B Cell–Specific Deletion of CR6‐Interacting Factor 1 Drives Lupus‐like Autoimmunity by Activation of Interleukin‐17, Interleukin‐6, and Pathogenic Follicular Helper T Cells in a Mouse Model

Abstract

Objective CR6‐interacting factor 1 (CRIF1) is a nuclear transcriptional regulator and a mitochondrial inner membrane protein; however, its functions in B lymphocytes have been poorly defined. This study was undertaken to investigate the effects of CRIF1 on B cell metabolic regulation, cell function, and autoimmune diseases. Methods Using mice with B cell–specific deletion of CRIF1 (Crif1ΔCD19 mice), we assessed the relevance of CRIF1 function for lupus disease parameters, including anti–double‐stranded DNA (anti‐dsDNA), cytokines, and kidney pathology. RNA sequencing was performed on B cells from Crif1ΔCD19 mice. The phenotypic and metabolic changes in immune cells were evaluated in Crif1ΔCD19 mice. Roquinsan/+ mice crossed with Crif1ΔCD19 mice were monitored to assess the functionality of CRIF1‐deficient B cells in lupus development. Results Crif1ΔCD19 mice showed an autoimmune lupus‐like phenotype, including high levels of autoantibodies to dsDNA and severe lupus nephritis with increased mesangial hypercellularity. While loss of CRIF1 in B cells showed impaired mitochondrial oxidative function, CRIF1‐deficient B cells promoted the production of interleukin‐17 (IL‐17) and IL‐6 and was more potent in helping T cells develop into follicular helper T cells. In a mouse model of autoimmune lupus, depletion of CRIF1 in B cells exacerbated lupus severity, and CRIF1 overexpression prevented lupus development in roquinsan/san mice. Conclusion These results demonstrated that CRIF1 negatively correlates with disease severity and that overexpression of CRIF1 ameliorates disease development. Our findings suggest that CRIF1 is essential for preventing lupus development by maintaining B cell self tolerance.

Characterization of Serum Cytokine Profiles of Patients with Active Lupus Nephritis

“…IL-17 can sustain LN both through recruitment of T cells to the kidneys, and by activating B cells to secrete autoantibodies. Previous studies on patients with LN showed abnormal levels of IL-17A both in serum and urine; importantly, serum IL-17A levels heralded major kidney damage in patients with class IV or V glomerulonephritis [10,26,[33][34][35][36], in keeping with our data.…”

TSLP promoting B cell proliferation and polarizing follicular helper T cell as a therapeutic target in IgG4-related disease

“…Instead of DC, we focused on the TSLP contribution on Th differentiation through B cell activation because immunofluorescence revealed a colocalization of TSLPR with B cells. More importantly, B cells was also required for Tfh response, as B cells could induce Bcl-6 expression in CD4+ T cells to induce and sustain Tfh differentiation [36][37][38][39][40]. We observed an induction of Tfh by TSLP activated-B cells.…”

The differentiation courses of the Tfh cells: a new perspective on autoimmune disease pathogenesis and treatment

“…The transcription factor CR6-interacting factor 1 (CRIF1) is a multifunctional protein expressed in the nucleus and cytoplasm that regulates cell cycle and growth by regulating the expression of nerve growth factor IB, androgen receptor, STAT3 and others, and is also essential for mitochondrial function. The deletion of CRIF1 in B cells impairs mitochondrial oxidative function, increases STAT3 phosphorylation levels, expresses more ICOSL and intercellular adhesion molecule (ICAM) related to T-B cell interaction, and up-regulates the expression of Tfh cells characteristic genes such as signaling lymphocytic activation molecule family member 5 ( SLAMF5 ), IFNG and C-X-C chemokine receptor 3 ( CXCR3 ), thereby increasing the frequency of Tfh cells [ 85 ]. B cells expressing PD-L1 and PD-L2 and T cells expressing PD-1 regulate the production of long-lived plasma cells and memory B cells through T-B cell interactions [ 76 ].…”