Date: Sunday, October 21, 2018
Session Title: 3S080 ACR Abstract: Cytokines & Cell Trafficking (840–845)
Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Acquired or self antigens in tissues are taken to lymphoid organs to elicit protective immunity or tolerance, respectively. This is accomplished by dendritic cells (DC) that reside in tissues. Here, we used the skin model of tissue-resident DC to investigate mechanisms of tissue-DC migration and its role in lupus dermatitis. Skin harbors at least three subsets of DC: Langerhans cells (LC) that reside in the epidermis, langerin-expressing dermal DC that reside in the dermis (LangdDC), and langerin– dermal DC. Here, we investigated the roles of skin-resident DC subsets in lupus dermatitis.
Methods: 1. To evaluate skin DC migration in lupus-prone MRL-Faslpr/lpr (MRL-lpr) and MRL-Fas+/+ (MRL+/+) mice and control C3H, B10.BR and B6 mice, we: a) applied fluorophores (FITC/TRITC) to the skin of mice and detected FITC/TRITC+ cells in the skin-draining lymph nodes to track in vivo migration of skin-resident DC; b) verified in vivo migration of skin DC at the steady state (without any external manipulation) using langerin-driven eGFP knock-in mice in the lupus and control backgrounds; c) assessed in situ migration where skin explants were floated on a culture medium containing chemokines in a culture chamber, followed by staining and counting for DC in the epidermis (for DC that have not emigrated), dermis (for DC that are migrating through lymphatics), and in culture wells (for DCs that have migrated out). 2. We treated MRL mice with glycolipid αGalCer that ameliorates lupus dermatitis and determined its effect on skin DC migration. 3. We investigated mechanisms of skin DC migration using TCR γδ–/– and CD40L–/– mice and respective blocking antibodies. 4. We used diphtheria toxin receptor knock-in MRL mice to conditionally ablate LC and/or LangdDC, and determined the effect on lupus disease.
Results: We found a reduced migration of LC but increased trafficking of LangdDC to skin-draining lymph nodes in lupus dermatitis-prone MRL-lpr and MRL+/+ mice as compared to control mice. Such altered pattern of migration of these two skin DC subsets was corrected by αGalCer treatment. However, αGalCer did not increase LC migration through its well-known target iNKT cells but increased epidermal γδ T cells that were otherwise reduced in lupus mice compared to controls. Epidermal γδ T cells increased LC migration in vitro. The role of γδ T cells in modulating LC migration was confirmed using knockout animals as well as blocking antibodies. CD40L deficiency or antibody blockade abrogated the ability of γδ T cells to enhance LC migration. Finally, conditional ablation of LC worsened lupus dermatitis; this effect was abrogated when both LC and LangdDC were ablated together. LC depletion or αGalCer treatment did not affect kidney or lung disease.
Conclusion: The two skin DC subsets play opposite, balancing roles in the pathogenesis of lupus dermatitis: LC protect and LangdDC harm. The two skin DC are also regulated differently: LC migrate less, but LangdDC traffic more, to skin-draining lymph nodes of lupus mice that also have less epidermal γδ T cells. γδ T cells regulate LC migration via CD40-CD40L interaction. αGalCer that corrects these defects ameliorates dermatitis.
To cite this abstract in AMA style:Singh RR, Gutierrez MA, Kim P, Randhawa D, Philips R, King JK, Eriksson A. New Insights in Lupus Dermatitis: Differential Regulation and Roles of Tissue-Resident Dendritic Cell Subsets in the Pathogenesis of Autoimmune Skin Inflammation [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/new-insights-in-lupus-dermatitis-differential-regulation-and-roles-of-tissue-resident-dendritic-cell-subsets-in-the-pathogenesis-of-autoimmune-skin-inflammation/. Accessed July 2, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/new-insights-in-lupus-dermatitis-differential-regulation-and-roles-of-tissue-resident-dendritic-cell-subsets-in-the-pathogenesis-of-autoimmune-skin-inflammation/