Objective Systemic lupus erythematosus (SLE) disease manifestations are highly variable among patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum ...tumor necrosis factor alpha (TNFalpha) levels are elevated in some SLE patients and may play a role in disease pathogenesis. The aim of this study was to look for associations between serum TNFalpha levels, clinical manifestations of SLE, autoantibodies, and serum interferon-alpha (IFNalpha) levels in a large multiancestral SLE cohort. Methods We studied serum TNFalpha levels in 653 SLE patients (214 African Americans, 298 European Americans, and 141 Hispanic Americans). TNFalpha was measured using an enzyme-linked immunosorbent assay, and IFNalpha 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 TNFalpha levels were significantly higher in SLE patients than in non-autoimmune disease controls (P < 5.0 × 10-3 for each ancestral background). High serum TNFalpha levels were positively correlated with high serum IFNalpha levels when tested in the same sample across all ancestral backgrounds (odds ratio range 1.76-1.86, P = 4.8 × 10-3 by Fisher's combined probability test). While serum TNFalpha levels alone did not differ significantly among SLE patients of different ancestral backgrounds, the proportion of patients with concurrently high levels of TNFalpha and IFNalpha was highest in African Americans and lowest in European Americans (P = 5.0 × 10-3). Serum TNFalpha levels were not associated with autoantibodies, clinical criteria for the diagnosis of SLE, or age at the time of sampling. Conclusion Serum TNFalpha levels are high in many SLE patients, and we observed a positive correlation between serum TNFalpha and IFNalpha levels. These data support a role for TNFalpha in the pathogenesis of SLE across all ancestral backgrounds and suggest important cytokine subgroups within the disease. PUBLICATION ABSTRACT
Objective
Systemic lupus erythematosus (SLE) disease manifestations are highly variable among patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum ...tumor necrosis factor α (TNFα) levels are elevated in some SLE patients and may play a role in disease pathogenesis. The aim of this study was to look for associations between serum TNFα levels, clinical manifestations of SLE, autoantibodies, and serum interferon‐α (IFNα) levels in a large multiancestral SLE cohort.
Methods
We studied serum TNFα levels in 653 SLE patients (214 African Americans, 298 European Americans, and 141 Hispanic Americans). TNFα was measured using an enzyme‐linked immunosorbent assay, and IFNα 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 TNFα levels were significantly higher in SLE patients than in non–autoimmune disease controls (P < 5.0 × 10−3 for each ancestral background). High serum TNFα levels were positively correlated with high serum IFNα levels when tested in the same sample across all ancestral backgrounds (odds ratio range 1.76–1.86, P = 4.8 × 10−3 by Fisher's combined probability test). While serum TNFα levels alone did not differ significantly among SLE patients of different ancestral backgrounds, the proportion of patients with concurrently high levels of TNFα and IFNα was highest in African Americans and lowest in European Americans (P = 5.0 × 10−3). Serum TNFα levels were not associated with autoantibodies, clinical criteria for the diagnosis of SLE, or age at the time of sampling.
Conclusion
Serum TNFα levels are high in many SLE patients, and we observed a positive correlation between serum TNFα and IFNα levels. These data support a role for TNFα in the pathogenesis of SLE across all ancestral backgrounds and suggest important cytokine subgroups within the disease.
Objective Interferon-alpha (IFNalpha) is a primary pathogenic factor in systemic lupus erythematosus (SLE), and high IFNalpha 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 IFNalpha 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 IFNalpha 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 IFNalpha activity was associated with anti-Ro and anti-double-stranded 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 IFNalpha 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-IFNalpha relationships were similar across backgrounds. IFNalpha activity and autoantibodies were not associated with ACR clinical features in multivariate models. Conclusion Our findings indicate that serum IFNalpha activity is strongly and consistently associated with autoantibodies, and not independently associated with clinical features in SLE. IFNalpha may be more relevant to humoral tolerance and initial pathogenesis than later clinical disease manifestations. PUBLICATION ABSTRACT
Objective Interferon- (IFN) is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variation near IRF7 is implicated in SLE susceptibility. SLE-associated autoantibodies can ...stimulate IFN production through the Toll-like receptor/IRF7 pathway. This study was undertaken to determine whether variants of IRF7 act as risk factors for SLE by increasing IFN production and whether autoantibodies are important to this phenomenon. Methods We studied 492 patients with SLE (236 African American, 162 European American, and 94 Hispanic American subjects). Serum levels of IFN were measured using a reporter cell assay, and single-nucleotide polymorphisms (SNPs) in the IRF7/PHRF1 locus were genotyped. Results In a joint analysis of European American and Hispanic American subjects, the rs702966 C allele was associated with the presence of anti-double-stranded DNA (anti-dsDNA) antibodies (odds ratio OR 1.83, P = 0.0069). The rs702966 CC genotype was only associated with higher serum levels of IFN in European American and Hispanic American patients with anti-dsDNA antibodies (joint analysis P = 4.1 X 10-5 in anti-dsDNA-positive patients and P = 0.99 in anti-dsDNA-negative patients). In African American subjects, anti-Sm antibodies were associated with the rs4963128 SNP near IRF7 (OR 1.95, P = 0.0017). The rs4963128 CT and TT genotypes were associated with higher serum levels of IFN only in African American patients with anti-Sm antibodies (P = 0.0012). In African American patients lacking anti-Sm antibodies, an effect of anti-dsDNA-rs702966 C allele interaction on serum levels of IFN was observed, similar to the other patient groups (overall joint analysis P = 1.0 X 10-6). In European American and Hispanic American patients, the IRF5 SLE risk haplotype showed an additive effect with the rs702966 C allele on IFN level in anti-dsDNA-positive patients. Conclusion Our findings indicate that IRF7/PHRF1 variants in combination with SLE-associated autoantibodies result in higher serum levels of IFN, providing a biologic relevance for this locus at the protein level in human SLE in vivo.
PDF
