title: Enhanced Expression of Bruton's Tyrosine Kinase in B Cells Drives Systemic Autoimmunity by Disrupting T Cell Homeostasis.
abstract: Upon BCR stimulation, naive B cells increase protein levels of the key downstream signaling molecule Bruton's tyrosine kinase (BTK). Transgenic CD19-hBtk mice with B cell-specific BTK overexpression show spontaneous germinal center formation, anti-nuclear autoantibodies, and systemic autoimmunity resembling lupus and Sjögren syndrome. However, it remains unknown how T cells are engaged in this pathology. In this study, we found that CD19-hBtk B cells were high in IL-6 and IL-10 and disrupted T cell homeostasis in vivo. CD19-hBtk B cells promoted IFN-γ production by T cells and expression of the immune-checkpoint protein ICOS on T cells and induced follicular Th cell differentiation. Crosses with CD40L-deficient mice revealed that increased IL-6 production and autoimmune pathology in CD19-hBtk mice was dependent on B-T cell interaction, whereas IL-10 production and IgM autoantibody formation were CD40L independent. Surprisingly, in Btk-overexpressing mice, naive B cells manifested increased CD86 expression, which was dependent on CD40L, suggesting that T cells interact with B cells in a very early stage of immune pathology. These findings indicate that increased BTK-mediated signaling in B cells involves a positive-feedback loop that establishes T cell-propagated autoimmune pathology, making BTK an attractive therapeutic target in autoimmune disease.
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; and.
authors.forename: Odilia B J
authors.initials: OB
authors.lastname: Corneth
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; and.
authors.forename: Marjolein J W
authors.initials: MJ
authors.lastname: de Bruijn
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; and.
authors.forename: Jasper
authors.initials: J
authors.lastname: Rip
authors.affiliation: Department of Rheumatology, Erasmus MC, 3000 CA Rotterdam, the Netherlands.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Asmawidjaja
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; and.
authors.forename: Laurens P
authors.initials: LP
authors.lastname: Kil
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands; and r.hendriks@erasmusmc.nl.
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics; D001327:Autoimmune Diseases / Q000276:immunology* / Q000628:therapy; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000502:physiology*; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D002450:Cell Communication; D006706:Homeostasis; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018941:Antigens, CD19; D015850:Interleukin-6; D016753:Interleukin-10; D023201:CD40 Ligand; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse