Linkage of type I interferon activity and TNF-alpha levels in serum with sarcoidosis manifestations and ancestry

Abstract

Background: Both 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.

Methods: We 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.

Results: Significant 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.

Conclusions: Our 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.

Figure 1. Serum TNF-α levels in sarcoidosis patients and controls in each ancestral background.

Lines represent the median, boxes show the interquartile ranges, and error bars show the 10^th and 90^th percentiles with dots indicating outliers. P-values by Mann-Whitney U test.

Figure 2. Serum type I IFN activity in sarcoidosis patients and controls in each ancestral background.

Lines represent the median, boxes show the interquartile ranges, and error bars show the 10^th and 90^th percentiles with dots indicating outliers. P-values by Mann-Whitney U test.

Figure 3. Serum TNF-α levels in African-American controls and sarcoidosis patients stratified by presence or absence of neurologic involvement.

Lines represent the median, boxes show the interquartile ranges, and error bars show the 10^th and 90^th percentiles with dots indicating outliers. P-values by Mann-Whitney U test.

Figure 4. Serum type I IFN activity in European-American controls and sarcoidosis patients stratified by presence or absence of extra-pulmonary manifestations.

Lines represent the median, boxes show the interquartile ranges, and error bars show the 10^th and 90^th percentiles with dots indicating outliers. P-values by Mann-Whitney U test.