LZ and DZ GC B cell throughout lupus
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ABSTRACT:
PROVIDER: PRJNA1054613 | ENA |
REPOSITORIES: ENA
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Project description:Systemic autoimmunity is driven by the production of pathogenic autoantibodies that can arise from germinal centers (GCs). Typically, B cells that acquire autoreactivity following somatic hypermutation in the GC die of neglect, but in autoimmunity these autoreactive clones still receive T cell help, driving aberrant selection. GC B cells cycle between the dark zone (DZ), where proliferation and mutation occur, and the light zone (LZ) where selection occurs. Temporal assessment comparing GCs from mice with chronic infection or lupus revealed a shared accumulation of LZ B cells while lupus GC B cells had a unique reduction in proliferation and a progressive loss of MYC and FOXO1 in lupus. This loss in proliferative capacity coincided with a reduction in B cell receptor repertoire diversity and mutational burden. Furthermore, we identified persistent dominant GC B cell clones associated with an expansion in plasma cell differentiation throughout disease. Together, our findings suggest that lupus disease progression is characterized by an inability for proper LZ selection, preventing zonal recycling, thereby driving the permissive selection and differentiation of autoreactive B cells.
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Project description:The pathways regulating the formation of the germinal center (GC) dark- (DZ) and light- (LZ) zones are unknown. We show that FOXO1 expression is restricted to the GC DZ and is required for DZ formation, since its absence in mice leads to the complete loss of DZ gene programs and the formation of LZ-only GCs. FOXO1-negative GC B-cells display normal somatic hypermutation, but defective affinity maturation and class switch recombination. The function of FOXO1 in sustaining the DZ program involves the transactivation of the chemokine receptor CXCR4, and the cooperation with BCL6 in the trans-repression of genes involved in immune activation, DNA-repair and plasma cell differentiation. These results have also implications for understanding the role of FOXO1 mutations in lymphomagenesis. We used microarrays to determine the consequences of FOXO1 deletion in the GC B cell comparment, and correlate these data with phenotypic changes
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Project description:The pathways regulating the formation of the germinal center (GC) dark- (DZ) and light- (LZ) zones are unknown. We show that FOXO1 expression is restricted to the GC DZ and is required for DZ formation, since its absence in mice leads to the complete loss of DZ gene programs and the formation of LZ-only GCs. FOXO1-negative GC B-cells display normal somatic hypermutation, but defective affinity maturation and class switch recombination. The function of FOXO1 in sustaining the DZ program involves the transactivation of the chemokine receptor CXCR4, and the cooperation with BCL6 in the trans-repression of genes involved in immune activation, DNA-repair and plasma cell differentiation. These results have also implications for understanding the role of FOXO1 mutations in lymphomagenesis. We used microarrays to determine the consequences of FOXO1 deletion in the GC B cell comparment, and correlate these data with phenotypic changes GC B cell subpopulations were collected by Fluorescence Activated Cell Sorting (FACS) from B cell enriched fractions of splenic mononuclear cell pools (12 days after SRBC immunization). 20ng of total RNA (RIN>9) for each sample was used as a template for linear cDNA amplification (Ovation RNA amplification Kit, NuGen). cDNA was labeled using the Encore Biotin Labeling Kit (NuGen) and hybridized to Affymetrix Mouse 430.2 gene expression arrays
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