UVB light exposure promotes IgE autoantibody production and skin autoreactivity in mice that express a lupus-associated isoform of Foxp3

• Published in: The Journal of immunology (1950) Vol. 204; no. 1_Supplement; pp. 143 - 143.11
• Main Authors: Domeier, Phillip P, Chang, Sarah E, Spath, Sabine, Utz, Paul J, Zhou, Baohua, Ziegler, Steven F
• Format: Journal Article
• Language: English
• Published: 01.05.2020
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.204.Supp.143.11

Abstract Foxp3 activity is required for the maintenance of self-tolerance, but humans encode an additional exon 2-deficient splice variant isoform of FOXP3 with no known function. To determine how exon 2 of FOXP3 contributes to Treg activity, we generated mice that express exon 2-deficient FoxP3 (called B6.FoxP3ΔExon2). B6.FoxP3ΔExon2 mice develop mild autoimmunity (splenomegaly, autoantibodies and kidney nephritis) with significantly elevated titers of skin-reactive IgE. We also observed skin-reactive IgE antibodies in SLE patients with active photosensitivity, so we challenged B6 and B6.FoxP3ΔExon2 mouse skin with ultraviolet B (UVB) light to determine if UVB damage can induce skin-reactive IgE production. When compared to B6 controls, B6.FoxP3ΔExon2 mice developed greater skin inflammation with increased infiltration of Tregs (CD4+Foxp3+), effector T cells (CD4+CD44+Foxp3−) and IgE+ plasma cells (B220lowCD138+Blimp1+) at the site of UVB damage. B6.FoxP3ΔExon2 mice also had higher numbers of IgE+ antibody-forming cells, IL4-producing T cells (CD4+CD44+Foxp3−) and IgE-producing B cells, but lower numbers of CTLA4+ Tregs in draining lymph nodes from UVB-treated skin. Finally, UVB-treated B6.FoxP3ΔExon2 mice also had worsened kidney disease, phenocopying multi-systemic flares that occur in SLE patients with photosensitivity. Collectively, we found that exon 2 of the Foxp3 gene is required to control UVB-induced cutaneous inflammation though the regulation of type 2 immune activation and skin-reactive IgE. Thus, our findings suggest that photosensitivity reactions in SLE patients may be mediated by altered Foxp3 activity and skin-reactive IgE that could be therapeutically targeted to control systemic autoimmune flares.