Systemic lupus erythematosus (SLE), the archetypal systemic autoimmune disease, is believed to be caused by a combination of genetic and environmental factors. Different studies have shown that systemic inflammatory and autoimmune diseases may arise in mice and humans from imbalances in the commensal microorganism’s community that exist in a mutualistic relationship within the gastrointestinal tract. While genetic defects and other environmental factors may predispose some individuals to immune-mediated diseases, we hypothesized that pathogenic symbionts (termed pathobionts) among the commensal intestinal microbiota may be the direct trigger(s) for the SLE pathogenesis.

In collaboration with Jill P. Buyon, MD, and Peter M. Izmirly, MD, the B-cell Immunobiology Lab has recruited a new cohort of SLE patients and a cohort of healthy controls (HCTL) from our urban clinics. We performed surveys of the intestinal microbiota of our SLE cohort, with next generation sequencing of the 16S bacterial rRNA genes. The data analysis revealed that SLE patients displayed decreased richness or diversity in their microbiome community, with reductions in taxonomic complexity most pronounced in those with high SLE disease activity index (SLEDAI) compared to the HCTL subjects (p<0.002). SLE subjects also demonstrated greater intra-group diversity (p<0.005) than HCTL.

Strikingly, SLE patients with high SLEDAI score had an overall five-fold greater representation of Ruminococcus gnavus (RG) of the Lachnospiraceae family (p=0.001, Figure 1A), this representation was found highest in patients with active renal disease, which, in turn, raised our attention to RG as a candidate pathobiont in SLE with active renal disease. (Figures 1–3, see Azzouz et al., 2019, Annals of the Rheumatic Diseases.)

To understand the link between the RG expansion and renal involvement, particularly, and to evaluate for an impact on the immune system, we evaluated the IgG levels in the SLE sera against eight different strains of RG. A high level of IgG against a distinct antigen in only one strain (RG2) was found more in SLE comparing to HCTL (Figure 1, B and C) and correlated significantly with high SLEDAI score, with gut abundance of RG (Figure 1D) and with anti-dsDNA IgG (a biomarker of lupus renal disease). These findings were validated in three independent cohorts (Figure 2, A–C).

This immune recognition of the RG2 distinct antigen by SLE serum IgG (Figure 1C) is directed against a cell wall/capsular antigen in the RG2. We used the electron microscopy approach to detect and visualize the IgG-specific binding to this glycan structure binding on the cell surface (Figure 3A). Structural chemical analysis, H-NMR and MS, showed a typical oligosaccharides and fatty acid signals indicative of a cell wall-associated lipoglycan structure (and not a teichoic acid) that is an immunodominant immunogenic antigen on the CC_55 RG strain (Figure 3B)(in collaboration with N. Gisch and co-workers at Borstel Institute). By performing in vitro stimulation assays with a reporter cell line, we discovered that this lipoglycan is a TLR2 ligand and has a potent immune modulator role that are inhibited in a dose-dependent fashion by monoclonal antibodies that are specific for human TLR2.

We are currently developing approaches to test whether we can target the induced shifts in the microbiome, more specifically target the RG and its immune response pathway, moreover, use it as a prognostic and as a predictor marker of developing renal involvement in SLE patients.

Supported by the Lupus Research Institute, NYU Langone’s Judith and Stewart Colton Center for Autoimmunity, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.