Pathogenesis of juvenile chronic arthritis
Last reviewed: 23.04.2024
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The pathogenesis of juvenile rheumatoid arthritis has been intensively studied in recent years. The development of the disease is based on the activation of both cellular and humoral immunity.
The foreign antigen is absorbed and processed by antigen-presenting cells (dendritic, macrophages and others), which, in turn, present it (or information about it) to T-lymphocytes. The interaction of the antigen-presenting cell with CD4 + lymphocytes stimulates the synthesis of the corresponding cytokines. Interleukin-2 (IL-2), produced by the activation of T-helper type 1, interacts with specific IL-2 receptors on various cells of the immune system. This causes the clonal expansion of T-lymphocytes and stimulates the growth of B-lymphocytes. The latter leads to a massive synthesis of immunoglobulins G by plasma cells, an increase in the activity of natural killers, and activates macrophages. Interleukin-4 (IL-4), synthesized by T-helper type 2, causes activation of the humoral link of immunity (antibody synthesis), stimulation of eosinophils and mast cells, and the development of allergic reactions.
Activated T-lymphocytes, macrophages, fibroblasts and synoviocytes are capable of producing a specific set of pro-inflammatory cytokines that play a significant role in the development of systemic manifestations and in maintaining chronic inflammation in the joints.
Cytokines in juvenile rheumatoid arthritis
Cytokines are a group of polypeptides that mediate immune response and inflammation. They activate the growth, differentiation and activation of cells. Cytokines can be produced by a large number of cells, those that are synthesized by leukocytes are called interleukins. At present, 18 interleukins are known. Leukocytes also produce interferon-gamma and tumor necrosis factors alpha and beta.
All interleukins are divided into two groups. The first group includes IL-2, IL-3, IL-4, IL-5, IL-9 and IL-10, they provide immunoregulation, in particular, proliferation and differentiation of lymphocytes. The second group includes IL-1, IL-6, IL-8 and TNF-alpha. These cytokines provide the development of inflammatory reactions. The precursor of T-lymphocytes (TIO) is differentiated into two main types of T-helperaa. The degree of polarization and heterogeneity of T-lymphocytes reflects the nature of antigenic stimuli directed to certain cells. Polarization of Th1 / 2 is determined in infectious diseases: leishmaniasis, listeriosis, mycobacterium infection with helminths, as well as in the presence of non-infectious persistent antigens, in particular, in allergies and autoimmune diseases. Moreover, the degree of polarization of lymphocytes increases with the chronization of immune responses. Differentiation of T-helpers occurs mainly under the influence of two cytokines - IL-12 and IL-4. Iterleukin-12 is produced by monocytic antigen-presenting cells, in particular dendritic cells, and causes Th0 to differentiate into Th1, which are involved in the activation of the cellular immunity. Interleukia-4 promotes the differentiation of Th0 into Th2, which activate the humoral link of immunity. These 2 ways of differentiation of T-lymphocytes are antagonistic. For example, IL-4 and IL-10, produced by the Th2 type, inhibit Th1-type activation.
Th1 synthesize interleukin-2, interferon-gamma and tumor necrosis factor-beta, which cause activation of the cellular immunity. Th2-type synthesize IL-4, IL-5, IL-b, IL-10 and IL-13 are cytokines that promote the activation of the humoral immunity unit. Th0 can produce all kinds of cytokines.
Cytokines are conventionally divided into pro- and anti-inflammatory, or cytokine cytokines. Proinflammatory cytokines include IL-1, TNF-alpha, IL-6, interferon-gamma, anti-inflammatory - IL-4, IL-10 and IL-13, IL-1 receptor antagonist, growth factor-beta soluble receptor to tumor necrosis factors. The imbalance of pro- and a of inflammatory cytokines underlies the development of the process of inflammation can be acute, as, for example, in Lyme disease, when there is an abnormal increase in IL-1 and TNF-alpha, as well as prolonged, as in autoimmune diseases. The long-term imbalance of cytokines may be due to the presence of a persistent antigen or a genetically determined imbalance in the cytokine network. In the presence of the latter after an immune response to a trigger agent, which may be a virus or a bacterium, the homeostasis is not restored and an autoimmune disease develops.
Analysis of cell response characteristics in different variants of juvenile rheumatoid arthritis showed that in the systemic version there is a mixed Thl / Th2-1 response with a predominance of helper activity of the first type. The pachiarticular and polyarticular variants of juvenile rheumatoid arthritis flow are more associated with the activation of the humoral link of immunity and the production of antibodies », therefore, with the predominant activity of the type 2 helper.
Considering that the biological effect of cytokines depends on their concentration and the relationship with their inhibitors, a number of studies have been carried out whose purpose is to reveal the correlation of the activity of different variants of the course of juvenile rheumatoid arthritis with cytokines. The results obtained during the research were ambiguous. In most studies, it has been shown that the systemic variant of the disease correlates with an increase in the level of the soluble IL-2 receptor, as well as IL-6 and its soluble receptor, which enhances the activity of the cytokine itself, the IL-1 antagonist, the synthesis of which is stimulated by IL-6, Synthesis of IL -6 also increases TNF-alpha. Analysis of levels of soluble TNF receptors of the 1 st and 2 nd types showed their increase and correlation with the activity of the systemic variant of the course of juvenile rheumatoid arthritis.
In patients with spirocytic juvenile rheumatoid arthritis and spondyloarthropathy, an elevated level of IL-4 and IL-10 was predominantly associated with a lack of development of significant erosive changes in the joints and, accordingly, disability of patients, and a better outcome of this variant of the disease course. Unlike the polyarticular and systemic juvenile rheumatoid arthritis.
Immunopathogenesis of juvenile chronic arthritis
An unknown antigen is perceived and processed by dendritic cells and macrophages, which, in turn, present to its T-lymphocytes.
The interaction of the antigen-presenting cell (APC) with CD4 + lymphocytes stimulates the synthesis of the corresponding cytokines. Interleukin-2, produced by the activation of Thl, binds to specific IL-2 receptors, which are expressed on various cells of the immune system. The interaction of IL-2 with specific receptors causes clonal expansion of T-lymphocytes, enhances the growth of B-lymphocytes. The latter leads to an uncontrolled synthesis of immunoglobulins G (IgG) by plasma cells, increases the activity of natural killer cells (EC), and activates macrophages. Interleukin-4, synthesized by Th2 cells, leads to the activation of the humoral link of immunity, manifested by the synthesis of antibodies, as well as the activation of eosinophils, mast cells and the development of allergic reactions.
Activated T-lymphocytes, macrophages, fibroblasts and synoviocytes also produce pro-inflammatory cytokines, which play a leading role in the development of systemic manifestations and the maintenance of chronic inflammation in the joints.
Various clinical and biological manifestations of systemic juvenile rheumatoid arthritis, including fever, rash, arthritis, lymphadenopathy, muscle atrophy, weight loss, anemia, synthesis of acute phase proteins, activation of T and B cells, fibroblasts, synovial membrane cells and bone resorption are associated with increased synthesis and activity of interleukin-1 (IL-1) alpha and beta, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-b).
Proinflammatory cytokines not only determine the development of extraarticular manifestations, but also the activity of rheumatoid synagogue.
Rheumatoid synovitis from the first manifestations has a tendency to chronicization, followed by the development of destruction of soft tissues, cartilage and bone. The causes of destruction of cartilage and bone tissue attract special attention. Destruction of all components of the constitution is caused by the formation of a pannus consisting of activated macrophages, fibroblasts and actively proliferating synovial cells. Activated macrophages and synoviocytes produce a large number of pro-inflammatory cytokines: IL-1, TNF-alpha, IL-8, granulocyte macrophage colony-stimulating factor and IL-6. Proinflammatory cytokines play a leading role in maintaining chronic inflammation and destruction of cartilage and bone in juvenile rheumatoid arthritis. Interleukin-1 and TNF-alpha stimulate the proliferation of synoviocytes and osteoclasts, enhance the synthesis of prostatandins, collagenase and stromelysin by synovial cells, chondrocytes and osteoblasts, and induce the synthesis and excretion of other cytokines by synovial membrane cells, in particular IL-6 and IL-8. Interleukin-8 enhances chemotaxis and activates polymorphonuclear leukocytes. Activated leukocytes produce a large number of proteopytic enzymes, which intensifies the process of resorption of cartilage and bone. In juvenile rheumatoid arthritis, not only the cartilage, but also the bone can be destroyed at a distance from the pannus because of the influence of cytokines, which are produced by the iunocompetent cells and cells of the synovial membrane.
T-lymphocytes stimulated in the course of the immune reaction produce an osteoclasta- tivating factor that increases the function of osteoclasts and thereby increases bone resorption. The isolation of this factor is enhanced by the influence of prostaglandins. Their production in juvenile rheumatoid arthritis is significantly increased by different types of cells: macrophages, neutrophils, synoviocytes, chondrocytes.
Thus, uncontrolled reactions of the immune system lead to the development of chronic inflammation, sometimes irreversible changes in joints, extraarticular manifestations and disability of patients. Given that the etiological factor of juvenile rheumatoid arthritis is unknown, its etiotropic therapy is impossible. From this follows the logical conclusion that control over the course of this severe disabling process can be obtained only through pathogenetic therapy, which purposefully influences the mechanisms of its development, in particular suppressing the abnormal reactions of the immune system.
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