Journal
ANNALS OF NEUROLOGY
Volume 75, Issue 5, Pages 739-758Publisher
WILEY-BLACKWELL
DOI: 10.1002/ana.24165
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Funding
- German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]) [CRC Transregio 128-A9, B1, Z2, Lo817/2-1]
- DFG Cells in Motion-Cluster of Excellence, Munster, Germany [EXC 1003, DFG_GR3946_1_1]
- Competence Network for Multiple Sclerosis - Federal Ministry of Education and Research [FKZ 01GI1308B]
- Interdisciplinary Center of Clinical Research grant [Lo2/004/11]
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Objective: Environmental conditions (eg, latitude) play a critical role in the susceptibility and severity of many autoimmune disorders, including multiple sclerosis (MS). Here, we investigated the mechanisms underlying the beneficial effects of immune regulatory processes induced in the skin by moderate ultraviolet B (UVB) radiation on central nervous system (CNS) autoimmunity. Methods: Effects of UVB light were analyzed in a murine model of CNS autoimmunity (experimental autoimmune encephalomyelitis). Additionally, patients with relapsing-remitting MS were treated with narrowband UVB phototherapy. Immunomodulatory effects were examined in skin biopsies, serum samples, and immune cells of the peripheral blood. Results: Regulatory T cells (Tregs), which are induced locally in the skin-draining lymph nodes in response to UVB exposure, connect the cutaneous immune response to CNS immunity by migration to the sites of inflammation (blood, spleen, CNS). Here, they attenuate the inflammatory response and ameliorate disease symptoms. Treg-inducing tolerogenic dendritic cells (DCs) were further necessary for induction of this systemic immune regulation by UVB radiation, because ablation of Langerhans cells abolished the UVB-induced phenotype. MS patients treated with UVB phototherapy showed an increase in induced Tregs and tolerogenic DCs accompanied by the downregulation of the T-cell effector cytokine interleukin 21. The treatment further induced elevated serum levels of vitamin D. Interpretation: Local UVB radiation of the skin influences systemic immune reactions and attenuates systemic autoimmunity via the induction of skin-derived tolerogenic DCs and Tregs. Our data could have implications for the understanding or therapeutic modulation of environmental factors that influence immune tolerance.
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