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Abstract
Altered expression and function of the Toll-like receptor (TLR) homologue CD180 molecule in B cells have been associated with autoimmune disorders. In this study, we report decreased expression of CD180 at protein and mRNA levels in peripheral blood B cells of diffuse cutaneous systemic sclerosis (dcSSc) patients. To analyze the effect of CD180 stimulation, together with CpG (TLR9 ligand) treatment, on the phenotype defined by CD19/CD27/IgD/CD24/CD38 staining, and function (CD69 and CD180 expression, cytokine and antibody secretion) of B cell subpopulations, we used tonsillar B cells. After stimulation, we found reduced expression of CD180 protein and mRNA in total B cells, and CD180 protein in B cell subpopulations. The frequency of CD180+ cells was the highest in the CD19+CD27+IgD+ non-switched (NS) B cell subset, and they showed the strongest activation after anti-CD180 stimulation. Furthermore, B cell activation via CD180 induced IL-6 and natural autoantibody secretion. Treatment with the combination of anti-CD180 antibody and CpG resulted in increased IL-6 and IL-10 secretion and natural autoantibody production of B cells. Our results support the role of CD180 in the induction of natural autoantibody production, possibly by NS B cells, and suggest an imbalance between the pathologic and natural autoantibody production in SSc patients.
Highlights
The production of scleroderma-specific autoantibodies and secretion of pro-inflammatory and pro-fibrotic cytokines by B cells is a well-described result that reflects immune dysregulation affecting B cells in systemic sclerosis (SSc) [1,2,3,4]
We investigated the expression of CD180 at protein and mRNA levels in peripheral blood B cells of early diffuse cutaneous SSc patients, and compared to healthy control (HC) B cells
CD180 Expression Is Decreased in diffuse cutaneous systemic sclerosis (dcSSc) B Cells. Since it was described in other autoimmune diseases that differential expression of CD180 (RP105) might have a pathological role in B cell activation and autoantibody production [10,11,12,15], first we determined the CD180 expression of monocytes, T cells, and B cells
Summary
The production of scleroderma-specific autoantibodies and secretion of pro-inflammatory and pro-fibrotic cytokines by B cells is a well-described result that reflects immune dysregulation affecting B cells in systemic sclerosis (SSc) [1,2,3,4]. CD180 was originally defined as a B cell surface molecule mediating polyclonal B cell activation, proliferation, and immunoglobulin production [7,8]. When CpG and anti-CD180 were used simultaneously, the proliferation of peripheral blood B cells was enhanced, and IgG and IgM production increased [13]. We investigated the expression of CD180 at protein and mRNA levels in peripheral blood B cells of early diffuse cutaneous SSc (dcSSc) patients, and compared to healthy control (HC) B cells. To investigate the CD180-mediated activation of B cell subsets, we used anti-CD180 antibody to ligate the receptor, and combined with treatment with CpG, a TLR9 ligand. Treatment with the combination of anti-CD180 antibody and CpG resulted in increased IL-10 secretion and anti-citrate synthase IgM natural autoantibody production of B cells. Our results support the role of CD180 in the induction of natural autoantibody production, possibly by NS B cells, which are diminished in SSc patients, resulting in an imbalance between the pathologic and natural autoantibody production
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