Systemic translocation of Staphylococcus drives autoantibody production in HIV disease

Abstract

Background Increased autoreactive antibodies have been reported in HIV disease; however, the mechanism accounting for autoantibody induction in HIV remains unknown. Results Herein, 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. Conclusions Our 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. Electronic supplementary material The online version of this article (10.1186/s40168-019-0646-1) contains supplementary material, which is available to authorized users.

HIV-1 elite controllers present a high frequency of activated regulatory T and Th17 cells

“…This setting leads to a pro-inflammatory state that disrupts the gut mucosal barrier and enhances microbial translocation. The increase in microbial translocation, as previously stated, is believed to be one of the most significant causes of the increased immune activation observed in HIVinfected patients [80,81,104], highlighting the importance of Th17 cells for the control of immune activation in the context of HIV infection.…”

“…These data reinforce the idea that, although driven by HIV infection, immune activation is boosted by factors that go beyond the direct effects of viral replication. Bystander activation of CD8 + T cells in HIV infection has been observed to be associated with the reactivation of other viruses [76,77] and with the circulation of proinflammatory cytokines [78,79], while microbial translocation due to CD4 + T cell depletion in the gut mucosa is considered one of the major mechanisms driving immune activation [80][81][82]. Besides, suboptimal penetration of drugs in anatomical sites such as the central nervous system, GALT, and lymph nodes is associated with persistence of viral replication in those tissues despite plasma viral load <LDL [83][84][85][86].…”

Rigorous Plasma Microbiome Analysis Method Enables Disease Association Discovery in Clinic

“…In addition, another study led by Nejman’s group found that distinct microbiome composition in seven cancer types and that the bacteria localized within both tumors and immune cells ( Nejman et al, 2020 ). Microbe or microbial components were found in the blood from individuals with chronic inflammatory diseases ( Potgieter et al, 2015 ; Lelouvier et al, 2016 ; Luo et al, 2019 ). Using bacterial 16S rRNA sequencing, Massier’s group showed bacteria in the blood and adipose tissue samples, which were associated with increased tissue inflammation in obesity and type 2 diabetes ( Massier et al, 2020 ).…”

“…Moreover, the translocated microbial products were shown to induce immune perturbations and may contribute to some disease immunopathogenesis such as autoimmune diseases and central nervous system diseases ( Niebauer et al, 1999 ; Brenchley et al, 2006 ; Klatt et al, 2010 ; Yoshimoto et al, 2013 ; Costa et al, 2016 ; Vieira et al, 2018 ). Our recent study showed that translocation of Staphylococcus promotes germinal center B cell activation and autoantibody production in mice and HIV+ individuals ( Luo et al, 2019 ). All of these studies indicated that plasma or tissue microbiome might contribute to immune perturbations and disease pathogenesis.…”

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“…In addition, another study led by Nejman's group found that distinct microbiome composition in seven cancer types and that the bacteria localized within both tumors and immune cells (Nejman et al, 2020). Microbe or microbial components were found in the blood from individuals with chronic inflammatory diseases (Potgieter et al, 2015;Lelouvier et al, 2016;Luo et al, 2019). Using bacterial 16S rRNA sequencing, Massier's group showed bacteria in the blood and adipose tissue samples, which were associated with increased tissue inflammation in obesity and type 2 diabetes (Massier et al, 2020).…”