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-γ and IL-4. This study was undertaken to investigate whether IL-13 receptor α1 (IL-13Rα1), 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-13Rα1-knockout mice. IL-13Rα1-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-13Rα1 than follicular B cells. The absence of IL-13Rα1 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-13Rα1 also prolonged survival and delayed the development of tissue inflammation. IL-13Rα1 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-13Rα1 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-13Rα1 in controlling ABC generation and differentiation, suggesting that IL-13Rα1 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.
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-γ and IL-4. This study was undertaken to investigate whether IL-13 receptor α1 (IL-13Rα1), 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-13Rα1-knockout mice. IL-13Rα1-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-13Rα1 than follicular B cells. The absence of IL-13Rα1 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-13Rα1 also prolonged survival and delayed the development of tissue inflammation. IL-13Rα1 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-13Rα1 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-13Rα1 in controlling ABC generation and differentiation, suggesting that IL-13Rα1 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.
Authors: Shaun W Jackson; Nicole E Scharping; Nikita S Kolhatkar; Socheath Khim; Marc A Schwartz; Quan-Zhen Li; Kelly L Hudkins; Charles E Alpers; Denny Liggitt; David J Rawlings Journal: J Immunol Date: 2014-04-07 Impact factor: 5.422
Authors: Carl D Langefeld; Hannah C Ainsworth; Deborah S Cunninghame Graham; Jennifer A Kelly; Mary E Comeau; Miranda C Marion; Timothy D Howard; Paula S Ramos; Jennifer A Croker; David L Morris; Johanna K Sandling; Jonas Carlsson Almlöf; Eduardo M Acevedo-Vásquez; Graciela S Alarcón; Alejandra M Babini; Vicente Baca; Anders A Bengtsson; Guillermo A Berbotto; Marc Bijl; Elizabeth E Brown; Hermine I Brunner; Mario H Cardiel; Luis Catoggio; Ricard Cervera; Jorge M Cucho-Venegas; Solbritt Rantapää Dahlqvist; Sandra D'Alfonso; Berta Martins Da Silva; Iñigo de la Rúa Figueroa; Andrea Doria; Jeffrey C Edberg; Emőke Endreffy; Jorge A Esquivel-Valerio; Paul R Fortin; Barry I Freedman; Johan Frostegård; Mercedes A García; Ignacio García de la Torre; Gary S Gilkeson; Dafna D Gladman; Iva Gunnarsson; Joel M Guthridge; Jennifer L Huggins; Judith A James; Cees G M Kallenberg; Diane L Kamen; David R Karp; Kenneth M Kaufman; Leah C Kottyan; László Kovács; Helle Laustrup; Bernard R Lauwerys; Quan-Zhen Li; Marco A Maradiaga-Ceceña; Javier Martín; Joseph M McCune; David R McWilliams; Joan T Merrill; Pedro Miranda; José F Moctezuma; Swapan K Nath; Timothy B Niewold; Lorena Orozco; Norberto Ortego-Centeno; Michelle Petri; Christian A Pineau; Bernardo A Pons-Estel; Janet Pope; Prithvi Raj; Rosalind Ramsey-Goldman; John D Reveille; Laurie P Russell; José M Sabio; Carlos A Aguilar-Salinas; Hugo R Scherbarth; Raffaella Scorza; Michael F Seldin; Christopher Sjöwall; Elisabet Svenungsson; Susan D Thompson; Sergio M A Toloza; Lennart Truedsson; Teresa Tusié-Luna; Carlos Vasconcelos; Luis M Vilá; Daniel J Wallace; Michael H Weisman; Joan E Wither; Tushar Bhangale; Jorge R Oksenberg; John D Rioux; Peter K Gregersen; Ann-Christine Syvänen; Lars Rönnblom; Lindsey A Criswell; Chaim O Jacob; Kathy L Sivils; Betty P Tsao; Laura E Schanberg; Timothy W Behrens; Earl D Silverman; Marta E Alarcón-Riquelme; Robert P Kimberly; John B Harley; Edward K Wakeland; Robert R Graham; Patrick M Gaffney; Timothy J Vyse Journal: Nat Commun Date: 2017-07-17 Impact factor: 14.919
Authors: Valerie M Harris; Kristi A Koelsch; Biji T Kurien; Isaac T W Harley; Jonathan D Wren; John B Harley; R Hal Scofield Journal: Front Immunol Date: 2019-10-21 Impact factor: 7.561