Abstract
Systemic sclerosis (SSc) is a rare chronic autoimmune disease associated with significant morbidity and mortality. Two main subsets of SSc are recognized: (i) diffuse cutaneous SSc with rapidly progressive fibrosis of the skin, lungs, and other internal organs; and (ii) limited cutaneous SSc, which is dominated by vascular manifestations, with skin and organ fibrosis generally limited and slowly progressing. In spite of intense investigation, both etiology and pathogenesis of SSc are still unknown. Genetic and environmental factors, as well as abnormalities of immune functions, are strongly suggested for etiology, while microvascular abnormalities, immune system activation, and oxidative stress are suggested for the pathogenesis. Recently, it has been found that a multitude of mediators and cytokines are implicated in the fibrotic processes observed in SSc. Among these, a central role could be exerted by “alarmins”, endogenous and constitutively expressed proteins/peptides that function as an intercellular signal defense. This review describes, in a detailed manner, the role of alarmins in the pathogenesis of scleroderma.
Highlights
Systemic sclerosis (SSc) is a rare autoimmune disease characterized by microvascular damage, fibrosis of the skin and internal organs, and aberrant immune activation
Based on the extent of skin involvement, two main subsets of SSc are recognized: (i) diffuse cutaneous SSc with rapidly progressive fibrosis of the skin, lungs, and other internal organs; and (ii) limited cutaneous SSc, which is dominated by vascular manifestations, with skin and organ fibrosis generally limited and slowly progressing
Growing evidence corroborates the notion that a complex interplay between genetic, environmental, and immunological factors plays a causative role in the development of systemic sclerosis
Summary
SSc is a rare autoimmune disease characterized by microvascular damage, fibrosis of the skin and internal organs, and aberrant immune activation. It has been hypothesized that its expression in vascular endothelial cells located within malignant lesions may play a role in tumor angiogenesis and cancer metastasis [141] Another finding favoring the involvement of α-defensins in SSc pathogenesis is the correlation found between the increased levels of α-defensins in bronchoalveolar lavage fluid of SSc patients and clinical disease parameters of interstitial lung disease, including ILD biomarkers, pulmonary function tests, the ratio of neutrophils and eosinophils in BALF, tricuspid regurgitation peak gradient (TRPG), and the extent of high-resolution computed tomography (HRCT) findings in the lung [145]. LL-37 levels were significantly higher in SSc patients, in comparison to healthy controls, and positively associated with skin score and the activity of alveolitis and were considerably higher in subjects with digital ulcers compared with those without [152]
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