ZAP70 B Cells and Plasmablasts As Markers of Disease Activity and Remission in Systemic LUPUS Erythematosus Nephritis

Background/Purpose: To analyze differences in B cells subsets distribution in patients with renal systemic lupus erythematosus (SLE). To define possible cellular biomarkers of active nephritis and of remission in renal disease in SLE patients. Methods: 60 SLE patients with renal involvement 49 females (82%); mean age 36.9 11.0 years; 37 with active disease and 23 with disease in remission) were analyzed for the distribution of circulating peripheral blood B cell subpopulations by staining for surface markers CD45, CD19, CD38, IgD, CD27 (CD27/IgD classification (Sanz et al. SeminImmunol 2008) and intracellular marker ZAP-70 (Tolusso et al. ClinImmunol 2009) by flow cytometry. All patients had a WHO class III or IV nephritis diagnosed by renal biopsy. Patients with active nephritis were recruited at the renal disease onset, while patients in remission were recruited if the nephritis was in stable remission for at least 12 months. Fourteen patients with active disease at the study entry were reassessed for PB B cell subpopulations at the time of renal remission (nephritis remission criteria in at least two consecutive observations and on an oral steroid dosage 7.5 mg/day). Results: The 37 subjects with active renal involvement showed higher percentages of CD19/ZAP70 cells compared to 23 patients with nephritis remission (13.1 10.5% vs5.4 4.5%, respectively; p 0.002), as well as of plasmablasts (CD27/CD38 cells: 10.6 7.4% vs 6.3 5.8%, respectively; p 0.03).There was no differences in other B cells subpopulations between active and inactive lupus nephritis. In the 60 SLE renal patients, the percentage of CD19 /ZAP-70 cells directly correlated with disease activity index (SLEDAI) (r 0.44, p 0.002), inversely with complement fractions C3 and C4 (C3: r 0.44, p 0.001, C4: 0.45, p 0.001), with the number of lymphocytes (r 0.55, p 0.001) and of the CD19 B cells (r 0.61, p 0.001). Moreover, the pool of ZAP70 B cells directly correlated with the memory cells subsets (CD27 IgD-: r 0.41, p 0.002, CD27-IgD-: r 0.34, p 0.01) and with plasmablasts (r 0.39, p 0.004) and inversely with naive B cells (CD27-IgD : r 0.48, p 0.001). The 14 patients evaluated in the follow-up showed a significant reduction of the percentage of ZAP70 B cells at remission (4.3 2.8%) with respect to nephritis onset (14.4 11.6%, p 0.002), as well as of the plasmablasts (CD19 /CD27 CD38 : 10.7 8.0% at baseline vs 5.7 2.9% at remission; p 0.05). Conclusion: The pool of CD19 /ZAP70 cells is associated with SLE activity parameters (SLEDAI, low complement, low lymphocytes and CD19 count) and with the B cell memory compartment in SLE patients with renal involvement. The expansion of ZAP70 B cells and plasmablasts characterizes active renal disease and their reduction is associated with the remission state, suggesting their possible role as biomarker in SLE nephritis.