Background/Purpose: Mothers of children with neonatal lupus offer a unique opportunity to study the drivers and consequences of autoantibody production in the absence of ongoing maternal inflammation/damage or concurrent immunotherapeutics since many of these women are clinically asymptomatic with high titer anti-Ro antibodies identified solely by disease in the child.  This study was initiated to assess the contribution of soluble mediators in the  innate, adaptive and effector arms of the immune system to the production of anti-Ro responses independent of other autoantibodies or established systemic lupus erythematosus (SLE), Sjogren’s syndrome (SS) or rheumatoid arthritis (RA).    

Methods: Soluble mediators (N= 32) were examined including cytokines, chemokines, and soluble receptors using validated multiplex bead-based (xMAP) or enzyme-linked immunosorbent assays in serum from 44 anti-Ro positive women within 5 years of a pregnancy complicated by either heart block (N=36) or skin rash (N=8). Autoantibodies were measured by Bio-Rad Bioplex ANA2200 and recombinant and native Ro60/52 proteins by ELISA.  Antibodies to dsDNA, Sm, and RNP were all negative. Based on questionnaire, phone interview, and review of medical records, 18 mothers were completely asymptomatic, 8 had either photosensitivity or Raynauds, and 18 had a combination of mild complaints, including articular and cutaneous symptoms and did not fulfill SLE (ACR or SLICC), SS or RA criteria. Comparisons were made with sera obtained from 156 healthy controls and 94 SLE patients (30 = anti-Ro positive). 

Results:   Compared to healthy controls, asymptomatic/undifferentiated anti-Ro positive mothers had significant (p<0.0001) alterations in 21 of 32 tested mediators. These mothers had higher levels of IFN g and associated molecules (MIG, MIP-1a) (p<0.0001) than ANA negative healthy controls at levels that were comparable with SLE patients. However, levels of IFNa and associated molecules important in SLE (BLyS, IP-10) were much lower in anti-Ro positive mothers than SLE patients, and similar to healthy controls (p<0.0001). These anti-Ro positive mothers also had higher levels of Th17 (IL-17A, IL-21, IL-6), Th1 (IL-2, TNFa), Th2 (IL-4, IL-6), shed TNF receptors (TNFRI, TNFRII, sCD40L) and regulatory responses (IL-1RA) compared to healthy controls (p<0.0001). In addition, these anti-Ro positive mothers had dramatically higher levels of IL-1RA and TGFb compared to SLE patients including those with anti-Ro (p<0.0001). No significant differences in soluble mediator levels were noted between anti-Ro positive mothers who were completely asymptomatic and those with mild rheumatic symptoms.

Conclusion: High titer anti-Ro positive asymptomatic neonatal lupus mothers have dysregulated levels of soluble mediators across several inflammatory and immune pathways; however, BlyS and IP10, which appear temporally important in transition to clinical SLE, are not elevated.  This cohort provides a unique opportunity to dissect critical pathways resulting in autoimmunity absent overt disease, thus guiding the  development of targeted therapeutics for decreasing anti-Ro antibodies and risk of neonatal lupus, as well as providing insights into lupus pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/elevated-regulatory-mediators-and-interferon-gamma-associated-responses-but-not-interferon-alpha-blys-or-ip-10-accompany-high-titer-anti-ro-autoantibodies-in-asymptomatic-mothers-of-children-with-n/