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In-dept study The Immune Antinfectious Reaction in the Atherogenetic Process Author: Angelo MICOZZI E-mail: [email protected] The assessment criteria of chronical diseases adopted by Hahnemann is requited by basic research in modern immunopathology. According to the original homeopathic model, chronical diseases are triggered by an infectious process determining a gradual and increasingly serious alteration of an individual’s vital force. This alteration is expressed through an evoluting symptomatology and can be easily compared to the immune reaction by which an individual interacts in a specific way with the triggering pathogenic agent. Based on this model, the role of infectious agents is not determinant to the pathogenetic consequences, but it is mediated by a specific immune reaction and provides a good example of pathologic model shared by homeopathic methodology. Atherogenesis is an evoluting process that can be effectively studied and evaluated in the light of modern immunopathological findings and provide an interesting reading for the chronical disease model called psoric by Hahnemann. The atherogenetical mechanism shows a typical, slow evolution: a “clinical” silence [1] very similar to what Hahnemann says on psoric latency [2] in its general aspects. In fact, this latency shows itself through a minimum, often not emphasised, symptomatology, to which the patient adjusts due to its slow and gradual course [3]. Its clinical expression can be chronical, as in stress angina or claudicatio intermittens - as the atherosclerotic lesions increase their seriousness - but sometimes it expresses itself through a dramatic and acute event, such as myocardial infarction and ictus. Atherosclerosis is best known as an occlusive event due to stenotic lesions limiting arterial blood circulation. However, vascular walls ectasias are not unlikely to be found, and an aneurismatic disease is often developed especially in major arteries such as aorta [4]. Atherosclerotic lesions are caused by a focal storage of lipoproteins in the arterial intima. These lipoproteins carry molecules of lipids such as cholesterol and triglycerides, together with proteins and phospholipids enabling their blood solubility. Lipoprotein storage is realised through their link with some elements of arterious extracellular matrix, especially proteoglycans. This causes an increase in their permanence in the intima, which in turn generates a series of modifications needed for the gradual development of lesions. Lipoproteins, LDL (Low Density Lipoproteins) in particular, oxidize very easily. The storage of oxidized LDL represents the first and main phase in the atherosclerotic mechanism. In a subsequent phase, monocytes and lymphocytes are recruited, which link to adhesion molecules (especially ICAM-1, also called CD54) [5], present on the endothelium surface. This is a typically inflammatory event that shows an increased number of cytokines in the lesion site, cytokines of the acute phase, such as IL-1 and TNF. If the presence of lymphocytes is a signal of a specific immune reaction to possible pathogenic agents involved, monocytes have a twofold role. Besides their phagocytizing function, they differentiate themselves into macrophages and tend to undergo a subsequent transformation into foam cells. This transformation depends on the insertion of oxidized LDL into the cells, whose functional meaning can be seen as an attempt to rinse lipids in their intimal storage. Contrary to expectations, LDL endocytosis within the macrophages is strictly linked to a reduced expression of their receptors. The latter belong to a family of molecules © OmeoNet, 2: 10-11. Page 1/2 whose most significant representative is CD36, present on the macrophagus membrane [6]. In a subsequent phase to the LDL storage, macrophages stimulate the proliferation of smooth muscular cells and addition of extracellular matrix in atherosclerotic plaques through the production of some growth factors such as PDGF (Platelet-Derivated Growth Factor) and FGF (Fibroblast Growth Factor). If we carefully read the pathogenetic mechanism of atherosclerosis, we must consider LDL receptors as the key molecules of the whole process. Two classes can be observed in the family of these receptors, called “scavenger A and B” and showing different functions. Class “A” receptors enable the degradation of oxidized LDL in peritoneal macrophages, whereas class “B” receptors have an impact on the degradation at hepatic level, mainly helping the metabolism of cholesterol esters from HDL (High Density Lipoprotein). A diet rich in cholesterol provokes an 80% reduction of B receptors in the liver [7]. The main representative of B receptors is a small 88kD glycoprotein, called CD36, that penetrates the membrane of macrophages. CD36-null strains show a 76.5% increase in aortic atheromatosic lesions [8], in a highly variated diet (i.e. a diet rich in fat). Moreover, recent studies have shown that a reduced CD36 expression is associated to a LDL increase also in human beings [9]. The pathogenetic role of infectious and inflammatory processes in the deregulation of LDL receptors was hypothesised long ago. An elegant experimental model with Syrian hamsters the inoculation of bacteric LPS (lipopolysaccharides) and zymosan, aiming respectively at reproducing infectious and inflammatory conditions - showed that oxidised LDL levels were 4-6 times higher than controls. Among the infectious agents who cause an increase in oxidised LDL, Chlamydia pneumoniae has undoubtedly raised the attention of many researchers. Assumed for a long time as the cause of atypical pneumonia, this intracellular-forced bacterium causes several chronical effects [10], among which atherosclerosis. One of the most important phases of this process seems to be the interaction between chlamydia and monocytes/macrophages, whose final event is the creation of foam cells. In this matter, two pathogenetic mechanisms can be observed: the direct action of bacteric lipopolysaccharides, if LDL are present, and the action of Hsp60 (heat shock proteins of chlamydia), the latter contributing to the oxidation of low density lipoproteins. Contrary to expectations, the entrance of LDL in the macrophages is independent from their link with scavenger receptors [11]. This can be explained by saying that receptors bind themselves only to non-oxidised lipomolecules and prevent endocytosis. To this end, the interaction between chlamydia pneumoniae and the scavenger receptor could have a key role [12]. Also cytomegalovirus (CMV) was related to atherogenesis, especially in young patients. Many epidemiological studies, animal models and molecular analysis confirm this assumption since they show the presence of viral Dna in atherosclerotic lesions [13]. Serocholesterol concentrations appears to be strictly related to the IgG antibody positivity of CMV. This aspect offers an interesting scenario on the role of the specific immune reaction in the pathenogenesis of many diseases, including atherosclerosis. All epidemiological studies underline the strict relation between the infectious memory, expressed in permanent IgG immunoglobulins, and the atherogenetic mechanism. According to homeopathic methodology, the idea of persistent infectious agent has been known for a long time [14], as the ensuing alteration of the vital force, which can be represented as the modification of the balance preexistent to infection, for many aspects similar to the immune reaction. In particular, IgG seropositivity in Chlamydia pneumoniae is now considered as an important risk factor in coronary artery diseases, because of its high association with the lipidic profile and its procoagulant activity [15]. Elegant animal models suggest that the immunitary reaction to CMV has a role in the aetiopathogenesis of vascular damage, especially as concerns the high endothelial sensitivity to infection [16], also when viral Dna is not present in the atherosomatic site. Similarly, other works show that the presence of specific IgG to Helicobacter pylori and HAV (hepatitis A virus) has a significant role in the formation of atherosomatic plaques [17]. To stress how the immune reaction affects the pathologic process, intimal lesions have revealed to contain T specific lymphocytes able to react to Chlamydia pneumoniae antigens [18]. This specific reaction seems to occur also in thromboembolic venous disease [19]. Some Authors stressed also the possible antigenic similarity between Chlamydia and some lipoproteins, with creation of immunocirculating complexes, containing specific IgG, that increase the risk of atherogenesis [20]. Chlamydia pneumoniae can infect many cells, among which monocytes © OmeoNet, 2: 10-11. Page 2/2 and macrophages, who play a fundamental role in the development of atherosclerosis. The infectious persistence inside the macrophages allows the maintenance of a local immune reaction, mediated by T specific lymphocytes [21]. The pathogenic model of atherosclerosis shows very interesting similarities with the methodology left by Hahnemann and used to study chronical diseases. According to this analogy, whose characterising element is the infectious trigger, a drug offering a good similarity with the patient’s general symptomatology and with aetiologic elements of atherosclerosis can be detected. We have seen that Chlamydia pneumoniae has a clear role in the specific activation of this process, inducing an immune reaction that can be considered the real atherogenetic boost. Following Hahnemann’s anti-infectious “specific” remedy, the study of medical issues allows us to detect a drug having an action on anti-chlamydia immune reaction. We have proposed for long time the use of nitric acid, in LM potency, with the aim of seroconverting specific IgG and IgA antibodies of both Chlamydia pneumoniae and thrachomatis [22]. This study aims at proposing a clinical experimentation on the effects of nitric acid in reducing the quantity of LDL, in presence of IgG/IgA anti-chlamydia pneumoniae antibodies. Our initial data enable us to stress the efficacious action of this drug not only on LDL reduction, but also on the seroconvertion of antibodies. Bibliografy [] Libby P. Atherosclerosis, in: Harrison's Principles of Internal Medicine. McGraw-Hill, New York, 14° ed.: 1346. [2] Hahnemann S. Chronic Diseases: their peculiar nature and their homeopathic cure. B. Jain Publishers, New Delhi, 2° edition; vol. I: 44. [3] Micozzi A. Il periodo di latenza: Psora latente, in: Infezioni Croniche in Omeopatia. Verduci Editore, Roma: 46. [4] Lindholt JS, et al. Vascular surgical society of great britain and ireland: immunoglobulin A antibodies against chlamydia pneumoniae are associated with expansion of small abdominal aortic aneurysms and declining ankle blood pressure. Br J Surg 1999 May; 86(5): 698. [5] Micozzi A. Immunofarmacologia omeopatica. Edi-Lombardo, Roma, 2000: 59-60. [6] Nicholson AC, et al. CD36 in atherosclerosis. The role of a class B macrophage scavenger receptor. Ann N Y Acad Sci 2000 May; 902: 128-31; discussion 131-3. [7] Van Berkel TJ, et al. Scavenger receptor classes A and B. Their roles in atherogenesis and the metabolism of modified LDL and HDL. Ann N Y Acad Sci 2000 May; 902: 113-26; discussion 1267. [8] Febbraio M, et al. Targeted disruption of the class B scavenger receptor CD36 protects agaisnt atherosclerotic lesion development in mice. J Clin Invest 2000 Apr; 105(8): 1049-56. [9] Yanai H, et al. Human CD36 deficiency is associated with elevation in low-density lipoproteincholesterol. Am J Med Genet 2000 Aug 14; 93(4): 299-304. [10] Memon RA, et al. Infection and inflammation induce LDL oxidation in vivo. Arterioscler Thromb Vasc Biol 2000 Jun; 20(6): 1536-42. [] Byrne GI, Kalayoglu MV. Chlamydia pneumoniae and atherosclerosis: link ti the disease process. Am Heart J 1999; 138(5 Pt 2): S488-90. [2] Kalayoglu MV, et al. Characterization of low-density lipoprotein uptake by murine macrophages exposed to Chlamydia pneumoniae. Microbes Infect 1999 May; 1(6): 419-18. [3] Kalayoglu MV, Byrne GI. Induction of macrophage foam cell formation by Chlamydia pneumoniae. J Infect Dis 1998 Mar; 177(3): 725-9. © OmeoNet, 2: 10-11. Page 3/2 [4] Froberg MK, et al. Cytomegalovirus seropositivity and serum total cholesterol levels in young patients. Ann Clin Lab Sci 2001 Apr; 31(2): 157-61. [5] Hahnemann S. Chronic Diseases: their peculiar nature and their homeopathic cure. B. Jain Publishers, New Delhi, 2° edition; vol. I: 37. [6] Kaftan AH, Kaftan O. Coronary artery disease and infection with chlamydia pneumoniae. Jpn Heart J 2000 Mar; 41(2): 165-72. [7] Zhou YF, et al. Chronic non-vascular cytomegalovirus infection: effects on the neointimal response to experimental vascular injury. Cardiovasc Res 2000 Mar; 45(4): 1019-25. [8] Zhu J, et al. The possible role of hepatitis A virus in the pathogenesis of atherosclerosis. J Infect Dis 2000 Dec; 182(6): 1583-7. [9] Curry AJ, et al. T lymphocyte lines isolated from atheromatous plaque contain cells capable of responding to Chlamydia antigens. Clin Exp Immunol 2000 Aug; 121(2): 261-9. [20] Lozinguez O, et al. Demonstration of an association between Chlamydia pneumoniae infection and venous thromboembolic disease. Thromb Haemost 2000 Jun; 83(6): 887-91. [21] Glader CA, et al. The proatherogenic properties of lipoprotein(a) may be enhanced through the formation of circulating immune complexes containing Chlamydia pneumoniae-specific IgG antibodies. Eur heart J 2000 Apr; 21(8): 639-46. [22] Airenne S, et al. Chlamydia pneumoniae infection in human monocytes. Infect Immun 1999 Mar; 67(3): 1445-9. [23] Micozzi A. Discorso sul metodo, in: Immunofarmacologia omeopatica. Edi-Lombardo, Roma, 2000: 23. © OmeoNet, 2: 10-11. Page 4/2