Abstract: SA-PO100

Lupus Nephritis Is Linked to Immunity to an Intestinal Commensal Lachnospiracaea Species

Session Information

Category: Glomerular

  • 1005 Clinical Glomerular Disorders

Authors

  • Rovin, Brad H., Ohio State University Wexner Medical Center , Columbus, Ohio, United States
  • Azzouz, Doua F, NYU School of Medicine, New York, New York, United States
  • Buyon, Jill P, NYU School of Medicine, New York, New York, United States
  • Alekseyenko, Alexander, Medical University of South Carolina, Charleston, South Carolina, United States
  • Silverman, Gregg, NYU School of Medicine, New York, New York, United States
Background

A transmissible agent has long been suspected in the pathogenesis of SLE. We therefore investigated the potential contribution of the intestinal microbiome to LN.

Methods

Blood and fecal samples from SLE patients were obtained, unless a patient had selective IgA deficiency, prior cytotoxic drugs, or antibiotics within four months. Fecal 16S rRNA NGS was performed. Sera samples were profiled for autoantibodies. Sera from two independent lupus cohorts were studied for validation.

Results

Compared to controls, the intestinal microbiome from SLE patients (N=61) showed decreased species richness diversity. The microbiomes of patients in clinical remission (based on SLEDAI) were most similar to healthy controls, while reductions in taxonomic complexity were most pronounced in those with high disease activity. Notably, SLE patients had an overall 5-fold greater representation of a particular species in the Blautia genus of the Lachnospiracaea family of obligate anaerobic Gram-positive cocci. Abundance of this species significantly correlated with serum IgG to a cell wall moiety from a strain of this species (P=0.002, N=61, Spearman) but not with 7 other strains. There was also a significant correlation between the distribution of SLEDAI scores and levels of these circulating anti-strain IgG antibodies (P=0.02, N=48). Using antigen treated with DNAse/proteinase K, levels of IgG anti-strain antibodies were significantly higher in those with active nephritis at time of sampling compared to SLE without renal activity (Cohort 1 P=0.01 N=48; Cohort 2 P=0.001, N=53, Mann-Whitney). Levels of anti- strain antibodies also significantly correlated with high-titer serum IgG to native DNA (P<0.0001, N=27), and inversely correlated with C3 and C4 (each P<0.01, N=61). High titers of these anti-bacterial antibodies were found in active Class III, IV and V LN.

Conclusion

These findings suggest a novel paradigm for the pathogenesis of LN: Specific strains of common intestinal commensal bacteria affect IgG-autoantibody responses in patients with LN. This is reminiscent of post-streptococcal GN, although the postulated intestinal bacterial bloom occurs without clinical infection.

Funding

  • Private Foundation Support