TY - JOUR
T1 - Systemic translocation of Staphylococcus drives autoantibody production in HIV disease
AU - Luo, Zhenwu
AU - Li, Min
AU - Wu, Yongxia
AU - Meng, Zhefeng
AU - Martin, Lisa
AU - Zhang, Lumin
AU - Ogunrinde, Elizabeth
AU - Zhou, Zejun
AU - Qin, Shenghui
AU - Wan, Zhuang
AU - Westerink, Maria Anna Julia
AU - Warth, Stephanie
AU - Liu, Hui
AU - Jin, Ping
AU - Stroncek, David
AU - Li, Quan Zhen
AU - Wang, Ena
AU - Wu, Xueling
AU - Heath, Sonya L.
AU - Li, Zihai
AU - Alekseyenko, Alexander V.
AU - Jiang, Wei
N1 - Funding Information:
This work was supported by grants from the National Institutes of Allergy and Infectious Diseases: R01 AI091526 (Jiang), R01 AI128864 (Jiang), R01 CA213290 (Li), P30 AI027767 (Saag/Health), R01 AG045973 (Westerink), UL1TR001450, and R01 AI114380 (Wu), and the Medical Research Service at the Ralph H. Johnson VA Medical Center Merit grant VA CSRD MERIT (CX001211, Gilkeson), R01LM012517 (Alexander).
PY - 2019/2/14
Y1 - 2019/2/14
N2 - 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.
AB - 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.
KW - Autoantibodies
KW - Plasma microbial 16S rDNA
KW - Staphylococcus
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U2 - 10.1186/s40168-019-0646-1
DO - 10.1186/s40168-019-0646-1
M3 - Article
C2 - 30764863
AN - SCOPUS:85061603507
VL - 7
JO - Microbiome
JF - Microbiome
SN - 2049-2618
IS - 1
M1 - 25
ER -