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BACKGROUND: Adiponectin (AN) is a protein synthesized by adipocytes that has regulatory effects on lipid and lipoprotein metabolism, increases tissue sensitivity to insulin, and modulates endothelial functions and inflammatory response. However, its involvement in the processes of atherogenesis remains poorly understood. OBJECTIVE: To determine the localization and sources of AN in atherosclerotic and normal human aortic intima. MATERIAL AND METHODS: Immunohistochemical study was performed on sections of atherosclerotic and normal human aorta obtained during autopsy. Reverse transcription real-time PCR was performed using biopsies of para-aortic and abdominal adipose tissue, intima-media of the thoracic aorta, atherosclerotic plaques of the human carotid and femoral arteries, as well as on endothelial cells isolated from the human thoracic aorta. Transendothelial transport of AN was evaluated in a two-chamber model using a monolayer of human endothelial cell hybridoma EA.Hy926. RESULTS: It has been established that AN is present in atherosclerotic but not in normal human aortic intima. At the same time, AN ADIPOQ mRNA was not detected either in the intima media of the human aorta, nor in isolated endothelial cells of the aorta, nor in cells of atherosclerotic plaques of the carotid and femoral arteries. AN slowly penetrated the endothelial monolayer in vitro, but this transport was significantly enhanced by the action of tumor necrosis factor-alpha (TNFa). CONCLUSION: Obtained data indicate that AN is present in atherosclerotic but not in normal aortic intima. We assume that AN is not synthesized by the cells of normal and atherosclerotic arterial walls, but permeates from the plasma. Transendothelial transport of AN, like many other plasma proteins, is activated during the development of atherosclerotic lesions, apparently under the action of pro-inflammatory cytokines, in particular, TNFα.

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Comparative study of the walls of the aorta, coronary artery, and a. basilaris detected for the first time intra- and extracellular depositions of Chlamydia pneumoniae in unstable atherosclerotic plaques. No chlamydia were detected in the intima of normal sites of the vascular wall and just negligible levels thereof in stable atherosclerotic plaques. An unstable plaque with intra- and extracellular colonies was characterized by infiltration of the cap and intima adjacent to the atheromatous core with mononuclear cells, primarily T cells. These data suggested that Chlamydia pneumoniae could play an important role in the development of immunoinflammatory processes in the vascular wall and promote destabilization and progressive development of atherosclerotic plaques in humans.

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Precise location of IL-18 in cell and tissue elements of the atherosclerotic lesions in humans and its role in destabilization of the atherosclerotic plaque were detected. The data suggested a hypothesis on indirect involvement of IL-18 in destruction of the elastic and collagen fibers in an unstable plaque due to this cytokine capacity to induce the production of IFN-γ in T cells and macrophages, this eventually leading to inhibition of collagen and elastin synthesis in smooth muscle cells of the vascular wall and to loosening of the plaque cap.

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The combination of HSP60-specific humoral and cellular reactions is handled as the new diagnostic sign, reflecting the risk of the development of atherosclerosis, which is independent of other classic risk factors. Chaperones are identified as important pathogen-related antigens used to design vaccines against atherosclerosis. The high evolutionary homology of HSPs raises the issue on the safety of such vaccines.

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Whether antigens are involved in the development of arterial atherosclerotic lesions is discussed. The complex of antigens determines the course of atherosclerotic lesion. By acting on the antigens, it is possible to prevent atherosclerosis and to induce its regression. The methodology for studying atherosclerosis and many other diseases is shown to be difficult and multifaceted and need the participation of specialists of diverse specialties in the solution of the problems associated with the treatment of atherosclerosis.

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Five known to-day causes of the isolated aortal valve stenosis are reviewed: 1) atherosclerosis, 2) premature calcinosis of congenital bicuspidalis aortal valve; 3) rheumatism; 4) infectious endocarditis; 5) mesenchymal dysplasia. The authors consider that aortal valve calcinosis developing against the background of valve atherosclerosis complicates the above diseases and differential diagnosis of aortal stenosis causes.

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The paper demonstrates that lymph nodes situated in the vicinity of magistral blood vessels are the source of immune and inflammatory response to LDL as the main pathogenetic factor in atherosclerosis. The activation of T-cell-mediated immunity takes place in them at the very early stages of the disease, resulting in forming of CD4+T-lymphocytes, activated mononuclear cells and immunostabilizing B-lymphocytes. The cell changes in lymph nodes correlate with the severity of atherosclerotic lesions in the vessel intima and closely reflect the peculiarities of immune inflammation development in fatty streaks and atherosclerotic plaques in human atherogenesis. A paradoxical reaction was observed in cases with Chlamydia pneumoniae found in the wall of aorta and paraaortal lymph nodes. No evident immune response on the part of immunocompetent cells took place, but, on the contrary, the function of mononuclear cells, including T-lymphocytes, was suppressed. This phenomenon may be explained by the fact that intracellular localization of Chlamydia pneumoniae hides it from immune system control or by the possible microorganism capability of direct immunosuppressive influence on lymphoid cells both in the blood vessel wall and in regional lymph nodes.

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The role of immune inflammation at atherogenesis is studied in the paper. Two etiological factors of atherosclerosis pathogeny are under examination: the role of modified low density lipoproteins (mLDL) and essential parasites (Chlamydia pneumoniae and Cytomegaloviruses). Generality of immune response during persistent infection into a blood vessel wall and deposit or formation of mLDL are discussed. The point of view is substantiated that the development of atherosclerotic damages of blood vessels is speeded up by a combination of the two mentioned etiological factors.

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The content of lymphocytes producing different classes of immunoglobulins (IgA, IgM and IgG) and immunoregulatory T cell subpopulations (CD3, CD4, CD8) was assessed in structural components of T- and B- zones of lymph nodes of visceral and somatic groups and spleen in man. Forensic autopsy material obtained from 48 men of 2 age groups: 31-60 and 61-75 years was studied. The absence of direct correlation between the quantity of plasma cells in B-zone of peripheral lymphoid organs and their functional activity was shown. The results obtained may serve as an initial point in studying immunomorphological reorganizations of human peripheral lymphoid organs in development of immunopathological processes.

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Data from literature are given on the role of "acute phase" proteins in inflammation and their connection with lipoproteins. Intensive production of acute phase proteins is shown to take place in modelling of experimental atherosclerosis. The hypothesis is proposed that allows to consider the acute phase reaction of the liver as a very important condition of modified lipoproteins formation acquiring autoantigenic properties.

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The paper summarizes the data on the role of immunoglobulin Fc-receptor proteins of group A streptococci as one of the leading agents of the pathogenicity that initiates severe poststreptococcal complications in the comprehensive immunological and morphological study of acute experimental glomerulonephritis. In addition to some pathogenic effects, evidence is presented for the capacity of IgG FcR-positive, rather than IgG FcR-negative, group A streptococci of inducing the synthesis of great quantities of anti-IgG which has been detected both in free circulation and as part of immune complexes. IgG FcR proteins induced the release of antiinflammatory cytokines (TNF-alpha in particular) and anti-IgG FcR proteins, concurrently with complement C, formed deposits in the structures of glomerules, resulting in destructive and degenerative changes. The morphological criteria for delayed hypersensitivity processes, which are typical of inflammatory reactions in immunopathologies are discussed in the paper. Immunomorphological and electron microscopic studies at early stages revealed signs of membrane-proliferative glomerulonephritis with a predominant response of podocytes and mesangial cells, which later progressed to developed fibrous, atrophic, glomerulonephritis. It should be stressed that IgG FcR proteins, such as A and G staphylococcal protein, group G streptococcal protein, unlike group A streptococcal protein with the similar function either failed to cause the described events or the latter occurred rarely or delayed. The findings provide evidence for the author's concept of the role of IgG Fc-receptors of group A streptococci in the development of complications of streptococcal etiology.

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The composition and functional activity of lymphocytes populating T- and B-zones of human lymph nodes and spleen in atherogenesis were studied. Structural, functional alterations first involved T- and B-zones of the spleen and para-aortal lymph nodes this being probably conditioned by immune response to formation of autoantigenic forms of apoB-containing lipoproteins. Along with the development of atherosclerotic damage to the arteries the immunomorphological restructuration became more generalized and could be observed in the lymph nodes non-regional to the aorta. These changes were obviously connected at a higher degree with the development of sensitization to the vascular wall antigens.

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Immunomodulating drug tactivin was used for treatment of 29 IHD patients with low T-suppressor activity and high cell sensitization to apoprotein B-containing lipoproteins and with lipoprotein-antibody immune complex detected in the blood. Tactivin was injected subcutaneously in the dose 10 micrograms (5 injections for 12 days). Tactivin treatment normalized T-suppressor activity, lowered concentration of plasma lipoprotein-antibody immune complex and improved clinical course of IHD. The beneficial effect of tactivin was observed in 70% of patients during 2 months. 30% of patients needed a second course of treatment of recover normal immunological and clinical indices. The treatment with tactivin of IHD patients must be combined with application of routine antianginal drugs.

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A comprehensive clinicoimmunological examination was made of 105 male patients aged 35-65 years who suffered from coronary heart disease. The authors identified a group of 33 patients whose unstable course of angina pectoris was associated with pronounced apolipoprotein B sensitization, as well as with the presence of the autoimmune lipoprotein-antibody complex and abnormalities in the cellular link of immunity. All 33 patients received antianginal agents. Out of them, 15 patients took additionally a course of T-activin therapy to modulate immunological shifts. The results of the examination demonstrated that the immunomodulator exerted a beneficial effect both on the course of CHD (reduction in the number of anginal episodes, improvement of left ventricular contractility) and the immune system (recovery of T-suppressor function, disappearance of lipoprotein sensitization, decrease in the patient's blood detection rates of the autoimmune lipoprotein-antibody complexes from 83 to 28%). The highest effect was reached by T-activin 1.5-2 months following termination of the course therapy. Immunomodulating therapy is regarded as an additional approach to the treatment of CHD patients with marked lipoprotein sensitization.

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