Comparison of Lesional Juvenile Myositis and Lupus Skin Reveals Overlapping Yet Unique Disease Pathophysiology

Abstract

Objective. Skin inflammation heralds systemic disease in juvenile myositis, yet we lack an understanding of pathogenic mechanisms driving skin inflammation in this disease. We undertook this study to define cutaneous gene expression signatures in juvenile myositis and identify key genes and pathways that differentiate skin disease in juvenile myositis from childhood-onset systemic lupus erythematosus (SLE).Methods. We used formalin-fixed paraffin-embedded skin biopsy samples from 15 patients with juvenile myositis (9 lesional, 6 nonlesional), 5 patients with childhood-onset SLE, and 8 controls to perform transcriptomic analysis and identify significantly differentially expressed genes (DEGs; q ≤ 5%) between patient groups. We used Ingenuity Pathway Analysis (IPA) to highlight enriched biologic pathways and validated DEGs by immunohistochemistry and quantitative real-time polymerase chain reaction.Results. Comparison of lesional juvenile myositis to control samples revealed 221 DEGs, with the majority of upregulated genes representing interferon (IFN)-stimulated genes. CXCL10, CXCL9, and IFI44L represented the top 3 DEGs (fold change 23.2, 13.3, and 13.0, respectively; q < 0.0001). IPA revealed IFN signaling as the top canonical pathway. When compared to childhood-onset SLE, lesional juvenile myositis skin shared a similar gene expression pattern, with only 28 unique DEGs, including FBLN2, CHKA, and SLURP1. Notably, patients with juvenile myositis who were positive for nuclear matrix protein 2 (NXP-2) autoantibodies exhibited the strongest IFN signature and also demonstrated the most extensive Mx-1 immunostaining, both in keratinocytes and perivascular regions.Conclusion. Lesional juvenile myositis skin demonstrates a striking IFN signature similar to that previously reported in juvenile myositis muscle and peripheral blood. Further investigation into the association of a higher IFN score with NXP-2 autoantibodies may provide insight into disease endotypes and pathogenesis.

Morphological Characteristics of Idiopathic Inflammatory Myopathies in Juvenile Patients

“…Tubuloreticular inclusions can occur in OM, especially in lupus erythematosus, but were not present in our cases [ 65 , 66 ]. MxA upregulation was weak on scattered fibers, but was not in a perifascicular distribution in OM, consistent with the upregulation of type I IFN in childhood SLE [ 18 , 67 ].…”

“…Myositis, in conjunction with skin lesions, is also seen in other rheumatologic disorders, such as systemic lupus erythematosus (SLE), connective tissue diseases, and some monogenic autoinflammatory diseases, further impeding the diagnosis and treatment of jIIM [ 14 , 17 , 18 , 19 , 20 ]. Moreover, in jIIM patients with negative autoantibodies, finding a precise diagnosis can be problematic (although it is currently not known whether autoantibodies have the same relevance in children as in adults).…”

Imaging Mass Cytometry Reveals Predominant Innate Immune Signature and Endothelial–Immune Cell Interaction in Juvenile Myositis Compared to Lupus Skin

“…The finding of a stronger innate immune signature versus adaptive immune signature in juvenile DM compared to cSLE at both transcriptional and protein levels suggests differences in pathophysiology. Consistent with this, our previously published gene expression data identified a stronger type II IFN signature in cSLE skin lesions compared to juvenile DM skin lesions (11), supporting a larger role for adaptive immunity in cSLE. While innate immunity likely plays an important role in both juvenile DM and cSLE pathogenesis, the influence of innate immune mechanisms in regulation of cutaneous inflammation in juvenile DM as compared to cSLE has not been well studied to date.…”

Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis

“…50 Studies have also demonstrated that single nucleotide polymorphisms or altered copy number within mtDNA are associated with the development of adult idiopathic inflammatory myopathies. 51 These studies, taken together with the high mitochondrial content in skeletal muscle 52 and the growing interest in understanding immune cell function within inflamed tissues, 53 demonstrate that new research is needed to interrogate mitochondrial biology within biopsies from JDM muscle.…”