Pathogenesis of juvenile chronic arthritis

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.

A 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 an antigen-presenting cell with CD4 ⁺ lymphocytes stimulates their synthesis of the corresponding cytokines. Interleukin-2 (IL-2), produced during the activation of type 1 T-helpers, interacts with specific IL-2 receptors on various cells of the immune system. This causes clonal expansion of T-lymphocytes and stimulates the growth of B-lymphocytes. The latter leads to massive synthesis of immunoglobulins G by plasma cells, increased activity of natural killers, and activates macrophages. Interleukin-4 (IL-4), synthesized by type 2 T-helpers, causes activation of the humoral component 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 certain set of proinflammatory cytokines, which 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 the immune response and inflammation. They activate cell growth, differentiation, and activation. Cytokines can be produced by a large number of cells, and those produced by leukocytes are called interleukins. There are currently 18 known interleukins. 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 (T-lymphocytes) is differentiated into two main types of T-helpers. 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 lymphocyte polarization increases with chronicization of immune responses. Differentiation of T-helpers occurs mainly under the influence of two cytokines - IL-12 and IL-4. Interleukin-12 is produced by monocytic antigen-presenting cells, in particular dendritic ones, and causes differentiation of Th0 into Th1, which participate in the activation of the cellular link of immunity. Interleukin-4 promotes differentiation of Th0 into Th2, which activate the humoral link of immunity. These two ways of differentiation of T-lymphocytes are antagonistic. For example, IL-4 and IL-10, produced by the Th2 type, inhibit the activation of the Th1 type.

Th1 synthesize interleukin-2, interferon-gamma and tumor necrosis factor-beta, which cause activation of the cellular component of immunity. Th2-type synthesize IL-4, IL-5, IL-6, IL-10 and IL-13 - cytokines that promote activation of the humoral component of immunity. Th0 can produce all types of cytokines.

Cytokines are conventionally divided into pro- and anti-inflammatory, or cytokine inhibitors. Pro-inflammatory cytokines include IL-1, TNF-alpha, IL-6, interferon-gamma, anti-inflammatory cytokines include IL-4, IL-10 and IL-13, as well as the IL-1 receptor antagonist, transforming growth factor-beta soluble receptor for tumor necrosis factors. Imbalance of pro- and a-inflammatory cytokines underlies the development of the inflammatory process; it can be acute, such as in Lyme disease, when a significant increase in IL-1 and TNF-alpha is observed, and long-term, such as in autoimmune diseases. A long-term cytokine imbalance can be a consequence of 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 bacteria, homeostasis is not restored and an autoimmune disease develops.

Analysis of the features of the cellular response in various variants of the course of juvenile rheumatoid arthritis showed that in the systemic variant there is a mixed Thl/Th2-1 response with a predominance of the activity of type 1 helpers. Pauciarticular and polyarticular variants of the course of juvenile rheumatoid arthritis are associated to a greater extent with the activation of the humoral link of immunity and the production of antibodies, therefore, with the predominant activity of type 2 helpers.

Considering that the biological effect of cytokines depends on their concentration and relationships with their inhibitors, a number of studies have been conducted to identify a correlation between the activity of different variants of juvenile rheumatoid arthritis and cytokines. The results obtained in the course of the studies were ambiguous. Most studies have shown that the systemic variant of the disease correlates with an increase in the level of soluble IL-2 receptor, as well as IL-6 and its soluble receptor, which enhances the activity of the cytokine itself, an IL-1 antagonist, the synthesis of which is stimulated by IL-6. The synthesis of IL-6 is also enhanced by TNF-alpha. Analysis of the levels of soluble TNF receptors of types 1 and 2 showed their increase and correlation with the activity of the systemic variant of juvenile rheumatoid arthritis.

In patients with pauciarticular juvenile rheumatoid arthritis and spondyloarthropathy, elevated levels of IL-4 and IL-10 were predominantly detected, which is associated with the absence of the development of significant erosive changes in the joints, respectively, patient disability, and a better outcome of this variant of the disease, in contrast to polyarticular and systemic juvenile rheumatoid arthritis.

Immunopathogenesis of juvenile chronic arthritis

The unknown antigen is perceived and processed by dendritic cells and macrophages, which in turn present it to T lymphocytes.

The interaction of the antigen-presenting cell (APC) with CD4+ lymphocytes stimulates the synthesis of the corresponding cytokines. Interleukin-2, produced during 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 and enhances the growth of B lymphocytes. The latter leads to uncontrolled synthesis of immunoglobulins G (IgG) by plasma cells, increases the activity of natural killer cells (NK) and activates macrophages. Interleukin-4, synthesized by Th2 cells, leads to activation of the humoral component of immunity, manifested by the synthesis of antibodies, as well as to the activation of eosinophils, mast cells and the development of allergic reactions.

Activated T-lymphocytes, macrophages, fibroblasts and synoviocytes also produce proinflammatory cytokines, which play a leading role in the development of systemic manifestations and the maintenance of chronic inflammation in the joints.

The various clinical and biological manifestations of systemic juvenile rheumatoid arthritis, including fever, rash, arthritis, lymphadenopathy, muscle wasting, weight loss, anemia, acute phase protein synthesis, activation of T and B cells, fibroblasts, synovial 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-6).

Proinflammatory cytokines not only determine the development of extra-articular manifestations, but also the activity of rheumatoid synovial fluid.

Rheumatoid synovitis from the first manifestations tends to become chronic with subsequent 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 joint is caused by the formation of 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, granulocytomacrophage colony-stimulating factor and IL-b. Pro-inflammatory 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 membrane 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 proteolytic enzymes, which enhances the process of cartilage and bone resorption. In juvenile rheumatoid arthritis, not only cartilage but also bone can be destroyed at a distance from the pannus due to the influence of cytokines produced by immunocompetent cells and synovial membrane cells.

T-lymphocytes stimulated during the immune reaction produce osteoclast-activating factor, which increases osteoclast function and thereby increases bone resorption. The release of this factor is enhanced by prostaglandins. Their production in juvenile rheumatoid arthritis is significantly increased by various 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 the joints, extra-articular manifestations and disability of patients. Considering 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 achieved only through pathogenetic therapy, purposefully influencing the mechanisms of its development, in particular suppressing abnormal reactions of the immune system.

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