Pathogenesis of systemic lupus erythematosus

A distinctive feature of the pathogenesis of systemic lupus erythematosus is a disturbance of immune regulation, accompanied by a loss of immunological tolerance to one's own antigens and the development of an autoimmune response with the production of a wide range of antibodies, primarily to chromatin (nucleosome) and its individual components, native DNA and histones.

Genetic predisposition

Systemic lupus erythematosus is a multifactorial disease based on hereditary predisposition, realized in combination with the impact of environmental factors. Polymorphisms in the genes encoding proteins of the HLA system (especially HLA-DR2 and HLA-DR3) disrupt the process of antigen presentation and contribute to the formation of an autoimmune response. Deficiency or functional abnormalities of complement components (C1q, C2, C4) prevent the effective removal of apoptotic cells and immune complexes. These changes create conditions for the accumulation of the body's own cellular structures, which are perceived by the immune system as foreign. In addition, mutations in the genes regulating the activation of toll-like receptors (TLR7 and TLR9) increase sensitivity to nucleic acids and contribute to hyperactivation of the innate immunity.

Epigenetic changes

Patients with SLE have pronounced epigenetic shifts that affect the expression of genes involved in the regulation of the immune response. Global DNA hypomethylation in CD4⁺ T cells leads to activation of genes encoding adhesion molecules (CD70, CD11a) and pro-inflammatory cytokines. This contributes to a decrease in the threshold for T-lymphocyte activation and their autoaggressiveness. Disruption of histone modifications (e.g., acetylation and methylation) further enhances the expression of pro-inflammatory genes. These epigenetic changes can be induced by external factors such as ultraviolet radiation, tobacco smoke, and viral infections, which cause oxidative stress and destabilize the enzymes that maintain epigenetic homeostasis.

Impaired clearance of apoptotic bodies

Normally, apoptotic cells are quickly removed by macrophages and dendritic cells, preventing leakage of intracellular contents. In patients with SLE, the clearance process is impaired due to a deficiency of complement components and functional abnormalities of phagocytes. This leads to the accumulation of apoptotic bodies containing nuclear antigens (DNA, histones, ribonucleoproteins). These antigens become targets for autoantibodies and form immune complexes that are deposited in various tissues (kidneys, skin, joints, blood vessels), causing inflammation and damage.

Hyperactivation of innate immunity and the role of type I interferons

Plasmacytoid dendritic cells (pDCs) play a key role in the pathogenesis of SLE because they actively produce type I interferons (IFN-α and IFN-β) in response to interaction with immune complexes containing nucleic acids. These complexes activate toll-like receptors (TLR7 and TLR9) on pDCs, which triggers a powerful cascade of interferon production. IFN-Is stimulate the expression of interferon-stimulated genes (ISGs) in various cells, including T and B lymphocytes, monocytes, and neutrophils. This “interferon storm” amplifies the autoimmune response and maintains chronic inflammation.

Th17/Treg imbalance and the cytokine cascade

In the immune system of patients with SLE, the ratio between effector Th17 cells and regulatory Treg cells is disrupted. Th17 cells produce interleukin-17 (IL-17), which activates neutrophils, increases the production of proinflammatory cytokines (IL-6, TNF-α), and contributes to tissue damage. At the same time, Treg cells, which normally suppress autoimmune reactions, are insufficient in number or have functional defects. Such a bias towards the Th17 response maintains chronic inflammation and autoaggression.

NET formation and the role of neutrophils

Neutrophils in SLE patients are prone to excessive NET (neutrophil extracellular trap) formation. These networks, consisting of DNA and granular proteins, are released into the intercellular space and contribute to increased inflammation. NET structures contain autoantigens and stimulate pDC to produce interferons, creating a vicious circle of pathological activation of the immune system.

Autoantibodies and the formation of immune complexes

Activation of B lymphocytes and their differentiation into plasma cells leads to the production of a wide range of autoantibodies: antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA), anti-Sm, anti-Ro (SSA), anti-La (SSB), etc. These autoantibodies bind to the corresponding antigens, forming immune complexes that are deposited in tissues and activate the complement system. Subsequent activation of a cascade of inflammatory mediators leads to vasculitis, glomerulonephritis, and other organ damage.

Modern biomarkers of SLE activity

Proteomic studies have identified a number of molecules associated with disease activity and relapse risk. Among them, serum amyloid A1 (SAA1) is of particular importance, as it is involved in the activation of Th17 cells and the maintenance of the inflammatory process. Such biomarkers offer opportunities for early prediction of disease flares and monitoring of treatment effectiveness.

The influence of environmental factors and hormones

Ultraviolet radiation, infections (e.g. Epstein-Barr viruses), air pollution (PM2.5, NO₂) and smoking provoke oxidative stress and activation of innate immunity. These effects increase epigenetic shifts and promote SLE exacerbations. Hormonal factors (especially estrogens) increase the activity of the immune system and explain the high prevalence of SLE in women of reproductive age.

Integrated model of SLE pathogenesis

1. Genetic base + exogenous triggers → epigenetic changes (hypomethylation of DNMT1, promoters and ISG genes)
2. Accumulation of angiogenic debris due to complement deficiency
3. Activation of pDC and IFN-I production → ISG overexpression → increased cell sensitivity
4. Disturbances in Th17/Treg balance, increased IL-17, IL-6, TNF-α
5. B-cell provocation – products: ANA, anti-dsDNA; immune complex formation
6. Proteomics markers (SAA1) – early recognition of exacerbations
7. Chronic autoimmune inflammation and multisystem damage

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Discoid lupus erythematosus

The main symptoms of the disease are erythema, follicular hyperkeratosis and skin atrophy. The preferred localization is the face, where the lesions often resemble a "butterfly" in their outline. Clinical varieties: centrifugal erythema, rosacea-like, hyperkeratotic, gypsum-like, seborrheic, warty, papillomatous, dyschromic, pigmented, hemorrhagic, tumor-like, tuberculoid. B.M. Pashkov et al. (1970) identified three forms of lupus erythematosus on the oral mucosa: typical, exudative-hyperemic and erosive-ulcerative.

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Pathomorphology of discoid lupus erythematosus

The main histological signs of discoid lupus erythematosus are hyperkeratosis, atrophy of the Malpighian layer, hydropic degeneration of the cells of the basal layer, edema with vasodilation, sometimes extravasation of erythrocytes of the upper part of the dermis and the presence of focal, predominantly lymphocytic, infiltrates located mainly around the skin appendages. It should be noted that the existence of all the listed signs is not always possible, moreover, the intensification of any of them causes the appearance of clinical varieties of one or another form of lupus erythematosus.

In the acute period of the disease, there is a sharp swelling of the dermis, expansion of the blood and lymphatic vessels, which form the so-called lymphatic lakes. The walls of the capillaries are edematous, sometimes fibrin can be detected in them, extravasations of erythrocytes are possible, sometimes significant. Inflammatory infiltrates and mainly of a lymphohistiocytic nature with an admixture of neutrophilic granulocytes, are located both perivascularly and perifollicularly, often penetrating into the epithelial sheaths of the hair. This is accompanied by vacuolization of basal cells, as well as sebaceous glands. Collagen and elastic fibers in the places of infiltrates, as a rule, are destroyed. Changes in the epidermis of a secondary nature and in the initial stages are not particularly pronounced; only slight hyper- and parakeratosis are noted. Edema changes in the form of vacuolization of basal layer cells, on the contrary, are expressed significantly and are a prognostic sign of this disease even in the initial stages of the process.

In chronic stages of discoid lupus erythematosus changes are more pronounced and typical. Edema of the dermis decreases; infiltrates, preserving perivascular and perifollicular location, consist mainly of lymphocytes. Among which are plasma cells. Hair follicles are atrophic, hair is absent in them, in their place there are horny masses. Capillary walls are thickened, homogenized. PAS-positive. Collagen fibers in the area of infiltrates are the same. as in the acute form, plastic fibers are destroyed with phenomena of thickening in the subepidermal sections. In the epidermis - hyperkeratosis with the presence of horny plugs in the depressions and mouths of hair follicles (follicular hyperkeratosis), as well as edema and vacuolization of cells of the basal layer, which is pathognomonic for this disease. The Malpighian layer may be of varying thickness, but for the most part it is thinned with smoothing of epidermal outgrowths. Most epidermal cells appear edematous with palely stained nuclei; as a rule, there is a pronounced hyperkeratosis, in warty forms - papillomatosis. Often two types of hyaline or colloid bodies (Civatte bodies) are found, round or oval, eosinophilic, 10 μm in diameter. The first type of bodies are formed as a result of dystrophic changes in epidermal cells, they are more often found in its basal layer or in the dermal papillae, the second type of bodies arise when the basement membrane changes. Both types of hyaline gels are PAS-positive, diastase-resistant, give a direct immunofluorescence reaction, contain IgG, IgM, IgA, complement and fibrin.

The varieties of discoid lupus erythematosus depend on the severity of one or another symptom of the disease. Thus, in erythematous foci, hydropic degeneration of the basal layer cells and edema of the dermis are more common, hemorrhages give the foci a hemorrhagic character, and the appearance of a large amount of melanin in the upper parts of the dermis as a result of its incontinence by the affected basal epithelial cells causes pigmentation, etc.

In the tumor-like form, hyperkeratosis with focal parakeratosis and horny plugs in the expanded openings of the hair follicles are found histologically. The Malpighian layer is atrophic, and vacuolar dystrophy is present in the basal cells. In the dermis, there is pronounced edema and telangiitis, dense lymphocytic infiltrates located in foci in the thickness of the dermis and subcutaneous tissue. In this dense infiltrate, so-called reactive centers are always found, resembling the structures of lymph nodes, consisting of cells with large, chromatin-poor nuclei. These centers may contain giant cells and mitotic figures. The infiltrate with epidermotropism invades follicular structures. The basal membrane is thickened, the elastic network is sparse. Direct immunofluorescence reveals deposits of IgG, IgM, C3 and C1q complement components in the basement membrane zone.

Epidermal changes in discoid lupus erythematosus should be differentiated from those in lichen planus, especially if vacuolar dystrophy of the banal layer of the epidermis is sharply expressed and a subepidermal blister is formed. In these cases, attention should be paid to the characteristic changes in the epidermis in lichen planus, in which the epidermal outgrowths acquire the shape of "saw teeth". Changes in the dermis may resemble Spiegler-Fendt lymphocytoma and Jesner-Kanof lymphocytic infiltration. However, in lymphocytic infiltration and lymphocytoma, the infiltrate does not tend to be located around the hair follicles, and in these diseases, immature cells are often found in the infiltrate, while in Spiegler-Fendt lymphocytoma, there are many histiocytes among the lymphocytes, and in places, light centers resembling the germinal centers of lymphatic follicles are found in the infiltrate. In Jesner-Kanof lymphoid infiltration, the dermal infiltrate does not differ from that in the early stages of lupus erythematosus. In these cases, immunofluorescence microscopy is used in differential diagnosis to detect immunoglobulins, as well as a test for the detection of circulating LE cells.

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Disseminated lupus erythematosus

Disseminated lupus erythematosus is characterized by multiple lesions similar to those in the discoid form. More often than in the discoid form, signs of damage to internal organs are detected, there is a high probability of developing a systemic process.

Pathomorphology

The changes are expressed much more strongly than in the discoid form. Particularly sharply revealed are atrophy of the epidermis, vacuolar degeneration of the cells of the basal layer and edema of the dermis, which in some cases leads to the formation of subepidermal cracks and even blisters. The inflammatory infiltrate has a diffuse character, its composition is similar to that in the chronic discoid form. Fibrinoid changes in collagen fibers are more significant.

Histogenesis

Immunohistochemical study of lymphocytic infiltrate in discoid lupus erythematosus using monoclonal antibodies showed that most patients have OKT6-positive epidermal macrophages and HLA-DP-positive activated T-lymphocytes. CD4+ populations of T-lymphocytes are mainly detected, CD8+ cells are found predominantly in the epidermis in the zone of damage to basal keratinocytes. The role of genetic factors in the pathogenesis of discoid lupus erythematosus is indicated. Thus, V. Voigtlander et al. (1984) found that in familial forms of this disease, C4 deficiency was detected both in patients and in healthy relatives.

Deep lupus erythematosus

Deep lupus erythematosus (syn. lupus panniculitis) is rare and does not tend to develop into a systemic form. It is clinically characterized by the presence of one or more deeply located dense nodular formations, the skin above which is unchanged or of a stagnant-bluish color. The lesions are located mainly in the area of the shoulders, cheeks, forehead, buttocks, exist for a long time, and calcification is possible. After regression, deep skin atrophy remains. Typical lesions of discoid lupus erythematosus are usually detected simultaneously. It develops mainly in adults, but can also be observed in children.

Pathomorphology

The epidermis is usually without any significant changes; in the papillary layer of the dermis, there are small perivascular lymphohistiocytic infiltrates. In some areas, the fat lobules are almost completely necrotic; homogenization and hyalinosis of the collagen fibers of the stroma are noted. In addition, foci of mucoid transformation and dense focal lymphohistiocytic infiltrates are found in it, among which a large number of plasma cells are found, sometimes eosinophilic granulocytes. Areas consisting of the remains of necrotic cells are revealed. The vessels are infiltrated with lymphocytes and histiocytes, individual arterioles with fibrinoid necrosis. The method of direct immunofluorescence revealed deposits of IgG and the C3 component of complement in the zone of the basal membrane of the epidermis and follicular epithelium.

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Systemic lupus erythematosus

Systemic lupus erythematosus is a severe disease with damage to various internal organs and systems (lupus nephritis, polyserositis, arthritis, etc.). Skin changes are polymorphic: such as centrifugal erythema, erysipelas-like hyperemia of the face, erythematous, erythematous-urticarial, erythematous-squamous, spotty, nodular elements. Rashes can resemble scarlet fever, psoriatic, seborrheic, toxicoderma, often have a hemorrhagic component, sometimes blisters are formed, as in erythema multiforme exudative. Capillaritis on the skin of the hands is characteristic, especially on the fingertips. Leukopenia, hypergammaglobulinemia, thrombocytopenia, impaired cellular immunity are noted, LE cells and antinuclear factor are detected. Children whose mothers suffered from systemic lupus erythematosus may have limited or confluent erythematous spots on the face during the neonatal period, less often on other parts of the body, which usually disappear by the end of the first year of life and leave dyschromia or atrophic changes in the skin. With age, such children may develop systemic lupus erythematosus.

Pathomorphology

In the initial stages of the process, changes in the skin are nonspecific and weakly expressed. Later, in more developed foci, the histological picture resembles that of discoid lupus erythematosus, but with more pronounced changes in collagen and the main substance of the dermis. Epidermal atrophy, moderate hyperkeratosis and vacuolar degeneration of the cells of the basal layer, severe edema of the upper parts of the dermis are observed, erythrocyte extravasates and perivascular lymphohistiocytic infiltrates are often visible. In sharply edematous and erythematous foci, fibrin deposits are found in the form of homogeneous eosinophilic masses located both in the main substance and around the capillaries (fibrinoid). Similar masses can also be located deeper, among swollen and homogenized collagen fibers. Diffuse proliferation of histiocytes and fibroblasts is noted. Systemic lupus erythematosus is characterized by mucoid swelling of the ground substance of the dermis, collagen fibers and vessel walls. In the stage of mucoid swelling, collagen fibers thicken, acquire a basophilic color, are stained yellow with picrofuchsin, and pink with toluidine blue (metachromasia). Later, a deeper disorganization of connective tissue occurs - fibrinoid swelling, which is based on the destruction of collagen and intercellular substance, accompanied by a sharp violation of vascular permeability. The altered fibers are stained red with azan, which is associated with their impregnation with plasma proteins, sometimes with an admixture of fibrin, they are sharply argyrophilic and give a pronounced PAS reaction. Fibrinoid changes can also be observed in the walls of blood vessels. Similar changes are also present in the subcutaneous fat layer, where focal mucoid dystrophy with reactive lymphocytic infiltration develops. The trabeculae separating the lobules of adipose tissue are thickened, edematous, with signs of fibrinoid cessation. Changes in the subcutaneous tissue are similar to those in deep lupus erythematosus and are called "lupus panniculitis". Pagognomonic are changes in the vessels of the skin, which are similar to those in the internal organs. Some researchers note proliferative-destructive vasculitis with infiltration of the vascular walls by lymphocytes, plasma cells and histiocytes in systemic lupus erythematosus, in some of them - the phenomena of sclerosis and pycnosis. V.V. Serov et al. (1974), studying renal vessels by electron microscopy, also discovered significant changes in the basal membranes of glomerular capillaries ("membranous transformation") associated with the presence of subendothelial deposits of immune complexes. In some cases, a histological picture of leukoclastic vasculitis is noted, especially in urticaria-like foci. The occasionally encountered phenomena of atrophy in systemic lupus erythematosus are very similar clinically and histologically to malignant atrophic papulosis of Legos.

Bullous rashes of lupus erythematosus are very difficult to differentiate from various bullous dermatoses, especially if the course of lupus erythematosus is relatively calm. Differentiation from pemphitoid can only be based on immunohistochemistry. Direct immunofluorescence reveals deposits of IgG and C3 complement component located linearly on the dermoepidermal membrane, namely in the basal plate, and not in the lamina lucida. Immunoelectron examination revealed deposits of IgA and IgG near the basal membrane in the zone of anchoring fibrils, which is typical for systemic lupus erythematosus.

Histologically, the epidermis is atrophic, hyperkeratosis with horny plugs in the mouths of hair follicles, vacuolization of basal layer cells. The dermis is sharply edematous, especially in its upper half with the formation of blisters filled with fibrin threads in these areas. Similar changes are observed near atrophic hair follicles.

Histogenesis

As indicated, lupus erythematosus is an autoimmune disease, with both humoral and T-cell (T-suppressor defect) disorders identified. The most diverse tissue and cellular structures can serve as antigens: collagen, DNA, RNA, nucleoproteins, histones, cardiolipin, ribosomes, etc. Antibodies against DNA are of the greatest diagnostic importance. It has been found that the detection of antibodies against denatured DNA (ssDNA) is a highly sensitive method, while antibodies against native DNA (nDNA) are a more specific but less sensitive method, pathognomonic for systemic lupus erythematosus. Antibodies to small nuclear and cytoplasmic ribonucleoproteins (Ro (SS-A); Sm; La (SS-B)) are detected with lower frequency and variability depending on the form and activity of the process. The formation of immune complexes deposited in the walls of small vessels and under the basement membrane of the epidermis, the suppression of T-lymphocytes, mainly due to T-suppressors, the activation of B-cells, association with other autoimmune diseases, including skin diseases (Duhring's dermatitis herpetiformis, pemphigoid) also confirm the development of inflammation in the skin in this disease on an immune basis. In addition, BS Andrews et al. (1986) found in the lesions a decrease in the number of epidermal macrophages, reduced expression of HLA-DR antigen on the surface of epithelial cells and the predominance of T-helpers among the infiltrate cells, an increase in the number of mononuclear macrophages with rare detection of B-cells. The cause of the appearance of autoantibodies has not been established. The role of genetic predisposition with a possible autosomal dominant type of inheritance is evidenced by family cases, including the development of the disease in twins, the association of lupus erythematosus and its individual forms with some genetic markers, such as HLA-A1, HLA-A24, HLA-B25, HLA-B7, HLA-B8, HLA-B15, HLA-C4, HLA-DR2, HLA-DR3, HLA-DRw6, etc., hereditary deficiency of some complement components, especially C2 and C4, and the detection of immune disorders in healthy relatives. The role of chronic infection, the appearance of autoantigens under the influence of ultraviolet radiation and other adverse effects, drugs (hydrolysine, procainamide, isothiazide, penicillamine, griseofulvin, reserpine, methyldopa, contraceptives, etc.), the presence of mutations in lymphoid stem cells in genetically predisposed individuals are assumed. The significance of nucleotide metabolism disorders is shown. The occurrence of disorders in neuroendocrine dysfunctions, especially hyperestrogenism and adrenal cortex hypofunction, is noted. V.K. Podymov (1983) attaches primary importance to N-acetyltransferase deficiency and lysyl oxylase inhibition. Probably, this may be one of the factors contributing to the development of systemic lupus erythematosus provoked by drugs. Paraneoplastic syndrome may occur as a subacute cutaneous form of lupus erythematosus.