Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the involvement of multiple organ systems. Previous studies have demonstrated that restoration of immune tolerance through targeting diverse immune cell subsets represents a promising therapeutic strategy. In this study, we developed a novel approach to induce SLE antigen-specific immune tolerance, aiming to achieve therapeutic efficacy or attenuate disease progression by promoting immune tolerance toward lupus-associated autoantigens.

Chromatin as SLE-associated autoantigens was isolated and subjected to immunological characterization. Several lupus animal models were treated with topically-applied chromatin to induce immune tolerance. Flow cytometry was employed to analyze alterations in immune cell subsets, while enzyme-linked immunosorbent assay (ELISA) was used to quantify autoantibody levels. Histopathological analyses were performed on harvested tissues. In addition, an ovalbumin (OVA) model system was utilized to validate the efficacy of antigen-specific tolerance. Single cell RNA sequencing was conducted to find the responsible cell subsets.

Immunological characterization of chromatin demonstrated strong immunogenicity and antigenicity. In an imiquimod (IMQ)-induced lupus-like mouse model, epicutaneous immunization of chromatin effectively ameliorated lupus-like phenotypes and significantly increased the proportion of interleukin-10 (IL-10)-producing dendritic cells. In the spontaneous lupus model MRL/Lpr mice, epicutaneous chromatin treatment significantly reduced proteinuria levels, alleviated skin lesions and lymphadenopathy, and markedly decreased serum autoantibody titers. Furthermore, histological analysis revealed reduced immune complex deposition in the kidneys and substantial improvement in renal pathology in treated mice. Single cell RNA-seq indentified tolerogenic dendritic cells in the spleen, which might be the underlying mechanism. Adoptive transfer of lymphocytes from OT-II mice into CD45.1 recipient mice followed by topical OVA application successfully induced OVA-specific immune tolerance, thereby indirectly validating the feasibility of transdermal tolerance induction. 

This study demonstrates that epicutaneous administration of lupus-associated autoantigen (chromatin) can induce lupus-specific immune tolerance in two distinct murine models. Compared with conventional immunotherapies, this approach exhibits therapeutic efficacy with potentially fewer systemic side effects, providing a novel strategy for the treatment of SLE.