Berthier, C. | bioRxiv Science

bioRxiv2025

Cross-disease comparison of dermatomyositis and lupus skin identifies inflammatory monocytes and JAK-1 signaling as drivers of vasculopathy in dermatomyositis

Dermatomyositis (DM) is a rare yet devastating autoimmune disease characterized by inflammatory and vasculopathic changes in skin and muscle. DM and systemic lupus erythematosus (lupus) skin lesions have overlapping clinical and histopathological features, yet disparate responses to available therapeutics. DM skin disease is often relapsing and recalcitrant. To investigate DM immunopathogenesis, non-lesional skin, lesional skin, and circulating immune cells from DM patients were analyzed using single-cell RNA-sequencing. Samples were analyzed in parallel with lesional and non-lesional lupus skin, healthy control skin, and peripheral blood. We demonstrate a pervasive type I interferon (IFN) signature in DM stroma that persists in culture and is distinguished from lupus by upregulation of VEGF and IL-18 signaling in DM keratinocytes. Furthermore, endothelial cells (ECs) in lesional DM exhibit decreased proliferation that was not observed in lupus. Using cell communication networks, we identified a population of DM-specific monocytes interacting with non-proliferating DM ECs. Co-culture of monocytes from DM patients with ECs resulted in increased EC apoptosis inhibited by JAK1 blockade. JAK1 inhibition also resulted in reversal of DM-stromal and inflammatory signatures. Together, our data provide a comprehensive cross-disease characterization of lesional and non-lesional skin of DM compared to lupus and implicate monocyte-mediated EC dysfunction in DM vasculopathy and support JAK inhibition for refractory skin disease.

immunology↗

bioRxiv2025

Col6 deficiency in a zebrafish model of Bethlem myopathy leads to dysfunction of the muscle dihydropyridine receptor

Bethlem myopathy (BM) results from mutations in genes encoding one of the three chains of collagen VI (ColVI). This muscle disease is characterized by skeletal muscle weakness and wasting worsening with age. How alteration in ColVI present outside muscle fibers in the extracellular matrix induces dysfunction within muscle fibers is still misunderstood. Here we explored intracellular Ca2+ handling properties in isolated fast skeletal muscle fibers from adult zebrafish harboring a mutation (col6a1{Delta}ex14) that is the most frequently found in BM patients. Col6a1{Delta}ex14 fish muscle exhibited progressive loss of ColVI deposition, defects in basement membrane and ColVI intracellular accumulation. By combining voltage-clamp and intracellular Ca2+ measurements on isolated fibers, we showed that voltage-dependence of intramembrane charge movements produced by the activation of CaV1.1 controlling sarcoplasmic reticulum (SR) Ca2+ release and voltage-dependence of depolarization-induced SR Ca2+ release were shifted toward negative potentials in col6a1{Delta}ex14 fish. These changes in voltage-dependence gave rise to larger SR Ca2+ leak at voltages close to resting values and to higher frequency of spontaneous SR Ca2+ release elementary events in mutant fish. Trunk muscle force and swimming performance were also found to be reduced in col6a1{Delta}ex14 fish and mis-localization of CaV1.1 subunits clusters was observed in mutant fibers t-tubules. These data indicate that ColVI deficiency in BM leads to CaV1.1 dysfunction that contributes to promote a pathogenic SR Ca2+ leak responsible for progressive muscle weakness and wasting. CaV1.1 could represent the still elusive transmembrane link allowing altered myomatrix to transduce pathogenic signals within muscle.

pathology↗