Trib1 Is Overexpressed in Systemic Lupus Erythematosus, While It Regulates
Immunoglobulin Production in Murine B Cells
#MMPMID29599769
Simoni L
; Delgado V
; Ruer-Laventie J
; Bouis D
; Soley A
; Heyer V
; Robert I
; Gies V
; Martin T
; Korganow AS
; Reina-San-Martin B
; Soulas-Sprauel P
Front Immunol
2018[]; 9
(?): 373
PMID29599769
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Systemic lupus erythematosus (SLE) is a severe and heterogeneous autoimmune
disease with a complex genetic etiology, characterized by the production of
various pathogenic autoantibodies, which participate in end-organ damages. The
majority of human SLE occurs in adults as a polygenic disease, and clinical
flares interspersed with silent phases of various lengths characterize the usual
evolution of the disease in time. Trying to understand the mechanism of the
different phenotypic traits of the disease, and considering the central role of B
cells in SLE, we previously performed a detailed wide analysis of gene expression
variation in B cells from quiescent SLE patients. This analysis pointed out an
overexpression of TRIB1. TRIB1 is a pseudokinase that has been implicated in the
development of leukemia and also metabolic disorders. It is hypothesized that
Trib1 plays an adapter or scaffold function in signaling pathways, notably in
MAPK pathways. Therefore, we planned to understand the functional significance of
TRIB1 overexpression in B cells in SLE. We produced a new knock-in model with
B-cell-specific overexpression of Trib1. We showed that overexpression of Trib1
specifically in B cells does not impact B cell development nor induce any
development of SLE symptoms in the mice. By contrast, Trib1 has a negative
regulatory function on the production of immunoglobulins, notably IgG1, but also
on the production of autoantibodies in an induced model. We observed a decrease
of Erk activation in BCR-stimulated Trib1 overexpressing B cells. Finally, we
searched for Trib1 partners in B cells by proteomic analysis in order to explore
the regulatory function of Trib1 in B cells. Interestingly, we find an
interaction between Trib1 and CD72, a negative regulator of B cells whose
deficiency in mice leads to the development of autoimmunity. In conclusion, the
overexpression of Trib1 could be one of the molecular pathways implicated in the
negative regulation of B cells during SLE.
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