Enhanced expression of Bruton's tyrosine kinase in B cells drives systemic autoimmunity by disrupting T cell homeostasis

OBJ Corneth, MJW de Bruijn, J Rip… - The Journal of …, 2016 - journals.aai.org
OBJ Corneth, MJW de Bruijn, J Rip, PS Asmawidjaja, LP Kil, RW Hendriks
The Journal of Immunology, 2016journals.aai.org
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 …
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.
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