Type I Interferon Predicts an Alternate Immune System Phenotype in Systemic Lupus Erythematosus

Abstract

ObjectiveType I interferon (IFN) is important to systemic lupus erythematosus (SLE) pathogenesis, but it is not clear how chronic elevations in IFN alter immune function. We compared cytokine responses after whole blood stimulation with Toll‐like receptor (TLR) agonists in high‐ and low‐IFN SLE patient subgroups.MethodsSLE patients and nonautoimmune controls were recruited, and SLE patients were categorized as either high or low IFN. Whole blood was dispensed into tubes coated with lipopolysaccharide (LPS), oligonucleotides with cytosine‐guanine repeats, Resiquimod, IFN‐α, and IFN‐α + LPS. Cytokine production in patient sera and after whole blood TLR stimulation was measured by multiplex assay, and type I IFN was assessed using a functional assay.ResultsCirculating plasmacytoid dendritic cell numbers were specifically reduced in high‐IFN SLE patients and not in low‐IFN SLE patients. In serum, we observed that the correlations between cytokines in serum differed to a much greater degree between the high‐ and low‐IFN groups (P < 0.0001) than the absolute cytokine levels differed between these same groups. In stimulated conditions, the high‐IFN patients had less cytokine production in response to TLR ligation than the low‐IFN SLE patients. LPS produced the most diverse response, and a number of interactions between type I IFN and LPS were observed.ConclusionWe find striking differences in resting and stimulated cytokine patterns in high‐ vs. low‐IFN SLE patients, which supports the biological importance of these patient subsets. These data could inform personalized treatment approaches and the pathogenesis of SLE flare following infection.

Type I interferon pathway assays in studies of rheumatic and musculoskeletal diseases: a systematic literature review informing EULAR points to consider

“… 29–38 In two studies concurrent validity was tested between the IFN-inducible protein and two other techniques (flow cytometry for SIGLEC-1 22 39 as well as IFN-α protein 21 26 ; and gene expression as well as a reporter cell assay). 30 40 …”

“…Bauer et al 29 selected IFN chemokines whose transcripts were induced by IFN-α in a microarray study but did not check whether other IFNs or inflammatory mediators also induced these proteins. Thanarajasingam et al 30 evaluated stimulation of whole blood including IFN-α, oligonucleotides with cytosine‐guanine repeats, Resiquimod (R848), LPS, IFN‐α+LPS and null (no stimulant) then measured cytokines/chemokines and IFN-α. Most of the other studies cite the evidence from Bauer et al 29.…”

“…Concurrent validity: Of 42, 16 studies demonstrated concurrent validity against another test for IFN-I. 11/16 used an ISG expression assay 29–38. In two studies concurrent validity was tested between the IFN-inducible protein and two other techniques (flow cytometry for SIGLEC-122 39 as well as IFN-α protein21 26; and gene expression as well as a reporter cell assay) 30 40…”

Type I Interferons in Autoimmunity: Implications in Clinical Phenotypes and Treatment Response

“…In autoimmune diseases such as SLE, pSS, and SSc, both the numbers and function, including cytokine production, of circulating pDCs are reduced. [46][47][48] In fact, a previous study showed that pDCs from patients with SLE and at-risk patients (ie, those with some features of autoimmunity but without a disease diagnosis) exhibit a senescent phenotype. 46 However, it is possible that the population of circulating pDCs is not representative of the tissue infiltrating pDC, which could still have significant pathogenic roles in autoimmunity both dependent and independent of excessive IFN-α production by these cells.…”