Serum type I interferon activity is dependent on maternal diagnosis in anti-SSA/Ro-positive mothers of children with neonatal lupus

Abstract

Objective: The type I interferon (IFN) pathway is activated in many patients with systemic lupus erythematosus (SLE), and high serum levels of IFN are associated with anti-SSA/Ro autoantibodies. To investigate the clinical features associated with type I IFN production in vivo, we compared serum IFN activity in individuals with anti-SSA/Ro antibodies who were asymptomatic with that in individuals with clinical manifestations of SLE or Sjögren's syndrome (SS).

Methods: Antibody-positive sera from 84 mothers of children with manifestations of neonatal lupus were studied for type I IFN activity, using a functional reporter cell assay. Maternal health status was characterized as asymptomatic, SS, SLE, pauci-SLE, or pauci-SS, based on a screening questionnaire, telephone interview, and review of medical records. The prefix "pauci-" indicates symptoms insufficient for a formal classification of the disease.

Results: Only 4% of asymptomatic mothers had high serum type I IFN activity, compared with 73% with pauci-SLE (P = 5.7 x 10(-5)), 35% with SLE (P = 0.011), and 32% of patients with SS (P = 0.032). One of the 4 patients with pauci-SS had high levels of IFN. The majority of patients for whom longitudinal data were available had stable type I IFN activity over time, and changes in IFN activity were not clearly accompanied by changes in the clinical diagnosis.

Conclusion: Patients with SLE, patients with pauci-SLE, and patients with SS are more likely to have high serum IFN activity than asymptomatic individuals with SSA/Ro autoantibodies, suggesting that these autoantibodies are insufficient for activation of the type I IFN pathway, and that disease-specific factors are important for type I IFN generation in vivo.

Figure 1

a, Proportions of mothers of children with neonatal lupus erythematosus (NLE), stratified by clinical diagnosis, and healthy donors with high serum type I interferon (IFN) activity. n = total number of patients with the given diagnosis; if a patient had >1 sample available from different dates, the most recent sample and corresponding diagnosis were used. b, Quantitative serum type I IFN activity in mothers of children with NLE, stratified by clinical diagnosis, and healthy donors. Values are the mean and SD. P values were determined by Fisher's exact test. SLE = systemic lupus erythematosus; SS = Sjögren's syndrome; Asym. = asymptomatic.

Figure 2

Titers of anti-SSA/Ro antibodies (a) and anti-SSB/La antibodies (b), as determined by enzyme-linked immunosorbent assay, in individuals with high versus low type I interferon (IFN) activity, regardless of health status. Autoantibodies were measured in serum samples that were obtained at the time of entry into the Research Registry for Neonatal Lupus. Although all individuals had positive test results for SSA/Ro and some had positive results for SSB/La, precise titer data for SSA/Ro were available on only 83 (99%) of 84 subjects, and precise SSB/La titer data were available on only 80 (95%) of 84 subjects in whom IFN activity was later quantified. Bars show the medians.