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Systemic Sclerosis (SS)
Systemic sclerosis (SS) is also called systemic scleroderma, diffuse scleroderma or progressive systemic sclerosis, which is an autoimmune disease of the connective tissue. Its pathology involves excessive collagen production, resulting in fibrosis of skin and internal organs. CREST syndrome, standing for calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia, is a limited form of the scleroderma disorder. SS is typically diagnosed in people 30 to 50 years old and women are susceptible population than men. There are two widely accepted classification of SS: localized (limited) SS and systemic (diffuse) SS. The former only affects the skin the face, hands, and feet, while in the latter case, visceral organs, most typically the kidneys, gastrointestinal tract, heart, and lungs, are more severely affected.
Signs and Symptoms of Systemic Sclerosis
Beyond the thickening and shiny areas in the skin, there are a number of other symptoms of SS disease, which can be divided into two categories: skin symptoms and organs symptoms.
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Skin symptoms
Mainly include: tight, reddish, or scaly of the skin; severe and recurrent itching of large skin areas; calcium deposits, or white lumps under the skin; small, dilated blood vessels under the skin’s surface.
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Organs symptoms
Diffuse scleroderma can cause musculoskeletal, pulmonary, gastrointestinal, renal and other complications. Mainly include joint pain; shortness of breath; a dry cough; diarrhea; constipation; difficulty swallowing; esophageal reflux; abdominal bloating after meals.
SS patients may suffer from various complications, mainly include heart failure, cancer, kidney failure, and high blood pressure.
Fig. 1 Fundamental mechanisms underlying vasculopathy in systemic sclerosis.1
Pathogenesis of Systemic Sclerosis
Although the pathogenesis of SS is complicated and poorly understood, recent studies suggest that the genetic predisposition, together with environmental agents, such as viruses or chemical agents, might contribute to the development of the disease. Three physiological processes are involved in the pathologic manifestations of SS: (1) innate/adaptive immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity; (2) microvascular endothelial cell/small vessel fibroproliferative vasculopathy; and (3) fibroblast dysfunction resulting in excessive accumulation of collagen and other matrix components in skin and internal organs. There are multiple factors can lead to immunologic system disturbances and dysregulated vascular remodeling and vasculopathy.
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Cells
There are a variety of cells contribute to the pathogenesis of SS. Fibroblasts, T lymphocytes, macrophages, and mast cells are activated to secrete multifarious substances, including cytokines and their soluble receptors and inhibitors, which can generate changes in the extracellular matrix compounds, including fibronectin, proteoglycans, and especially, collagen types I, III, V, and VII. Increased collagen deposition in tissues is a characteristic feature of SS, collagen deposition is the result of increased collagen production or disturbances in its degradation.
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Immunological Mediators
Increased levels of growth factors (including TGF-β, CTGF, VEGF, fibroblast growth factor), ILs (including IL-2, IL-4, IL-6, IL-10, IL-13), chemokines and cytokines [including monocyte chemoattractant protein-1 (MCP-1), IL-8, thymus, and activation-regulated chemokine, fractalkine and TNF-α] are detectable in SS.
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Complements
In SS, complement may be activated or inherently abnormal. C1q, C2, C3, C4A, C3bBbP, C5, C6, C7, C9, and factor B were significantly increased in skin biopsies of SS patients but not in healthy subjects.
Fig. 2 The shared pathological cascade in various organs specific to systemic sclerosis.2
Creative Biolabs has established advanced Complement Therapeutics Platform including antibody engineering platform, protease inhibitor platform, and drug discovery platform, and is equipped to offer a full range of biotherapeutics development services regarding drug discovery and validation for SS. Please contact us for detailed information.
References
1. Zanin-Silva, Djúlio César, et al. "Management of endothelial dysfunction in systemic sclerosis: Current and developing strategies." Frontiers in Medicine 8 (2021): 788250.
Asano, Yoshihide. "The pathogenesis of systemic sclerosis: An understanding based on a common pathologic cascade across multiple organs and additional organ-specific pathologies." Journal of clinical medicine 9.9 (2020): 2687.
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Questions & Answer
A: Preclinical studies often show reduced inflammation, fibrosis, and vascular damage in animal models when complement inhibition is applied, providing evidence for its potential as a therapeutic approach.
A: Yes, complement components like C5a and C3 have been identified as potential therapeutic targets in systemic sclerosis. Blocking or modulating these components may help alleviate disease symptoms.
A: While promising, the translation of experimental findings into clinical treatments may require further preclinical studies, including those assessing safety, efficacy, and appropriate dosing, to ensure the effectiveness of complement therapeutics in treating systemic sclerosis patients.
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