Objective. Interferon-␣ (IFN␣) is a primary pathogenic factor in systemic lupus erythematosus (SLE), and high IFN␣ levels may be associated with particular clinical manifestations. The prevalence of individual clinical and serologic features differs significantly by ancestry. This study was undertaken to detect associations between clinical and serologic disease manifestations and serum IFN␣ activity in a large diverse SLE cohort, using multivariate and network analyses.Methods. We studied 1,089 SLE patients (387 African American, 186 Hispanic American, and 516 European American patients). The presence or absence of individual American College of Rheumatology (ACR) clinical criteria for SLE, autoantibodies, and serum IFN␣ activity data were analyzed in univariate and multivariate models. Iterative multivariate logistic regression was performed in each ancestral background group separately to establish the network of associations between variables that were independently significant following Bonferroni correction.Results. In all ancestral backgrounds, high IFN␣ activity was associated with anti-Ro and anti-doublestranded DNA antibodies (P ‫؍‬ 4.6 ؋ 10 ؊18 and P ‫؍‬ 2.9 ؋ 10 ؊16 , respectively). Younger age, non-European ancestry, and anti-RNP were also independently associated with increased serum IFN␣ activity (P < 6.7 ؋ 10 ؊4 ). We found 14 unique associations between variables in network analysis, and only 7 of these associations were shared among >1 ancestral background. Associations between clinical criteria were different for different ancestral backgrounds, while autoantibody-IFN␣ relationships were similar across backgrounds. IFN␣ activity and autoantibodies were not associated with ACR clinical features in multivariate models.Conclusion. Our findings indicate that serum IFN␣ activity is strongly and consistently associated with autoantibodies, and not independently associated with clinical features in SLE. IFN␣ may be more relevant to humoral tolerance and initial pathogenesis than later clinical disease manifestations.

Despite recent progress in the understanding of systemic lupus erythematosus (SLE), the striking 9:1 female to male ratio of disease incidence remains largely unexplained. In addition, peak SLE incidence rates occur during the early reproductive years in women. Studies which illuminate potential causes underlying this sex difference and characteristic onset during the reproductive years have the potential to fundamentally advance our understanding of disease pathogenesis in SLE. Similarly, progress in this area will likely inform human reproductive immunology. Studies of sex hormone function in the immune system are of obvious importance; however, it seems likely that many other types of sex-related genetic and immunological differences will contribute to SLE. In this review, we will focus on recent work in sex-related differences in cytokine pathways and genetics of these pathways as they relate to SLE pathogenesis. It seems quite possible that many of these sex-related differences could be important to reproductive fitness, which may explain the conservation of these immune system features and the observed female predominance of SLE.

Background SLE disease manifestations are highly variable between patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum tumor necrosis factor alpha (TNF-α) is elevated in some SLE patients, and may play a role in disease pathogenesis. We detected associations between serum TNF-α, clinical manifestations, autoantibodies, and serum IFN-α in a large multi-ancestral SLE cohort. Methods We studied serum TNF-α in 653 SLE patients, including 214 African-American, 298 European-Americans and 141 Hispanic-American subjects. TNF-α was measured using ELISA, and IFN-α was measured with a functional reporter cell assay. Stratified and multivariate analyses were used to detect associations in each ancestral background separately, with meta-analysis when appropriate. Results Serum TNF-α levels were significantly higher in SLE patients than in nonautoimmune controls (p<5.0×10−3 for each ancestral background). High serum TNF-α was positively correlated with high serum IFN-α when tested in the same sample across all ancestral backgrounds (meta-analysis OR=1.8, p=1.2×10−3). While serum TNF-α levels alone did not differ significantly between SLE patients of different ancestral backgrounds, the proportion of patients with concurrently high TNF-α and high IFN-α was highest in African-Americans and lowest in European-Americans (p=5.0×10−3). Serum TNF-α was not associated with autoantibodies, clinical criteria for the diagnosis of SLE, or age at time of sample. Conclusions Serum TNF-α levels are high in many SLE patients, and we observed a positive correlation between serum TNF-α and IFN-α. These data support a role for TNF-α in SLE pathogenesis across all ancestral backgrounds, and suggest important cytokine subgroups within the disease.

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