Background/Purpose: Localized scleroderma (morphea) is characterized by inflammation and sclerosis of the dermis and underlying tissue and may be associated with significant morbidity. Overproduction of type I and III collagen by fibroblasts is thought to be a factor in the pathogenesis of morphea but, little is known about the mechanism by which these fibroblasts are activated.  Endothelial cell injury, immunologic and inflammatory activation, and dysregulation of collagen production have all been proposed.  The purpose of this study is to describe the transcriptosome of lesional morphea skin relative to non-lesional controls.   

Methods: Skin samples from adult patients in the Morphea in Adults and Children Cohort (MAC) with active, untreated lesions were collected from the inflammatory border, sclerotic center, and site matched non-lesional skin.  Gene expression analysis of the three tissue types was conducted using Illumina Human HT4 arrays. The gene expression profile of each tissue type was then compared to that of corresponding normal tissue in a self-controlled fashion.  We considered differentially expressed genes (DEGs) with a cut-off of fold change >2.0 and a p<0.05.  The data was evaluated without correction and with the Benjamini–Hochberg procedure.  Ingenuity Pathway Analysis (IPA) was utilized to identify canonical pathways among differentially expressed genes.  The DEGs were compared to known type I interferon genes as collected by Monash University’s Interferome database. 

Results: Principal components analysis demonstrated a clear difference between gene expression patterns of the inflammatory border and sclerotic center when compared to normal skin and each other.  The total number of DEGs when comparing the inflammatory border (IB) and the sclerotic center (SC) grouped together compared to unaffected skin (UA) was 724.    The number of genes shared between Morphea skin and UA skin was 397.  The number of genes unique to the IB compared with the UA was 647 and to the sclerotic center were 562.  Comparison with the Interferome database showed that 35 IB genes and 23 SC genes overlapped with the interferon pathway.  Specifically we saw that CXCL10, a major component of the interferon pathway, showed a14.3 fold change when compared to normal skin.  Through IPA analysis we showed that the top five pathways include iCOS-iCOSL Signaling in T Helper Cells, CD28 Signaling in T Helper Cells, CTLA4 Signaling in Cytotoxic T Lymphocytes, OX-40 Signaling Pathway, and Dendritic Cell Maturation. 

Conclusion: These results demonstrate that gene expression differs between matched pairs of lesional morphea skin and non-lesional skin from the same patient.  Interestingly the inflammatory border and sclerotic center showed different levels of gene expression with greater activation of CXCL10 in the IB versus the SC, implicating different molecular mechanisms at play in the initiation of lesions. Our results support the theory that therapeutics targeting the CXCL10 pathway may lead to future treatments for Morphea.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gene-expression-variation-and-the-role-of-interferon-in-patients-with-morphea-from-the-morphea-in-adults-and-children-cohort/