Background/Purpose: High titer anti-Ro+ mothers of children with neonatal lupus (NL), often completely asymptomatic, offer a unique opportunity to uncover insights into permissive and protective factors related to the clinical progression to SLE. This study evaluated the abundance of the gut microbe Streptococcus as part of a complex interplay with other lupus-risk factors, including blood cytokines and HLA SLE-risk alleles, in elucidating the spectrum of health status in anti-Ro+ NL mothers.

Methods: Clinical phenotyping, HLA profiling and gut microbiome composition were assessed in a cohort of 44 anti-Ro+ NL mothers and 10 healthy controls. Mothers were adjudicated and assigned into 2 clinical groups: asymptomatic/undifferentiated autoimmune disease (N = 25) and criteria based SLE (N = 19). Soluble mediators (N = 52) were examined including cytokines, chemokines, and soluble receptors using validated multiplex bead-based (xMAP) or enzyme-linked immunosorbent assays.

Results: Streptococcus relative abundance varied as a combined function of both DQB1*06:02 status and clinical state. Overall, Streptococcus relative abundance was higher in those women without the DQB1*06:02 allele. In anti-Ro+ mothers with the DQB1*06:02 allele, Streptococcus relative abundance increased with clinical severity (HC < Asym/UAS < SLE), while the reverse pattern was observed in those without the allele (HC > Asym/UAS >SLE), suggesting DQB1*06:02 modifies the relationship between Streptococcus and clinical disease state in this cohort (interaction p = 0.018). Evaluating cytokine correlations, in a linear regression model with ICAM1 as the outcome and adjusting for 16S batch processing and clinical state (N = 25 Asym/UAS, N = 19 SLE) as covariates, Streptococcus was negatively associated with ICAM1 (β = -43.64, SE(β) = 20.51; p = 0.04) which may be modified by the presence of the DQB1*06:02 allele (p = 0.067). In a parallel analysis with BAFF as the outcome, Streptococcus was also negatively associated with BAFF (β = -65.50, SE(β) = 29.70; p = 0.033), but DQB1*06:02 did not seem to modify this effect (p = 0.50).We then tested whetherStreptococcus was associated with clinical state after adjusting for ICAM and BAFF. Streptococcus relative abundance was positively associated with SLE (N = 25 Asym/UAS vs. N = 19 SLE; OR = 3.29 per 1 standard deviation in Streptococcus, p = 0.034) after adjusting for batch, ICAM and BAFF. A comparable effect was observed within each stratum when stratifying by DQB1*06:02 status and adjusting for batch, ICAM and BAFF serum levels. Specifically, in the 16 mothers that had at least one DQB1*06:02 allele (N = 11 Asym/UAS vs. N = 5 SLE), the Streptococcus pattern remained, though significance was dampened due to reduced sample size (p = 0.087). In the 28 anti-Ro+ mothers with no DQB1*06:02 alleles (N = 14 Asym/UAS vs. N = 14 SLE), the Streptococcus association similarly had dampened significance due to reduced sample size (p = 0.11).

Conclusion: These data support that a focus on Streptococcus, serum soluble mediators (ICAM1 and BAFF) and the HLA allele DQB1*0602 may yield insights into the complex interplay of factors associated with lupus that are inherent in the anti-Ro+ NL mothers who progress to established disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-gut-microbiome-streptococcus-health-status-cytokines-and-hla-class-in-anti-ro-mothers-of-children-with-neonatal-lupus-insights-into-progression-of-clinical-autoimmunity/