Brief Report: Large‐scale analysis of tumor necrosis factor α levels in systemic lupus erythematosus

Abstract

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.

Antimalarial drugs inhibit IFNα-enhanced TNFα and STAT4 expression in monocytes: Implication for systemic lupus erythematosus

“…These data are in line with the elevated and directly correlated serum levels of TNFa and IFNa detected in SLE patients that were previously described in a large group [23,24]. Other authors observed that the -308ATNFa allele, associated with an increased production of this cytokine, was positively correlated with higher IFNa serum levels in untreated patients of dermatomyositis at disease onset, suggesting that the relationship between both cytokines could be influenced by the treatment or the disease progression [37].…”

“…However, in SLE patients with low IFNa production, a feature associated with a low presence of autoantibodies [24] and TNFa [23,56], antimalarial therapy could be ineffective in reducing STAT4 expression, thus suggesting the use of IFNa as a possible biomarker of the clinical response to antimalarials.…”

“…Although the mechanisms for antimalarials are not completely known, it has been described they may block the TLR interaction with nucleic acid ligands by altering lysosomal acidification and disrupting endosomal maturation [22], constituting an interesting therapy for the IFNa blockade, which could prevent the activation of proinflammatory pathways. In fact, it has been previously observed a notable positive correlation between serum levels of IFNa and TNFa [23,24], both cytokines considered essential elements in the etiopathology of the SLE [5,25].…”

17&beta;-estradiol contributes to the accumulation of myeloid-derived suppressor cells in blood by promoting TNF-&alpha; secretion

“…However, there is no report about the effects of estrogens on MDSC accumulation. Tumor necrosis factor-alpha (TNF-α) is a key inflammatory cytokine involved in the pathogenesis of SLE [33,34]. Much evidence has demonstrated that TNF-α can drive the accumulation of MDSCs [35,36].…”

Caspase-12 and Lupus: The Curious Case of the Dog That Didn’t Bark

“…While malaria would be an obvious candidate for a positive selective effect upon maintenance of CASP12, there is no association between CASP12 genotype and either the presentation of severe malaria or outcomes in individual clinical parameters in malaria patients [29] . CASP12's effects upon TNF production, which is elevated in all lupus patients, especially African-Americans [30] , is also contradictory [5,28,31] . Further, while hepatitis C virus is an IL-1β inducer [32] , CASP12 genotype has no effect on the clearance of this pathogen [33] .…”