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.

摘要

抗 SSA/Ro 抗体虽然与胎儿心脏损伤和新生儿皮疹密切相关，但可能与母亲的一系列疾病相关，从完全无症状到明显的系统性红斑狼疮 (SLE) 或干燥​​综合征 (SS)。这项研究旨在检验微生物组部分受遗传影响的假设，该假设有助于疾病状态。将健康对照组 (HC) 的粪便微生物组与儿童患有新生儿狼疮的抗 SSA/Ro 阳性妇女的粪便微生物组进行比较。在取样时，这些女性要么无症状（Asym），要么有轻微的风湿症状或被认为是未分化自身免疫综合征（UAS）的体征，要么被诊断为 SLE 或 SS。假设临床严重程度排序（HC< Asym/UAS<SS/SLE) 然后再次没有序数假设。然后测试显示不同相对丰度的那些分类群是否影响大小取决于女性的 HLA SLE 风险等位基因基因型（DRB1*03:01、DRB1*15:01、DQB1*02:01 和 DQB1*06:02 ) 或抗 SSA/Ro 自身抗体水平。家庭中的多个属瘤胃球菌科和毛螺菌科显示出 HLA-by-genus 相互作用的证据 (P < .05)。四个属表现出与抗 Ro52 IgA 相互作用的证据：Lachnoclostridium、Romboutsia、拟杆菌属和放线菌属(P < .01)。除了记录疾病临床严重程度中微生物相对丰度的差异外，这些数据还首次证明微生物差异与 HLA SLE 风险等位基因相关。总之，这些数据表明，从良性到明显的临床自身免疫的临床谱可能部分是由特定微生物谱、抗 Ro 自身抗体和遗传学之间复杂的相互作用引起或触发的。