1.1.4. Age features of rheumatic diseases at children. JUvenilnyj a pseudorheumatism: clinico-pathogenetic variants

JUvenilnyj the pseudorheumatism is the general term for arthritises which begin aged till 16 years and remain within more than 6 weeks. JURA is the most widespread chronic rheumatic disease at children and is one of principal causes of an invalidism [29].

The American board of rheumatologists allocates three basic clinical variants JURA: oligoartrit, a polyarthritis and a system variant of illness [6]. Heterogeneity JURA assumes, that various factors bring the contribution to a pathogenesis of the given disease. Though the exact mechanism leading to development JURA remains to unknown persons, proinflammatory cytokines are responsible, at least, for a part of clinical implications at all types JURA.

Sinovialnye covers of patients JURA contain activated T - and In - lymphocytes, plasmocytes and the activated macrophages which are involved by means of intensive process of a neovascularization. Cells of immune system, including activated sinovialnye fibroblasts, chondrocytes and osteoclasts, initiate a destruction of a cartilage and an osteal tissue. It has been established, that "recruitment", activation and effektornaja function of each of these lines is carried out, mainly, through a network of cytokines [85]. The T-cage Antigen-specific, most likely, play the central role in an arthritis pathogenesis. T-cellular infiltrates consist basically from T-helperov 1 (Th1) cells which express the high
Concentration of receptors of chemokines [178,200]. Th1 cells stimulate In - cells, monocytes, macrophages, and sinovialnye fibroblasts which, in turn, develop immunoglobulins and inflammation mediators. The activated V-cages produce immunoglobulins, including the rhematoid factor (Russian Federation) and antinuclear antibodies. The exact pathogenetic role of the Russian Federation remains to the unknown person, but it can lead to activation of system of a complement by formation of immune complexes. Antinuclear antibodies which basically are bound oligoartriticheskim by a beginning variant as it is informed, operate against the various nuclear targets, any of which is not specific for RA. The activated macrophages, lymphocytes and fibroblasts, and also their products, including the factor of growth of an endothelium of vessels (VEGF) and osteopontin, can stimulate an angiogenesis. VEGF expresses at high level in sinovialnoj tissues while osteopontin raises in sinovialnoj liquids and tissues, and correlates with "new" vascularization [61,212].

FNO and ИЛ-1, produced by the activated monocytes, macrophages, and sinovialnymi fibroblasts, most likely, play the basic role in pathogenesis RA. These cytokines are found out in sinovialnoj a liquid or tissues of the majority of patients with RA and, as is known, stimulate mesenchymal cells, such as sinovialnye fibroblasts, osteoclasts and chondrocytes, to liberate blasting tissues matrix metalloproteinazy [142,174,217]. FNO and ИЛ-1 also suppress production of fabric inhibitors metalloproteinaz sinovialnymi fibroblasts. In aggregate, this double action leads to damage of joints. Really, data of researches on animal models convincingly testify that FNO and ИЛ-1 play an essential role in pathogenesis RA. For example, at transgene mice which expressed a noncontrollable human FNO gene, the inflammatory and destructive polyarthritis similar RA [228] spontaneously developed.

It has been shown, that introduction ИЛ-1 in knee joints of rabbits leads to cartilage degradation while, introduction of antibodies against ИЛ-1 reduces damages of a cartilage [16,175].

Pseudorheumatism one of the first diseases at whom substantial growth of expression ИЛ-6 has been described, both in plasma, and in sinovialnoj liquids [173]. ИЛ-6 represents a multipurpose cytokine which possesses a wide spectrum of biological activity on various cells-targets and regulates the immune answer, reactions of an acute phase of an inflammation, a hemopoiesis and a metabolism of an osteal tissue [166]. IL-6 a small polypeptide from the big family of cytokines, such as ИЛ-11, kardiotropin-1 (CT-1), kardiotropin a similar cytokine (CLC), nejropoetin (NPN), onkostatin M (OSM), extended recently at the expense of including ИЛ-27 and ИЛ-31. All of them share very widespread cellular receptor presented practically on all cells: gp130, capable to transfer an intracellular signal by means of fosforilirovanija their intracellular the domain assotsiirovannyh proteins. However ИЛ-6 it is not capable to contact gp130 for lack of the second specific receptor known as SILT-BI which expression becomes perceptible in hepatocytes, neutrophils, monocytes/macrophages and some lymphocytes [126]. Its level in a blood plasma varies quickly in the same direction, as activity, gravity and the answer to therapy, the same as also its indirect marker C-reactive fiber [17,201]. Main effects of system augmentation ИЛ-6 at RA are growth of level of fibers of an acute phase and, hence, a secondary amyloidosis, an anaemia of chronic diseases and, probably, system osteoporosis and augmentation of risk of a lesion of vessels [25,45,87]. In sinovialnoj tissues as mononuclear cells, and sinovialnye fibroblasts or sinoviotsity bring the contribution to superfluous synthesis ИЛ-6 [64]. Hyperplasia sinoviotsitov, action of cytokines, such as the TNF and ИЛ-1 on them (sinoviotsity) and, at last, stable fenotipicheskie changes, promote overproduction ИЛ-6 in these cells [154]. Many cells involved in a synovitis (chondrocytes, sinoviotsity,
Fibroblasts, endothelial cells) have no SILT-BI and, nevertheless, are sensitive to influence ИЛ-6 through the trans-alarm mechanism. In an articulate liquid there is a set soluble SILT-BI which are produced by leukocytic infiltrates, guaranteeing action ИЛ-6 on all these cellular elements [125]. Local or system effects Silt on cells of immune system, autoimmune V-cages or various populations T - cells it is not known in context RA. Nevertheless, its functions in these cells and researches in models of an arthritis at animals well-known in a general view that allows to predict theoretically action ИЛ-6 on T - and the V-cages participating in pathogenesis RA. Silt is capable to cause growth and a survival of plasmocytes and to induce synthesis of antibodies - 2 effects which can locally or is system to promote maintenance rhematoid autoimmune the answer [171].

Recently new forms proinflammatory effektornyh the T-cages named T-helperami 17 (Th17) have been described. ИЛ-17 it is made Th17 and stimulates reactions of many tissues in connection with a wide circulation of receptors of this cytokine. Last data testify that the Silt - 17 produced Th17 by cells, plays very important role in a pathogenesis of an autoimmune inflammation [8б, 198]. In particular, ИЛ-17 promotes production of proinflammatory cytokines in joints, stimulating manufacture FNO and ИЛ-1 macrophages and synergetic augmentation of production Silt and ИЛ-8 [59,105,139]. Besides, ИЛ-17 brings the immediate contribution to destruction of joints, raising production matrix metalloproteinaz and stimulating osteoklastogenez, activating through receptors an induction of the nuclear factor - kv ligand (RANKL) [39,103,215]. ИЛ-17 it is raised at patients with active form RA in comparison with patients in a remission stage [2б]. Data of researches on animals also show, that ИЛ-17 plays the important role in a cartilage destruction. For example, ИЛ-17-дефицитные mice have shown fastness to development collagen-induced of an arthritis [211]. Besides, an inflammation
Joints, cartilages and an osteal destruction choked after introduction анти-ИЛ-17-antibodies to mice about collagen-induced with an arthritis [229].

Two most known antiinflammatory cytokines bound with RA, are ИЛ-10 and ИЛ-4. It has been shown, that ИЛ-10 causes processes return destructions of a cartilage mediated an antigen - stimulirovannymi mononuclear cells in adult patients with an arthritis [187]. Besides, depression of production ИЛ-10 is bound to more serious type of an arthritis [180]. ИЛ-4 suppresses activation Th1 of cells, that in turn, reduces production FNO and ИЛ-1 and interferes with damage of a cartilage [188]. ИЛ-4 and ИЛ-10 co-operate with a view of inhibition of production of proinflammatory cytokines, including ИЛ-6 and ИЛ-8 [120]. Higher levels ИЛ-4 and ИЛ-10 mrnk are defined at softer not erosive a current oligoartrita [121].

Difference of system form JURA consists in absence of communication with HLA-type and absence of autoantibodies or autoreaktivnyh T-cages [164,192]. Thus, patients with a system variant of the beginning of disease do not have signs of the immune answer limfotsitarno-mediated an antigen-specific. Instead of it, typical clinical signs of the system form of disease assotsiirovany with granulotsitozom, thrombocytosis, and rising of level of fibers of an acute phase which specify in uncontrollable activation of immune system [11,66,157,177]. During initial implications and general disease attacks, perivascular infiltration by neutrophils and the monocytes producing proinflammatory cytokines, participating in a pathogenesis of this disease [51] takes place. Prevailing role of native immune system in development of system form JURA the high expression and serumal concentration also underlines calcium-binding of fibers S100A8, S100A9 and S100A12 which are specifically allocated at activation of neutrocytes and monocytes [65]. Extremely high serumal concentration of these fibers are closely bound to activity system
Forms JURA, also have not been found out in patients with other forms of an inflammation of joints or others autoimmune and infectious diseases [б2,15б]. S100 fibers possess proinflammatory action on leucocytes and endothelial cells, and, thus, can be immediately involved in inflammatory process at the system form [1б0,17б].

Last data show, that ИЛ-1 plays the important role in a pathogenesis of the system form of disease. It has been shown, that treatment by means of antagonists of receptors ИЛ-1 reduces clinical and laboratory implications of activity of disease at patients with system a variant of beginning JURA which are steady to anti-fno therapies [198]. Besides, activated monocytes at patients with a system variant of the beginning allocate considerably larger quantity ИЛ-1 in comparison with the level allocated with monocytes of healthy people while production FNO essentially does not differ between these groups. It has been established, that one more member of family of cytokines ИЛ-1 - ИЛ-18 is extremely raised at patients with adult variant Stilla, in comparison with its level at patients with various other rheumatic diseases and at healthy people. So sharp augmentation of concentration ИЛ-18 was revealed in blood serum at children with system variant JURA, while its levels at children with a polyarthritis or oligoartritom slightly above, than at healthy children [124]. Besides, concentration ИЛ-18 it is appreciable above at patients with any serositis or gepatosplenomegaliej, than at patients without these implications [100]. Concentration circulating Silt is considerably enlarged at patients with system form JURA and correlates with degree of a lesion of joints [40,203]. Besides, concentration Silt considerably above in sinovialnoj liquids of patients with the system form, than at patients with other forms JURA [49]. The hyperproduction Silt can explain many of extraarticular implications of this disease, including an anaemia and retardation of growth [47,111]. Treatment by means of the monoclonal antibodies referred against receptors ИЛ-6
It is bound to the expressed clinical improvement and restoration of normal level of fibers of an acute phase at patients with system variant JURA [224].

Clinical and pathological implications of a syndrome of activation of macrophages (MAS) as believe, grow out of activation and uncontrollable proliferation T-limfotsitov and vysokodifferentsirovannyh macrophages that leads to unlimited remission of proinflammatory cytokines, such as FNO, ИЛ-1 and ИЛ-6. Nevertheless, the reason of the immunologic disturbances bound with MAS is unknown. The last researches have shown the expressed depression of function of normal killers (NK-cages), and in some cases, expression depression perforina at patients with system variant JURA [161,194]. Also it has been defined, that the macrophages participating in a hemophagocytosis express on surface CD163 - a receptor which binds a complex haemoglobin-gaptoglobin and starts the mechanism important for adaptation to the oxidising stress induced by free iron. The augmentation of number of these macrophages, observed more than at 30 % of patients with system form JURA, can represent an early stage of a syndrome of activation of macrophages [81].