A Link Between Plasma Microbial Translocation, Microbiome, and Autoantibody Development in First‐Degree Relatives of Systemic Lupus Erythematosus Patients

Abstract

Objective Systemic lupus erythematosus (SLE) is characterized by the production of antibodies against self antigens. However, the events underlying autoantibody formation in SLE remain unclear. This study was undertaken to investigate the role of plasma autoantibody levels, microbial translocation, and the microbiome in SLE. Methods Plasma samples from 2 cohorts, one with 18 unrelated healthy controls and 18 first‐degree relatives and the other with 19 healthy controls and 21 SLE patients, were assessed for autoantibody levels by autoantigen microarray analysis, measurement of lipopolysaccharide (LPS) levels by Limulus amebocyte assay, and determination of microbiome composition by microbial 16S ribosomal DNA sequencing. Results First‐degree relatives and SLE patients exhibited increased plasma autoantibody levels compared to their control groups. Parents and children of lupus patients exhibited elevated plasma LPS levels compared to controls (P = 0.02). Plasma LPS levels positively correlated with plasma anti–double‐stranded DNA IgG levels in first‐degree relatives (r = 0.51, P = 0.03), but not in SLE patients. Circulating microbiome analysis revealed that first‐degree relatives had significantly reduced microbiome diversity compared to their controls (observed species, P = 0.004; Chao1 index, P = 0.005), but this reduction was not observed in SLE patients. The majority of bacteria that were differentially abundant between unrelated healthy controls and first‐degree relatives were in the Firmicutes phylum, while differences in bacteria from several phyla were identified between healthy controls and SLE patients. Bacteria in the Paenibacillus genus were the only overlapping differentially abundant bacteria in both cohorts, and were reduced in first‐degree relatives (adjusted P [Padj] = 2.13 × 10−12) and SLE patients (Padj = 0.008) but elevated in controls. Conclusions These results indicate a possible role of plasma microbial translocation and microbiome composition in influencing autoantibody development in SLE.

Triggers of Autoimmunity: The Role of Bacterial Infections in the Extracellular Exposure of Lupus Nuclear Autoantigens

“…To account for all of these findings, we envision that, in susceptible humans and mice, a genetic predisposition for immune dysfunction may increase the host exposure to nucleic acid material during infections and trigger a lymphocyte repertoire already prone to autoreactivity in the presence of specific HLA haplotypes, while in non-autoimmune-prone humans and mice, infections normally result in less prolonged exposure of a repertoire more self-tolerant to nucleic acid material. This is supported by reports of high levels of circulating endotoxin and more frequent bacteremia in SLE patients (68, 69, 89, 104).…”

“…The gut microbiota have been subject of intense investigation because of the intriguing findings that gut dysbiosis has local and systemic effects on the immune system (81–84), but microbiota also reside beyond the gut, colonizing mucosal tissues and specific niches, from the skin to oral cavity, vagina, or the bladder, where they are expected to exercise major effects as well (85). Studies focused on lupus specifically found a reduction in species diversity in the gut microbiota that is associated with specific enteric bacteria in SLE patients (86–88) or their first-degree relatives (89) and was present in cohorts from different continents with different ethnicities (90). DNA from Enterococcus gallinarum was found in the liver of SLE patients, and colonization of autoimmune-prone mice with these bacteria induced autoantibodies and decreased survival (91).…”

Alternative Explanations for the Divergence in Plasma Microbial Translocation and Microbiome Composition Results Between Patients With Systemic Lupus Erythematosus and First‐Degree Relatives: Comment on the Article by Ogunrinde et al

“…Many studies have showed that race/ethnicity has significant effects not only on manifestations, complications, and prognosis of SLE (5-7), but also on microbiota in various populations (8). Moreover, in this study, plasma LPS levels appeared to be lower (as seen in Figures 2A and B) and microbiota diversity appeared higher (as seen in Figures 5A and B) in unrelated healthy controls of the first cohort than in those of the second cohort (4). As a result, it is very possible that the difference in genetic background leads to the divergence in the results between first-degree relatives and SLE patients.…”

Persistent Bacteriuria and Antibodies Recognizing Curli/eDNA Complexes From Escherichia coli Are Linked to Flares in Systemic Lupus Erythematosus

“…E coli and S typhimurium –representing 2 members of the Enterobacteriaceae family–are characterized by the production of curli/eDNA complexes and form biofilms that are associated with bacteremia in SLE (33). Interestingly, activation of the innate immune system by bacteremia is supported by studies showing that lupus patients have increased plasma levels of lipopolysaccharide and that the peripheral blood mononuclear cells of lupus patients exhibit a transcriptome suggestive of chronic exposure to bacterial products (34,35). We have previously demonstrated that systemic injection of curli/eDNA complexes accelerated the pathologic development of lupus in lupus‐prone mice, as did systemic infections with E coli or S typhimurium , in a curli‐dependent manner (12).…”