Causes of systemic lupus erythematosus

The causes of systemic lupus erythematosus development remain unclear to this day, which causes difficulties in diagnosis and treatment. It is assumed that various endo- and exogenous factors influence the development of the disease.

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Genetic predisposition and systemic lupus erythematosus

The role of heredity is evidenced by:

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

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, clearance of the immune complex, apoptosis, regulation of inflammation, etc. Different combinations of these independently segregating defective genes cause various disorders of the immune response, 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 HLA-DR2 or HLA-DR3 independently increases the risk of developing systemic lupus erythematosus by 2-3 times, and the presence of the Al, B8, DR3 haplotype determines a 10-fold increase in risk in representatives of the Caucasian race. In patients with systemic lupus erythematosus, associations of some alleles of the 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.

A connection has been noted between the development of systemic lupus erythematosus and genetically determined deficiency of various complement components (Clq, C2, C4), which is associated with impaired clearance of the immune complex. The presence of the "C4A null allele" in most cases is associated with a deletion of a segment of the HLA class III region, including the C4A and CYP21A genes. Complete absence of C4 (the result of homozygosity in both loci) determines a 17-fold increase in the risk of developing systemic lupus erythematosus.

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

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

Point mutations have been discovered in the structure of a gene that affects the serum concentration of a lectin necessary for effective complement activation.

Metabolic features are likely to play a certain role; in particular, an association has been found between systemic lupus erythematosus and “null alleles” of the glutathione-S-transferase enzyme gene.

Hormonal factors in the 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 increased AT synthesis, while androgens, on the contrary, have an immunosuppressive effect, reducing the formation of antibodies and suppressing cellular reactions. This is associated with the predominance of women among patients with systemic lupus erythematosus, the relationship between the onset of the disease and the onset of menarche in adolescent girls, and an increase in disease activity during pregnancy and after childbirth.

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

Environmental factors

Of primary importance is insolation, the impact of which often provokes the onset and subsequent exacerbations of systemic lupus erythematosus. UVR leads to degradation of DNA in skin cells, which begins to show antigen determination, stimulates apoptosis of keratinocytes, accompanied by the expression of ribonucleoproteins on their surface, disrupts the metabolism of phospholipids of the cell membrane, stimulating B cells and causing autoimmune reactions in predisposed individuals. UVR increases the release of IL-1, IL-3, IL-6 and TNF-alpha, contributing to the development of local inflammation, and also increases the overall level of the immune response.

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Infection

Patients often have high titers of antibodies to the Epstein-Barr virus, retroviruses, and others, including AT to protein regions homologous to human HLA antigens, in the absence of overt infection, suggesting their possible role as triggers of systemic lupus erythematosus. Most likely, elevated titers of antibodies to viruses are the result of polyclonal activation of B cells, rather than evidence of their specific role in the genesis of the disease.

Indirect evidence of the role of bacterial infection includes the ability of DNA of some bacteria to stimulate the synthesis of antinuclear autoantibodies, the frequent development of exacerbations of systemic lupus erythematosus after bacterial infection, etc.