CC BY
13
Neurotrophic factors and steroid hormones interact in the processes of regulation of various neuronal processes, such as the growth of neurites, differentiation and neuroprotection. The use of testosterone for therapeutic purposes protects motor neurons from atrophy caused by the death of adjacent motor neurons.
There are studies that androgens greatly contribute to the reorganization of the neural chains of the spinal cord of adults, in particular, are crucial for maintaining the organization of synaptic inputs of spinal motor neurons. Androgens provide neuroprotection of CNS neurons due to the lack of growth factors in apoptosis. Androgens can affect the turnover of a cytoskeleton matrix responsible for the structure of the axon. Testosterone has a neuroprotective effect in nerve fibers and the testosterone deficiency can lead to various forms of degeneration of the nerves, which may ultimately result in even anatomical changes. Neuroprotective effects are manifested at the physiological concentration of the hormone and due to the interaction with the receptors of androgens. Some data suggest that neuroprotection of androgens may be mediated by the mitigation of oxidative stress. Thus, directly through membrane or nuclear receptors, or indirectly by metabolic effects, androgens affect all the links in the somatic reflex arc. However, very few studies show the peculiarities of their functioning, in vivo, and electrophysiological studies have almost not been conducted, which provides the basis for further searches for answers to questions about the influence of male sex hormones on the nervous system. Key words: testosterone, androgens, receptors, nervous system, neuron, axon.
Рецензент - проф. Мщенко I. В. Стаття наджшла 22.01.2019 року
DOI 10.29254/2077-4214-2019-1-1-148-65-70 UDC 616.832-004.2
Filenko B. M., Roiko N. V., Proskurnia S. A., Sovhyria S. M., Vynnyk N. I.
MULTIPLE SCLEROSIS: SOME ASPECTS ON PATHOGENESIS AND MORPHOLOGY Ukrainian Medical Stomatological Academy (Poltava)
Publication relation to planned scientific research projects. This work is part of the scientific theme "Patterns of morphogenesis of organs, tissues and vascular-nerve formations are normal, with pathology and under the influence of external ones factors" № 0118U004457.
Multiple sclerosis (MS) is a chronic, progressive de-myelinating disease of the central nervous system.
It affects mostly young people of working age with the peak incidence at the age of 20-40 years. MS is more often observed in women and manifests 1-2 years earlier than in men [1]. The publications report that the incidence of MS is progressively growing from year to year, especially in economically developed countries. The prevalence of this disease depends on the geographic latitude, designating three zones of morbidity risk: high risk zone (more than 50 cases per 100 000 people), moderate risk zone (10-50 cases per 100 000 people) and low risk zone (less than 10 cases per 100 000 people). Notably, Ukraine is located on the border of the high and moderate risk zones, and the morbidity rate in Ukraine is rapidly growing. Progression of MS leads to early disability and death [2,3,4]. All these facts confirm the relevance of the problem and necessity for its comprehensive study.
Currently, the etiology of multiple sclerosis is unknown and considered as the multifactorial disease. Genetic and immunological factors, viral infection and influence of exogenous factors play the crucial role.
Genetic susceptibility to multiple sclerosis is confirmed by numerous findings of genealogical, twin and population studies. This provision is proved by the fact that the risk for MS development in monozygotic twins is 7 times higher than in dizygotic ones [2]. However, the index of MS concordance in monozygotic twins is accounted for only 25-30% that does not fit the framework of the monogenic model of inheritance and can be explained by the polygenic inheritance and genetic polymorphism, as well as the influence of external factors. This is also confirmed by the study of the MS mor-
bidity in migrants, the rate of which is dependent on the variety of medical and social factors, though its growth in migration from region with low risk to region of the high risk is self-evident [5].
It has been established that intoxication and diet are considered the most possible external factors. Recently, the impact of insolation and associated vitamin D deficiency [6,7], as the main factor of geographical dissemination, smoking [7,8] and ecological characteristics of the habitat of patients [4,9,10] have been the issue for discussion.
Viral hypothesis for the development of multiple sclerosis appears to be of main importance, since high IgG concentration to many viruses has been found in the cerebrospinal fluid and blood of more than 90% of patients with MS. Indirect evidence that MS is caused by viruses is the relation of several viruses with demy-elinating encephalopathy in people and induced demy-elination in experimental animals infected with viruses. However, none of the viruses were isolated from the brain of patients with multiple sclerosis [11].
Notwithstanding the important or even critical role of various microorganisms, only Epstein-Barr virus stands out as a consistent and strong risk factor among the infectious agents that can be related to MS. The comparison of the risk for MS in infected and uninfected people has shown that the possible onset of multiple sclerosis is 10 times higher in young people with HIV infection, whereas it is 20 times higher in people with mononucleosis in the past history. The presence of an-tigenic mimicry between the main myelin protein and Epstein-Barr virus pan-peptide has been found [12,13]. The role of other pathogens, namely, Human herpes virus 6 [14], Chlamydia pneumoniae [15], chicken pox, rubella, measles and others can be also considered [16,17]. In addition, some researchers believe the presence of inflammatory infiltrates in the brain plaques and tissue to be a strong evidence of the infectious nature of multiple sclerosis [18].
Currently, no etiological theory and unambiguous consensus on the pathogenesis of lesions in multiple sclerosis exists. Apparently, no single view on the mechanism of the onset and development of this disease is given.
Immunologists consider multiple sclerosis as an autoimmune disease when the specific T-lymphocytes that are myelin antigens activate the inflammatory response in the central nervous system, which eventually leads to demyelination and subsequent damage to the axons. Such a view on the pathogenesis of multiple sclerosis comes up from the analysis of the animal model of experimental autoimmune encephalomyelitis [19]. Unfortunately, this oversimplified view reproduces the incomplete picture of the pathogenesis of multiple sclerosis, urging the experts to conduct further searches in different directions.
Currently, the studies of the role of genetic disorders are at the forefront in the development of multiple sclerosis. This is substantiated by more frequent detection of A3, B7, DW2, DR2 antigens in patients with MS as compared with healthy people. It is hypothesized that the occurrence of certain combination of tissue histocompatibility antigents in single chromosome and gene of susceptibility to MS is crucial in the onset of the disease [20].
Consequently, the interaction of environmental factors and genetically determined susceptibility results in the initiation of immunopathological processes that are the triggering mechanism of pathogenesis of multiple sclerosis.
Currently, the pathogenesis of MS is seen as a phased process, involving the initial inflammatory phase, which is accompanied by demyelination, and the neurodegen-erative phase [21,22].
T-cells with various functional differentiation and corresponding regulatory interactions are crucial in the development of immunopathological reactions. Activation of inactive CD4 + T-cells occurs at the initial stage in the interaction of autoantigen, bound with II class molecules of the major histocompatibility complex on the antigen-presenting cells with the appropriate receptor. Subsequently, proliferation and differentiation of T-lymphocytes into effector T-helper (Th) of two types, namely, pro-inflammatory Th1 and anti-inflammatory Th2, occurs, depending on the exposure to the antigen, cytokine profile of the adjacent tissues and co-stimulation [23]. The secretion of pro-inflammatory cytokines promotes activation of B-lymphocytes, monocytes and other T-cells, which enhances the immune response [24].
Activated CD4 + T-cells, involving chemokines, adhesion molecules and proteases, penetrate through the blood-brain barrier. In the central nervous system the macrophages and microglia ensure reactivation of the T-cells, which secrete proinflammatory cytokines (interferon-y, tumor necrosis factor-a (TNF-a), lympho-toxin, etc.), potentiating the inflammatory response and enhancing the violation of permeability of blood-brain barrier [25].
Furthermore, hormonal factor plays an important role in the development and progression of immuno-pathological processes in MS, which can also explain a clear gender dimorphism of this disease. The debut of multiple sclerosis in women occurs at the age of
20 years, when the level of estradiol stabilizes, and in men the peak incidence is observed at the age of 25-30 years, which coincides with the period of maximal secretion of testosterone with its gradual decrease with age [26,27]. It has been found that lowering of the level of estrogen and testosterone is associated with increased activity of pro-inflammatory cytokines. It is confirmed by hyperproduction of interleukins (IL), IL1, IL6, IL8 and TNF-a and supported by IL2. The recovery of the level of steroid hormones leads to activation of anti-inflammatory cytokines. Noteworthy, the estriol suppresses the activity of IL2 and TNF-a, in men it increases the level of anti-inflammatory cytokine IL5, which is not observed in women. Androgens also trigger immunological cascade in response to the load by the main myelin protein, reducing the production of IL2 and TNF-a [28]. Consequently, gonadal hormones have a clear immunomodulatory action and are crucial in the pathogenesis of multiple sclerosis.
The specific pathomorphological changes in multiple sclerosis are caused by activation of immunological reactions, including macrophages, B-lymphocytes with production of antibodies, which leads to the myelin sheath damage. In the development of demyelination, antibodies activate the cascade of complement system with subsequent destruction of myelin and induction of macrophage reaction, inducing phagocytosis of damaged myelin areas [29]. Immunoinflammatory alterations and demyelination of the nerve fibers is accompanied by damage to the axons already at the early stages of the disease. The death of axons is considered a key link in the development of neurological symptoms and transformation of the remitting course into the secondary progressive one with the steady rise of the rate of invalidization [30].
Immunopathological reaction in MS leads not only to the destruction of myelin, but also to the development of vascular inflammatory and proliferative processes of the derivatives of mesenchyme and glia with subsequent formation of the multiple sclerosis plaques.
Macroscopically, no specific changes are revealed during the external examination of the brain and spinal cord in multiple sclerosis, though, sometimes, the edema and thickening of pia mater is noted. The mass of the brain can be reduced. Convolutions of brain are narrowed; sulci between them are broad and deep, indicating about growing atrophic processes. Ependyma is usually smooth, shiny, in some cases is tuberous, due to the subependimal gliosis [31].
In section, the brain and spinal cord is characterized by the presence of foci, heterogeneous in size and form that differ from normal tissue by color and texture. Fresh foci have a soft pink texture. Inactive, "old" plaque is gray with a pinkish or yellowish tinge has clear contours and dense on palpation. The dimensions of the plaques range from a few millimeters to a few centimeters; large conglomerates can be formed with the progression of the disease. Generally, plaques are located in the white matter and can rarely spread on the gray matter (cortex and subcortical nuclei). In the spinal cord and medulla oblongata the plaques are localized on the periphery and are wedge-shaped. In the cerebellum the plaques are located in the white matter near the dentate nuclei. Therefore, localization of the plaques is variable, but most often they are found paraventricularly in the sub-
ependymal portions, surrounding the lateral ventricles, in the thalami [32]. The life-time development of epileptiform or demented syndromes can be explained by the localization of the plaques in the area of the cortex of cerebrum. The following clinicomorphological forms of the disease can be distinguished, depending on the localization of the plaques in the CNS: spinal, cerebral, cerebrospinal, cerebellar, stem and optical [2].
Histologically, three types of the plaques are distinguished depending on the stage of morphogenesis: the acute plaques (active foci of demyelination), chronic (inactive foci) and chronic foci with signs of activation [31,32,33,34].
The acute active plaques are formed as a result of the acute perivascular inflammation and manifested by the destruction of myelin and brain tissue edema. Weigert stained micro-specimens of the brain have shown multiple foci of demyelination. First, the myelin sheaths swell and change their tinctorial properties; their contours are crenated and thickening along the fibers are marked. Subsequently, fragmentation and disintegration of the myelin sheaths occurs. The products of myelin disintegration are absorbed by the microglia cells, transforming into granular globules; the macrophages with foamy cytoplasm are also detected. The products of myelin degradation in the cytoplasm of the macrophages are the markers of acute demyelination. The zone of infiltration by lymphocytes and plasmacytes appears on the plaque's periphery. Such infiltrates can be found in the centre of the plaque if the blood vessel runs along its center. Usually, T-lymphocytes-suppressors and T-lymphocytes-helpers dominate around the blood vessels and on the periphery of demyelination areas, respectively. Astrocytes with thickened processes are found in the perifocal zone and scarce oligodendrocytes are found in the demyelination area.
Various interpretations of the mechanism of myelin destruction in the foci of multiple sclerosis have been proposed. Some researchers believe that the monocytes only absorb fragments of the myelin sheath, which was already disintegrated under the influence of other factors. The other ones argue that monocytes are directly involved in destruction of myelin. Clathrin-coated depressions, adjacent to the myelin sheath are found in the membrane of macrophages. Hypothetically, it in this area that Fc-dependent interaction between the antibody and the receptor occurs that leads to opsoniza-tion of the myelin by the monocytes. It has been also shown that macrophages penetrate directly into the myelin sheath, causing the formation of vesicles inside the myelin.
Chronic inactive plaque has clear borders and characterized by the increased amount of astrocytes, absence of active destruction of the myelin, decreased amount of oligodendrocytes and axonal degeneration. Lymphoplasmacytic infiltrates disappear and signs of perivascular sclerosis appear. In some cases, in the area of the plaque the processes of remyelination can be developed, resulted in the recovery of conductivity of some axons. The source of oligodendrocytes, which are responsible for remyelination, can be the mature cells that survived in the focus of lesion, or cells that migrated from the adjacent area, or young oligodendrocytes formed from the cells-predecessors. It is hypothesized that the degree of destruction of mature oligodendro-
cytes determines the potential of remyelination in the focus. Compared with normal axons, remyelinized axons have thinner myelin sheath with truncated myelin segments and dilated nodes of Ranvier.
Chronic active plaques appear on the stage of acute exacerbation of the disease and are characterized by the occurrence of circumferential chronic inactive plaque of the macrophages due to progressive disintegration of the myelin, as well as T-lymphocytes and reactive astrocytes. The first signs of damage to axons occur in these plaques in the form of swelling and fragmentation of the axial cylinders.
Apparently, the axonal changes only partially correlated with the processes of demyelination. Their close relationships with the prominence of the inflammatory process are markedly expressed [35]. Morphological study of foci of demyelination indicates about heterogeneous changes in MS, enabling to distinguish the main groups of pathological changes: T-cells, macrophage-and antibody-mediated demyelination; distal oligoden-drogliopathy and apoptosis of oligodendrocytes, which mechanisms are unknown [29]. Notably, single mechanism of demyelination is specific for single patient. It is assumed that only one pathogenetic mechanism exists that is based on genetic determinant [36].
Demyelination is found not only in multiple sclerosis, but also in other pathological conditions and diseases that must be considered for differentiated microscopic diagnosis of lesions of the central nervous system. My-elin-oligodendrocytic complex is sensitive to the action of multiple factors, namely, metabolic, infectious, inflammatory and ischemic. Consequently, demyelination is possible in multiple diseases. A common feature of demyelinating diseases is the destruction of the myelin sheath in relative preservation of axons and other supporting elements.
Three types of demyelination can be distinguished according to the origin and mechanism of development [37].
The first type of demyelination is characterized by the primary damage to oligodendrocytes, known as my-elin-forming cells, which are sensitive to hypoxia, toxins, viruses (the inclusion of the virus genome in the cell genome with impaired myelin formation). Possibly, the primary damage to oligodendrocytes is caused by the metabolic processes disorder that occurs in affection of the endocrine glands, liver, gastrointestinal tract.
The second type of demyelination is characterized by disintegration of the myelin with preservation of oligodendrocytes. It occurs in sensitization and development of immediate hypersensitivity reactions to the myelin and products of its disintegration. Autoimmune process, which is specific not only for multiple sclerosis, but also for the vaccine, serum, parainfectious, paraneoplastic processes in the nervous system, is developed. Such mechanism of demyelination is specific for experimental allergic encephalomyelitis and polyneuritis.
The third kind of demyelination is characterized by the destruction of the myelin with the simultaneous death of oligodendrocytes, marked by the intensity and rate of the development of pathological process: hyperimmune reaction with release of the pro-inflammatory cytokines (TNF-a, interferon), the development of acidosis, accumulation of toxic factors.
Consequently, the main diagnostic criterion of MS development of multiple sclerosis. Demyelination and is not only the existence of foci of demyelination, but death of axons lead to atrophy of the brain and spinal
also the formation of the fibrous-cellular gliosis at the Cord. Morphologically, the nature and progress of the
certain stages. Gliosis is one of the specific morphologi- .. , , , , , . . . . .
pathological process, developed in multiple sclerosis, is
cal manifestations of MS, which is characterized by the
decreased amount of oligodendrocytes in the plaques in heterogeneous. It is known that autoimmune responses the increased percentage of composition of astrocytes, in MS> manifested by the foci of demУe|ination, are in-
whereas their absolute amount is decreasing [31]. volved in the pathogenesis of other diseases of the ner-Some authors consider the definition of "gliosis" to be vous system (inflammatory, vascular, etc.). In addition,
incorrect which is characterized by the reduction of the the cause of the myelin disintegration can be a chronic amount of glia cells and the increase in the number of
,.,,.. ■ - ^. i ».i .. hypoxia and metabolic disorders. They are crucial in the
glial fibers in the form of the fibrous isomorphic matrix
[38 39] differentiated diagnosis of the disease. Multifactorial
In conclusion, edema, inflammation, re- and demy- nature of multiple sclerosis to a certain extent reflects
elination, gliosis, damage to axons is observed in the heterogeneity of the demyelinating process.
References
1. Orton SM, Herrera BM, Yee IM, Valdar W, Ramagopalan SV, Sadovnick AD, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 2006;5:932-6.
2. Guseva EY, Zavalyshyna YA, Bojko AN, redaktory. Rasseyannyj skleroz: klynycheskoe rukovodstvo. Moskva: Real Tajm; 2011. 520 s. [in Russian].
3. Lytvynenko NV, Pinchuk VA, Sylenko GY, Blazhivska YuV, Bordyug YO. Kognityvnyj profil' paciyentiv iz rozsiyanym sklerozom. Problemy ekologiyi ta medycyny. 2012;16(3-4):13-5. [in Ukrainian].
4. Shmydt TE, Yakhno NN. Rasseyannyj skleroz: rukovodstvo dlya vrachej. 5-e yzd. Moskva: MEDpress-ynform; 2016. 272 s. [in Russian].
5. Hammond SR, English DR, McLeod JG. The age-range of risk of developing multiple sclerosis: evidence from a migrant population in Australia. Brain. 2000;123:968-74.
6. Simon KC, Munger KL, Ascherio A. Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics. Current opinion in neurology. 2012;25(3):246-51.
7. Hedstrom AK, Hillert J, Olsson T, Alfredsson L. Smoking and multiple sclerosis susceptibility. Eur J Epidemiol. 2013;28(11):867-74. Available from: https://doi.org/10.1007/s10654-013-9853-4
8. Handel AE, Williamson AJ, Disanto G, Dobson R, Giovannoni G. Smoking and Multiple Sclerosis: An Updated Meta-Analysis. PLOS ONE [Internet]. 2011;6(1):e16149. Available from: https://doi.org/10.1371/journal.pone.0016149
9. Hayes CE, Acheson ED. A unifying multiple sclerosis etiology linking virus infection, sunlight, and vitamin D, through viral interleukin-10. Medical Hypotheses. 2008;71(1):85-90.
10. Ruth AM. Environmental risk factors in multiple sclerosis aetiology. The Lancet Neurology. 2004;3(12):709-18.
11. Gilden DH. Infectious causes of multiple sclerosis. The Lancet Neurology. 2005;4(3):195-202.
12. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: The role of infection. Ann Neurol. 2007;61:288-99.
13. Popova EV, Bojko AN, Hachanova NV, Sharanova SN. Vyrus Epshtejna-Barr v patogeneze rasseyannogo skleroza (obzor). Zhurnal nevrologyy i psyxyatryy im. S.S. Korsakova. Speczvypusk. 2014;114(2):29-34. [in Russian].
14. Alvarez-Lafuente R, De Las Heras V, Bartolome M. Human herpesvirus 6 and multiple sclerosis: a one-year follow-up study. Brain Pathol. 2006;16:20-7.
15. Bagos PG, Nikolopoulos G, Ioannidis A. Chlamydia pneumoniae infection and the risk of multiple sclerosis: a meta-analysis. Mult Scler. 2006;12:397-411.
16. Hernán MA, Zhang SM, Lipworth L, Olek MJ, Ascherio A. Multiple Sclerosis and Age at Infection with Common Viruses. Epidemiology. 2001;12(3):301-6.
17. Schneider R. Neuronal degeneration in a viral model of multiple sclerosis. J. Neurosci. 2009;29:153-4.
18. Huseby ES, Liggitt D, Brabb Th, Schnabel B, Ohlén C, Goverman J. A Pathogenic Role for Myelin-Specific Cd8+ T Cells in a Model for Multiple Sclerosis. Journal of Experimental Medicine. 2001;194(5):669-76.
19. Gold R, Linington C, Lassmann H. Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain. 2006;129(8):1953-71.
20. de Bakker PI, McVean G, Sabeti PC, Miretti MM, Green T, Marchini J, et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet. 2006;38(10):1166-72.
21. Hemmer B, Archelos JJ, Hartung H-P. New concepts in the immunopathogenesis of multiple sclerosis. Nat. Rev. Neurosci. 2002;3:291-301.
22. Steinman L. Multiple sclerosis: a two-stage disease. Natl. Immunol. 2001;2:762-4.
23. Dong C, Flavell RA. Cell fate decision: T-helper 1 and 2 subsets in immune responses. Arthritis Res. 2000;2:179-88.
24. Zavalyshyn YA, Peresedova AV. Rasseyannyj skleroz: sovremennaya koncepcyya patogeneza i patogenetycheskogo lechenyya. Annaly klynych-eskoj i eksperymentalnoj nevrologyy. 2007;1(1):32-40. [in Russian].
25. Minagar A, Alexander JS Blood-brain barrier disruption in multiple sclerosis. Mult Scler. 2003;9(6):540-9.
26. Fazekas F, Enzinger C, Wallner-Blazek M. Gender Differences in MRI Studies on Multiple Sclerosis. J. Neurol. Sci. 2009;286:28-30.
27. Tomassini V, Pozzilli C. Sex Hormones, Brain Damage and Clinical Course of Multiple Sclerosis. J. Neurol. Sci. 2009;286:35-9.
28. Predtechenskaya AV, Nekrasova MF. Rol' polovyh steroydov v patogeneze rasseyannogo skleroza. Vestnyk NGU. Seryya: Byologyya, klynyches-kaya medycyna. 2011;9(3):211-8. [in Russian].
29. Neuhaus O, Archelos JJ, Hartung H-P. Immunomodulation in multiple sclerosis: from immunosuppression to neuroprotection. Trends Pharmacol. Sci. 2003;24:131-8.
30. Filippi M, Bozzali M, Rovaris M. Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain. 2003;126:433-7.
31. Bo L. The histopathology of grey matter demyelination in multiple sclerosis. Acta Neurologica Scandinavica. 2009;120:51-7.
32. Strukov AI, Syerov VV. Patologichna anatomiya 4-e vyd. Kharkiv: Fakt; 1999. 864 s. [in Ukrainian].
33. Bo L, Vedeler C, Nyland H, Traff B. Subpial Demyelination in the Cerebral cortex of Multiple Sclerosis Patients. J. Neuropath. Exp. Neurol. 2003;62(7):723-32.
34. Gilmore CP, Bo L, Owens T, Lowe J, Esiri MM, Evangelou N. Spinal Cord Gray Matter Demyelination in Multiple Sclerosis - A Novel Pattern of Residual Plaque Morphology. Brain Pathology. 2006;16:202-8.
35. Shmydt TE. Patogenez, lechenye i vedenye bolnykh rasseyannym sklerozom. Nevrologycheskyj zhurnal. 2003;3:46-9. [in Russian].
36. Paz Soldan MM, Rodriguez M. Heterogeneity of pathogenesis in multiple sclerosis: implications for promotion of remyelination. The Journal of infections diseases. 2002;186(2):248-53.
37. Nedzved GK, Nedzved MK. O nozologycheskoj samostoyatelnosty rasseyannogo skleroza. Nejroymmunologyya. 2003;1(2):103-4. [in Russian].
38. Haikova ON, Bysaha HN, Onyshchenko LS, Chykurova AA. Kharakterystyka hlyalnyh reaktsyi pry rasseiannom skleroze. Neiroymmunolohyia.
2003;1(2):35-6. [in Russian].
39. Pronina OM, Koptev MM, Bilash SM, Yeroshenko HA. Response of hemomicrocirculatory bed of internal organs on various external factors
exposure based on the morphological research data. Svit medytsyny ta biolohiyi. 2018;63(1):153-7.
ДЕЯК1 АСПЕКТИ ПАТОГЕНЕЗУ ТА МОРФОЛОГИ РОЗС1ЯНОГО СКЛЕРОЗУ
Филенко Б. М., Ройко Н. В., Проскурня С. А., Совгиря С. М., Винник Н. I.
Резюме. Сучасна iмунологiя розглядае розаяний склероз як ayToiMyHHe захворювання.
Макроскотчно тд час зовнiшнього огляду головного та спинного мозку при розаяному c^epo3i харак-терних змiн не вiдмiчaють, iнколи виявляють набряк i потовщення м'яких мозкових оболонок. Пстолопчно, в залежност вiд стади морфогенезу, розрiзняють три типи бляшок: гострi бляшки (активы осередки демiелi-шзацп), хрошчш (неaктивнi осередки) i хронiчнi вогнища з ознаками aктивiзaцií. Гострi активы бляшки фор-муються внaслiдок гострого периваскулярного запалення i проявляються руйнуванням мiелiну, набряком тканини мозку. Хрошчна неактивна бляшка чiтко окреслена, характеризуеться збтьшенням кiлькостi астро-цитiв, вщсутшстю активно'' деструкцп мiелiну, зменшенням кшькосл олiгодендроцитiв, аксональною дегене-рaцiею. З'являються ознаки периваскулярного склерозу. Хронiчнi активы бляшки характеризуются появою по перифери хрошчно! неактивно'! бляшки мaкрофaгiв, внаслщок прогресуючого розпаду мiелiну, а також Т-лiмфоцитiв i реактивних aстроцитiв.
Таким чином, при розвитку розаяного склерозу спостеркаються тaкi процеси, як набряк, запалення, де- i ремiелiнiзaцiя, глюз, ураження aксонiв. Демiелiнiзaцiя i загибель аксошв призводять до атрофи головного i спинного мозку.
Ключов1 слова: розаяний склероз, патогенез, морфолопя.
НЕКОТОРЫЕ АСПЕКТЫ ПАТОГЕНЕЗА И МОРФОЛОГИИ РАССЕЯННОГО СКЛЕРОЗА
Филенко Б. Н., Ройко Н. В., Проскурня С. А., Совгиря С. Н., Винник Н. И.
Резюме. Современная иммунология рассматривает рассеянный склероз как аутоиммунное заболевание.
Макроскопически при внешнем осмотре головного и спинного мозга при рассеянном склерозе характерных изменений не отмечают, иногда обнаруживают отек и утолщение мягких мозговых оболочек. Гистологически, в зависимости от стадии морфогенеза, различают три типа бляшек: острые бляшки (активные очаги де-миелинизации), хронические (неактивные очаги) и хронические очаги с признаками активизации. Острые активные бляшки формируются вследствие острого периваскулярного воспаления и проявляются разрушением миелина, отеком ткани мозга. Хроническая неактивная бляшка четко очерчена, характеризуется увеличением количества астроцитов, отсутствием активной деструкции миелина, уменьшением количества олиго-дендроцитов, аксональной дегенерацией. Появляются признаки периваскулярного склероза. Хронические активные бляшки характеризуются появлением по периферии хронической неактивной бляшки макрофагов, вследствие прогрессирующего распада миелина, а также Т-лимфоцитов и реактивных астроцитов.
Таким образом, при развитии рассеянного склероза наблюдаются такие процессы, как отек, воспаление, де- и ремиелинизация, глиоз, поражение аксонов. Демиелинизация и гибель аксонов приводят к атрофии головного и спинного мозга.
Ключевые слова: рассеянный склероз, патогенез, морфология.
MULTIPLE SCLEROSIS: SOME ASPECTS ON PATHOGENESIS AND MORPHOLOGY
Filenko B. M., Roiko N. V., Proskurnia S. A., Sovhyria S. M., Vynnyk N. I.
Abstract. Multiple sclerosis (MS) is a chronic, progressive demyelinating disease of the central nervous system.
Currently, the etiology of multiple sclerosis is unknown and considered as the multifactorial disease. Genetic and immunological factors, viral infection and influence of exogenous factors play the crucial role.
Genetic susceptibility to multiple sclerosis is confirmed by numerous findings of genealogical, twin and population studies. It has been established that intoxication and diet are considered the most possible external factors. Recently, the impact of insolation and associated vitamin D deficiency, as the main factor of geographical dissemination, smoking and ecological characteristics of the habitat of patients have been the issue for discussion.
Viral hypothesis for the development of multiple sclerosis appears to be of main importance, since high IgG concentration to many viruses has been found in the cerebrospinal fluid and blood of more than 90% of patients with MS.
Currently, no etiological theory and unambiguous consensus on the pathogenesis of lesions in multiple sclerosis exists. Apparently, no single view on the mechanism of the onset and development of this disease is given.
Immunologists consider multiple sclerosis as an autoimmune disease when the specific T-lymphocytes that are myelin antigens activate the inflammatory response in the central nervous system, which eventually leads to demyelination and subsequent damage to the axons.
Currently, the studies of the role of genetic disorders are at the forefront in the development of multiple sclerosis. This is substantiated by more frequent detection of A3, B7, DW2, DR2 antigens in patients with MS as compared with healthy people. It is hypothesized that the occurrence of certain combination of tissue histocompatibility antigents in single chromosome and gene of susceptibility to MS is crucial in the onset of the disease.
Currently, the pathogenesis of MS is seen as a phased process, involving the initial inflammatory phase, which is accompanied by demyelination, and the neurodegenerative phase.
The specific pathomorphological changes in multiple sclerosis are caused by activation of immunological reactions, including macrophages, B-lymphocytes with production of antibodies, which leads to the myelin sheath damage. Immunopathological reaction in MS leads not only to the destruction of myelin, but also to the development of vascular inflammatory and proliferative processes of the derivatives of mesenchyme and glia with subsequent formation of the multiple sclerosis plaques.
Macroscopically, no specific changes are revealed during the external examination of the brain and spinal cord in multiple sclerosis, though, sometimes, the edema and thickening of pia mater is noted. The mass of the brain can be reduced. Convolutions of brain are narrowed; sulci between them are broad and deep, indicating about growing atrophic processes. Ependyma is usually smooth, shiny, in some cases is tuberous, due to the subependimal gliosis.
Histologically, three types of the plaques are distinguished depending on the stage of morphogenesis: the acute plaques (active foci of demyelination), chronic (inactive foci) and chronic foci with signs of activation.
Edema, inflammation, re- and demyelination, gliosis, damage to axons is observed in the development of multiple sclerosis. Demyelination and death of axons lead to atrophy of the brain and spinal cord. Morphologically, the nature and progress of the pathological process, developed in multiple sclerosis, is heterogeneous. It is known that autoimmune responses in MS, manifested by the foci of demyelination, are involved in the pathogenesis of other diseases of the nervous system (inflammatory, vascular, etc.). In addition, the cause of the myelin disintegration can be a chronic hypoxia and metabolic disorders. They are crucial in the differentiated diagnosis of the disease. Multifactorial nature of multiple sclerosis to a certain extent reflects heterogeneity of the demyelinating process.
Key words: multiple sclerosis, pathogenesis, morphology.
Рецензент - проф. Старченко 1.1.
Стаття надшшла 22.01.2019 року
DOI 10.29254/2077-4214-2019-1-1-148-70-75 УДК 575.174.015.3:618.19-006.6-02 *Чорнобай А. В., **Чорнобай М. А.
МЕДИКАМЕНТОЗНЕ Л1КУВАННЯ РАКА ШЛУНКА *УкраТнська медична стоматолопчна академт (м. Полтава) **Нацюнальна медична академ1я шслядипломноТ освгги iMeHi П.Л. Шупика (м. Кшв)
Зв'язок публшацм з плановими науково-дослщ-ними роботами. Дана робота е фрагментом НДР «Дослщження ролi полiморфiзму гешв ТоИ-под!бного рецептора 2(Arg753Gin) в прогнозуванш рецидивiв та метао^в злояшсних новоутворень», № державно! реестрацп 0114U004770.
Вступ. Рак шлунка (РШ) залишаеться одним з най-поширешших онколопчних захворювань i займае четверте мкце по частой в структурi онкозахворю-ваносл, а як причина смерт онколопчних хворих, знаходиться на другому мкц i на його частку припа-дае понад 10% смертей. Ш^чно в свт рееструеться бтьше 750 тисяч випадшв захворювання i близько 620 000 випадмв смерт вщ РШ. УкраТна за рiвнем за-хворюваност займае 8-9 мкце в десятц краТн з най-бтьш високою захворювашстю РШ - 24, 7 (чоловти 42, 1, жшки - 16, 2), щорiчно вперше дiаrностуеться близько 14 000 хворих, переважно в III-VI а^ях, тому однорiчнa летальшсть досягае 63% [1].
В США з числа хворих з локальною формою раку шлунка, виявлено! при первиннш дiarностицi, у 45% протягом 5 рошв розвиваються метастази. Репонар-на форма у 85% пащенлв прогресуе i переходить в метастатичну фазу хвороби. У Великобританп серед пащенлв з резектабельною пухлиною, ям отримали дооперaцiйну хiмiотерaпiю, 5-рiчнa виживашсть ста-новить 36%. Однак при поширених або метастатич-них формах порога 5^чно! виживaностi досягають ттьки 5-20% хворих. З числа щорiчно дiarностовa-них хворих в 85% випадмв вiдрaзу або протягом 2-3 ромв хвороба переходить в метастатичний етап. При цьому необхщно зазначити, що медiaнa виживаност1 хворих на метастатичний рак шлунка, яких лтува-ли симптоматично, обчислюеться термiном на 3-4 мкяц [2].
Хiрурriчне лтування е основним методом при раку шлунка. В даний час у свтэвш практик накопи-чений величезний кл^чний мaтерiaл щодо застосу-вання рiзних вaрiaнтiв втручання при злоямсних пух-линах шлунка: розширенi i супер розширенi операцп, а також розширеш i супер розширенi лiмфодiссекцi! (ЛД) (D2, D3, D4) [2,3]. Анaлiз результaтiв показав, що виконання подiбних оперaцiй дозволило полiпшити вщдалеш результати лiкувaння практично при вах стaдiях захворювання [3]. З шшого боку, виникають сумнiви в доцтьносл подальшого нарощування хи рурпчноТ агресивносл при вирiшеннi щеТ проблеми [4]. Хiрурriчний метод лiкувaння практично досяг межi своТх можливостей, що вщбиваеться на стабЫ-заци покaзникiв виживання прооперованих па^енлв протягом остaнньоrо десятилiття [3,4].
Аrресивний перебir раку шлунка, рання дисеми нaцiя вимагають розробки додаткових системних методiв лiкувaння, в першу чергу - ад'ювантноТ хи мiотерaпiТ (АХТ). На момент встановлення дiarнозу, близько 46% хворих, вже мають III стадш захворювання, тобто вщносяться до категорй' па^енлв пiдляraють в тому числi i медикaментознiй терапГТ. Ад'ювантна хiмiотерaпiя нацтена на мiкрометaстa-зи РШ, що залишилися шсля хiрурriчноrо видален-ня первинноТ пухлини. На даний момент не кнуе стaндaртiв АХТ при РШ, так як результати мiжнa-родних дослщжень суперечливi [5,6]. Так, в Японп в ад'ювантному режимi позитивно зарекомендували себе похiднi фтортримщишв препарат S1, UFT [7]. Але ^ результати виявилося неможливим екстрапо-лювати на европейськi краТни i Америку. У рядi евро-пейських i американських дослiджень АХТ при РШ не привела до полтшення виживаносп, як безрецидив-ноТ [8], так i загальноТ [8,9,10,11,12,13]. Також немае
