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Abstract Number: 1906

IL-13Ra1-Mediated Signaling Regulates Age-Associated/Autoimmune B-Cell Expansion and Lupus Pathogenesis

Danny Flores Castro1, Zhu Chen2, Sanjay Gupta3, Michela Manni3, Juan Rivera Correa3, Max Chao4, Yurii Chinenov4, Tania Pannellini5, Habib Zaghouni6, Rolf Jessberger7 and Alessandra Pernis8, 1Autoimmunity and Inflammation Program, Hospital for Special Surgery, Palisades Park, NJ, 2Department of Rheumatology and Immunology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China (People's Republic), 3Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY, 4David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, 5Research Division and Precision Medicine Laboratory, Hospital for Special Surgery, New York, NY, 6Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO, 7Institute of Physiological Chemistry, Technische Universitat, Dresden, Germany, 8Department of Medicine, Weill Cornell Medicine, New York, NY

Meeting: ACR Convergence 2021

Keywords: Age Associated/Autoimmune B cells, IL-13Ra1, Mouse Models, Lupus, TLR7, X-linked genes

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Session Information

Date: Tuesday, November 9, 2021

Session Title: Abstracts: B Cell Biology & Targets in Autoimmune & Inflammatory Disease (1905–1908)

Session Type: Abstract Session

Session Time: 2:15PM-2:30PM

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.


Disclosures: D. Flores Castro, None; Z. Chen, None; S. Gupta, None; M. Manni, None; J. Rivera Correa, None; M. Chao, None; Y. Chinenov, None; T. Pannellini, None; H. Zaghouni, None; R. Jessberger, None; A. Pernis, None.

To cite this abstract in AMA style:

Flores Castro D, Chen Z, Gupta S, Manni M, Rivera Correa J, Chao M, Chinenov Y, Pannellini T, Zaghouni H, Jessberger R, Pernis A. IL-13Ra1-Mediated Signaling Regulates Age-Associated/Autoimmune B-Cell Expansion and Lupus Pathogenesis [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/il-13ra1-mediated-signaling-regulates-age-associated-autoimmune-b-cell-expansion-and-lupus-pathogenesis/. Accessed February 6, 2023.
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