Interferon-inducible chemokines reflect severity and progression in sarcoidosis

Abstract

BackgroundIdentification of serum proteins that track with disease course in sarcoidosis may have clinical and pathologic importance. We previously identified up-regulated transcripts for interferon-inducible chemokines CXCL9, and CXCL10, in blood of sarcoidosis patients compared to controls. The objective of this study was to determine whether proteins encoded by these transcripts were elevated in serum and identified patients with remitting vs. chronic progressive sarcoidosis longitudinally.MethodsSerum levels of CXCL9, CXCL10, and proteins associated with inflammation and/or disease activity (sIL2R, ACE, ESR and CRP) were measured in a prospective cohort of sarcoidosis subjects and controls. Comparisons were made between groups and clinical course using pulmonary function measures and a severity score developed by Wasfi et al.ResultsIn a cross-sectional analysis of 36 non-immunosuppressed sarcoidosis subjects, serum CXCL9, CXCL10, and sIL2R were significantly elevated compared to 46 controls (p < 0.0001). CXCL9 and CXCL10 were strongly inter-correlated (p = 0.0009). CXCL10 and CXCL9 were inversely correlated with FVC% predicted and DLCO% predicted, respectively. CXCL10 and CXCL9 significantly correlated with sarcoidosis severity score. sIL2R, ESR, CRP, and ACE serum levels did not correlate with pulmonary function measures or severity score. In the longitudinal analysis of 26 subjects, changes in serum CXCL10 level over time corresponded with progression versus remission of disease.ConclusionsInterferon-γ–inducible chemokines, CXCL9 and CXCL10, are elevated in sarcoidosis and inter-correlated with each other. Chemokine levels correlated with measures of disease severity. Serial measurements of CXCL10 corresponded to clinical course.

Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes

“…CXCL9 is an IFN-cinducible chemokine that, upon binding to its receptor CXCR3, facilitates recruitment of T-cells to inflamed tissues in human autoimmune diseases. We and others have demonstrated elevations in CXCL9 protein levels in sarcoidosis sera [15,21], bronchoalveolar lavage (BAL) fluid [15,21,33] and granulomas [34]. We further show that CXCL9 gene expression inversely correlated with DLCO % predicted, independent of time from diagnosis.…”

“…Unexpectedly, the IFN-inducible chemokine CXCL9 gene (factor 7) was not intercorrelated with the other IFN-related genes in factor 1. We had particular interest in CXCL9 (factor 7), as CXCL9 is upregulated in gene network analyses of sarcoidosis organ tissues [19,20], and we and others have previously shown that serum protein levels of this chemokine are upregulated in sarcoidosis [15,21]. In summary, factor analysis of the qPCR results provided confirmation of the IFN, pattern recognition and TCR pathways in a separate replicate cohort, and additionally demonstrated a separate factor for CXCL9.…”

“…In prior studies, the course of sarcoidosis disease has been characterised as chronic if disease activity persisted beyond 2 years [11][12][13][14][15][16]. As such, the 2-year threshold was incorporated into our classification schema.…”

Sarcoidosis: treatments beyond prednisone and methotrexate

“…The authors were able to demonstrate that patients with more severe disease expressed higher levels of tumor necrosis factor alpha (TNFα), and also had a greater response to infliximab [27]. Novel biomarkers, such as CXCL9, are likely to provide additional avenues for precision medicine in sarcoidosis treatment [28].…”

The contribution of interleukin-2 to effective wound healing

“…86 SIL-2R is also elevated in sarcoidosis and has been extensively studied in the disease. 87,88 Su et al found that sIL-2R levels were elevated in sarcoidosis compared with healthy controls, although the sIL-2R levels did not correlate with lung disease severity. 87 The amount of sIL-2R does correlate, however, with eye inflammation in sarcoidosis patients.…”