Background/Purpose: Age-associated B cells (ABCs) are an emerging B cell subset that aberrantly expand in SLE. ABC generation and differentiation exhibit marked sexual dimorphism and TLR7 engagement is a key contributor to these sex differences. ABC generation is also controlled by IL-21 and its interplay with IFNg and IL-4. Here we investigated whether IL-13Ra1, an X-linked receptor that transmits IL-4/IL-13 signals, can regulate ABCs and lupus pathogenesis.

Methods: Mice lacking DEF6 and SWAP-70 (Double-Knock-out=DKO) that develop lupus preferentially in females were crossed with IL-13Ra1ko mice. IL-13Ra1 kos were also crossed to Yaa-DKO males, which develop severe disease due to TLR7 overexpression. ABCs were assessed by FACS and RNA-seq and lupus pathogenesis was evaluated by serologic and histological analyses.

Results: ABCs express higher levels of IL-13Ra1 than follicular B cells. Absence of IL-13Ra1 in either DKO females or Yaa-DKO males decreased the accumulation of ABCs, their differentiation into plasmablasts, and autoantibody production. Lack of IL-13Ra1 also prolonged survival and delayed the development of tissue inflammation. IL-13Ra1 deficiency diminished the in vitro generation of ABCs, an effect that, surprisingly, could be observed in response to IL-21 alone. RNAseq revealed that ABCs lacking IL-13Ra1 downregulated BCR signaling pathways but upregulated myeloid markers and proinflammatory mediators.

Conclusion: These studies uncover a novel role for IL-13Ra1 in the control of ABC generation and differentiation and suggest that IL-13Ra1 contributes to these effects by regulating a subset of IL-21-mediated signaling events. These studies also suggest that X-linked genes in addition to TLR7 participate in the regulation of the ABC compartment in lupus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-13ra1-mediated-signaling-regulates-age-associated-autoimmune-b-cell-expansion-and-lupus-pathogenesis/