title: Signals via the adaptor MyD88 in B cells and DCs make distinct and synergistic contributions to immune activation and tissue damage in lupus.
abstract: Detection of self nucleic acids by Toll-like receptors (TLR) preciptates autoimmune diseases, including systemic lupus erythematosus (SLE). It remains unknown how TLR signals in specific cell types contribute to distinct manifestations of SLE. Here, we demonstrate that formation of anti-nuclear antibodies in MRL.Fas(lpr) mice entirely depends on the TLR signaling adaptor MyD88 in B cells. Further, MyD88 deficiency in B cells ameliorated nephritis, including antibody-independent interstitial T cell infiltrates, suggesting that nucleic acid-specific B cells activate nephrotoxic T cells. Surprisingly, MyD88 deletion in dendritic cells (DCs) did not affect nephritis, despite the importance of DCs in renal inflammation. In contrast, MyD88 in DCs was critical for dermatitis, revealing a separate pathogenetic mechanism. DC-expressed MyD88 promoted interferon-α production by plasmacytoid DCs, which was associated with Death domain-associated protein 6 upregulation and B lymphopenia. Our findings thus reveal unique immunopathological consequences of MyD88 signaling in B cells and DCs in lupus.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Lino L
authors.initials: LL
authors.lastname: Teichmann
authors.forename: Dominik
authors.initials: D
authors.lastname: Schenten
authors.forename: Ruslan
authors.initials: R
authors.lastname: Medzhitov
authors.forename: Michael
authors.initials: M
authors.lastname: Kashgarian
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D016207:Cytokines; D007074:Immunoglobulin G; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88