Langerhans Cells Maintain Local Tissue Tolerance in a Model of Systemic Autoimmune Disease

Abstract

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. Here, we used skin as a model to determine the role of tissue-resident dendritic cells in local and systemic involvement within a systemic lupus disease model. Skin-resident dendritic cells, namely Langerhans cells (LC), 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 while lymphocytes from skin-draining lymph nodes of autoimmune-prone MRL/MpJ-Faslpr/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/MpJ-Faslpr/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/MpJ-Faslpr/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 dendritic cell 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.

Correction of Ductal CFTR Activity Rescues Acinar Cell and Pancreatic and Salivary Gland Functions in Mouse Models of Autoimmune Disease

“…We also used MRL/Mp-Fas mice treated with Poly IC. MRL/Mp-Fas mice at 12–17 weeks of age develop multiple autoimmune disorders, including lupus, glomerulonephritis and AIP 34 . Figure 4f shows modest infiltrate in the pancreas of 14 weeks old MRL/Mp-Fas mice that was reduced by treatment with C18 (4 mice).…”

The skin as an immune organ: Tolerance versus effector responses and applications to food allergy and hypersensitivity reactions

“…At low levels of antigen presentation, LCs induce expansion of skin-resident memory Treg cells that suppress autologous T-cell responses locally. 5,46 However, once a threshold of antigen is surpassed, the role of LCs is switched to favor effector T RM cells (Foxp3 lo , CD127 1 ), with activation, proliferation, and production of the effector cytokines IFN-g and IL-17. 5 In addition to driving tolerance at the site of antigen detection, studies in mice have shown that skin-resident DCs migrate from their cutaneous location and induce antigen-specific generation of Foxp3 1 Treg cells in LNs.…”

“…3,6,7 LCs also play a role in generation of IL-10-producing Foxp3 1 Treg cells. 5,46 IL-10 in turn inhibits macrophage function, downregulates MHCII and costimulatory molecules, decreases proinflammatory cytokines, and directs DCs toward a tolerogenic phenotype. 124 Notably, IL-10-deficient mice develop colitis.…”

The role of macrophages in skin homeostasis

“…To assess the role of LCs in immune tolerance in the skin, a group crossed systemic lupus erythematosus mice (MRL-lpr and MRL/MpJ-Fas +/+ ) which develop a syndrome that resembles lupus in humans, with B6 mice, in which the LC-specific gene CD207 (Langerin) is attached to the diphtheria toxin (DT) receptor, and a single dose of DT temporarily abates Langerin+Langerhans cells [28]. Mouse serum showed skin self-antigens (Dsg-3), and cells isolated from these mice displayed an immune response when cultured with Dsg-3.…”

“…Mouse serum showed skin self-antigens (Dsg-3), and cells isolated from these mice displayed an immune response when cultured with Dsg-3. The authors conclude that autoimmune-prone mice, LCs are capable of protecting mice from acquiring autoimmune dermatitis, and maintaining skin tolerance [28]. …”