Polymorphic estrogen receptor binding site causes Cd2-dependent sex bias in the susceptibility to autoimmune diseases.

Autor: Fernandez Lahore G; Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden., Förster M; Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden., Johannesson M; Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden.; Division of Rheumatology, Department of Medicine Solna, Karolinska Institute, Karolinska University Hospital, SE-171 76, Stockholm, Sweden., Sabatier P; Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden., Lönnblom E; Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden., Aoun M; Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden., He Y; Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden., Nandakumar KS; Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden.; SMU-KI United Medical Inflammation Centre, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China., Zubarev RA; Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden.; Department of Pharmacological & Technological Chemistry, I.M. Sechenov First Moscow State Medical University, Moscow, 119146, Russia., Holmdahl R; Division Medical Inflammation Research, Dept. Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden. rikard.holmdahl@ki.se.; The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), 710004, Xi'an, China. rikard.holmdahl@ki.se.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Sep 22; Vol. 12 (1), pp. 5565. Date of Electronic Publication: 2021 Sep 22.
DOI: 10.1038/s41467-021-25828-5
Abstrakt: Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors probably controls the sex discrepancy in the immune response, but the underlying mechanisms are unclear. Here we positionally identify a polymorphic estrogen receptor binding site that regulates Cd2 expression, leading to female-specific differences in T cell-dependent mouse models of autoimmunity. Female mice with reduced Cd2 expression have impaired autoreactive T cell responses. T cells lacking Cd2 costimulation upregulate inhibitory Lag-3. These findings help explain sexual dimorphism in human autoimmunity, as we find that CD2 polymorphisms are associated with rheumatoid arthritis and 17-β-estradiol-regulation of CD2 is conserved in human T cells. Hormonal regulation of CD2 might have implications for CD2-targeted therapy, as anti-Cd2 treatment more potently affects T cells in female mice. These results demonstrate the relevance of sex-genotype interactions, providing strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.
(© 2021. The Author(s).)
Databáze: MEDLINE
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