Enhanced Expression of Bruton's Tyrosine Kinase in B Cells Drives Systemic Autoimmunity by Disrupting T Cell Homeostasis.
J Immunol
; 197(1): 58-67, 2016 07 01.
Article
in En
| MEDLINE
| ID: mdl-27226091
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Autoimmune Diseases
/
Protein-Tyrosine Kinases
/
B-Lymphocytes
/
T-Lymphocytes
/
Autoimmunity
Limits:
Animals
/
Humans
Language:
En
Journal:
J Immunol
Year:
2016
Document type:
Article