Abstract
BackgroundIncreased autoreactive antibodies have been reported in HIV disease; however, the mechanism accounting for autoantibody induction in HIV remains unknown.ResultsHerein, we show that seasonal influenza vaccination induces autoantibody production (e.g., IgG anti-nuclear antibody (ANA) and anti-double-stranded DNA antibody (anti-dsDNA)) in some viral-suppressed antiretroviral therapy (ART)-treated HIV+ subjects, but not in healthy controls. These autoantibodies were not derived from antigen-specific B cells but from activated “bystander” B cells analyzed by single-cell assay and by study of purified polyclonal ANAs from plasma. To explore the mechanism of autoantibody generation in HIV+ subjects, plasma level of microbial products, gene expression profile of B cells, and B cell receptor (BCR) repertoires were analyzed. We found that autoantibody production was associated with increased plasma level of microbial translocation; the patients with high autoantibodies had skewed B cell repertoires and upregulation of genes related to innate immune activation in response to microbial translocation. By analyzing circulating microbial 16S rDNA in plasma, the relative abundance of Staphylococcus was found to be associated with autoantibody production in HIV+ subjects. Finally, we found that injection of heat-killed Staphylococcus aureus promoted germinal center B cell responses and autoantibody production in mice, consistent with the notion that autoantibody production in HIV+ patients is triggered by microbial products.ConclusionsOur results showed that translocation of Staphylococcus can promote B cell activation through enhancing germinal center response and induces autoantibody production. It uncovers a potential mechanism linking microbial translocation and autoimmunity in HIV+ disease and provides a strong rationale for targeting Staphylococcus to prevent autoantibody production.
Highlights
In healthy people, most autoreactive B cells are effectively removed from the germinal center (GC), and only a small portion of self-reactive GC B cells can escape from deletion [1]
Autoantibodies induced by seasonal influenza vaccination in HIV+ subjects Following immunization with the 2013–2014 seasonal influenza vaccine in 16 healthy controls and 26 antiretroviral therapy (ART) aviremic HIV-infected subjects (Additional file 1: Table S1), we found that the IgG Antinuclear antibody (ANA) were increased in HIV+ subjects (P < 0.0001), but there was no change in healthy controls (P = 0.53) (Fig. 1a)
To identify if other autoantibodies besides ANA were generated after immunization, we measured plasma IgG anti-dsDNA antibody, a pathologic autoantibody in systemic lupus erythematosus (SLE) [27]
Summary
Most autoreactive B cells are effectively removed from the germinal center (GC), and only a small portion of self-reactive GC B cells can escape from deletion [1]. In HIV+ individuals, many autoantibodies are reported and autoimmune diseases occur during immunological recovery after antiretroviral therapy (ART) [2,3,4]. ART-treated patients suffer from autoimmune symptoms associated with increased levels of B cell activation, pathologic autoantibodies, and residual systemic microbial translocation [6, 7]. Toll-like receptor (TLR) ligands play a role in B cell perturbation, autoantibody production, and autoimmune diseases [14,15,16,17,18]. Vaccine-mediated autoantibody production was associated with baseline increased plasma level of microbial translocation and relative enrichment of translocation of Staphylococcus in HIV+ subjects but not in healthy controls. Increased autoreactive antibodies have been reported in HIV disease; the mechanism accounting for autoantibody induction in HIV remains unknown
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