2 / 2019-06-02 23:30:28

Lymphocyte-bound C4d and immunoglobulins for diagnosis and activity monitoring of Systemic Lupus Erythematosus

Systemic lupus erythematosus; complement; C4d; autoantibody; immunoglobulin

Object: High level of complement activation product C4d is found to be deposited onto the surfaces of a variety of peripheral blood cells including erythrocyte, lymphocyte and platelet of patient with Systemic Lupus Erythematosus (SLE). Cell-specific auto-antibodies were considered to be responsible for C4d deposition. However, the complexity of cells, especially activated lymphocytes, and large scale of auto-antibodies in SLE make it not a simple question. The aim of this study was to detect the levels of lymphocyte-bound C4d and immunoglobulins (Igs: IgG and IgM) in patients with SLE, analyze their formation mechanism and eventually evaluate their utility for diagnosis and monitoring of SLE. Method: The levels of C4d and Igs on peripheral T and B lymphocytes (LB-C4d/Igs: T-C4d, T-IgG, T-IgM, B-C4d, B-IgG and B-IgM) were measured by flow cytometry in 172 patients with SLE, 174 patients with other non-SLE inflammatory diseases and 100 healthy individuals. Among 172 patients with SLE, 63 of them were followed up longitudinally. Disease activity was evaluated for each SLE patient at each visit using Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Immunobinding experiment was performed to characterize Igs from SLE patients to generate T-C4d, T-IgG, T-IgM, B-C4d, B-IgG and B-IgM in vitro. Other biomarkers including ANA, anti-dsDNA, and anti-Smith antibody were measured. Result: Patients with SLE had significantly higher median levels of LB-C4d/Igs compared with patients with non-SLE inflammatory diseases and healthy individuals (all P<0.001). Patients with non-SLE inflammatory diseases also had significantly higher median levels of LB-C4d/Igs compared with healthy individuals (all P<0.001). Purified Igs from SLE plasma could generate higher levels of LB-C4d/Igs with peripheral blood mononuclear cells derived from healthy individuals than Ig-deleted SLE plasma (all P<0.001). T-C4d was found to have significant but weak positive association with T-Igs (r value were 0.335 and 0.303 respectively, P<0.001), as well as B-C4d vs. B-Igs (r value were 0.120 and 0.230 respectively, P<0.007). LB-C4d/Igs confer excellent diagnostic value to SLE singly or jointly, independent of anti-dsDNA (AUCs ranged between 0.705 and 0.907, all p<0.001). Linear regression demonstrated that LB-C4d/Igs contributed to tracking SLE activity. Conclusion: This study demonstrated that auto-antibody was a key factor for LB-CAPs formation and LB-C4d/Igs could be used as reliable indicators for diagnosis and monitoring of SLE.