Association of gut commensal translocation with autoantibody production in systemic lupus erythematosus

Abstract Objective Bacterial translocation across the gut barrier has been implicated in the pathogenesis of systemic lupus erythematosus (SLE), though underlying mechanisms remain unclear. This study aimed to investigate the role of translocated bacteria in the context of molecular mimicry by utili...

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Published in:Rheumatology (Oxford, England) England), 2024-09
Main Authors: Katsushima, Masao, Nakayama, Yoichi, Yoshida, Tsuneyasu, Nishida, Yuri, Shirakashi, Mirei, Nakashima, Ran, Yoshifuji, Hajime, Ito, Shinji, Satoh, Junko, Yamamoto, Masaki, Watanabe, Ryu, Emori, Takashi, Kamiya, Tomonori, Nitahara, Yuko, Nakagama, Yu, Ohtani, Naoko, Kido, Yasutoshi, Morinobu, Akio, Hashimoto, Motomu
Format: Article
Language:English
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Summary:Abstract Objective Bacterial translocation across the gut barrier has been implicated in the pathogenesis of systemic lupus erythematosus (SLE), though underlying mechanisms remain unclear. This study aimed to investigate the role of translocated bacteria in the context of molecular mimicry by utilizing lupus model mice and blood samples from untreated SLE patients. Methods Bacterial translocation was evaluated using nonselective cultured mesenteric lymph nodes (MLNs) from B6SKG mice, a lupus model characterized by impaired TCR signalling and gut dysbiosis. The relationships of detected pathobionts with autoantibody production were examined using in vivo experiments, enzyme-linked immunosorbent assay, immunoblotting, and epitope mapping. Results Culture-based bacterial profiling in MLNs demonstrated that Lactobacillus murinus was enriched in B6SKG mice with elevated anti-dsDNA IgG levels. Subcutaneous injection of heat-killed L. murinus induced anti-dsDNA IgG production without altering T- or B cell subset composition. Immunoblotting and mass spectrometry analysis identified a peptide ATP-binding cassette (ABC) transporter as a molecular mimicry antigen, with its cross-reactivity in lupus mice confirmed by serological assays and in vivo immunization. The L. murinus ABC transporter exhibited surface epitopes that were cross-reactive with sera from lupus mice and patients. The ABC transporter from R. gnavus, known for its pathogenic role in lupus patients, had a similar epitope sequence to that of the L. murinus ABC transporter and reacted with lupus sera. Conclusion ABC transporters from gut bacteria can serve as cross-reactive antigens that may promote anti-dsDNA antibody production in genetically susceptible mice. These findings underscore the role of commensal-derived molecular mimicry and bacterial translocation in lupus pathogenesis.
ISSN:1462-0324
1462-0332
1462-0332
DOI:10.1093/rheumatology/keae476