Scleroderma pathophysiology in adults
Scleroderma, also known as systemic sclerosis, is a complex autoimmune disorder characterized primarily by fibrosis of the skin and internal organs, vascular abnormalities, and immune system dysregulation. In adults, its pathophysiology involves a multifaceted interplay of immune activation, vascular injury, and excessive connective tissue deposition, which collectively contribute to the disease’s progression and diverse clinical manifestations.
The initiation of scleroderma is believed to stem from immune system dysregulation. Autoantibodies, such as anti-centromere and anti-topoisomerase I (Scl-70), are frequently detected, indicating an autoimmune response. These autoantibodies may contribute to tissue injury by promoting complement activation and recruiting inflammatory cells, although their exact pathogenic roles remain under investigation. Early in the disease course, immune cells like T lymphocytes, macrophages, and mast cells infiltrate the affected tissues. These immune cells release cytokines, including transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and interleukins, which serve as key mediators in promoting fibrosis.
Vascular abnormalities are another hallmark of adult scleroderma. Small vessel vasculopathy involves endothelial cell injury, which leads to increased vascular permeability, perpetuating tissue hypoxia. Endothelial dysfunction is characterized by decreased production of vasodilators like nitric oxide and prostacyclin, alongside increased expression of adhesion molecules, facilitating leukocyte adhesion and infiltration. Microvascular damage results in characteristic capillary dropout and Raynaud’s phenomenon, often an early symptom. Persistent vascular injury sets the stage for ongoing tissue ischemia and contributes to the activation of fibroblasts.
The hallmark of scleroderma’s pathophysiology is the activation and proliferation of fibroblasts. Under normal circumstances, fibroblasts produce extracellular matrix (ECM) components in response to injury, aiding in tissue repair. However, in scleroderma, fibroblasts become aberrantly activated, driven predominantly by profibrotic cytokines like TGF-β and PDGF. These activated fibroblast
s produce excessive amounts of collagen and other ECM proteins, leading to fibrosis. This process is not limited to the skin but also affects internal organs such as the lungs, gastrointestinal tract, heart, and kidneys, causing organ-specific fibrosis and dysfunction.
The persistent cycle of immune activation, vascular damage, and fibroblast proliferation results in the progressive nature of scleroderma. The extent and distribution of fibrosis vary across patients, accounting for the heterogeneity in clinical presentation and severity. Notably, genetic predispositions, environmental triggers, and epigenetic factors influence disease susceptibility and progression.
In summary, scleroderma pathophysiology in adults involves an intricate cascade beginning with immune system dysregulation and endothelial injury, culminating in fibroblast-driven fibrosis. Understanding these underlying mechanisms is crucial for developing targeted therapies aimed at interrupting this pathogenic cycle, which could ultimately improve outcomes for affected individuals.
