Current Concepts on the Pathogenesis of Systemic Sclerosis

Abstract

From the clinical standpoint, systemic sclerosis (SSc) is characterized by skin and internal organ fibrosis, diffuse fibroproliferative vascular modifications, and autoimmunity. Clinical presentation and course are highly heterogenous and life expectancy variably affected mostly dependent on lung and heart involvement. SSc touches more women than men with differences in disease severity and environmental exposure. Pathogenetic events originate from altered homeostasis favored by genetic predisposition, environmental cues and a variety of endogenous and exogenous triggers. Epigenetic modifications modulate SSc pathogenesis which strikingly associate profound immune-inflammatory dysregulation, abnormal endothelial cell behavior, and cell trans-differentiation into myofibroblasts. SSc myofibroblasts show enhanced survival and enhanced extracellular matrix deposition presenting altered structure and altered physicochemical properties. Additional cell types of likely pathogenic importance are pericytes, platelets, and keratinocytes in conjunction with their relationship with vessel wall cells and fibroblasts. In SSc, the profibrotic milieu is favored by cell signaling initiated in the one hand by transforming growth factor-beta and related cytokines and in the other hand by innate and adaptive type 2 immune responses. Radical oxygen species and invariant receptors sensing danger participate to altered cell behavior. Conventional and SSc-specific T cell subsets modulate both fibroblasts as well as endothelial cell dysfunction. Beside autoantibodies directed against ubiquitous antigens important for enhanced clinical classification, antigen-specific agonistic autoantibodies may have a pathogenic role. Recent studies based on single-cell RNAseq and multi-omics approaches are revealing unforeseen heterogeneity in SSc cell differentiation and functional states. Advances in system biology applied to the wealth of data generated by unbiased screening are allowing to subgroup patients based on distinct pathogenic mechanisms. Deciphering heterogeneity in pathogenic mechanisms will pave the way to highly needed personalized therapeutic approaches.

Decreased Serum Levels of SIRT1 and SIRT3 Correlate with Severity of Skin and Lung Fibrosis and Peripheral Microvasculopathy in Systemic Sclerosis

“…Systemic sclerosis (SSc, scleroderma) is a severe autoimmune disease characterized by widespread microvasculopathy, clinically manifesting with Raynaud’s phenomenon, refractory ischemic digital ulcers (DUs), pulmonary artery hypertension (PAH), and renal crisis, as well as by cutaneous and visceral fibrosis, finally leading to significant organ dysfunction [ 1 , 2 , 3 , 4 ]. Such a highly heterogeneous spectrum of pathological manifestations associates with a widely variable prognosis, with lung fibrosis that clinically manifests as interstitial lung disease (ILD) representing the principal cause of death [ 5 , 6 , 7 ].…”

Circulating Neurovascular Guidance Molecules and Their Relationship with Peripheral Microvascular Impairment in Systemic Sclerosis

“…Systemic sclerosis (SSc, scleroderma) is a severe multisystem connective tissue disease that is dominated by the pathogenic triad of autoimmunity, widespread peripheral microvasculopathy, and progressive cutaneous and visceral fibrosis eventually leading to substantial organ dysfunction [ 1 , 2 , 3 ]. Peripheral microvascular tone dysregulation, manifesting with Raynaud’s phenomenon (RP), as well as microcirculatory abnormalities, mirrored by nailfold capillaroscopic changes, represent the earliest clinical manifestations of SSc and may precede both cutaneous and organ fibrosis by months or years [ 1 , 2 , 3 ]. Such a microvascular dysfunction is characterized by vascular repair impairment and defective angiogenesis culminating in capillary network disruption, and frequently leads to significant peripheral ischemic manifestations such as digital ulcers (DUs) [ 4 , 5 ].…”

Sex, Allergic Diseases and Omalizumab

“…On the other hand, male sex hormones perform immunosuppressive and anti-inflammatory activities. Scleroderma, multiple sclerosis, rheumatoid arthritis and asthma, in particular, reflect these gender differences [ 25 , 26 , 27 , 28 , 29 , 30 ]. The incidence and course of systemic lupus erythematosus (SLE) differ between the sexes, with a nine-fold higher incidence in women linked to the influence of estrogen on epigenetic, immune and genetic factors (X-linked genes such as Foxp3, TNF and Tlr7) [ 31 , 32 ].…”