Causes of juvenile systemic scleroderma

The causes of scleroderma have not been studied sufficiently. They suggest a complex combination of hypothetical and already known factors: genetic, infectious, chemical, including medicinal, which lead to the launch of a complex of autoimmune and fibrosis-forming processes, microcirculatory disorders.

The connection between scleroderma and viral infections is discussed. It is assumed that viruses are capable of provoking the disease due to molecular mimicry. It is known that scleroderma often develops in children after acute infectious diseases, vaccination, stress, excessive insolation or hypothermia.

Genetic predisposition to scleroderma is confirmed by the presence of familial cases of the disease, including monozygotic twins, as well as a burdened heredity for rheumatic and immune-mediated diseases. Cohort studies have shown that systemic scleroderma is observed in 1.5-1.7% of first-degree relatives of patients, which significantly exceeds the population frequency.

The number of environmental factors that damage the vascular endothelium with subsequent development of immune reactions and formation of fibrosis is constantly growing. In recent years, scleroderma and scleroderma-like syndromes have been identified upon contact with vinyl chloride, silicone, paraffin, organic solvents, gasoline, after taking certain medications [bleomycin, tryptophan (L-tryptophan)], consumption of poor-quality food products ("Spanish toxic oil syndrome").

Pathogenesis

The main links in the pathogenesis of systemic scleroderma are the processes of increased collagen and fibrosis formation, microcirculation disorders as a result of inflammatory changes and spasm of small arteries, arterioles and capillaries, and disorders of humoral immunity with the production of autoantibodies to components of connective tissue - laminin, type IV collagen, and components of the cell nucleus.

Patients with scleroderma develop a scleroderma-specific phenotype of fibroblasts that produce excessive amounts of collagen, fibronectin, and glycosaminoglycans. The excess amount of synthesized collagen is deposited in the skin and underlying tissues, in the stroma of internal organs, leading to the development of characteristic clinical manifestations of the disease.

Generalized vascular damage of the microcirculatory bed is the second important link in the pathogenesis of the disease. Endothelial damage in systemic scleroderma is explained by the presence of granzyme A enzyme in the serum of some patients, which is secreted by activated T-lymphocytes and breaks down type IV collagen, causing damage to the vascular basement membrane. Endothelial damage is accompanied by an increase in the level of coagulation factor VIII and von Willebrand factor in the serum. Binding of von Willebrand factor to the subendothelial layer promotes platelet activation, release of substances that increase vascular permeability, and the development of edema. Activated platelets secrete platelet growth factor and transforming growth factor beta (TGF-beta), which cause proliferation of smooth muscle cells, fibroblasts, stimulate collagen synthesis, cause fibrosis of the intima, adventitia and perivascular tissues, which is accompanied by a violation of the rheological properties of the blood. Fibrosis of the intima of arterioles, thickening of the walls and narrowing of the lumen of the vessels up to their complete occlusion, microthrombosis and, as a consequence, ischemic changes develop.

Impaired cellular immunity also plays a role in the pathogenesis of scleroderma. This is evidenced by the formation of mononuclear cellular infiltrates in the skin in the early stages of the disease, around vessels and in places where connective tissue accumulates, impaired function of T-helpers and natural killers. TGF-beta-platelet growth factor, connective tissue growth factor and endothelin-I are found in the affected skin of patients with systemic scleroderma. TGF-beta stimulates the synthesis of extracellular matrix components, including collagen types I and III, and also indirectly promotes the development of fibrosis by inhibiting the activity of metalloproteinases. In systemic scleroderma, not only cellular but also humoral immunity is impaired, in particular, the presence of certain antibodies suggests the role of autoimmune reactions.

An important link in pathogenesis is the disturbances of fibroblast apoptosis found in systemic scleroderma. Thus, a population of fibroblasts resistant to apoptosis and functioning in an autonomous mode of maximum synthetic activity without additional stimulation is selected.

The appearance of Raynaud's syndrome is probably the result of a disruption in the interaction of some endothelial (nitric oxide, endothelin-I, prostaglandins), platelet mediators (serotonin, beta-thromboglobulin) and neuropeptides (calcitonin gene-related peptide, vasoactive intestinal polypeptide).

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