Causes of juvenile systemic scleroderma

The causes of scleroderma have not been studied enough. They assume 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 fibro-forming processes, microcirculatory disorders.

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

Genetic predisposition to scleroderma is confirmed by the presence of family cases of the disease, including in monozygotic twins, as well as weighed down by heredity in rheumatic and immuno-mediated diseases. Cohort studies have shown that systemic scleroderma is noted in 1.5-1.7% of relatives of patients of the 1st degree of kinship, which significantly exceeds the population frequency.

The number of environmental factors that damage the vascular endothelium, followed by the development of immune responses and the formation of fibrosis, is continuously growing. In recent years, scleroderma and scleroderm-like syndromes have been established in contact with chlorovinil, silicone, paraffin, organic solvents, gasoline, after taking certain drugs [bleomycin, tryptophan (L-tryptophan)], eating poor-quality food ("Spanish Toxic Oil Syndrome" ).

Pathogenesis

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

Scleroderma patients develop a scleroderm-specific phenotype of fibroblasts that produce an excessive amount of collagen, fibronectin and glycosaminoglycans. An excessive 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.

The generalized lesion of the vessels 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 in the serum of some patients, which is secreted by activated T lymphocytes and splits type IV collagen, causing damage to the basal membrane of the vessels. Endothelial damage is accompanied by an increase in the level of factor VIII coagulation and serum von Willebrand factor. The binding of von Willebrand factor to the subendothelial layer promotes platelet activation, the release of substances that increase vascular permeability, and the development of edema. Activated platelets release platelet growth factor and transforming growth factor beta (TGF-beta), which cause the proliferation of smooth muscle cells, fibroblasts, stimulate the synthesis of collagen, cause fibrosis of intima, adventitia and perivascular tissue, which is accompanied by a violation of the rheological properties of the blood. The fibrosis of intima arterioles, thickening of the walls and narrowing of the lumen of the vessels up to their full occlusion, microthrombosis and, consequently, ischemic changes develop.

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

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

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

[1], [2], [3], [4], [5], [6]