I.P. Pavlov Journal of Higher Nervous ActivityI.P. Pavlov Journal of Higher Nervous ActivityЖурнал высшей нервной деятельности им. И.П. Павлова0044-46773034-5316The Russian Academy of Sciences65202210.31857/S0044467723040056WCJJOEОБЗОРЫ И ТЕОРЕТИЧЕСКИЕ СТАТЬИNEUROINFLAMMATION AND IMMUNE DYSFUNCTION IN THE PATHOGENESIS OF PARKINSON’S DISEASEНейровоспаление и иммунные нарушения в механизмах развития болезни ПаркинсонаIdovaG. V.ИдоваГ. В.galina-idova@mail.ruAlperinaE. L.АльперинаЕ. Л.galina-idova@mail.ruZhanaevaS. Ya.ЖанаеваС. Я.galina-idova@mail.ruScientific Research Institute of Neurosciences and MedicineФедеральное государственное бюджетное научное учреждение “Научно-исследовательский институт нейронаук и медицины”0107202373445447802022025Copyright ©; 2023, Г.В. Идова, Е.Л. Альперина, С.Я. ЖанаеваCopyright ©; 2023, Г.В. Идова, Е.Л. Альперина, С.Я. Жанаева2023Г.В. Идова, Е.Л. Альперина, С.Я. ЖанаеваГ.В. Идова, Е.Л. Альперина, С.Я. Жанаеваhttps://transsyst.ru/0044-4677/article/view/652022

Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder, characterized by dopaminergic neuronal loss, aggregation of alpha-synuclein and severe motor impairments. This review summarizes current data on the key role of neuroinflammation and immune dysfunction in neurodegeneration and disease development. We examine clinical and experimental evidence for microglia activation, participation of Toll-like receptors in this process, a wide range of chemokines and pro- and anti-inflammatory cytokines in the course of the disease. Emphasis is also made on the impact of the innate and adaptive immune responses in the mechanisms of systemic inflammation both in the brain and in the periphery. The involvement of brain-infiltrating immune cells and their subpopulations in the process of neuroinflammation and neurodegeneration, changes in the composition and phenotype of peripheral immune cells and their functional characteristics are discussed. Analysis of immune cell subsets and their ratios reveals subtle PD-specific changes in cellular populations that can be used as reliable biomarkers for diagnosis, prognosis of the disease course, and development of new approaches for anti-inflammatory and targeted therapies in PD.

Болезнь Паркинсона (БП) – хроническое прогрессирующее нейродегенеративное расстройство, проявляющееся гибелью дофаминовых нейронов, агрегацией α-синуклеина и выраженными моторными нарушениями. В обзоре рассматриваются современные данные о ключевой роли нейровоспаления и иммунной дисфункции в нейродегенерации и развитии заболевания. Приведены клинические и экспериментальные доказательства активации микроглии, участия в этом процессе Toлл-подобных рецепторов, широкого спектра хемокинов и про- и противовоспалительных цитокинов в динамике течения заболевания. Особое внимание уделено роли врожденного и адаптивного иммунного ответа в механизмах системного воспаления в мозге и на периферии. Продемонстрировано включение в процесс нейровоспаления и нейродегенерации инфильтрирующих мозг иммунных клеток и их субпопуляций, изменение состава и фенотипа периферических иммунных клеток и их функциональных характеристик. Анализ подмножеств иммунных клеток и их соотношения позволяет выявить тонкие, специфичные для БП, изменения в клеточных популяциях, которые могут быть использованы в качестве надежных биомаркеров для диагностики, прогнозирования течения заболевания и разработки новых подходов к противовоспалительной и таргетной терапии БП.

Parkinson’s diseasedopamineToll-like receptorschemokinespro- and anti-inflammatory cytokinesmonocytessubpopulations of T- and B-cellsболезнь Паркинсонадофаминα-синуклеиннейровоспалениемикроглияТолл-подобные рецепторыхемокиныпро- и противовоспалительные цитокинымоноцитысубпопуляции Т- и В-клетокАбдурасулова И.Н., Екимова И.В.,Чернышев М.В., Мацулевич А.В. Пастухов Ю.Ф.Нарушение когнитивных функций у крыс Вистар в модели доклиничской сталдии болезни Паркинсона. Журн. высш. нервн. деят. им И.П. Павлова. 2019. 69 (3): 364–381.Альперина Е.Л. Вклад дофаминергической системы в механизмы иммуномодуляции. Успехи физиол. наук. 2014. 45 (3): 45–56.Белова О.В., Арефьева Т.И., Москвина С.Н. Иммуновоспалитльные аспекты болезни Паркинсона. Журн. неврол. психиатр. им. С.С. Корсакова. 2020. 120(2): 110–119.Воронина Н.А., Кучеряну В.Г., Ветрилэ Л.А., Голоборщева В.В., Капица И.Г., Воронина Т.А., Морозов С.Г. Изучение влияния гимантана на уровень провоспалительных цитокинов в нигрокудатном комплексе мозга мышей при экспериментальном паркинсонизме. Патогенез. 2021. 19 (2): 45–49.Жанаева С.Я., Альперина Е.Л., Геворгян М.М., Дземедович С.С., Идова Г.В. В-клетки в периферической крови при болезни Паркинсона. Клинические и экспериментальные данные. Сибирский вестник психиатрии наркологии. 2020. 3 (108): 11–16.Идова Г.В., Альперина Е.Л., Жанаева С.Я., Тихонова М.А., Геворгян М.М. Экспрессия Toll-пообных рецепторов TLR2 и TLR4 типа на иммунных клетках и продукция про- и противовоспалитльных цитокинов в трангенной модели болезни Паркинсона. Патогенез. 2022. 20 (3): 38–43.Милюхина И.В., Карпенко М.Н., Клименко В.М. Клинические показатели и уровень цитокинов в крови и цереброспинальной жидкости пациентов с болезнью Паркинсона. Клин. мед. 2015. 93 (1): 51–55.Пирожков С.В., Теребилина Н.Н., Литвицкий П.Ф. Роль инфламмасом в развитии нервных и психических заболеваний. Журн. неврол. психиатр. им. С.С. Корсакова. 2018. 118 (12): 81–91.Пухальский А.Л., Шмарина Г.В., Алешкин В.А. Регуляторные T-клетки: современные подходы к оптимизации их численности. Вест. РАМН. 2011. 8: 24–33.Aftanas L.I., Gevorgyan M.M., Zhanaeva S.Y., Dzemidovich S.S., Kulikova K., Al’perina E.L., Danilenko K.V., Idova G.V. Therapeutic Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on Neuroinflammation and Neuroplasticity in Patients with Parkinson’s Disease: a Placebo-Controlled Study. Bull Exp Biol Med. 2018. 165: 195–199.Ahn J.J., Abu-Rub M., Miller R.H. B Cells in Neuroinflammation: New Perspectives and Mechanistic Insights. Cells. 2021. 10 (7): 1605.Akhtar R.S., Licata J.P., Luk K.C., Shaw L.M., Trojanowski J.Q., Lee V.M. Measurements of Auto-Antibodies to α-Synuclein in the Serum and Cerebral Spinal Fluids of Patients With Parkinson’s Disease. J. Neurochem. 2018. 145 (6): 489–503.Álvarez-Luquín D.D., Arce-Sillas A., Leyva-Hernández J., Sevilla-Reyes E., Boll M.C., Montes-Moratilla E., Vivas-Almazán V., Pérez-Correa C., Rodríguez-Ortiz U., Espinoza-Cárdenas R., Fragoso G., Sciutto E., Adalid-Peralta L. Regulatory impairment in untreated Parkinson’s disease is not restricted to Tregs: other regulatory populations are also involved. J Neuroinflammation. 2019. 16 (1): 212.Amin J., Holmes C., Dorey R.B., Tommasino E., Casal Y.R., Williams D.M., Dupuy C., Nicoll J.A.R., Boche D. Neuroinflammation in dementia with Lewy bodies: a human post-mortem study. Transl Psychiatry. 2020. 10 (1): 267.Arce-Sillas A., Sevilla-Reyes E., Álvarez-Luquín D.D., Guevara-Salinas A., Boll M.C., Pérez-Correa C.A., Vivas-Almazan A.V., Rodríguez-Ortiz U., Castellanos Barba C., Hernandez M., Fragoso G., Sciutto E., Cárdenas G., Adalid-Peralta L.V. Expression of Dopamine Receptors in Immune Regulatory Cells. Neuroimmunomodulation. 2019. 26 (3): 159–166.Baba Y., Kuroiwa A., Uitti R.J., Wszolek Z.K., Yamada T. Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat Disord. 2005. 11 (8): 493–498.Baird J.K., Bourdette D., Meshul C.K., Quinn J.F. The key role of T cells in Parkinson’s disease pathogenesis and therapy. Parkinsonism Relat Disord. 2019. 60: 25–31.Balestrino R., Schapira A.H.V. Parkinson disease. Eur. J. Neurol. 2020. 27 (1): 27–42.Barcia C., Ros C.M., Annese V., Gómez A., Ros-Bernal F., Aguado-Yera D., Martínez-Pagán M.E., de Pablos V., Fernandez-Villalba E., Herrero M.T. IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson’s disease. Cell Death Dis. 2011. 2 (4): e142.Bas J., Calopa M., Mestre M., Molleví D.G., Cutillas B., Ambrosio S., Buendia E. Lymphocyte populations in Parkinson’s disease and in rat models of parkinsonism. J. Neuroimmunol. 2001. 113 (1): 146–52.Bengoa-Vergniory N., Roberts R.F., Wade-Martins R., Alegre-Abarrategui J. Alpha-synuclein oligomers: a new hope. Acta Neuropathol. 2017. 134 (6): 819–838.Benner E.J., Banerjee R., Reynolds A.D., Sherman S., Pisarev V.M., Tsiperson V., Nemachek C., Ciborowski P., Przedborski S., Mosley R.L., Gendelman H.E. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One. 2008. 3 (1): e1376.Bhatia D., Grozdanov V., Ruf W.P., Kassubek J., Ludolph A.C., Weishaupt J.H., Danzer K.M. T-cell dysregulation is associated with disease severity in Parkinson’s Disease. J. Neuroinflammation. 2021. 18 (1): 250.Blauwendraat C., Nalls M.A., Singleton A.B. The genetic architecture of Parkinson’s disease. Lancet Neurol. 2020. 19 (2): 170–178.Boyko A.A., Troyanova N.I., Kovalenko E.I., Sapozhnikov A.M. Similarity and Differences in Inflammation-Related Characteristics of the Peripheral Immune System of Patients with Parkinson’s and Alzheimer’s Diseases. Int. J. Mol. Sci. 2017. 18 (12): 2633.Braak H., Del Tredici K., Rüb U., de Vos R.A., Jansen Steur E.N., Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003. 24 (2): 197–211.Brochard V., Combadière B., Prigent A., Laouar Y., Perrin A., Beray-Berthat V., Bonduelle O., Alvarez-Fischer D., Callebert J., Launay J.M., Duyckaerts C., Flavell R.A., Hirsch E.C., Hunot S. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest. 2009. 119 (1): 182–192.Brodacki B., Staszewski J., Toczyłowska B., Kozłowska E., Drela N., Chalimoniuk M., Stepien A. Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci Lett. 2008. 441 (2): 158–162.Burré J. The Synaptic Function of α-Synuclein. J.Pa kinsons Dis. 2015. 5 (4): 699–713.Camacho-Hernández N.P., Peña-Ortega F. Fractalkine/CX3CR1-Dependent Modulation of Synaptic and Network Plasticity in Health and Disease. Neural Plast. 2023. 2023: 4637073.Campos-Acuña J., Elgueta D., Pacheco R. T-Cell-Driven Inflammation as a Mediator of the Gut-Brain Axis Involved in Parkinson’s Disease. Front Immunol. 2019. 10: 239.Cardinale A., Calabrese V., de Iure A., Picconi B. Alpha-Synuclein as a Prominent Actor in the Inflammatory Synaptopathy of Parkinson’s Disease. Int. J. Mol. Sci. 2021. 22 (12): 6517.Cebrián C., Zucca F.A., Mauri P., Steinbeck J.A., Studer L., Scherzer C.R., Kanter E., Budhu S, Mandelbaum J., Vonsattel J.P., Zecca L., Loike J.D., Sulzer D. MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Commun. 2014. 5: 3633.Cen L., Yang C., Huang S., Zhou M., Tang X., Li K., Guo W., Wu Z., Mo M., Xiao Y., Chen X., Yang X., Huang Q., Chen C., Qu S., Xu P. Peripheral lymphocyte subsets as a marker of Parkinson’s disease in a Chinese population. Neurosci. Bull. 2017. 33 (5): 493–500.Cerri S., Mus L., Blandini F. Parkinson’s Disease in Women and Men: What’s the Difference? J. Parkinsons Dis. 2019. 9 (3): 501–515.Chakrabarty P., Ceballos-Diaz C., Lin W.L., Beccard A., Jansen-West K., McFarland N.R., Janus C., Dickson D., Das P., Golde T.E. Interferon-γ induces progressive nigrostriatal degeneration and basal ganglia calcification. Nat. Neurosci. 2011. 14 (6): 694–696.Chen H., Zhang S.M., Hernán M.A., Schwarzschild M.A., Willett W.C., Colditz G.A., Speizer F.E., Ascherio A. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol. 2003. 60 (8): 1059–1064.Chen J., Liu X., Zhong Y. Interleukin-17A: The Key Cytokine in Neurodegenerative Diseases. Front Aging Neurosci. 2020. 12: 566922.Chen S., Le W.D., Xie W.J., Alexianu M.E., Engelhardt J.I., Siklós L., Appel S.H. Experimental Destruction of Substantia Nigra Initiated by Parkinson Disease Immunoglobulins. Arch Neurol. 1998. 55 (8): 1075–1080.Chen S., Liu Y., Niu Y., Xu Y., Zhou Q., Xu X., Wang J., Yu M. Increased abundance of myeloid-derived suppressor cells and Th17 cells in peripheral blood of newly-diagnosed Parkinson’s disease patients. Neurosci Lett. 2017. 648: 21–25.Chen X., Feng W., Ou R., Liu J., Yang J., Fu J., Cao B., Chen Y., Wei Q., Shang H. Evidence for Peripheral Immune Activation in Parkinson’s Disease. Front Aging Neurosci. 2021. 13: 617370.Chen Y., Qi B., Xu W., Ma B., Li L., Chen Q., Qian W., Liu X., Qu H. Clinical correlation of peripheral CD4+-cell sub-sets, their imbalance and Parkinson’s disease. Mol Med Rep. 2015. 12 (4): 6105–6111.Chen Z., Chen S., Liu J. The role of T cells in the pathogenesis of Parkinson’s disease. Prog Neurobiol. 2018. 169: 1–23.Clark I.A., Vissel B.Therapeutic implications of how TNF links apolipoprotein E, phosphorylated tau, alpha-synuclein, amyloid-beta and insulin resistance in neurodegenerative diseases. Br J Pharmacol. 2018. 175 (20): 3859–3875.Contaldi E., Magistrelli L., Comi C. T Lymphocytes in Parkinson’s Disease. J. Parkinsons Dis. 2022. 12 (s1): S65–S74.Cyster J.G., Allen C.D.C. B Cell Responses: Cell Interaction Dynamics and Decisions. Cell. 2019. 177 (3): 524–540.Daneman R., Prat A. The blood-brain barrier. Cold Spring HarbPerspect Biol. 2015. 7 (1): a020412.Dauer W., Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003. 39 (6): 889–909.Doorn K.J., Moors T., Drukarch B., van de Berg W.Dj, Lucassen P.J., van Dam A.M. Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson’s disease patients. Acta Neuropathol Commun. 2014. 2: 90.DuPage M., Bluestone J.A. Harnessing the plasticity of CD4(+) T cells to treat immune-mediated disease. Nat Rev Immunol. 2016. 16 (3): 149–163.Dursun E., Gezen-Ak.D., Hanagasi H., Bilgiç B., Lohmann E., Ertan S., Atasoy İ.L., Alaylıoğlu M., Araz Ö.S., Önal B., Gündüz A., Apaydın H., Kızıltan G., Ulutin T., Gürvit H., Yılmazer S. The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer’s disease, mild cognitive impairment or Parkinson’s disease. J. Neuroimmunol. 2015. 283: 50–57.Dzamko N., Gysbers A., Perera G., Bahar A., Shankar A., Gao J., Fu Y., Halliday G.M. Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology. Acta Neuropathol. 2017. 133 (2): 303–319.Eidson L.N., Kannarkat G.T., Barnum C.J., Chang J., Chung J., Caspell-Garcia C.,Taylor P., Mollenhauer B., Schlossmacher M.G., Ereshefsky L., Yen M., Kopil C., Frasier M., Marek K., Hertzberg V.S., Tansey M.G. Candidate inflammatory biomarkers display unique relationships with alpha-synuclein and correlate with measures of disease severity in subjects with Parkinson’s disease. J. Neuroinflammation. 2017. 14 (1): 164.Fellner L., Irschick R., Schanda K., Reindl M., Klimaschewski L., Poewe W., Wenning G.K., Stefanova N. Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. Glia. 2013. 61 (3): 349–60.Ferrari C.C., Tarelli R. Parkinson’s disease and systemic inflammation. Parkinsons Dis. 2011. 2011: 436813.Filiano A.J., Gadani S.P., Kipnis J. How and why do T cells and their derived cytokines affect the injured and healthy brain? Nat Rev Neurosci. 2017. 18 (6): 375–384.Funk N., Wieghofer P., Grimm S., Schaefer R., Bühring H.J., Gasser T., Biskup S. Characterization of peripheral hematopoietic stem cells and monocytes in Parkinson’s disease. Mov Disord. 2013. 28 (3): 392–395.Fuzzati-Armentero M.T., Cerri S., Blandini F. Peripheral-Central Neuroimmune Crosstalk in Parkinson’s Disease: What Do Patients and Animal Models Tell Us? Front Neurol. 2019. 10: 232.Gadani S.P., Cronk J.C., Norris G.T., Kipnis J. IL-4 in the brain: a cytokine to remember. J. Immunol. 2012. 189 (9): 4213–4219.Galiano-Landeira J., Torra A., Vila M., Bové J. CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson’s disease. Brain. 2020. 143 (12): 3717-3733.Gao H.M., Zhang F., Zhou H., Kam W., Wilson B., Hong J.S. Neuroinflammation and α-synuclein dysfunction potentiate each other, driving chronic progression of neurodegeneration in a mouse of Parkinson’s disease. Environ Health Perspect. 2011. 119 (6): 807–814.Garfias S., Tamaya Domínguez B., Toledo Rojas A., Arroyo M., Rodríguez U., Boll C., Sosa A.L., Sciutto E., Adalid-Peralta L., Martinez López Y., Fragoso G., Fleury A. Peripheral blood lymphocyte phenotypes in Alzheimer and Parkinson’s diseases. Neurologia (Engl Ed). 2022. 37 (2): 110–121.Garretti F., Monahan C., Sette A., Agalliu D., Sulzer D. T cells, α-synuclein and Parkinson disease. Handb Clin Neurol. 2022. 184: 439–455.Gerhard A. TSPO imaging in parkinsonian disorders. Clin Transl Imaging. 2016. 4: 183–190.Golovko M.Y., Barceló-Coblijn G., Castagnet P.I., Austin S., Combs C.K., Murphy E.J. The role of alpha-synuclein in brain lipid metabolism: a downstream impact on brain inflammatory response. Mol. Cell. Biochem. 2009. 326 (1–2): 55–66.González H., Contreras F., Pacheco R. Regulation of the neurodegenerative process associated to Parkinson’s disease by CD4+ T-cells. J. Neuroimmune Pharmacol. 2015. 10 (4): 561–575.González H., Contreras F., Prado C., Elgueta D., Franz D., Bernales S., Pacheco R. Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons during Parkinson’s disease. J. Immunol. 2013. 190 (10): 5048–5056.Grigoryan G.A., Gray J.A., Rashid T., Chadwick A., Hodges H. Conditionally immortal neuroepithelial stem cell grafts restore spatial learning in rats with lesions at the source of cholinergic forebrain projections cholinergic forebrain projections. Restor Neurol Neurosci. 2000. 17 (4): 1.Grozdanov V., Bliederhaeuser C., Ruf W.P., Roth V., Fundel-Clemens K., Zondler L., Brenner D., Martin-Villalba A., Hengerer B., Kassubek J., Ludolph A.C., Weishaupt J.H., Danzer K.M. Inflammatory dysregulation of blood monocytes in Parkinson’s disease patients. Acta Neuropathol. 2014. 128 (5): 651–663.Gruden M.A., Sewell R.D., Yanamandra K., Davidova T.V., Kucheryanu V.G.., Bocharov E.V., Bocharova O.A., Polyschuk V.V., Sherstnev V.V., Morozova-Roche L.A. Immunoprotection against toxic biomarkers is retained during Parkinson’s disease progression. J. Neuroimmunol. 2011. 233 (1–2): 221–227.Gruden M.A., Yanamandra K., Kucheryanu V.G., Bocharova O.R., Sherstnev V.V., Morozova-Roche L.A., Sewell R.D. Correlation between protective immunity to α-synuclein aggregates, oxidative stress and inflammation. Neuroimmunomodulation. 2012. 19 (6): 334–342.Gupta V., Garg R.K., Khattri S. Levels of IL-8 and TNF-α decrease in Parkinson’s disease. Neurol Res. 2016. 38 (2): 98–102.Harms A.S., Ferreira S.A., Romero-Ramos M. Periphery and brain, innate and adaptive immunity in Parkinson’s disease. Acta Neuropathol. 2021. 141 (4): 527–545.Harms A.S., Thome A.D., Yan Z., Schonhoff A.M., Williams G.P., Li X., Liu Y., Qin H., Benveniste E.N., Standaert D.G. Peripheral monocyte entry is required for alpha-Synuclein induced inflammation and Neurodegeneration in a model of Parkinson disease. Exp Neurol. 2018. 300: 179–187.Heidari A., Yazdanpanah N., Rezaei N. The role of Toll-like receptors and neuroinflammation in Parkinson’s disease. J Neuroinflammation. 2022. 19 (1): 135.Hickman S., Izzy S., Sen P., Morsett L., El Khoury J. Microglia in neurodegeneration. Nat Neurosci. 2018. 21 (10): 1359–1369.Hirsch E.C., Standaert D.G. Ten Unsolved Questions About Neuroinflammation in Parkinson’s Disease. Mov Disord. 2021. 36 (1): 16–24.Horvath I., Iashchishyn I.A., Forsgren L., Morozova-Roche L.A. Immunochemical Detection of α-Synuclein Autoantibodies in Parkinson’s Disease: Correlation Between Plasma and Cerebrospinal Fluid Levels. ACS Chem Neurosci. 2017. 8 (6): 1170–1176.Hu Z.X., Song W.N., Lu X.D., Zhou M.L., Shao J.H. Peripheral T lymphocyte immunity and l-dopamine in patients with Parkinson’s disease. J. Biol. Regul. Homeost. Agents. 2018. 32 (3): 687–691.Huang Y., Liu Z., Wang X.Q., Qiu Y.H., Peng Y.P. A dysfunction of CD4+ T lymphocytes in peripheral immune system of Parkinson’s disease model mice. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2014. 30 (6). 567–576.Iba M., Kim C., Sallin M., Kwon S., Verma A., Overk C., Rissman R.A., Sen R., Sen J.M., Masliah E. Neuroinflammation is associated with infiltration of T cells in Lewy body disease and α-synuclein transgenic models. J. Neuroinflammation. 2020. 17 (1): 214.Idova G.V., Alperina E.L., Cheido M.A. Contribution of brain dopamine, serotonin and opioid receptors in the mechanisms of neuroimmunomodulation: evidence from pharmacological analysis. Int. Immunopharmacol. 2012. 12 (4): 618–625.Idova G.V., Al’perina E.L., Gevorgyan M.M., Tikhonova M.A., Zhanaeva S.Y. Content of Peripheral Blood T- and B-Cell Subpopulations in Transgenic A53T Mice of Different Age (A Model of Parkinson’s Disease). Bull. Exp. Biol. Med. 2021. 170 (4): 401–404.Jiang S., Gao H., Luo Q., Wang P., Yang X. The correlation of lymphocyte subsets, natural killer cell, and Parkinson’s disease: a meta-analysis. Neurol. Sci. 2017. 38 (8): 1373–1380.Kalia L.V., Lang A.E. Parkinson’s disease. Lancet. 2015. 386 (9996): 896–912.Kalkonde Y.V., Morgan W.W., Sigala J., Maffi S.K., Condello C., Kuziel W., Ahuja S.S., Ahuja S.K. Chemokines in the MPTP model of Parkinson’s disease: absence of CCL2 and its receptor CCR2 does not protect against striatal neurodegeneration. Brain Res. 2007. 1128 (1): 1–11.Kam T.I., Hinkle J.T., Dawson T.M., Dawson V.L. Microglia and astrocyte dysfunction in parkinson’s disease. Neurobiol. Dis. 2020. 144: 105028.Kannarkat G.T., Boss J.M., Tansey M.G. The role of innate and adaptive immunity in Parkinson’s disease J Parkinsons Dis. 2013. 3 (4): 493–514.Karpenko M.N., Vasilishina A.A., Gromova E.A., Muruzheva Z.M., Miliukhina I.V., Bernadotte A. Interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-10, and tumor necrosis factor-α levels in CSF and serum in relation to the clinical diversity of Parkinson’s disease. Cell Immunol. 2018. 327: 77–82.Kawano M., Takagi R., Saika K., Matsui M., Matsushita S. Dopamine regulates cytokine secretion during innate and adaptive immune responses. Int. Immunol. 2018. 30(12): 591–606.Kessel A., Haj T., Peri R., Snir A., Melamed D., Sabo E., Toubi E. Human CD19(+)CD25(high) B regulatory cells suppress proliferation of CD4(+) T.cells and enhance Foxp3 and CTLA-4 expression in T-regulatory cells. Autoimmun Rev. 2012. 11 (9): 670–677.Khakh B.S., Sofroniew M.V. Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci. 2015. 18 (7): 942–952.Kim C., Ho D.H., Suk J.E., You S., Michael S., Kang J., Joong Lee S., Masliah E., Hwang D., Lee H.J., Lee S.J. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 2013. 4: 1562.King E., Thomas A. Systemic Inflammation in Lewy Body Diseases: A Systematic Review. Alzheimer Dis Assoc Disord. 2017. 31 (4): 346–356.Klein C., Westenberger A. Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med. 2012. 2 (1): a008888.Kortekaas R., Leenders K.L., van Oostrom J.C., Vaalburg W., Bart J., Willemsen A.T., Hendrikse N.H. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann. Neurol. 2005. 57 (2): 176–179.Kouli A., Camacho M., Allinson K., Williams-Gray C.H. Neuroinflammation and protein pathology in Parkinson’s disease dementia. Acta Neuropathol Commun. 2020. 8 (1): 211.Kustrimovic N., Comi C., Magistrelli L., Rasini E., Legnaro M., Bombelli R., Aleksic I., Blandini F., Minafra B., Riboldazzi G., Sturchio A., Mauri M., Bono G., Marino F., Cosentino M. Parkinson’s disease patients have a complex phenotypic and functional Th1 bias: cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug-naïve and drug-treated patients. J. Neuroinflammation. 2018. 15 (1): 205.La Vitola P., Balducci C., Baroni M., Artioli L., Santamaria G., Castiglioni M., Cerovic M., Colombo L., Caldinelli L., Pollegioni L., Forloni G. Peripheral inflammation exacerbates α-synuclein toxicity and neuropathology in Parkinson’s models. Neuropathol Appl Neurobiol. 2021. 47 (1): 43–60.Lai T.T., Kim Y.J., Ma H.I., Kim Y.E. Evidence of Inflammation in Parkinson’s Disease and Its Contribution to Synucleinopathy. J. Mov. Disord. 2022. 15 (1): 1–14.Lavisse S., Goutal S., Wimberley C., Tonietto M., Bottlaender M., Gervais P., Kuhnast B., Peyronneau M.A., Barret O., Lagarde J., Sarazin M., Hantraye P., Thiriez C., Remy P. Increased microglial activation in patients with Parkinson disease using [18F]-DPA714 TSPO PET imaging. Parkinsonism Relat. Disord. 2021. 82: 29–36.Li R., Tropea T.F., Baratta L.R., Zuroff L., Diaz-Ortiz M.E., Zhang B., Shinoda K., Rezk A., Alcalay R.N., Chen-Plotkin A., Bar-Or A. Abnormal B-Cell and Tfh-Cell Profiles in Patients With Parkinson Disease: A Cross-sectional Study. Neurol Neuroimmunol. Neuroinflamm. 2021a. 9 (2): e1125.Li W., Luo Y., Xu H., Ma Q., Yao Q. Imbalance between T helper 1 and regulatory T cells plays a detrimental role in experimental Parkinson’s disease in mice. J. Int. Med. Res. 2021б. 49 (4): 300060521998471.Lindestam Arlehamn C.S., Dhanwani R., Pham J., Kuan R., Frazier A., Rezende Dutra J., Phillips E., Mallal S., Roederer M., Marder K.S., Amara A.W., Standaert D.G., Goldman J.G., Litvan I., Peters B., Sulzer D., Sette A. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease. Nat Commun. 2020. 11 (1): 1875.Lira A., Kulczycki J., Slack R., Anisman H., Park D.S. Involvement of the Fc gamma receptor in a chronic N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of dopaminergic loss. J. Biol. Chem. 2011. 286 (33): 28783–28793.Liu Z., Huang Y., Cao B.B., Qiu Y.H., Peng Y.P. Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson’s Disease. Mol. Neurobiol. 2017. 54 (10): 7762–7776.Liu Z., Zhai X.R., Du Z.S., Xu F.F., Huang Y., Wang X.Q., Qiu Y.H., Peng Y.P. Dopamine receptor D2 on CD4+T cells is protective against neuroinflammation and neurodegeneration in a mouse model of Parkinson’s disease. Brain Behav Immun. 2021. 98: 110–121.Luo P., Chu S.F., Zhang Z., Xia C.Y., Chen N.H. Fractalkine/CX3CR1 is involved in the cross-talk between neuron and glia in neurological diseases. Brain Res Bull. 2019. 146: 12–21.MacMahon Copas A.N., McComish S.F., Fletcher J.M., Caldwell M.A. The Pathogenesis of Parkinson’s Disease: A Complex Interplay Between Astrocytes, Microglia, and T Lymphocytes? Front. Neurol. 2021. 12: 666737.Magistrelli L., Storelli E., Rasini E., Contaldi E., Comi C., Cosentino M., Marino F. Relationship between circulating CD4+ T lymphocytes and cognitive impairment in patients with Parkinson’s disease. Brain Behav. Immun. 2020. 89: 668–674.Majbour N.K., Aasly J.O., Hustad E., Thomas M.A., Vaikath N.N., Elkum N., van de Berg W.D.J., Tokuda T., Mollenhauer B., Berendse H.W., El-Agnaf O.M.A. CSF total and oligomeric α-Synuclein along with TNF-α as risk biomarkers for Parkinson’s disease: a study in LRRK2 mutation carriers. Transl Neurodegener. 2020. 9 (1): 15.McGeer P.L., Itagaki S., Boyes B.E., McGeer E.G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology. 1988. 38 (8): 1285–1291.McGinley A.M., Sutton C.E., Edwards S.C., Leane C.M., DeCourcey J., Teijeiro A., Hamilton J.A., Boon L., Djouder N., Mills K.H.G. Interleukin-17A Serves a Priming Role in Autoimmunity by Recruiting IL-1β-Producing Myeloid Cells that Promote Pathogenic T Cells. Immunity. 2020. 52 (2): 342–356.e6.Melzer N., Hicking G., Bittner S., Bobak N., Göbel K., Herrmann A.M., Wiendl H., Meuth S.G. Excitotoxic neuronal cell death during an oligodendrocyte-directed CD8+ T cell attack in the CNS gray matter. J. Neuroinflammation. 2013. 10: 121.Nagatsu T., Mogi M., Ichinose H., Togari A. Cytokines in Parkinson’s disease. J. Neural. Transm. Suppl. 2000. (58): 143–151.Nash K.R., Moran P., Finneran D.J., Hudson C., Robinson J., Morgan D., Bickford P.C. Fractalkine over expression suppresses α-synuclein-mediated neurodegeneration. Mol. Ther. 2015. 23 (1): 17–23.Nissen S.K., Ferreira S.A., Nielsen M.C., Schulte C., Shrivastava K., Hennig D., Etzerodt A., Graversen J.H., Berg D., Maetzler W., Panhelainen A., Møller H.J., Brockmann K., Romero-Ramos M. Soluble CD163 Changes Indicate Monocyte Association With Cognitive Deficits in Parkinson’s Disease. Mov. Disord. 2021. 36 (4): 963–976.Niwa F., Kuriyama N., Nakagawa M., Imanishi J. Effects of peripheral lymphocyte subpopulations and the clinical correlation with Parkinson’s disease. Geriatr Gerontol Int. 2012. 12 (1): 102–107.O’Shea J.J., Paul W.E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science. 2010. 327: 1098.Orr C.F., Rowe D.B., Mizuno Y., Mori H., Halliday G.M. A possible role for humoral immunity in the pathogenesis of Parkinson’s disease. Brain. 2005. 128 (Pt 11): 2665–2674.Parillaud V.R., Lornet G., Monnet Y., Privat A.L., Haddad A.T., Brochard V., Bekaert A., de Chanville C.B., Hirsch E.C., Combadière C., Hunot S., Lobsiger C.S. Analysis of monocyte infiltration in MPTP mice reveals that microglial CX3CR1 protects against neurotoxic over-induction of monocyte-attracting CCL2 by astrocytes. J. Neuroinflammation. 2017. 14 (1): 60.Pawelec P., Ziemka-Nalecz M., Sypecka J., Zalewska T. The Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders. Cells. 2020. 9 (10): 2277.Pey P., Pearce R.K., Kalaitzakis M.E., Griffin W.S., Gentleman S.M. Phenotypic profile of alternative activation marker CD163 is different in Alzheimer’s and Parkinson’s disease. Acta Neuropathol Commun. 2014. 2: 21.Prots I., Winner B. Th17 cells: a promising therapeutic target for Parkinson’s disease? Expert Opin. Ther. Targets. 2019. 23 (4): 309–314.Ransohoff R.M., Liu L., Cardona A.E. Chemokines and chemokine receptors: multipurpose players in neuroinflammation. Int. Rev. Neurobiol. 2007. 82: 187–204.Reale M., Iarlori C., Thomas A., Gambi D., Perfetti B., Di Nicola M., Onofrj M. Peripheral cytokines profile in Parkinson’s disease. Brain Behav Immun. 2009. 23 (1): 55–63.Reynolds A.D., Banerjee R., Liu J., Gendelman H.E., Mosley R.L. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J. Leukoc. Biol. 2007. 82: 1083–1094.Reynolds A.D., Stone D.K., Hutter J.A., Benner E.J., Mosley R.L., Gendelman H.E. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J. Immunol. 2010. 184: 2261–2271.Rosser E.C., Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity. 2015. 42 (4): 607–612.Rostami J., Fotaki G., Sirois J., Mzezewa R., Bergström J., Essand M., Healy L., Erlandsson A. Astrocytes have the capacity to act as antigen-presenting cells in the Parkinson’s disease brain. J. Neuroinflammation. 2020. 17 (1): 119.Sabatino J.J.Jr, Pröbstel A.K., Zamvil S.S. B cells in autoimmune and neurodegenerative central nervous system diseases. Nat Rev Neurosci. 2019. 20 (12): 728–745.Saunders J.A., Estes K.A., Kosloski L.M., Allen H.E., Dempsey K.M., Torres-Russotto D.R., Meza J.L., Santamaria P.M., Bertoni J.M., Murman D.L., Ali H.H., Standaert D.G., Mosley R.L., Gendelman H.E. CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J. Neuroimmune Pharmacol. 2012. 7 (4): 927–938.Schetters S.T.T., Gomez-Nicola D., Garcia-Vallejo J.J., Van Kooyk Y. Neuroinflammation: Microglia and T Cells Get Ready to Tango. Front Immunol. 2018. 8: 1905.Sergeyeva T.N., Sergeyev V.G. Administration of LPS-stimulated autologous macrophages induces α-synuclein aggregation in dopaminergic neurons of rat brain. Bull. Exp. Biol. Med. 2011. 150 (4): 406–408.Shi Y., Wei B., Li L., Wang B., Sun M. Th17 cells and inflammation in neurological disorders: Possible mechanisms of action. Front Immunol. 2022. 13: 932152. https://doi.org/10.3389/fimmu.2022.932152Sommer A., Fadler T., Dorfmeister E., Hoffmann A.C., Xiang W., Winner B., Prots I. Infiltrating T lymphocytes reduce myeloid phagocytosis activity in synucleinopathy model. J. Neuroinflammation. 2016. 13 (1): 174.Sommer A., Marxreiter F., Krach F., Fadler T., Grosch J., Maroni M., Graef D., Eberhardt E., Riemenschneider M.J., Yeo G.W., Kohl Z., Xiang W., Gage F.H., Winkler J., Prots I., Winner B. Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson’s Disease. Cell Stem Cell. 2018. 23 (1): 123–131.e6.Stefanis L., Emmanouilidou E., Pantazopoulou M., Kirik D., Vekrellis K, Tofaris GK. How is alpha-synuclein cleared from the cell? J. Neurochem. 2019. 150 (5): 577–590.Stevens C.H., Rowe D., Morel-Kopp M.C., Orr C., Russell T., Ranola M., Ward C., Halliday G.M. Reduced T helper and B lymphocytes in Parkinson’s disease. J. Neuroimmunol. 2012. 252 (1–2): 95–99.Su Y., Shi C., Wang T., Liu C., Yang J., Zhang S., Fan L., Zheng H., Li X., Luo H., Zhang S., Hu Z., Fan Y., Hao X., Zhang C., Song B., Mao C., Xu Y. Dysregulation of peripheral monocytes and pro-inflammation of alpha-synuclein in Parkinson’s disease. J. Neurol. 2022. 269 (12): 6386–6394.Sulzer D., Alcalay R.N., Garretti F., Cote L., Kanter E., Agin-Liebes J., Liong C., McMurtrey C., Hildebrand W.H., Mao X., Dawson V.L., Dawson T.M., Oseroff C., Pham J., Sidney J., Dillon M.B., Carpenter C., Weiskopf D., Phillips E., Mallal S., Peters B., Frazier A., Lindestam Arlehamn C.S., Sette A. T cells from patients with Parkinson’s disease recognize α-synuclein peptides. Nature. 2017. 546 (7660): 656–661.Sulzer D., Edwards R.H. The physiological role of α-synuclein and its relationship to Parkinson’s Disease. J. Neurochem. 2019. 150 (5): 475–486.Sun C., Zhao Z., Yu W., Mo M., Song C, Si Y., Liu Y. Abnormal subpopulations of peripheral blood lymphocytes are involved in Parkinson’s disease. Ann. Transl. Med. 2019. 7 (22): 637.Sweeney M.D., Zhao Z., Montagne A., Nelson A.R., Zlokovic B.V. Blood-Brain Barrier: From Physiology to Disease and Back. Physiol Rev. 2019. 99 (1): 21–78.Tan E.K., Chao Y.X., West A., Chan L.L., Poewe W., Jankovic J. Parkinson disease and the immune system – associations, mechanisms and therapeutics. Nat Rev Neurol. 2020. 16 (6): 303–318.Tansey M.G., Wallings R.L., Houser M.C., Herrick M.K., Keating C.E., Joers V. Inflammation and immune dysfunction in Parkinson disease. Nat. Rev. Immunol. 2022. 22 (11): 657–673.Tentillier N., Etzerodt A., Olesen M.N., Rizalar F.S., Jacobsen J., Bender D., Moestrup S.K., Romero-Ramos M. Anti-Inflammatory Modulation of Microglia via CD163-Targeted Glucocorticoids Protects Dopaminergic Neurons in the 6-OHDA Parkinson’s Disease Model. J. Neurosci. 2016. 36 (36): 9375–9390.Terada T., Yokokura M., Yoshikawa E., Futatsubashi M., Kono S., Konishi T., Miyajima H., Hashizume T., Ouchi Y. Extrastriatal spreading of microglial activation in Parkinson’s disease: a positron emission tomography study. Ann. Nucl. Med. 2016. 30 (8): 579–587.Theodore S., Cao S., McLean P.J., Standaert D.G. Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J. Neuropathol. Exp. Neurol. 2008. 67 (12): 1149–1158.Thome A.D., Standaert D.G., Harms A.S. Fractalkine Signaling Regulates the Inflammatory Response in an α-Synuclein Model of Parkinson Disease. PLoS One. 2015. 10 (10): e0140566.Tian J., Dai S.B., Jiang S.S., Yang W.Y., Yan Y.Q., Lin Z.H., Dong J.X., Liu Y., Zheng R., Chen Y., Zhang B.R., Pu J.L. Specific immune status in Parkinson’s disease at different ages of onset. NPJ Parkinsons Dis. 2022. 8 (1): 5.Ugrumov M. Development of early diagnosis of Parkinson’s disease: Illusion or reality? CNS Neurosci. Ther. 2020. 26 (10): 997–1009.Usenko T.S., Nikolaev M.A., Miliukhina I.V., Bezrukova A.I., Senkevich K.A., Gomzyakova N.A., Beltceva Y.A., Zalutskaya N.M, Gracheva E.V., Timofeeva A.A., Petrova O.A., Semenov A.V., Lubimova N.E., Totolyan A.A., Pchelina S.N. Plasma cytokine profile in synucleinophaties with dementia. J. Clin. Neurosci. 2020. 78: 323–326.Wang P., Luo M., Zhou W., Jin X., Xu Z., Yan S., Li Y., Xu C., Cheng R., Huang Y., Lin X., Yao L., Nie H., Jiang Q. Global Characterization of Peripheral B Cells in Parkinson’s Disease by Single-Cell RNA and BCR Sequencing. Front. Immunol. 2022. 13: 814239.Wang P., Yao L., Luo M., Zhou W., Jin X., Xu Z., Yan S., Li Y., Xu C., Cheng R., Huang Y., Lin X., Ma K., Cao H., Liu H., Xue G., Han F., Nie H., Jiang Q. Single-cell transcriptome and TCR profiling reveal activated and expanded T cell populations in Parkinson’s disease. Cell Discov. 2021. 7 (1): 52.Wang W., Nguyen L.T., Burlak C., Chegini F., Guo F., Chataway T., Ju S., Fisher O.S., Miller D.W., Datta D., Wu F., Wu C.X., Landeru A., Wells J.A., Cookson M.R., Boxer M.B., Thomas C.J., Gai W.P., Ringe D., Petsko G.A., Hoang Q.Q. Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein. Proc. Natl. Acad. Sci. USA. 2016. 113 (34): 9587–9592.Weiss F., Labrador-Garrido A., Dzamko N., Halliday G. Immune responses in the Parkinson’s disease brain. Neurobiol Dis. 2022. 168: 105700.Wijeyekoon R.S., Kronenberg-Versteeg D., Scott K.M., Hayat S., Jones J.L., Clatworthy M.R., Floto R.A., Barker R.A., Williams-Gray C.H. Monocyte Function in Parkinson’s Disease and the Impact of Autologous Serum on Phagocytosis. Front Neurol. 2018. 9: 870.Williams G.P., Schonhoff A.M., Jurkuvenaite A., Gallups N.J., Standaert D.G., Harms A.S. CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson’s disease. Brain. 2021. 144 (7): 2047–2059.Williams G.P., Schonhoff A.M., Sette A., Lindestam Arlehamn C.S. Central and Peripheral Inflammation: Connecting the Immune Responses of Parkinson’s Disease. J Parkinsons Dis. 2022. 12 (s1): S129–S136.Williams-Gray C.H., Wijeyekoon R., Yarnall A.J., Lawson R.A., Breen D.P., Evans J.R., Cummins G.A., Duncan G.W., Khoo T.K., Burn D.J., Barker R.A., ICICLE-PD Study Group. Serum immune markers and disease progression in an incident Parkinson’s disease cohort (ICICLE-PD). Mov. Disord. 2016. 31: 995–1003.Xiao W., Shameli A., Harding C.V., Meyerson H.J., Maitta R.W. Late stages of hematopoiesis and B cell lymphopoiesis are regulated by α-synuclein, a key player in Parkinson’s disease. Immunobiology. 2014. 219 (11): 836–844.Yan Y., Jiang W., Liu L., Wang X., Ding C., Tian Z., Zhou R. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell. 2015. 160: 62–73.Yan Z., Yang W., Wei H., Dean M.N., Standaert D.G., Cutter G.R., Benveniste E.N., Qin H. Dysregulation of the Adaptive Immune System in Patients With Early-Stage Parkinson Disease. Neurol. Neuroimmunol. Neuroinflamm. 2021. 8 (5): e1036.Qu Y., Li J., Qin Q., Wang D., Zhao J., An K., Mao Z., Min Z., Xiong Y., Li J., Xue Z. A systematic review and meta-analysis of inflammatory biomarkers in Parkinson’s disease. NPJ Parkinsons Dis. 2023. 9 (1): 18.Yang J., Ran M., Li H., Lin Y., Ma K., Yang Y., Fu X., Yang S. New insight into neurological degeneration: Inflammatory cytokines and blood-brain barrier. Front. Mol. Neurosci. 2022. 15: 1013933.Yu S.Y., Zuo L.J., Wang F., Chen Z.J., Hu Y., Wang Y.J., Wang X.M., Zhang W. Potential biomarkers relating pathological proteins, neuroinflammatory factors and free radicals in PD patients with cognitive impairment: a cross-sectional study. BMC Neurol. 2014. 14: 113.Zhang S., Sun C., Zhang L., Cen L., Mo M., Liu Z., Huang W., Zhu F., Kang P., Chen Z., Yi L., Xu P. Clinical analysis of subpopulation of peripheral T and B lymphocytes in Chinese Parkinson’s disease patients. Zhonghua Yi Xue Za Zhi. 2014. 94 (47): 3726–3730.Zhu J., Yamane H., Paul W.E. Differentiation of effector CD4 T cell populations. Annu Rev. Immunol. 2010. 28: 445.