Esclerose múltipla: uma abordagem imunológica
DOI:
https://doi.org/10.37951/2358-9868.2020v8i2.p122-137Palavras-chave:
Esclerose Múltipla. Neuroinflamação. Autoimunidade. Etiopatogenia.Resumo
Objetivo: Abordar os principais mecanismos imunológicos envolvidos na patogenia da Esclerose Múltipla dando ênfase à neuroinflamação e às intervenções terapêuticas atuais. Métodos: Trata se de uma revisão bibliográfica narrativa, utilizando se as bases de dados: Periódicos da Capes, Biblioteca Virtual em Saúde e Pubmed. Foram incluídos 55 artigos publicados no período de 2004 a 2019. Resultados: A etiopatogenia da Esclerose Múltipla envolve fatores genéticos, imunológicos e ambientais, que em conjunto, induzem processos de quebra da autotolerância imunológica, lesão neuronal, neuroinflamação e neurodegeneração. A neuroinflamação pode ser iniciada por antígenos próprios ou estranhos que são expostos aos leucócitos do sistema nervoso central. Leucócitos periféricos, especialmente, monócitos e linfócitos T e B, podem se infiltrar no sistema nervoso devido a alteração da permeabilidade da barreira hematoencefálica e, juntamente com a micróglia, possuem importante papel na indução de lesões desmielinizantes. A neurodegeneração pode gerar mais estímulos antigênicos. Atualmente existem 17 drogas imunomoduladoras aprovadas pela Food and Drugs Administration para o tratamento da doença, mas diversos estudos estão sendo realizados, visando novas abordagens terapêuticas. Conclusão: A etiologia da Esclerose Múltipla mantem-se uma incógnita, apesar de estudos atuais apontarem teorias sobre possíveis desencadeadores, extrínsecos e intrínsecos da autoimunidade na doença e da própria neuroinflamação, sendo a última um importante fator indutor da lesão tecidual e perpetuador da doença. A identificação de antígenos alvo reconhecidos por linfócitos T e B residentes e pelas micróglias, juntamente com a caracterização de mediadores inflamatórios solúveis é fundamental para elucidar a etiopatogenia da doença e sugerir novas propostas terapêuticas.
Referências
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17. Chen J, Chia N, Kalari KR, Yao JZ, Novotna M, Soldan MM, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep. 2016;6:28484.
18. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523:337-341.
19. Høglund RA, Maghazachi AA. Multiple sclerosis and the role of immune cells. World J Exp Med. 2014;4: 27–37.
20. Fan X, Lin C, Han J, Jiang X, Zhu J, Jin T. Follicular helper CD4+T cells in human neuroautoimmune diseases and their animal models. Mediat Inflamm. 2015;1–11.
21. Jiang HR, Milovanovic M, Allan D, Niedbala W, Besnard AG, Fukada SY, et al. IL-33 atenuates EAE by supressing IL-17 and IFN-gamma production and inducing alternatively activated macrophages. Eur J Immunol. 2012;42:1804-1814.
22. Butovsky O, Landa G, Kunis G, Ziv Y, Avidan H, Greenberg N, et al. Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest. 2006;116:905-915.
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24. Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Ver Neurol. 2014;10: 225–238.
25. Du L, Zhang Y, Chen Y, Zhu J, Yang Y, Zhang HL. Role of microglia in neurological disorders and their potencials as a therapeutic target. Mol Neurobiol. 2017;54(10): 7567-7584.
26. Benarroch EE. Microglia: multiple roles in surveillance, circuit shaping, and response to injury. Neurology. 2013;81(12): 1079– 1088.
27. Napoli I, Neumann H. Protective effects of microglia in multiple sclerosis. Exp Neurol. 2010;225(1): 24–28.
28. Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol. 2013;39(1): 3–18.
29. Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. NatNeurosci. 2013;16(9): 1211–1218.
30. Van HJ, Singh S, van der Pol S, Kipp M, Lim JL, Peferoen L, et al. Clusters ofactivated microglia innormal-appearing white matter show signs of innate immune activation. J Neuroinflammation. 2012;9:156.
31. Mazzon C, Zanotti L, Wang L, Del Prete A, Fontana E, Salvi V, Poliani PL, Sozzani S. CCRL2 regulates M1/M2 polarization during EAE recovery phase. J Leukoc Biol. 2016;99(6):1027-33. doi:10.1189/jlb.3 MA0915-444RR
32. Mikita J, Dubourdieu-Cassagno N, Deloire MS, Vekris A, Biran M,Raffard G,Brochet B,Canron M, Hetal. AlteredM1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration. Mult Scler. 2011;17(1):2–15. doi:10.1177/1352458510379243
33. Zrzavy T, Hametner S, Wimmer I, Butovsky O; Weiner HL, Lassmann H. Loss of “homeostatic” microglia and patterns of their activation in active multiple sclerosis. Brain. 2017;140, 1900–1913.
34. Multiple Sclerosis Coalition. The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence, Updated June 2019.
35. Chastain EM, Duncan DS, Rodgers JM, Miller SD. The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta. 2010;1812(2):265-74.
36. Gandhi R, Laroni A, Weiner HL. Role of the innate immune system in the pathogenesis of multiple sclerosis. J Neuroimmunol. 2010;221(1-2):7–14. doi:10.1016/j.jneuroim.2009.10.015
37. Lassmann H. Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis.Front Immunol. 2019;9:3116. doi: 10.3389/fimmu.2018.03116. eCollection 2018.
38. Dendrou CA, Fugger L, Friese MA.Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545-58. doi: 10.1038/nri3871.
39. Ireland S, Monson N. Potential impact of B cells on T cell function in multiple sclerosis. Mult Scler Int, 2011:423971.
40. Gameiro, T. Alterações Imunológicas na Esclerose Múltipla e sua Contribuição para o Conhecimento da Fisiopatologia da Doença. Trabalho final do ciclo (mestrado integrado em medicina). Faculdade de medicina da universidade de Coimbra, 2012.
41. Kasper L, Shoemaker J. Multiple sclerosis immunology: The healthy immune system vs the MS immune system. Neurology. 2010;74 Suppl 1:S2-8.
42. Park H, Li Z, Yang X, Chang S, Nurieva R, Wang Y, Wang, YH, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133-41
43. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol. 2005;23:683-747.
44. Saxena A, Martin-Blondel G, Mars L, Liblau R. Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis. FEBS Lett., 2011;585(23):3758-63
45. McMurran, CE, Jones CA, Fitzgerald DC, Franklin RJ. CNS Remyelination and the innate immune system. Front. Cell Dev. Biol. 2016;4,38-41.
46. Perry A, Brat DJ. Practical Surgical Neuropathology: A Diagnostic Approach. Churchill Livingstone, 2010.
47. Prayson, R.A. Neuropathology. Saunders; 2nd edition, 2011.
48. Lassmann H. Multiple Sclerosis Pathology. Cold Spring Harbor Perspectives in Medicine. 2018;8(3), a028936. doi:10.1101/cshperspect.a028936
49. Rosai And Ackerman’s. Surgical pathology. Edinburgh; New York: Mosby, 2011.
50. Brück W. The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage. J Neurol. 2005; 252 [Suppl 5]: V/3–V/9.
51. Napier J, Rose L, Adeoye O, Hooker E, Walsh KB. Modulating acute neuroinflammation in intracerebral hemorrhage: the potential promise of currently approved medications for multiple sclerosis, Immunopharmacology and Immunotoxicology, 2019;41(1):7-15. DOI: 10.1080/08923973.2019.1566361
52. Muraro PA, Pasquini M, Atkins HL, Bowen JD, Farge D, Fassas, A. Multiple Sclerosis–Autologous Hematopoietic Stem Cell Transplantation (MS-AHSCT) Long-term Outcomes Study Group. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurology. 2017; 74(4), 459–469. doi:10.1001/jamaneurol.2016.5867
53. Mangalam A, Shahi SK, Luckey D, Karau M, Marietta E, Luo N, Murray J. Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease. Cell reports. 2017;20(6), 1269–1277. doi:10.1016/j.celrep.2017.07.031
54. Tourbah A, Lebrun-Frenay C, Edan G, Clanet M, Papeix C, Vukusic S., MS-SPI study group. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Multiple sclerosis (Houndmills, Basingstoke, England). 2016;22(13), 1719–1731. doi:10.1177/1352458516667568
55. Spain R, Powers K, Murchison C, Heriza E, Winges K, Yadav V, Cameron M, Kim E, Horak F, Simon J, Bourdette D, Lipoic acid in secondary progressive MS. Neurol Neuroimmunol Neuroinflamm 2017;4(5)e374; DOI: 10.1212/NXI.0000000000000374
2. Cox MB, Ban M, Bowden NA, Baker A, Scott RJ, LechnerScott J. Potential association of vitamin D receptor polymorphism Taq1 with multiple sclerosis. Mult Scler J. 2012;18:16-22.
3. Morales RR, Silva CH. Qualidade de vida em portadores de Esclerose Múltipla. Arq Neuropsiquiatr. 2007;65(2-B): 454-460.
4. Duffy SS., Lees JG., Moalem-Taylor G. The contribution of immune and glial cell types in experimental autoimmune encephalomyelitis and multiple sclerosis. Mult Scler Int. 2014;285245.
5. Gu C. KIR4.1: K+ channel illusion or reality in the autoimmune pathogenesis of multiple sclerosis. Front. Mol. Neurosci. 2016;9: 90.
6. Hohlfeld R, Dornmair K, Meinl E, Wekerle H. The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets. Lancet Neurol. 2016;15:198–209.
7. Zéphir H. Progress in understanding the pathophysiology of multiple sclerosis. Rev. Neurol. 2018;174: 358–363.
8. Gilden DH. Infectious causes of multiple sclerosis. Lancet. 2005; 4:195–202
9. Wagner ASS, Mesquita DJ, Pereira JAA, Tieko TT, Melo WC, Coelho LEA, et al. Sistema imunitário: parte III. O delicado equilíbrio do sistema imunológico entre os pólos de tolerância e autoimunidade. Rev. Bras. Reumatol. 2010;50(6):665-679.
10. Constantinescu CS, Farooqi N, O’Brien K, Gran B. Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis. Br J Pharmacol. 2011;164:1079-1106.
11. Ben-Nun A, Kaushansky N, Kawakami N, Krishnamoorthy G, Berer K, Liblau R, et al. From classic to spontaneous and humanized models of multiple sclerosis: impact on understanding pathogenesis and drug development. J Autoimmun. 2014;54:33-50.
12. Moutsianas I, Jostins I, Beecham AH, Dilthey AT, Xifara DK, Ban M, et al. Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat Genet. 2015;47:1107-13
13. Esmaeil MS, Heydarpour P, Reis J, Amiri M, Sahraian MA. Multiple sclerosis and air pollution exposure: mechanisms toward brain autoimmunity. Med. Hypotheses. 2017;100: 23–30.
14. De J, Philip L. The Multiple Sclerosis Genomic Map: role of peripheral immune cells and residente microglia in susceptibility. The International Multiple Sclerosis Genetics Consortium (IMSGC). 2017.
15. Farh KK, Marson A, Zhu J, Kleinewietfeld M, Housley WJ, Beik S, et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature. 2015;518:337–343.
16. Croxford AL, Kurschus FC, Waisman A. Mouse models for multiple sclerosis: historical facts and future implications. Biochim Biophys Acta. 2011;1812:177-183.
17. Chen J, Chia N, Kalari KR, Yao JZ, Novotna M, Soldan MM, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep. 2016;6:28484.
18. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523:337-341.
19. Høglund RA, Maghazachi AA. Multiple sclerosis and the role of immune cells. World J Exp Med. 2014;4: 27–37.
20. Fan X, Lin C, Han J, Jiang X, Zhu J, Jin T. Follicular helper CD4+T cells in human neuroautoimmune diseases and their animal models. Mediat Inflamm. 2015;1–11.
21. Jiang HR, Milovanovic M, Allan D, Niedbala W, Besnard AG, Fukada SY, et al. IL-33 atenuates EAE by supressing IL-17 and IFN-gamma production and inducing alternatively activated macrophages. Eur J Immunol. 2012;42:1804-1814.
22. Butovsky O, Landa G, Kunis G, Ziv Y, Avidan H, Greenberg N, et al. Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest. 2006;116:905-915.
23. Ben-Selma W, Ben-Fredj N, Chebel S, Frih-Ayed M, Aouni M, Boukadida J. Age- and gender specific effects on VDR gene polymorphisms and risk of the development of multiple sclerosis in Tunisians: a preliminary study. Int J Immunogenet. 2015;42: 174-81.
24. Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Ver Neurol. 2014;10: 225–238.
25. Du L, Zhang Y, Chen Y, Zhu J, Yang Y, Zhang HL. Role of microglia in neurological disorders and their potencials as a therapeutic target. Mol Neurobiol. 2017;54(10): 7567-7584.
26. Benarroch EE. Microglia: multiple roles in surveillance, circuit shaping, and response to injury. Neurology. 2013;81(12): 1079– 1088.
27. Napoli I, Neumann H. Protective effects of microglia in multiple sclerosis. Exp Neurol. 2010;225(1): 24–28.
28. Boche D, Perry VH, Nicoll JA. Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol. 2013;39(1): 3–18.
29. Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. NatNeurosci. 2013;16(9): 1211–1218.
30. Van HJ, Singh S, van der Pol S, Kipp M, Lim JL, Peferoen L, et al. Clusters ofactivated microglia innormal-appearing white matter show signs of innate immune activation. J Neuroinflammation. 2012;9:156.
31. Mazzon C, Zanotti L, Wang L, Del Prete A, Fontana E, Salvi V, Poliani PL, Sozzani S. CCRL2 regulates M1/M2 polarization during EAE recovery phase. J Leukoc Biol. 2016;99(6):1027-33. doi:10.1189/jlb.3 MA0915-444RR
32. Mikita J, Dubourdieu-Cassagno N, Deloire MS, Vekris A, Biran M,Raffard G,Brochet B,Canron M, Hetal. AlteredM1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration. Mult Scler. 2011;17(1):2–15. doi:10.1177/1352458510379243
33. Zrzavy T, Hametner S, Wimmer I, Butovsky O; Weiner HL, Lassmann H. Loss of “homeostatic” microglia and patterns of their activation in active multiple sclerosis. Brain. 2017;140, 1900–1913.
34. Multiple Sclerosis Coalition. The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence, Updated June 2019.
35. Chastain EM, Duncan DS, Rodgers JM, Miller SD. The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta. 2010;1812(2):265-74.
36. Gandhi R, Laroni A, Weiner HL. Role of the innate immune system in the pathogenesis of multiple sclerosis. J Neuroimmunol. 2010;221(1-2):7–14. doi:10.1016/j.jneuroim.2009.10.015
37. Lassmann H. Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis.Front Immunol. 2019;9:3116. doi: 10.3389/fimmu.2018.03116. eCollection 2018.
38. Dendrou CA, Fugger L, Friese MA.Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545-58. doi: 10.1038/nri3871.
39. Ireland S, Monson N. Potential impact of B cells on T cell function in multiple sclerosis. Mult Scler Int, 2011:423971.
40. Gameiro, T. Alterações Imunológicas na Esclerose Múltipla e sua Contribuição para o Conhecimento da Fisiopatologia da Doença. Trabalho final do ciclo (mestrado integrado em medicina). Faculdade de medicina da universidade de Coimbra, 2012.
41. Kasper L, Shoemaker J. Multiple sclerosis immunology: The healthy immune system vs the MS immune system. Neurology. 2010;74 Suppl 1:S2-8.
42. Park H, Li Z, Yang X, Chang S, Nurieva R, Wang Y, Wang, YH, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6(11):1133-41
43. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol. 2005;23:683-747.
44. Saxena A, Martin-Blondel G, Mars L, Liblau R. Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis. FEBS Lett., 2011;585(23):3758-63
45. McMurran, CE, Jones CA, Fitzgerald DC, Franklin RJ. CNS Remyelination and the innate immune system. Front. Cell Dev. Biol. 2016;4,38-41.
46. Perry A, Brat DJ. Practical Surgical Neuropathology: A Diagnostic Approach. Churchill Livingstone, 2010.
47. Prayson, R.A. Neuropathology. Saunders; 2nd edition, 2011.
48. Lassmann H. Multiple Sclerosis Pathology. Cold Spring Harbor Perspectives in Medicine. 2018;8(3), a028936. doi:10.1101/cshperspect.a028936
49. Rosai And Ackerman’s. Surgical pathology. Edinburgh; New York: Mosby, 2011.
50. Brück W. The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage. J Neurol. 2005; 252 [Suppl 5]: V/3–V/9.
51. Napier J, Rose L, Adeoye O, Hooker E, Walsh KB. Modulating acute neuroinflammation in intracerebral hemorrhage: the potential promise of currently approved medications for multiple sclerosis, Immunopharmacology and Immunotoxicology, 2019;41(1):7-15. DOI: 10.1080/08923973.2019.1566361
52. Muraro PA, Pasquini M, Atkins HL, Bowen JD, Farge D, Fassas, A. Multiple Sclerosis–Autologous Hematopoietic Stem Cell Transplantation (MS-AHSCT) Long-term Outcomes Study Group. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurology. 2017; 74(4), 459–469. doi:10.1001/jamaneurol.2016.5867
53. Mangalam A, Shahi SK, Luckey D, Karau M, Marietta E, Luo N, Murray J. Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease. Cell reports. 2017;20(6), 1269–1277. doi:10.1016/j.celrep.2017.07.031
54. Tourbah A, Lebrun-Frenay C, Edan G, Clanet M, Papeix C, Vukusic S., MS-SPI study group. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Multiple sclerosis (Houndmills, Basingstoke, England). 2016;22(13), 1719–1731. doi:10.1177/1352458516667568
55. Spain R, Powers K, Murchison C, Heriza E, Winges K, Yadav V, Cameron M, Kim E, Horak F, Simon J, Bourdette D, Lipoic acid in secondary progressive MS. Neurol Neuroimmunol Neuroinflamm 2017;4(5)e374; DOI: 10.1212/NXI.0000000000000374
