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Systemic lupus erythematosus
Lupus nephritis is linked to disease-activity associated expansions and immunity to a gut commensal
  1. Doua Azzouz1,
  2. Aidana Omarbekova1,
  3. Adriana Heguy2,
  4. Dominik Schwudke3,
  5. Nicolas Gisch3,
  6. Brad H Rovin4,
  7. Roberto Caricchio5,
  8. Jill P Buyon1,
  9. Alexander V Alekseyenko6,
  10. Gregg J Silverman1
  1. 1 Department of Medicine, New York University School of Medicine, New York, New York, USA
  2. 2 Department of Pathology, New York University School of Medicine, New York, New York, USA
  3. 3 Forschungszentrum Borstel, Leibniz Lungenzentrum, Borstel, Germany
  4. 4 Ohio State University, Columbus, Ohio, USA
  5. 5 Temple University, Philadelphia, Pennsylvania, USA
  6. 6 Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
  1. Correspondence to Dr Gregg J Silverman, New York University School of Medicine, New York, NY 10016, USA; gregg.silverman{at}nyumc.org

Abstract

Background/Purpose To search for a transmissible agent involved in lupus pathogenesis, we investigated the faecal microbiota of patients with systemic lupus erythematosus (SLE) for candidate pathobiont(s) and evaluated them for special relationships with host immunity.

Methods In a cross-sectional discovery cohort, matched blood and faecal samples from 61 female patients with SLE were obtained. Faecal 16 S rRNA analyses were performed, and sera profiled for antibacterial and autoantibody responses, with findings validated in two independent lupus cohorts.

Results Compared with controls, the microbiome in patients with SLE showed decreased species richness diversity, with reductions in taxonomic complexity most pronounced in those with high SLE disease activity index (SLEDAI). Notably, patients with SLE had an overall 5-fold greater representation of Ruminococcus gnavus (RG) of the Lachnospiraceae family, and individual communities also displayed reciprocal contractions of a species with putative protective properties. Gut RG abundance correlated with serum antibodies to only 1/8 RG strains tested. Anti-RG antibodies correlated directly with SLEDAI score and antinative DNA levels, but inversely with C3 and C4. These antibodies were primarily against antigen(s) in an RG strain-restricted pool of cell wall lipoglycans. Novel structural features of these purified lipoglycans were characterised by mass spectrometry and NMR. Highest levels of serum anti-RG strain-restricted antibodies were detected in those with active nephritis (including Class III and IV) in the discovery cohort, with findings validated in two independent cohorts.

Conclusion These findings suggest a novel paradigm in which specific strains of a gut commensal may contribute to the immune pathogenesis of lupus nephritis.

  • commensal
  • microbiome
  • autoantibodies
  • pathobiont
  • gut barrier

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/annrheumdis-2018-214856

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    Footnotes

    • Handling editor Josef S Smolen

    • Presented at Parts of this manuscript were orally presented as a plenary presentation at the 2017 ACR/ARHP Annual Meeting and as such the abstract was published in an online supplementary of Arthritis & Rheumatology.

    • Contributors DA, AVA and GJS designed research. DA, AO, DS and NG performed research. RC, BR and JPB recruited and characterised patients and critiqued the manuscript. DA, AVA and GJS analysed data and wrote the paper.

    • Funding This work was supported in part by National Institutes of Health Grants; R01AI090118 (GJS), R01AI068063 (GJS), R01-AR42455 (GJS), P50 AR070591 (GJS, JPB), NIAID contract for B Cell Epitope Discovery and Mechanisms of Antibody Protection, HHSN272201400019C (GJS), N01-AR-4-2271, an American Recovery and Reinvestment Act supplement (GJS), NIH-NIAMS R01-AR061569-01A1 (RC), P50 AR070591-01A1/COMPEL (GJS and JPB), R01 LM012517 (AVA and GJS), the Lupus Research Institute and the Judith and Stewart Colton Autoimmunity Center (GJS). 16S rRNA gene sequence determinations and analysis were supported by the P Robert Majumder Charitable Trust (GJS).

    • Competing interests NYU has filed intellectual property related to this report.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Data in the text will be freely available. Microbiome community 16S rRNA data will be made available on reasonable request.

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