Pathogenesis of systemic lupus erythematosus

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

At the heart of autoimmune disorders in systemic lupus erythematosus there are 2 interrelated processes: polyclonal activation of B lymphocytes in the early phase of the disease and antigen-specific T-dependent stimulation of autoantibody synthesis. In patients with systemic lupus erythematosus, an increase in the number of B cells is noted, which correlates with the presence of hypergammaglobulinemia; antigen-specific proliferation or congenital defect of their specific subtypes, synthesizing organ-specific autoantibodies; decrease in the number of natural killers and suppressor T cells; an increase in the population of CD4 ⁴ T cells (helpers); violation of the signaling functions of immune cells; hyperproduction of Th2-cytokines (IL-4, IL-6, IL-10); increased fetal microchimerism.

It was established that the activation and differentiation of B cells is regulated by the stimulator of B-lymphocytes (b-lymphcyte stimulator - BlyS). It is believed that the interaction of BlyS and the corresponding receptor belonging to the superfamily (TNF) plays an important role in the pathogenesis of systemic lupus erythematosus, as demonstrated in the experiment (in transgenic mice with BlyS overexpression, a lupus-like syndrome resembling systemic lupus erythematosus in humans develops).

The main link in the pathogenesis of systemic lupus erythematosus is genetically determined or induced apoptosis defects (programmed cell death). The disruption of clearance of apoptotic cells (often with nuclear antigens expressed on their surface) and their fragments determines the accumulation of cellular antigens in blood and target tissues, which facilitates the initiation of an immune response.

The development of many symptoms of systemic lupus erythematosus is associated with tissue damage caused by the formation of antibodies and the formation of immune complexes.

In renal damage, immune complexes contain nuclear antigens (including DNA), complement-binding antinuclear antibodies (IgGl, IgG3) and AT to DNA. These complexes are formed in the vascular bed or are formed in situ, where the antibodies bind to nuclear antigens associated with glomerular components or native glomerular antigens. Forming deposits in the mesangium or subendothelial layer of the basal membrane, immune complexes activate the complement system, which leads to the generation of chemotactic factors and the migration of leukocytes and mononuclear cells. These cells phagocytize immune complexes and release mediators (cytokines and activators of blood coagulation) that support glomerular inflammation. A chronic inflammatory process can lead to the development of sclerosis and a reduction in renal function.

With membranous nephropathy, deposits are formed in the subepithelial layer and complement is activated in the region separated from the circulating cells in the blood by the basal membrane. Proteinuria in these patients develops as a result of damage to epithelial cells, rather than active inflammation.

Immune complexes are also found in immunofluorescence or electron microscopy in the dermo-epidermal skin junction, choroidal plexus, etc. In the development of vasculitis, thrombocytopenia, leukopenia, anemia, organic brain damage, antibodies to various antigens on the cell surface (leukocytes, erythrocytes, thrombocytes, neuronal cells, etc.).

Systemic immune inflammation in systemic lupus erythematosus can also be associated with cytokine-dependent (IL-1 and TNF-a) endothelial damage, activation of leukocytes and the complement system, which is of great importance in the defeat of organs that are inaccessible to immune complexes, for example, the CNS.

Recent years are characterized by increased attention to another group of autoantibodies - antiphospholipid antibodies, as well as antineutrophil cytoplasmic antibodies. The latter are considered as one of the potential mechanisms of tissue damage along with antibodies to DNA. They react with various cytoplasmic enzymes, primarily with proteinase and myeloperoxidase. When interacting with the latter, the degranulation of neutrophils, leading to damage to endothelial cells, production of nitric oxide, increases. Immune complexes, fixing in the tissues, cause the activation of the complement system, the migration of neutrophils, promote the release of kinins, prostaglandins and other tissue damaging substances. These processes, in turn, lead to a variety of hemostasis disorders, the development of DIC syndrome, immune thrombocytopenia, the syndrome of multiple microthrombogenesis, which is characteristic of systemic lupus erythematosus.

In patients with systemic lupus erythematosus, an increased incidence of spontaneous apoptosis of blood lymphocytes is combined with a reduced ability to repair and a higher background level of defects in DNA, and the type of DNA defects can become a stable signal to apoptosis; with energy insecurity (ATP emptied cells) apoptosis passes into necrosis. It was shown that the topoisomerase inhibitor (etoposide) induces double-strand DNA ruptures in unstimulated human lymphocytes, triggering the mechanism of lymphocyte apoptosis.

Clinically, the predominantly skin discoid (limited, disseminated) and systemic (acute, subacute, rarely - chronic) form, which affects mainly the internal organs, and skin changes are not always observed. Between them, transitional forms are possible.

[1], [2], [3],

Discoid lupus erythematosus

The main symptoms of the disease are erythema, follicular hyperkeratosis and skin atrophy. Preferred location - a person where the outbreaks in their outlines often resemble a "butterfly". Clinical varieties: centrifugal erythema, rosace-like, hyperkeratotic, gypsum, seborrheic, verruzed, papillomatous, dyschromic, pigmentary, 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.

[4], [5], [6], [7]

Pathomorphology of discoid lupus erythematosus

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

In the acute period of the disease there is a sharp edema of the dermis, an expansion of the blood and lymphatic vessels, which form the so-called lymphatic lakes. The walls of the capillaries are edematic, sometimes they can reveal fibrin, extravasates of erythrocytes, sometimes significant, are possible. Inflammatory infiltrates and mainly lymphogistiocyte character with an admixture of neutrophilic granulocytes, are located both perivascularly and perifollikulyarno, often penetrate into the epithelial vagina of the hair. This is accompanied by vacuolization of basal cells, as well as sebaceous glands, collagen and elastic fibers in places of infiltration, as a rule, destroyed. Changes in the epidermis of a secondary nature and in the initial stages are not particularly pronounced; there is only a small hyper- and parakeratosis. Edematous changes in the form of vacuolization of cells of the basal layer, on the contrary, are expressed significantly and are the prognostic sign of this disease even in the initial stages of the process.

In the chronic stages of discoid lupus erythematosus, the changes are more pronounced and typical. Puffiness of the dermis decreases; Infiltrates, preserving perpvascular and perifollicular location, consist mainly of lymphocytes. Among which plasmocytes are found. Hair follicles are atrophic, there are no hair in them, in their place there are horny masses. The walls of the capillaries are thickened, homogenized. CHEC-positive. Collagen fibers in the field of infiltrates as well. As in the acute form, plastic fibers with condensation phenomena in the subepidermal regions are destroyed. In the epidermis - hyperkeratosis with the presence of horny plugs in the indentations and the mouths of the hair follicles (follicular hyperkeratosis), as well as swelling and vacuolization of the basal layer cells, which is pathognomonic for this disease. The Malpighian layer can be of different thickness, but for the most part it is thinned with smoothing of the epidermal outgrowths. Most epidermal cells look edematous with pale stained nuclei; as a rule, markedly expressed hyperkeratosis, with warty forms - papillomatosis. Often find two types of hyaline or colloid bodies (corpuscle Sivatta) round or oval, eosinophilic, with a diameter of 10 microns. Taurus of the first type is formed as a result of dystrophic changes in the cells of the epidermis, occur more often in its basal layer or in the papilla of the dermis; the second type of body appears when the basement membrane changes. Both types of hyaline gel CHIC-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 sign of the disease. Thus, in the erythematous foci the hydrophytic dystrophy of the basal layer cells and edema of the dermis are more common, hemorrhages give hemorrhagic character to the foci, the appearance of a large amount of melanin in the upper parts of the dermis as a result of incontinence of its affected basal epitheliocytes causes pigmentation, etc.

When the tumor form is histologically, hyperkeratosis is found with focal parakeratosis and horny plugs in the widened estuaries of the hair follicles. Malpighian layer is atrophic, in basal cells - vacuolar dystrophy. In the dermis - a pronounced edema and telangiectasia, dense lymphocytic infiltrates, located foci in the thickness of the dermis and subcutaneous tissue. In this dense infiltrate, there are always so-called reactive centers resembling lymph node structures, consisting of cells with large, poor chromatin nuclei. In these centers there may be giant cells and mitosis figures. Infiltrate with the phenomena of epidermotropism invades follicular structures. The basal membrane is thickened, the elastic network is diluted. With direct immunofluorescence in the basal membrane zone, deposits IgG, IgM are determined. C3 and C1q components of the complement.

Changes in the epidermis in the discoid form of lupus erythematosus should be differentiated from those with red flat lice, especially if the vacuole dystrophy of the banal layer of the epidermis is sharply expressed and a subepidermal bladder is formed. In these cases it is necessary to pay attention to the characteristic changes in the epidermis with red flat lichen, the epidermal outgrowths at which they take the form of "saw teeth". Changes in the dermis may resemble the Spiegler-Fendt lymphocyte and Esner-Canof lymphocytic infiltration. However, with lymphocytic infiltration and lymphocytoma, the infiltrate does not tend to be located around the hair follicles, in addition, immature cells are often found in the infiltrate, and in the Spiegler-Fendt lymphocytoma there are many histiocytes among the lymphocytes, in places in the infiltrate there are bright centers resembling the hermetic centers of the lymphatic follicles. With lymphoid infiltration of Esner-Canof, the dermal infiltrate does not differ from that in the early stages of lupus erythematosus. In these cases, differential diagnostics uses immunofluorescence microscopy to detect immunoglobulins, as well as a test for the detection of circulating LE cells.

[8], [9],

Disseminated lupus erythematosus

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

Pathomorphology

The changes are much more pronounced than in the discoid form. Especially sharply revealing atrophy of the epidermis, vacuolar degeneration of the basal layer cells and edema of the dermis, which in some cases leads to the formation of subepidermal slits and even blisters. Inflammatory infiltrate has a diffuse character, its composition is similar to that in chronic discoid form. More significant fibrinoid changes in collagen fibers.

Histogenesis

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

Deep Lupus Erythematosus

Deep lupus erythematosus (sinus lupus panniculitis) is rare, does not tend to transition to a systemic form. Clinically characterized by the presence of one or several deep-lying dense knobby formations, the skin over which is not changed or stagnant-cyanotic color. The foci are located mainly in the region of the shoulders, cheeks, forehead, buttocks, there is a long time, calcification possible. After regression, deep atrophy of the skin remains. Usually they simultaneously detect typical foci of discoid lupus erythematosus. It develops mainly in adults, but it can also occur in children.

Pathomorphology

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

[10], [11], [12], [13],

Systemic lupus erythematosus

Systemic lupus erythematosus is a serious disease with the defeat of various internal organs and systems (lupus-nephritis, polyserositis, arthritis, etc.). Skin changes are polymorphic: type of centrifugal erythema, erysipelas, erythematous, erythematous-urticarum, erythematoma-squamous, spotted, nodular elements. The rashes may resemble scarlet fever, psoriatic, seborrhoeic, toxicodermic, often have a hemorrhagic component, sometimes bubbles are formed, as with multiforme exudative erythema. Capillaritis on the skin of the hands, especially at the fingertips, is characteristic. There are leukopenia, hypergammaglobulinemia, thrombocytopenia, impaired cellular immunity, LE cells, antinuclear factor. Children whose mothers suffered systemic lupus erythematosus may have limited or fused erythematous spots on the face during infancy, rarely on other parts of the body, disappearing usually at the end of the first year of life and leaving dyschromia or atrophic skin changes. With age, such children may develop systemic lupus erythematosus.

Pathomorphology

In the initial stages of the process, changes in the skin are nonspecific and mild. Later in more developed foci, the histological pattern resembles that of discoid lupus erythematosus, but with more pronounced changes in collagen and the main substance of the dermis. There are atrophy of the epidermis, mild hyperkeratosis and vacuolar degeneration of the basal layer cells, sharp edema of the upper parts of the dermis, often seen extravasates of erythrocytes, perivascular lymphohistiocytic infiltrates. In sharply edematous and erythematous foci, fibrin deposits are found in the form of homogeneous eosinophilic masses, located both in the basic substance and around the capillaries (fibrinoid). Similar masses can be located deeper, among swollen and homogenized collagen fibers. Diffuse proliferation of histiocytes and fibroblasts is noted. For systemic lupus erythematosus, mucoid swelling of the main substance of the dermis, collagen fibers and vessel walls is characteristic. In the stage of mucoid swelling, the collagen fibers thicken, acquire a basophilic color, picrofuxin stain yellow, toluidine blue to pink (metachromasia). Later, 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 changed fibers are colored with azan in red, which is due to impregnation with plasma proteins, sometimes with an admixture of fibrin, they are sharply argyrophilic and give a pronounced Schick reaction. Fibrinoid changes can also occur in the walls of the vessels. Similar changes exist in the subcutaneous fat layer, where focal mucoid dystrophy develops with reactive lymphocytic infiltration. Trabeculae, separating the lobules of adipose tissue, thickened, edematous, with the phenomena of fibrinoid cessation. Changes in subcutaneous tissue are similar to those in deep red lupus erythematosus and are called "lupus-panniculitis". Pagmonognomichnymi are changes in the vessels of the skin, which are similar to those in internal organs. Some researchers note proliferative-destructive vasculitis in systemic lupus erythematosus with infiltration of vascular walls with lymphocytes, plasmocytes and histiocytes, in some of them - phenomena of sclerosis and pycnosis. V.V. Serov et al. (1974), studying the kidney vessels by electron microscopy, found significant changes in the basal membranes of glomerular capillaries ("membrane transformation") associated with the presence of subendothelial deposits of immune complexes. In some cases, a histological picture of leukoclastic vasculitis is noted. Especially in urticaro-like foci. Occasional phenomena of atrophy in systemic lupus erythematosus are very similar clinically and histologically with malignant atrophy papulosis of Legos.

Bullous eruptions of lupus erythematosus are very difficult to differentiate from various bullous dermatoses, especially if the course of red lupus is relatively calm. Differentiation from a pemphitoid can only be based on immunohistochemistry data. By the method of direct immunofluorescence, deposits of the IgG and C3 complement components are located linearly on the dermoepidermal membrane, namely in the basal plate, and not in the lamina lucida. In an immuno-electronic study, IgA and IgG deposits were found near the basal membrane in the zone of fixing fibrils, which is characteristic of systemic lupus erythematosus.

Histologically, the epidermis is atrophic, hyperkeratosis with horn corks in the mouths of the hair follicles, vacuolation of the basal layer cells. The dermis is sharply edematous, especially in its upper half with the formation in these places of blisters filled with filaments of fibrin. 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) detected. Antigens can serve a variety of tissue and cell structures: collagen, DNA, RNA, nucleoproteins, histones, cardiolipin, ribosomes, etc. The greatest diagnostic value is given to antibodies against DNA. It has been shown that the detection of antibodies against denatured DNA (ssDNA) is a highly sensitive method, and against native DNA (nDNA) is 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 basal membrane of the epidermis, suppression of T-lymphocytes, mainly due to T-suppressors, activation of B-cells, association with other autoimmune diseases, including skin (herpetiform dermatitis Dühringa, pemphigoid) also confirm the development of inflammation in the skin with this disease on an immune basis. In addition, BS Andrews et al. (1986) found in lesion lesions a decrease in the number of epidermal macrophages, a decreased expression of HLA-DR antigen on the surface of epithelial cells and the predominance of T-helper infiltrate among cells, an increase in the number of mononuclear macrophages with a rare detection of B cells. The reason for the appearance of autoantibodies is not 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, for example with HLA-A1, HLA-A24, HLA-B25, HLA -B7, HLA-B8, HLA-B15, HLA-C4, HLA-DR2, HLA-DR3, HLA-DRw6, etc., hereditary insufficiency of some complement components, especially C2 and C4, the detection of immune disorders in healthy relatives. The role of chronic infection, the appearance of autoantigens under the influence of ultraviolet irradiation and other adverse effects, drugs (hydrolysine, procainamide, isothiazide, penicillamine, griseofulvin, reserpine, methyldopa, contraceptives, etc.), the presence of mutations in stem cells of the lymphoid series in genetically predisposed persons. The value of the disturbance of the metabolism of nucleotides is shown. The occurrence of disturbances in neuroendocrine dysfunctions, especially hyperestrogenia and hypofunction of the adrenal cortex, is noted. VC. Podymov (1983) attaches the main importance to the deficiency of N-acetyltransferase and the inhibition of lysyloxylase. This may be one of the factors contributing to the development of systemic lupus erythematosus, triggered by drugs. As a subacute cutaneous form of lupus erythematosus, paraneoplastic syndrome may occur.