Foxp3 exon 2 regulates keratinocyte-specific IgE and basophil extracellular traps in cutaneous autoimmune photosensitivity.

Abstract

Abstract Ultraviolet B (UVB) light is a common environmental trigger that can induce flares in several autoimmune diseases, but the mechanisms that mediate UVB-induced photosensitivity remain poorly understood. We used mice which express an autoimmune-driving isoform of Foxp3, called FoxP3 ΔE2mice, to develop a model autoimmune cutaneous photosensitivity. In the steady-state, FoxP3 ΔE2mice have high serum titers of IgE that target skin-associated autoantigens, and increased numbers of IL4-producing T follicular helper cells that target skin-associated proteins (Keratin 14) in the absence of overt immune challenge. After skin exposure to UVB light, FoxP3 ΔE2mice had further elevated IgE, worsened skin inflammation, and increased IgE complex deposition that localized to the challenge site. IgE production in UVB-challenged mice correlated with increased frequencies of germinal center (GC) B cells, elevated percentages of IL-4 +T follicular helper cells, and numbers of basophils with high surface expression of IgE in the draining lymph nodes of UVB-challenged skin. We also observed a significant increase in IgE accumulation, increased numbers of Tug8 +basophil extracellular traps in UVB-challenged skin and increased frequencies of activated plasmacytoid dendritic cells (CD80 +CD86 +) in the skin and skin-draining lymph nodes of FoxP3 ΔE2mice when compared to wild-type littermates. Collectively, we found that T follicular regulatory cells in FoxP3 ΔE2mice fail to maintain self-tolerance in the GC, resulting in increased production of skin reactive IgE and worsened skin inflammation driven by basophil extracellular trap accumulation in UVB-damaged skin. Supported by grants from the NIH (F32 AI154787, R01 AI136475, R21 AI169418, and R21 AI152444)