Abstract
Dengue virus (DENV) infections may cause life-threatening dengue hemorrhagic fever (DHF). Suppressed protective immunity was shown in these patients. Although several hypotheses have been formulated, the mechanism of DENV-induced immunosuppression remains unclear. Previously, we found that cross-reactive antibodies against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4 [DR4]) were elicited in DHF patients, and that anti-DR4 autoantibody fractions were elicited by nonstructural protein 1 (NS1) immunizations in experimental mice. In this study, we found that anti-DR4 antibodies could suppress B lymphocyte function in vitro and in vivo. Treatment with the anti-DR4 immunoglobulin (Ig) induced caspase-dependent cell death in immortalized B lymphocyte Raji cells in vitro. Anti-DR4 Igs elicited by NS1 and DR4 immunizations markedly suppressed mouse spleen transitional T2 B (IgM+IgD+), bone marrow pre-pro-B (B220+CD43+), pre-B (B220+CD43−), and mature B cell (B220+IgD+) subsets in mice. Furthermore, functional analysis revealed that the pre-elicitation of anti-NS1 and anti-DR4 Ig titers suppressed subsequently neutralizing antibody production by immunization with DENV envelop protein. Our data suggest that the elicitation of anti-DR4 titers through DENV NS1 immunization plays a suppressive role in humoral immunity in mice.
Highlights
Dengue virus (DENV) infections may cause life-threatening dengue hemorrhagic fever (DHF)
Because death receptor families share structural similarity among members, in this study, we investigated whether antibody fractions against transmembrane activator and CAML interactor (TACI), B-cell maturation antigen (BCMA), and BAFF receptor 3 (BAFFR) are present in the serum samples of DHF patients and DENV nonstructural protein 1 (NS1)-immunized rabbits
We analyzed the anti-TACI, anti-BCMA, and anti-BAFFR Ig levels in patients infected with DENV using enzyme-linked immunosorbent assay (ELISA)
Summary
Dengue virus (DENV) infections may cause life-threatening dengue hemorrhagic fever (DHF). Clinical[15,16,17], cellular, and animal studies[18,19,20,21,22,23,24,25,26] have found that DENV infections and DENV nonstructural protein 1 (NS1) immunizations elicit autoantibodies against plasma, platelet, and endothelial antigens Among these autoantigens, our previous report suggest that endothelial TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4 [DR4]; known as TNFRSF10A) could be a potential autoantibody target leading to plasma leakage in severe DENV infections in our previous study[23]. If DENV elicits cross-reactive autoantibodies targeting to TACI, BCMA, and BAFFR, the lymphocyte regulation and B cell function may be impaired. We analyzed the association of the induction of anti-death receptor autoantibody fractions with the lymphocyte populations and neutralizing antibody production using a mouse model and discuss the potential immunosuppressive mechanism
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