Linkage of Type I Interferon Activity and TNF-Alpha Levels in Serum with Sarcoidosis Manifestations and Ancestry

Abstract

BackgroundBoth type I interferon (IFN), also known as IFN-α and tumor necrosis factor alpha (TNF-α) have been implicated in the pathogenesis of sarcoidosis. We investigated serum levels of these cytokines in a large multi-ancestral sarcoidosis population to determine correlations between cytokine levels and disease phenotypes.MethodsWe studied serum samples from 98 patients with sarcoidosis, including 71 patients of African-American ancestry and 27 patients of European-American ancestry. Serum type I IFN was measured using a sensitive reporter cell assay and serum TNF-α was measured using a commercial ELISA kit. Clinical data including presence or absence of neurologic, cardiac, and severe pulmonary manifestations of sarcoidosis were abstracted from medical records. Twenty age-matched non-autoimmune controls were also studied from each ancestral background. Differences in cytokine levels between groups were analyzed with Mann-Whitney U test, and correlations were assessed using Spearman's rho. Multivariate logistic regression models were used to detect associations between cytokines and clinical manifestations.ResultsSignificant differences in cytokine levels were observed between African- and European-American patients with sarcoidosis. In African-Americans, serum TNF-α levels were significantly higher relative to matched controls (P = 0.039), and patients with neurologic disease had significantly higher TNF-α than patients lacking this manifestation (P = 0.022). In European-Americans, serum type I IFN activity was higher in sarcoidosis cases as compared to matched controls, and patients with extra-pulmonary disease represented a high serum IFN subgroup (P = 0.0032). None of the associations observed were shared between the two ancestral groups.ConclusionsOur data indicate that significant associations between serum levels of TNF-α and type I IFN and clinical manifestations exist in a sarcoidosis cohort that differ significantly by self-reported ancestry. In each ancestral background, the cytokine elevated in patients with sarcoidosis was also associated with a particular disease phenotype. These findings may relate to ancestral differences in the molecular pathogenesis of this heterogeneous disease.

The Role of Type I IFN and TNF-α in the Pathogenesis of Sarcoidosis

“…In the study showing serum levels of TNF-α and IFN-α in sarocoidosis, significant differences in cytokine levels were found between sarcoidosis patients of different ancestral Sarcoidosis 36 backgrounds [9]. In this study, African-Americans had higher TNF-α levels than EuropeanAmerican patients or matched controls, and patients with neurologic disease had significantly higher TNF-α than patients lacking this manifestation.…”

“…In this study, African-Americans had higher TNF-α levels than EuropeanAmerican patients or matched controls, and patients with neurologic disease had significantly higher TNF-α than patients lacking this manifestation. In a European-American population, serum type I IFN activity was higher in sarcoidosis cases as compared to matched controls, and patients with extra-pulmonary disease represented a high serum IFN group [9]. This study demonstrated ancestral and subphenotype correlations with serum cytokine levels in patients with sarcoidosis.…”

“…The occurrence of sarcoidosis during monotherapy for diseases other than chronic hepatitis also supports this relationship. Another recent study found that in an European American population, serum IFN-α activity was higher in sarcoidosis cases as compared to matched controls [9].…”

“…Moreover, from a genetic standpoint, we recently showed an association between polymorphisms in the IFNA gene and susceptibility to sarcoidosis [8]. Another recent study found that in an European-American population, serum type I IFN activity was higher in sarcodosis cases as compared to matched controls [9]. In addition, besides IFN-induced sarcoidosis, a dozen case reports of sarcidosis have also been reported in patients treated with tumor necrosis factor (TNF) antagonists [10].…”

Deterioration of Cardiac Function during the Progression of Cardiac Sarcoidosis: Diagnosis and Treatment

“…Numerous studies have confirmed high TNF-α production in cases with sarcoidosis, and have shown an important role of TNF-α in granuloma formation (37)(38)(39)(40)(41). Moreover, mononuclear phagocytes, such as mature macrophages, are responsible for the TNF-α secretion in patients with sarcoidosis (42).…”