Interferon and Biologic Signatures in Dermatomyositis Skin: Specificity and Heterogeneity across Diseases

Abstract

BackgroundDermatomyositis (DM) is an autoimmune disease that mainly affects the skin, muscle, and lung. The pathogenesis of skin inflammation in DM is not well understood.Methodology and FindingsWe analyzed genome-wide expression data in DM skin and compared them to those from healthy controls. We observed a robust upregulation of interferon (IFN)-inducible genes in DM skin, as well as several other gene modules pertaining to inflammation, complement activation, and epidermal activation and differentiation. The interferon (IFN)-inducible genes within the DM signature were present not only in DM and lupus, but also cutaneous herpes simplex-2 infection and to a lesser degree, psoriasis. This IFN signature was absent or weakly present in atopic dermatitis, allergic contact dermatitis, acne vulgaris, systemic sclerosis, and localized scleroderma/morphea. We observed that the IFN signature in DM skin appears to be more closely related to type I than type II IFN based on in vitro IFN stimulation expression signatures. However, quantitation of IFN mRNAs in DM skin shows that the majority of known type I IFNs, as well as IFN g, are overexpressed in DM skin. In addition, both IFN-beta and IFN-gamma (but not other type I IFN) transcript levels were highly correlated with the degree of the in vivo IFN transcriptional response in DM skin.Conclusions and SignificanceAs in the blood and muscle, DM skin is characterized by an overwhelming presence of an IFN signature, although it is difficult to conclusively define this response as type I or type II. Understanding the significance of the IFN signature in this wide array of inflammatory diseases will be furthered by identification of the nature of the cells that both produce and respond to IFN, as well as which IFN subtype is biologically active in each diseased tissue.

Cytokines in immune-mediated inflammatory myopathies: cellular sources, multiple actions and therapeutic implications

“…The pathogenesis of skin inflammation in DM is less well characterized than in muscle. Gene microarray analysis demonstrated an IFN signature in DM skin, although this study did not assign this as being 'type I' or 'type II' [82]. An in-vitro study comparing muscle-and skin-derived T cells demonstrated differential cytokine production between the two tissue types.…”

CXCL10 Is Critical for the Progression and Maintenance of Depigmentation in a Mouse Model of Vitiligo

“…Our observation that the immune response in vitiligo is T H 1-specific is consistent with a previous report (38), and may explain why targeted treatments for psoriasis, a prototypic T H 17-mediated disease, are ineffective for vitiligo (20–22). The identification of an IFNG -specific signature in vitiligo is in sharp contrast to other inflammatory skin diseases, including dermatomyositis, cutaneous lupus erythematosus, and lichen planus, which express an IFN signature that reflects both Type I ( IFNA/B ) and Type II ( IFNG ) interferons, with a predominance of Type I over Type II (39, 40). Consistent with our findings, other studies report increased expression of IFNG in vitiligo skin, however they did not measure the expression of downstream gene targets or their functional/biological significance (13, 25, 38).…”

Quinacrine Suppresses Tumor Necrosis Factor-α and IFN-α in Dermatomyositis and Cutaneous Lupus Erythematosus

“…Two proinflammatory cytokines implicated in the pathogenesis of DM and CLE are TNF-α and IFN-α (Baechler et al, 2003; Braunstein et al, 2012; Moran and Mastaglia, 2014; Wong et al, 2012). Our study compares the effectiveness of two antimalarial drugs, QC and HCQ, at suppressing secretion of TNF-α and IFN-α from the PBMCs of DM and CLE patients and control subjects.…”

“…Given that both TNF-α and IFN-α have been implicated in the pathogenesis of DM and CLE, expanding understanding of the differential effects of antimalarials on proinflammatory cytokines may offer insight into why therapeutic responses vary (Braunstein et al, 2012; Nabatian et al, 2012; Wenzel et al, 2005; Wong et al, 2012). We examined the PBMCs of DM and CLE patients to quantify the ability of QC to inhibit secretion of TNF-α and IFN-α versus HCQ and controls.…”