Interleukin-13 Receptor α1-Mediated Signaling Regulates Age-Associated/Autoimmune B Cell Expansion and Lupus...

Area of Science:

• Immunology
• Autoimmunity
• Genetics

Background:

• Age-associated/autoimmune B cells (ABCs) are implicated in systemic lupus erythematosus (SLE).
• Toll-like receptor 7 (TLR-7) and interleukin-21 (IL-21) signaling influence ABC generation and exhibit sexual dimorphism in SLE.
• The X-linked IL-4/IL-13 receptor subunit alpha 1 (IL-13Rα1) is a potential regulator of these processes.

Purpose of the Study:

• To investigate the role of IL-13Rα1 in ABC generation, differentiation, and lupus pathogenesis.
• To determine if IL-13Rα1 influences sex-dimorphic ABC expansion in SLE models.

Main Methods:

• Generation of IL-13Rα1-knockout mouse models, including crosses with lupus-prone mice (DEF-6/switch-associated protein 70 double-knockout [DKO] and Y chromosome autoimmune accelerator [Yaa] DKO).
• Assessment of ABCs via flow cytometry and RNA-Seq.
• Evaluation of lupus pathogenesis through serologic and histologic analyses.

Main Results:

• IL-13Rα1 deficiency in DKO and Yaa DKO mice reduced ABC accumulation, plasmablast differentiation, and autoantibody production.
• Lack of IL-13Rα1 improved survival and delayed tissue inflammation in lupus models.
• IL-13Rα1 absence diminished in vitro ABC generation, even with IL-21 stimulation alone, and altered B cell gene expression towards myeloid and proinflammatory profiles.

Conclusions:

• IL-13Rα1 is a novel regulator of ABC generation and differentiation, potentially mediating IL-21 signaling.
• X-linked genes, including IL-13Rα1, contribute to ABC regulation in lupus beyond TLR7.