Abstract / Summary
Abstract The core pathology of dermatomyositis (DM) involves complement-mediated microvascular injury and abnormal type I interferon (IFN-I) signaling, but patients with the same antibody profile vary greatly in severity, suggesting that upstream amplifying factors also exist. This paper proposes a dual-core hypothesis centered on arterial hypoperfusion and sympathetic activation: if the investing fascia undergoes fibrosis similar to that of limb myofascia, its mechanical tension may be transmitted through the carotid sheath, directly compressing structures within the sheath in the head and neck and stimulating the cervical sympathetic trunk; in the proximal limbs, sympathetic activation causes α-adrenergic constriction of intramuscular small arteries and arterioles (resistance vessels), becoming a major upstream driver of microcirculatory ischemia. On the basis of the existing immune-mediated microvascular injury in DM, the two pathways may push the perifascicular “watershed” zone toward severe ischemia and convert mechanical signals into immune-amplifying signals through a candidate hypoxia–HIF-1α–RIG-I–IFN-I positive feedback loop. This positive feedback loop is more likely to hold true in juvenile dermatomyositis (JDM) and anti-MDA5-positive DM; in classic adult DM, IFN-I may be activated independently of hypoxia, and mechanical amplification is more likely to follow the branch of sympathetic activation → microcirculatory ischemia → muscle injury. Sympathetic activation may also regulate immune cells through norepinephrine (NE), but this is only a candidate auxiliary pathway and is not treated as a core mechanism. This paper positions the investing fascia as a “mechanical amplifier” rather than a “trigger” and provides testable predictions and a validation framework. Direct evidence for the investing fascia in DM is still lacking, and this is the premise of this hypothesis that most needs validation.