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Causes of systemic lupus erythematosus

, medical expert
Last reviewed: 23.04.2024
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The causes of systemic lupus erythematosus are still unclear, which causes difficulties in diagnosis and treatment. It is believed that various endo- and exogenous factors influence the development of the disease.

trusted-source[1], [2], [3], [4], [5]

Genetic predisposition and systemic lupus erythematosus

The role of heredity is evidenced by:

  • a high incidence of systemic lupus erythematosus in the families of patients (7-12% of cases of relatives of the 1st and 2nd degree of kinship);
  • higher concordance (the incidence of both partners of the twin pair) among monozygotic twins (69%) compared with dysygotic twins (2%);
  • detection in clinically asymptomatic relatives of patients with antinuclear antibodies, hypergammaglobulinemia, false-positive reaction of Wasserman et al.

The genetic predisposition to the development of systemic lupus erythematosus is probably due to the inheritance of predisposing genes, each of which determines some aspect of the immune response, immune complex clearance, apoptosis, inflammation regulation, etc. Different combinations of these independently segregating defective genes cause various immune response disorders, leading to pathological processes and the appearance of certain clinical signs of the disease.

Patients with systemic lupus erythematosus have a high frequency of specific genetic markers. Carrying out HLA-DR2 or HLA-DR3 independently increases the risk of developing systemic lupus erythematosus 2-3 times, and the presence of haplotype Al, B8, DR3 determines a 10-fold increase in risk in representatives of the Caucasoid race. In patients with systemic lupus erythematosus, associations of some alleles of DQ-locus genes with the presence of specific antibodies, in particular antibodies to DNA, AT to Sm antigen, antibodies to Ro- and La-antigens, etc., have been found.

The relationship of the development of systemic lupus erythematosus to the genetically caused deficiency of various components of complement (Clq, C2, C4), which is associated with a violation of the immune complex clearance. The presence of the "C4A null allele" in most cases is associated with the deletion of a segment of the HLA class III region, which includes the genes C4A and CUR21A. The total absence of C4 (the result of homozygosity in both loci) determines a 17-fold increase in the risk of developing systemic lupus erythematosus.

The association of systemic lupus erythematosus with the polymorphism of cytokine genes, in particular TNF-a, the IL-lRa gene (IL-1 receptor antagonist), the IL-10 promoter gene, etc., has been noted.

It has been shown that certain alleles of the FcyRIIa and FcyIIIA receptor genes binding the subclasses of IgG are associated with impaired clearance and the development of immune system-mediated manifestations of systemic lupus erythematosus, particularly lupus nephritis.

Point mutations were found in the structure of the gene, which affects the concentration in the serum of the lectin necessary for the effective activation of the complement.

Probably, the metabolic peculiarities have a certain significance, in particular, the association of systemic lupus erythematosus with the "zero alleles" of the gene of the glutathione-S-transferase enzyme is revealed.

Hormonal factors of development of systemic lupus erythematosus

The role of sex hormones in the etiology of systemic lupus erythematosus is due to their effect on the immune response: estrogens promote immunological hyperreactivity due to polyclonal activation of B cells and increase synthesis of AT, and androgens, on the contrary, have an immunosuppressive effect, reducing the formation of antibodies and suppressing cellular responses. This is due to the predominance of women among patients with systemic lupus erythematosus, the association of the onset of the disease with the onset of menarche in adolescent girls, an increase in the activity of the disease during pregnancy and after childbirth.

In women of reproductive age with systemic lupus erythematosus, low levels of testosterone, progesterone and high estrogen levels are observed, in both patients - increased prolactin level and low level of dehydroepiandrosterone.

Environmental factors

Of primary importance is insolation, the effect of which often provokes the onset and subsequent exacerbations of systemic lupus erythematosus. UVA leads to DNA degradation in skin cells, which begins to manifest antigenic determinism, stimulates keratinocyte apoptosis accompanied by the expression of ribonucleoproteins on their surface, disrupts the metabolism of cell membrane phospholipids, stimulates B cells and induces autoimmune reactions in predisposed individuals. UFO enhances the release of IL-1, IL-3, IL-6 and TNF-alpha, promoting the development of local inflammation, and also increases the overall level of immune response.

trusted-source[6], [7], [8], [9], [10], [11], [12], [13], [14], [15],

Infection 

Patients often notice high titers of antibodies to the Epstein-Barr virus, retroviruses and others, including AT to protein sites homologous to human HLA antigens, in the absence of an obvious infection, suggesting their possible role as triggers of systemic lupus erythematosus. It is more likely that elevated titers of antibodies to viruses are the result of polyclonal activation of B cells, and not evidence of their specific role in the genesis of the disease.

As an indirect evidence of the role of bacterial infection, the ability of the DNA of certain bacteria to stimulate the synthesis of antinuclear autoantibodies, the frequent development of exacerbations of systemic lupus erythematosus after bacterial infection, etc., are considered.

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