuria and serum creatinine in IL-33-treated BAFF-Tg mice compared to untreated BAFF-Tg mice. Glomerulosclerosis and tubular damage were significantly worse in IL-33-treated BAFF-Tg mice. CD19 B cells were increased in spleen and increased ILC2 cells in kidney and intestine in IL-33 treated BAFF-Tg mice. Th1/Th2 cytokines (IFN-γ, IL-13 and IL-4) were up-regulated in kidneys of IL-33 treated BAFF-Tg mice. Furthermore, BAFF-Tg mice that received IL-33 stimulated Rag splenocytes showed worse glomerulonephritis, but the mice that received ILC2-depleted Rag splenocytes had significantly less kidney injury. BAFF-Tg mice that received IL-33-treated Rag splenocytes had higher levels of IgA and IgG and worse histology than mice that had received IL-33- plus anti-CD90.2-treated Rag splenocytes.

Conclusions: IL-33-expanded ILC2s exacerbate a mouse model of IgA glomerulonephritis and potentially may play a role in clinical kidney disease.

 


Biography:

Yuan is a Senior Research Scientist and a Conjoint Senior Lecturer at the University of Sydney with a longstanding track record in kidney research and in teaching postgraduate students. Yuan is currently working at the Centre for Kidney Research, The Children’s Hospital at Westmead.  She has played a key role in developing nephritis models and a number of new techniques and protocols. Yuan was a Chief Investigator on seven successful NHMRC project grants for studying regulatory T cells and genetic kidney diseases. Her work has been published in top journals in nephrology and transplantation.

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