Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Presence of a type I interferon
(IFN) signature is described for several autoimmune diseases, including
systemic lupus erythematosus (SLE), multiple sclerosis (MS), myositis (IIM) and
rheumatoid arthritis (RA). While IFNα contributes to SLE pathology,
IFNβ therapy is beneficial for many MS patients, implying different immunoregulatory roles for these IFNs. This study aims to
investigate potential diversification of the IFNα- and IFNβ-mediated response
Methods: Peripheral blood gene expression
of 23 known type I IFN response genes (IRGs) was determined in healthy controls
(n=54), SLE (n=47), IFNβ-treated MS (3 months, n=72), untreated MS
(n=164), IIM (n=78) and RA patients (n=76) by multiplex qPCR.
An IFN score was calculated and patients with a type I IFN signature –defined
as an IFN score above the mean+2SD in HC– were selected for analysis.
Results: Unsupervised cluster analysis of SLE
(IFNα-driven) and IFNβ-treated MS patients showed excellent
separation based on two IRG clusters. Statistical testing revealed increased
expression of 5 IRGs in SLE (Gene cluster (GC-)A, p≤0.006)
and 13 IRGs in IFNβ-treated MS (Gene cluster (GC-)B, p≤0.044),
believed to reflect IFNα- and IFNβ-specific response programs,
respectively. Concordantly, the GC-A/GC-B log-ratio was positive for all SLE
patients and negative for virtually all IFNβ-treated MS patients.
Using this information, we determined the
nature of type I IFN signature in IIM, RA and untreated MS. IIM displayed
relative GC-A dominance as reflected by positive
GC-A/GC-B log-ratios, indicating predominant IFNα activity in this
disease. The GC-A/GC-B log-ratio in RA was lower and approached zero in part of
the patients, implying relative importance of both
clusters. Remarkably, GC-A/GC-B
log-ratios appeared most heterogeneous in untreated MS; half of the patients
displayed GC-A (IFNα) dominance, whereas others showed GC-B (IFNβ)
dominance or log-ratios near zero.
We confirmed these results for SLE,
RA and MS using two public microarray datasets containing 22 SLE patients, 112
RA patients, 58 IFNβ-treated MS patients and 62 untreated MS patients.
Exploring functional differences between GC-A
and GC-B genes revealed enrichment of the ISGF3-binding response element ISRE
and IRF8 binding sites only in GC-B, suggesting that IFNβ is more potent
in activating these transcription factors than IFNα.
Conclusion: We provide physiological evidence
for diversification of the type I IFN response in SLE (IFNα-driven) and
IFNβ-treated MS patients. Using this information we demonstrate that
IIM appears IFNα-driven, supporting the previously described pathogenic
role of IFNα in IIM. RA patients exhibited less distinct
IFNα/IFNβ dominance. Untreated MS patients displayed interindividual variation in GC-A or GC-B dominance,
suggesting a different pathogenic role of the type I IFNs in these patients.
To cite this abstract in AMA style:de Jong TD, Vosslamber S, Mantel E, de Ridder S, Wesseling JG, van der Pouw Kraan TCTM, Killestein J, Lundberg IE, Vencovsky J, Bultink IEM, Voskuyl AE, Pegtel M, van der Laken CJ, Bijlsma JW, Verweij CL. Physiological Evidence for Diversification of the IFNα- or IFNβ-Mediated Response Programs in Different Autoimmune Diseases [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/physiological-evidence-for-diversification-of-the-ifn-or-ifn-mediated-response-programs-in-different-autoimmune-diseases/. Accessed January 22, 2022.
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