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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Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of autoimmune origin, characterized by damage to connective tissue and multiple body systems. The etiopathogenesis of SLE remains the subject of active research, but accumulated data allow us to state that the disease has a polyetiological nature, that is, its development is caused by the interaction of many factors - genetic, epigenetic, immunological, hormonal and environmental.

I. Genetic predisposition

The genetic basis of SLE is supported by a high degree of familial aggregation, an increased risk of the disease in monozygotic twins, and the detection of specific genetic markers. Among the most significant genetic factors, the following should be highlighted:

1. Major histocompatibility complex (HLA) genes
   Of particular importance are the HLA class II alleles, in particular HLA-DR2 and HLA-DR3, which are associated with impaired presentation of autoantigens and reduced tolerance to them.

2. Complement system genes
   Mutations or deficiencies of C1q, C2, and C4 impair the efficient clearance of apoptotic cells, which promotes the accumulation of intracellular material and the development of an autoimmune response.

3. Genes of signaling molecules and transcription factors
   Polymorphisms in IRF5, IRF7, STAT4, TYK2, BLK, PTPN22, as well as mutations in TLR receptors (especially TLR7 and TLR9) enhance the activation of innate immunity, the production of interferons and contribute to the development of autoaggression.

Hereditary predisposition is not an obligatory cause of SLE, but it creates a biological basis on which pathological mechanisms are realized under the influence of other factors.

II. Epigenetic mechanisms

In recent years, epigenetic disturbances have been considered as key factors in the activation of autoimmune reactions in SLE, especially in the absence of hereditary mutations. The main epigenetic mechanisms include:

1. DNA hypomethylation
   CD4⁺ T lymphocytes from patients with SLE have been shown to have decreased methylation of genes that control the expression of surface receptors and cytokines, such as CD11a, CD70, and CD40L. This leads to abnormal activation and proliferation of autoaggressive cells.

2. Disruptions in histone modification
   Histone acetylation and methylation regulate access to genetic material. Changes in these processes alter the expression of key immune genes, including those that regulate the production of interferons and other pro-inflammatory molecules.

3. MicroRNA (miRNA)
   Imbalances between different miRNAs can affect the stability and translation of mRNAs involved in regulating the immune response. Particularly important are miR-146a, miR-155, miR-21, involved in regulating TLR signaling and B-lymphocyte activation.

Epigenetic modifications are largely induced by external factors, making them a key link in the implementation of environmental triggers on genetically predisposed soil.

III. Violation of immunological tolerance

The central element in the development of SLE is the loss of immune tolerance to one's own cellular antigens. This loss is realized in the following directions:

1. Activation of autoaggressive T-lymphocytes

In conditions of reduced regulatory T cell (Treg) function, autoactive CD4⁺ cells recognize self-antigens and induce a B cell response.

2. Hyperactivation of B-lymphocytes and formation of autoantibodies

B-lymphocytes, having received a signal from T-cells and dendritic cells, differentiate into plasma cells and begin to produce autoantibodies to DNA, histones, ribonucleoproteins and other components of the nucleus.

3. Activation of innate immunity through interferons

Plasmacytoid dendritic cells (pDCs), activated by immune complexes containing DNA and RNA, produce type I interferons, which enhance the inflammatory cascade and support the activation of autoimmune T and B cells.

IV. Hormonal and gender influences

The high prevalence of SLE among women (ratio up to 9:1) indicates an important role of hormonal factors in pathogenesis. Key observations:

• Estrogens enhance the immune response by increasing antibody production and activating T-helpers.
• Hormonal fluctuations during puberty, the menstrual cycle, pregnancy, or hormone therapy may trigger the manifestation or exacerbation of the disease.
• In men, the disease is more severe, which is explained by a compensatory hyperreaction in the absence of protective regulation of estrogens.

V. Environmental factors

Despite the genetic predisposition, the disease is often initiated by external triggers. Among them:

• Ultraviolet radiation - induces keratinocyte damage, apoptosis and release of nuclear antigens.
• Viral infections—Epstein-Barr virus, cytomegalovirus, herpes virus type 6—activate innate immunity and can promote molecular mimicry.
• Medicines such as hydralazine, procainamide, isoniazid, chlorpromazine, etc. can cause drug-induced lupus.
• Air pollution - chronic inhalation of fine particles (PM2.5, NO₂) is associated with an increased risk of SLE due to increased oxidative stress and epigenetic mutations.
• Psychoemotional stress can modulate neuroendocrine regulation of the immune system and act as a catalyst for clinical manifestation.

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Conclusion

Thus, systemic lupus erythematosus is the result of interaction of multiple causal factors. Genetic predisposition forms the basis for impaired immune regulation, but clinical implementation of the disease in most cases requires exposure to external triggers that cause epigenetic modifications, activation of innate immunity and production of autoantibodies. Understanding these causes opens up prospects for early diagnosis, prognosis and personalized approach to the treatment of SLE.