Background/Purpose

Systemic autoimmune diseases such as lupus affect multiple organs including skin and kidneys, usually in a diverse fashion where only certain organs are affected in individual patients. It is unclear whether the breakdown in tolerance manifested by global immune dysregulation can account for the tissue specificity in relation to heterogeneity of disease, or if local factors also contribute. We hypothesized that the local immune environment may regulate tissue specificity and chose to study skin tolerance within a systemic lupus disease model.  Here, we investigated whether a subset of skin-resident dendritic cells, namely Langerhans cells (LC), maintain immune tolerance in skin versus other target organs in a model of SLE.

Methods

We used genetically lupus-prone MRL/MpJ-Fas^+/+(MRL+/+) and MRL-lpr mice that develop lupus dermatitis, nephritis, arthritis, vasculitis, and dsDNA antibodies as models of systemic autoimmunity.  To conditionally ablate LC in these mice, we introgressed the Langerin-DTR-EGFP knockin mutation from the stock B6 onto the MRL by backcrossing >10 generations, and injected diphtheria toxin in adult mice. Recombinant desmoglein 3 (Dsg3) was used as a skin autoantigen to assess tissue-specific tolerance using an epicutaneous tolerization assay. Thymidine uptake/Ki67 expression was used for cell proliferation and Western blot for measuring autoantibodies against skin lysate. Disease was assessed by clinical and histological scoring. 

Results

We previously reported that MRL mice have reduced migration of langerin⁺DC from the skin to the skin-draining lymph nodes (dLN), with a profound defect in the emigration of LC from their epidermis.  This migration defect worsens with age and disease onset. We hypothesized that this impaired DC migration observed in MRL mice play a role in the loss of skin tolerance. Indeed, lymphocytes from dLN of MRL-lpr mice spontaneously proliferate to a skin autoantigen, desmoglein 3 (Dsg3), which can be reversed by the epicutaneous application of Dsg3. Such resumption of tolerance to skin antigen, however, is prevented upon a transient ablation of LC in these mice. We then asked that if reduced DC cell migration to the dLN contributes to lupus dermatitis, then the complete ablation of them would further exacerbate dermatitis. Indeed, an inducible LC ablation in adult MRL-lpr and MRL+/+, but not in B6 and B6-lpr mice, accelerated and exacerbated lupus dermatitis and increased circulating antibodies against skin antigens, along with reduced frequency of IL-10-producing CD4 T cells in dLN. However, LC ablation did not affect disease in other organs such as kidneys, lung, or liver, and serum levels of systemic autoantibodies such as anti-dsDNA.

Conclusion

These data indicate that LCs maintain skin tolerance in systemic lupus, and highlight the importance of the local immune milieu in regulating tissue-specific autoimmunity, without affecting systemic immunity.  Such immune regulation at the local level may explain the heterogeneity of multiorgan involvement in SLE. Our data have implications for therapy at the local organ level, providing a target for therapy to correct a local breakdown in tolerance rather than attempting correction at a systemic level.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/breakdown-of-tolerance-at-the-tissue-level-in-systemic-autoimmunity-role-of-tissue-resident-dendritic-cells/