title: 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. 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/lp) (r) (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.
authors.affiliation: Autoimmunity and Tolerance Laboratory, Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: King
authors.affiliation: Autoimmunity and Tolerance Laboratory, Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Philips
authors.affiliation: Autoimmunity and Tolerance Laboratory, Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Anna U
authors.initials: AU
authors.lastname: Eriksson
authors.affiliation: Autoimmunity and Tolerance Laboratory, Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kim
authors.affiliation: Autoimmunity and Tolerance Laboratory, Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Ramesh C
authors.initials: RC
authors.lastname: Halder
authors.affiliation: Dirks/Dougherty Laboratory for Cancer Research, Department of Translational Immunology, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA 90404;
authors.forename: Delphine J
authors.initials: DJ
authors.lastname: Lee
authors.affiliation: Autoimmunity and Tolerance Laboratory, Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; Molecular Toxicology Interdepartmental Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 RRSingh@mednet.ucla.edu.
authors.forename: Ram Raj
authors.initials: RR
authors.lastname: Singh
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002465:Cell Movement; D051184:Desmoglein 3 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D007801:Langerhans Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008178:Lupus Erythematosus, Cutaneous / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D012867:Skin / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D051184:Desmoglein 3; C495300:Dsg3 protein, mouse; C556062:IL10 protein, mouse; D016753:Interleukin-10