| First Author | Chen Z | Year | 2022 |
| Journal | Arthritis Rheumatol | Volume | 74 |
| Issue | 9 | Pages | 1544-1555 |
| PubMed ID | 35438841 | Mgi Jnum | J:336755 |
| Mgi Id | MGI:7488725 | Doi | 10.1002/art.42146 |
| Citation | Chen Z, et al. (2022) Interleukin-13 Receptor alpha1-Mediated Signaling Regulates Age-Associated/Autoimmune B Cell Expansion and Lupus Pathogenesis. Arthritis Rheumatol 74(9):1544-1555 |
| abstractText | OBJECTIVE: Age-associated/autoimmune B cells (ABCs) are an emerging B cell subset with aberrant expansion in systemic lupus erythematosus. ABC generation and differentiation exhibit marked sexual dimorphism, and Toll-like receptor 7 (TLR-7) engagement is a key contributor to these sex differences. ABC generation is also controlled by interleukin-21 (IL-21) and its interplay with interferon-gamma and IL-4. This study was undertaken to investigate whether IL-13 receptor alpha1 (IL-13Ralpha1), an X-linked receptor that transmits IL-4/IL-13 signals, regulates ABCs and lupus pathogenesis. METHODS: Mice lacking DEF-6 and switch-associated protein 70 (double-knockout [DKO]), which preferentially develop lupus in females, were crossed with IL-13Ralpha1-knockout mice. IL-13Ralpha1-knockout male mice were also crossed with Y chromosome autoimmune accelerator (Yaa) DKO mice, which overexpress TLR-7 and develop severe disease. ABCs were assessed using flow cytometry and RNA-Seq. Lupus pathogenesis was evaluated using serologic and histologic analyses. RESULTS: ABCs expressed higher levels of IL-13Ralpha1 than follicular B cells. The absence of IL-13Ralpha1 in either DKO female mice or Yaa DKO male mice decreased the accumulation of ABCs, the differentiation of ABCs into plasmablasts, and autoantibody production. Lack of IL-13Ralpha1 also prolonged survival and delayed the development of tissue inflammation. IL-13Ralpha1 deficiency diminished in vitro generation of ABCs, an effect that, surprisingly, could be observed in response to IL-21 alone. RNA-Seq revealed that ABCs lacking IL-13Ralpha1 down-regulated some histologic characteristics of B cells but up-regulated myeloid markers and proinflammatory mediators. CONCLUSION: Our findings indicate a novel role for IL-13Ralpha1 in controlling ABC generation and differentiation, suggesting that IL-13Ralpha1 contributes to these effects by regulating a subset of IL-21-mediated signaling events. These results also suggest that X-linked genes besides TLR7 participate in the regulation of ABCs in lupus. |
