title: Autoimmune disease in Lyn-deficient mice is dependent on an inflammatory environment established by IL-6.
abstract: Lyn-deficient mice develop Ab-mediated autoimmune disease resembling systemic lupus erythematosus where hyperactive B cells are major contributors to pathology. In this study, we show that an inflammatory environment is established in Lyn(-/-) mice that perturbs several immune cell compartments and drives autoimmune disease. Lyn(-/-) leukocytes, notably B cells, are able to produce IL-6, which facilitates hyperactivation of B and T cells, enhanced myelopoiesis, splenomegaly, and, ultimately, generation of pathogenic autoreactive Abs. Lyn(-/-) dendritic cells show increased maturation, but this phenotype is independent of autoimmunity as it is reiterated in B cell-deficient Lyn(-/-) mice. Genetic deletion of IL-6 on a Lyn-deficient background does not alter B cell development, plasma cell accumulation, or dendritic cell hypermaturation, suggesting that these characteristics are intrinsic to the loss of Lyn. However, hyperactivation of B and T cell compartments, extramedullary hematopoiesis, expansion of the myeloid lineage and autoimmune disease are all ameliorated in Lyn(-/-)IL-6(-/-) mice. Importantly, our studies show that although Lyn(-/-) B cells may be autoreactive, it is the IL-6-dependent inflammatory environment they engender that dictates their disease-causing potential. These findings improve our understanding of the mode of action of anti-IL-6 and B cell-directed therapies in autoimmune and inflammatory disease treatment.
authors.affiliation: Signal Transduction Laboratory, Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Tsantikos
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Oracki
authors.forename: Cathy
authors.initials: C
authors.lastname: Quilici
authors.forename: Gary P
authors.initials: GP
authors.lastname: Anderson
authors.forename: David M
authors.initials: DM
authors.lastname: Tarlinton
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hibbs
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D017578:Immunoglobulin Class Switching / Q000235:genetics; D018836:Inflammation Mediators / Q000502:physiology*; D015850:Interleukin-6 / Q000172:deficiency / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D038042:Myelopoiesis / Q000235:genetics / Q000276:immunology; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D000093242:Interleukin-6 Inhibitors
chemical_list: D001323:Autoantibodies; D018836:Inflammation Mediators; D015850:Interleukin-6; D019061:src-Family Kinases; D000093242:Interleukin-6 Inhibitors; C060902:lyn protein-tyrosine kinase