Gut dysbiosis and the clinical spectrum in anti-Ro positive mothers of children with neonatal lupus

Abstract

Anti-SSA/Ro antibodies, while strongly linked to fetal cardiac injury and neonatal rash, can associate with a spectrum of disease in the mother, ranging from completely asymptomatic to overt Systemic Lupus Erythematosus (SLE) or Sjögren’s Syndrome (SS). This study was initiated to test the hypothesis that the microbiome, influenced in part by genetics, contributes to disease state. The stool microbiome of healthy controls (HC) was compared to that of anti-SSA/Ro positive women whose children had neonatal lupus. At the time of sampling, these women were either asymptomatic (Asym), had minor rheumatic symptoms or signs considered as an undifferentiated autoimmune syndrome (UAS), or were diagnosed with SLE or SS. Differences in microbial relative abundances among these three groups were tested assuming an ordering in clinical severity (HC<Asym/UAS<SS/SLE) and then again without the ordinal assumption. Those taxa that showed differential relative abundances were then tested for whether the effect size differed depending on the women’s HLA SLE-risk allele genotype (DRB1*03:01, DRB1*15:01, DQB1*02:01 and DQB1*06:02) or anti-SSA/Ro autoantibody levels. Multiple genera within the families Ruminococcaceae and Lachnospiraceae showed evidence of an HLA-by-genus interaction (P < .05). Four genera exhibited evidence of an interaction with anti-Ro52 IgA: Lachnoclostridium, Romboutsia, Bacteroides and Actinomyces (P < .01). In addition to documenting differences in microbial relative abundances across clinical severity of disease, these data provide a first-time demonstration that microbial differences are correlated with HLA SLE-risk alleles. Taken together, these data suggest that the clinical spectrum from benign to overt clinical autoimmunity may partially result from or trigger a complex interplay among specific microbial profiles, anti-Ro autoantibodies, and genetics.

The Disease with a Thousand Faces and the Human Microbiome—A Physiopathogenic Intercorrelation in Pediatric Practice

“…In agreement with them, Clancy RM. et al underline the importance of mimicry (cross-reaction to microbial peptides from the oral or intestinal flora) in defining the microbiome-autoimmunity relationship, which seems to modulate the transition from latent disease to severe clinical damage among mothers who give birth to children with neonatal lupus [19][20][21][22].…”

The role of vitamin D in pediatric systemic lupus erythematosus - a double pawn in the immune and microbial balance

“…At the same time, it differs depending on the levels of the C3 and C4 factions of the complement ( 89 ). Studies in the specialized literature confirm both the involvement of intestinal and oral dysbiosis in dictating the risk of manifest autoimmunity, as well as the role of diet components (e.g., tryptophan) in modulating the intestinal microbiota in healthy people and SLE patients ( 90 – 93 ).…”

More Considerations for Risk Stratification of Fetal Atrioventricular Block Beyond Anti‐Ro Titer: comment on the article by Buyon et al

“…4 We wonder whether the anti-Ro titer can also serve as a guide to help shared decision-making regarding the use of HCQ for AVB prophylaxis, particularly for those without a history of fetal AVB. The only prospective clinical trial to date focused on patients with a history of fetal AVB, and the risk of AVB with HCQ use was 7.4%, which was lower than the historical control rate 5 of 18%. Current study data indicate that all patients with low anti-Ro titers do not experience AVB, irrespective of HCQ treatment (93 and 59 patients taking and not taking HCQ, respectively).…”

“…Furthermore, comparing maternal diagnoses between affected and unaffected pregnancies in the same woman would be insightful as some asymptomatic (Asym) women progress, 3,4 perhaps influenced by factors such as the microbiome. 5 A review of rheumatologic diagnoses in registries of larger numbers of fAVB in which mothers would be expected to have high-titer anti-SSA/Ro provides context for comparisons to prospective studies, such as STOP BLOQ. In an earlier study leveraging the Research Registry for Neonatal Lupus, which enrolled 138 mothers within one year of the fAVB birth (acknowledging most were cardiac, but some were cutaneous), 44 were Asym, 43 had undifferentiated autoimmune syndrome (UAS), 22 had probable or definite SS, 15 had SLE, and 14 had SLE and SS.…”