Journal
JOURNAL OF IMMUNOLOGY
Volume 195, Issue 2, Pages 464-476Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1402735
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Funding
- National Institutes of Health (NIH) [R01 AI080778, T32 AR053463, K08 AR062593, AR59126]
- Pilot Award from the University of California, Los Angeles (UCLA) Office of the Vice Chancellor for Research
- Ruth L. Kirschstein National Research Service Award Academic Training in Rheumatology [T32 AR053463]
- NIH K12 UCLA Building Interdisciplinary Research Careers in Women's Health
- Rheumatology Research Foundation
- Arthritis Foundation Postdoctoral Fellowship
- Lupus Foundation of America Gina Finzi Memorial Student Fellowship
- Arthritis Foundation Meyer Young Investigator Award
- Rheumatology Research Foundation Bridge Award
- Joseph B. Gould Foundation
- NIH-National Center for Research Resources [CJX1-443835-WS-29646]
- NSF [CHE-0722519]
- NIH [CA-16042, AI-28697]
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Systemic autoimmune diseases such as lupus affect multiple organs, usually in a diverse fashion where only certain organs are affected in individual patients. It is unclear whether the local immune cells play a role in regulating tissue specificity in relation to disease heterogeneity in systemic autoimmune diseases. In this study, we used skin as a model to determine the role of tissue-resident dendritic cells (DCs) in local and systemic involvement within a systemic lupus disease model. Skin-resident DCs, namely, Langerhans cells (LCs), have been implicated in regulating tolerance or autoimmunity using elegant transgenic models, however, their role in local versus systemic immune regulation is unknown. We demonstrate that although lymphocytes from skin-draining lymph nodes of autoimmune-prone MRL/MpJ-Fas lpr/lpr (MRL-lpr) mice react spontaneously to a physiological skin self-Ag desmoglein-3, epicutaneous applications of desmoglein-3 induced tolerance that is dependent on LCs. Inducible ablation of LCs in adult preclinical MRL-lpr and MRL/MpJ-Fas(+/+) mice resulted in increased autoantibodies against skin Ags and markedly accelerated lupus dermatitis with increased local macrophage infiltration, but had no effect on systemic autoantibodies such as anti-dsDNA Abs or disease in other organs such as kidneys, lung, and liver. Furthermore, skin-draining lymph nodes of LC-ablated MRL-lpr mice had significantly fewer CD4(+) T cells producing anti-inflammatory cytokine IL-10 than LC-intact controls. These results indicate that a skin-resident DC population regulates local tolerance in systemic lupus and emphasize the importance of the local immune milieu in preventing tissue-specific autoimmunity, yet have no effect on systemic autoimmunity.
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