Background IgG4-related disease (IgG4-RD) is a systemic fibro- inflammatory disorder characterized by fibrotic lesions infiltrated by IgG4 positive plasma cells (1). The prompt clinical responses obtained after B cell depletion with rituximab in IgG4-RD patients suggest that B lymphocytes drive the pathogenesis of this condition and sustain disease activity (2). This conclusion, however, requires further confirmation because IgG4-RD responds also to non-B cell depleting therapies such as glucocorticoids and methotrexate
Objectives To evaluate the effects of glucocorticoids and methotrexate-based therapeutic regimens on B lymphocyte subpopulations in patients with IgG4-RD.
Methods Sixteen patients with active IgG4-RD were studied. FACS analysis was performed on peripheral blood in order to identify the following B cell subpopulations: total B cells (CD19+CD20- and CD19+CD20+ cells), circulating plasmablasts (CD19+CD20- CD27+CD38++ cells), naïve B cells (CD19+CD20+CD27-CD38+ cells), memory B cells (CD19+CD20-CD27+CD38- cells), circulating plasma cells (CD38+CD138+ cells). Disease activity was assessed by means of the IgG4-RD responder index (IgG4-RD RI). Flow cytometry was performed at baseline and after six months of immunosuppressive therapy with glucocorticoids (0.6–1mg/kg/day) and/or methotrexate (10–20mg/week). 16 sex and age matched healthy subjects were used as controls.
Results At baseline, circulating plasmablasts were expanded in IgG4-RD patients (median 3780 cell/mL; range 330–9300) compared to controls (median 280 cell/mL; range 0–1000) (p<0.05); total B cells (median 133000 cell/mL; range 34000–569000) and naïve B cells (median 13080 cell/mL; range 1970–64270) were reduced in IgG4-RD patients compared to controls (median 280 cell/mL; range 194–330; and median 54020 cell/mL; range 21050–106780, respectively) (p<0.05). No circulating plasma cells were detected in healthy controls. No differences in memory B cells were observed (p>0.05). Circulating plasmablasts but not other B cell subsets positively correlated with serum IgG4 levels, number of organ involved, and IgG4-RD RI (p<0.05). At six months follow-up, the median IgG4-RD RI decreased from 9 to 2. Circulating plasmablasts, circulating plasma cells, and naïve B cells counts decreased in all patients together with disease improvement (p=0.0002, 0.0002 and 0.025 compared to baseline values, respectively); total B cells and memory B cells were unaffected by immunosuppressive therapy.
Conclusions Non-B cell depleting therapies based on glucocorticoids and/or methotrexate induce clinical improvement and deplete circulating plasmablasts, plasma cells and naïve B cells in patients with IgG4-RD; circulating total B cells and memory B cells are not affected by glucocorticoids and methotrexate. Our study, performed with non-B cell depleting agents, provides clinical evidences that circulating plasmablasts are likely linked to IgG4-RD pathogenesis and disease activity.
Della Torre E, Lanzillotta M, Doglioni C. Immunology of IgG4-related disease. Clin Exp Immunol. 2015.
Wallace ZS, Mattoo H, Carruthers M, et al. Plasmablast as a biomarker of IgG4-related disease, independent of serum IgG4 concentrations. 2014.
Disclosure of Interest None declared
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