A basic overview of multiple sclerosis immunopathology

European Journal of Neurology

Volumn 22, Issue , 2015, Pages 3-13

  Grigoriadis, N ^a   van Pesch, V ^b  

^a AHEPA UNIVERSITY HOSPITAL   (Greece)

^b CLINIQUES UNIVERSITAIRES SAINT LUC   (Belgium)

Author keywords

B cells; Immune dysregulation; Inflammation; Multiple sclerosis; Neurodegeneration; Pathophysiology; Th17 lymphocytes

Indexed keywords

CD8 ANTIGEN; CYCLOPHOSPHAMIDE; CYTOKINE; IMMUNOMODULATING AGENT; MITOXANTRONE; NITRIC OXIDE;

BRAIN SIZE; DEMYELINATION; DENDRITIC CELL; HUMAN; IMMUNE DYSREGULATION; IMMUNOMODULATION; IMMUNOPATHOLOGY; MACROPHAGE ACTIVATION; MEMORY CELL; MEMORY T LYMPHOCYTE; MICROGLIA; MULTIPLE SCLEROSIS; NERVE FIBER DEGENERATION; PRIORITY JOURNAL; REVIEW; TH1 CELL; TH17 CELL; IMMUNOLOGY; INFLAMMATION; PATHOLOGY;

HUMANS; IMMUNOMODULATION; INFLAMMATION; MULTIPLE SCLEROSIS;

EID: 84941654523     PISSN: 13515101     EISSN: 14681331     Source Type: Journal    
DOI: 10.1111/ene.12798     Document Type: Review

References (118)

1. Peterson LK, Fujinami RS. Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis. J Neuroimmunol 2007; 184: 37-44.
2. Compston A, Coles A. Multiple sclerosis. Lancet 2002; 359: 1221-1231.
3. Oksenberg JR, Baranzini SE. Multiple sclerosis genetics - is the glass half full, or half empty? Nat Rev Neurol 2010; 6: 429-437.
4. Ifergan I, Kébir H, Bernard M, et al. The blood-brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells. Brain 2008; 131: 785-799.
5. Pashenkov M, Huang YM, Kostulas V, Haglund M, Söderström M, Link H. Two subsets of dendritic cells are present in human cerebrospinal fluid. Brain 2001; 124: 480-492.
6. Serafini B, Rosicarelli B, Magliozzi R, et al. Dendritic cells in multiple sclerosis lesions: maturation stage, myelin uptake, and interaction with proliferating T-cells. J Neuropathol Exp Neurol 2006; 65: 124-141.
7. Nuyts AH, Lee WP, Bashir-Dar R, Berneman ZN, Cools N. Dendritic cells in multiple sclerosis: key players in the immunopathogenesis, key players for new cellular immunotherapies? Mult Scler 2013; 19: 995-1002.
8. International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2, Sawcer S, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476: 214-219.
9. Komiyama Y, Nakae S, Matsuki T, et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 2006; 177: 566-573.
10. Becher B, Durell BG, Noelle RJ. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 2002; 110: 493-497.
11. Hofstetter HH, Ibrahim SM, Koczan D, et al. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell Immunol 2005; 237: 123-130.
12. Chen Y, Langrish CL, McKenzie B, et al. Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Invest 2006; 116: 1317-1326.
13. Bielekova B, Goodwin B, Richert N, et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 2000; 6: 1167-1175.
14. Durelli L, Conti L, Clerico M, et al. T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol 2009; 65: 499-509.
15. Muls N, Jnaoui K, Dang HA, et al. Upregulation of IL-17, but not of IL-9, in circulating cells of CIS and relapsing MS patients. Impact of corticosteroid therapy on the cytokine network. J Neuroimmunol 2012; 243: 73-80.
16. Brucklacher-Waldert V, Stuerner K, Kolster M, Wolthausen J, Tolosa E. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain 2009; 132: 3329-3341.
17. Kebir H, Ifergan I, Alvarez JI, et al. Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann Neurol 2009; 66: 390-402.
18. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 2010; 33: 91-101.
19. Mehling M, Lindberg R, Raulf F, et al. Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology 2010; 75: 403-410.
20. Kivisäkk P, Healy BC, Viglietta V, et al. Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells. Neurology 2009; 72: 1922-1930.
21. Huppert J, Closhen D, Croxford A, et al. Cellular mechanisms of IL-17-induced blood-brain barrier disruption. FASEB J 2010; 24: 1023-1034.
22. Larochelle C, Alvarez JI, Prat A. How do immune cells overcome the blood-brain barrier in multiple sclerosis? FEBS Lett 2011; 585: 3770-3780.
23. Peters A, Pitcher LA, Sullivan JM, et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 2011; 35: 986-996.
24. Ponomarev ED, Shriver LP, Maresz K, Pedras-Vasconcelos J, Verthelyi D, Dittel BN. GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J Immunol 2007; 178: 39-48.
25. Zaheer A, Zaheer S, Sahu SK, Yang B, Lim R. Reduced severity of experimental autoimmune encephalomyelitis in GMF-deficient mice. Neurochem Res 2007; 32: 39-47.
26. Codarri L, Gyülvészi G, Tosevski V, et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 2011; 12: 560-567.
27. King IL, Kroenke MA, Segal BM. GM-CSF-dependent, CD103 + dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization. J Exp Med 2010; 207: 953-961.
28. King IL, Dickendesher TL, Segal BM. Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 2009; 113: 3190-3197.
29. Hemmer B, Nessler S, Zhou D, Kieseier B, Hartung HP. Immunopathogenesis and immunotherapy of multiple sclerosis. Nat Clin Pract Neurol 2006; 2: 201-211.
30. Piccio L, Cross AH. Immunology of multiple sclerosis. In: Giesser BS, ed. Primer on Multiple Sclerosis. Oxford University Press: New York, 2011: 47-56.
31. Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23: 683-747.
32. Compston A, Coles A. Multiple sclerosis. Lancet 2008; 372: 1502-1517.
33. Murphy AC, Lalor SJ, Lynch MA, Mills KH. Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis. Brain Behav Immun 2010; 24: 641-651.
34. Das Sarma J, Ciric B, Marek R, et al. Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis. J Neuroinflammation 2009; 6: 14.
35. Kawanokuchi J, Shimizu K, Nitta A, et al. Production and functions of IL-17 in microglia. J Neuroimmunol 2008; 194: 54-61.
36. Strachan-Whaley M, Rivest S, Yong VW. Interactions between microglia and T cells in multiple sclerosis pathobiology. J Interferon Cytokine Res 2014; 34: 615-622.
37. Trebst C, Sørensen TL, Kivisäkk P, et al. CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis. Am J Pathol 2001; 159: 1701-1710.
38. Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010; 330: 841-845.
39. Schulz C, Gomez Perdiguero E, Chorro L, et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 2012; 336: 86-90.
40. Yamasaki R, Lu H, Butovsky O, et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med 2014; 211: 1533-1549.
41. Maggi P, Macri SM, Gaitán MI, et al. The formation of inflammatory demyelinated lesions in cerebral white matter. Ann Neurol 2014; 76: 594-608.
42. Chuluundorj D, Harding SA, Abernethy D, La Flamme AC. Expansion and preferential activation of the CD14(+)CD16(+) monocyte subset during multiple sclerosis. Immunol Cell Biol 2014; 92: 509-517.
43. Raivich G, Banati R. Brain microglia and blood-derived macrophages: molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease. Brain Res Brain Res Rev 2004; 46: 261-281.
44. Czeh M, Gressens P, Kaindl AM. The yin and yang of microglia. Dev Neurosci 2011; 33: 199-209.
45. Napoli I, Neumann H. Protective effects of microglia in multiple sclerosis. Exp Neurol 2010; 225: 24-28.
46. Miron VE, Boyd A, Zhao JW, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 2013; 16: 1211-1218.
47. Stadelmann C, Kerschensteiner M, Misgeld T, Brück W, Hohlfeld R, Lassmann H. BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain 2002; 125: 75-85.
48. Jäger A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 2009; 183(11): 7169-7177.
49. Stromnes IM, Cerretti LM, Liggitt D, Harris RA, Goverman JM. Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat Med 2008; 14: 337-342.
50. Saxena A, Martin-Blondel G, Mars LT, Liblau RS. Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis. FEBS Lett 2011; 585: 3758-3763.
51. Denic A, Wootla B, Rodriguez M. CD8(+) T cells in multiple sclerosis. Expert Opin Ther Targets 2013; 17: 1053-1066.
52. Ifergan I, Kebir H, Alvarez JI, et al. Central nervous system recruitment of effector memory CD8+ T lymphocytes during neuroinflammation is dependent on α4 integrin. Brain 2011; 134: 3560-3577.
53. Babbe H, Roers A, Waisman A, et al. Clonal expansions of CD8(+) T-cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 2000; 192: 393-404.
54. Buckle GJ, Höllsberg P, Hafler DA. Activated CD8+ T-cells in secondary progressive MS secrete lymphotoxin. Neurology 2003; 60: 702-705.
55. Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Brück W. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 2000; 123: 1174-1183.
56. Cunnusamy K, Baughman EJ, Franco J, et al. Disease exacerbation of multiple sclerosis is characterized by loss of terminally differentiated autoregulatory CD8+ T cells. Clin Immunol 2014; 152: 115-126.
57. Lossius A, Johansen JN, Vartdal F, et al. High-throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8+ T cells. Eur J Immunol 2014; 44: 3439-3452.
58. Jaquiéry E, Jilek S, Schluep M, et al. Intrathecal immune responses to EBV in early MS. Eur J Immunol 2010; 40: 878-887.
59. Shimonkevitz R, Colburn C, Burnham JA, Murray RS, Kotzin BL. Clonal expansions of activated gamma/delta T cells in recent-onset multiple sclerosis. Proc Natl Acad Sci U S A 1993; 90: 923-927.
60. Schirmer L, Rothhammer V, Hemmer B, Korn T. Enriched CD161high CCR6+ γδ T cells in the cerebrospinal fluid of patients with multiple sclerosis. JAMA Neurol 2013; 70: 345-351.
61. Selmaj K, Brosnan CF, Raine CS. Colocalization of lymphocytes bearing gamma delta T-cell receptor and heat shock protein hsp65+ oligodendrocytes in multiple sclerosis. Proc Natl Acad Sci U S A 1991; 88: 6452-6456.
62. Chen Z, Freedman MS. CD16+ gammadelta T cells mediate antibody dependent cellular cytotoxicity: potential mechanism in the pathogenesis of multiple sclerosis. Clin Immunol 2008; 128: 219-227.
63. Zeine R, Pon R, Ladiwala U, Antel JP, Filion LG, Freedman MS. Mechanism of gammadelta T cell-induced human oligodendrocyte cytotoxicity: relevance to multiple sclerosis. J Neuroimmunol 1998; 87: 49-61.
64. Petermann F, Rothhammer V, Claussen MC, et al. γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism. Immunity 2010; 33: 351-363.
65. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 2009; 31: 331-341.
66. Vitale M, Della Chiesa M, Carlomagno S, et al. NK-dependent DC maturation is mediated by TNFalpha and IFNgamma released upon engagement of the NKp30 triggering receptor. Blood 2005; 106: 566-571.
67. Piccioli D, Sbrana S, Melandri E, Valiante NM. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med 2002; 195: 335-341.
68. Della Chiesa M, Romagnani C, Thiel A, Moretta L, Moretta A. Multidirectional interactions are bridging human NK cells with plasmacytoid and monocyte-derived dendritic cells during innate immune responses. Blood 2006; 108: 3851-3858.
69. Bielekova B, Catalfamo M, Reichert-Scrivner S, et al. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A 2006; 103: 5941-5946.
70. Fraussen J, Claes N, de Bock L, Somers V. Targets of the autoimmune response in multiple sclerosis. Autoimmun Rev 2014; 13: 1126-1137.
71. Levin MC, Lee S, Gardner LA, Shin Y, Douglas JN, Cooper C. Autoantibodies to non-myelin antigens as contributors to the pathogenesis of multiple sclerosis. J Clin Cell Immunol 2013; Jun 30; 4. doi: 10.4172/2155-9899.1000148.
72. Stern JN, Yaari G, Vander Heiden JA, et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med 2014; 6(248): 248ra107.
73. Palanichamy A, Apeltsin L, Kuo TC, et al. Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci Transl Med 2014; 6(248): 248ra106.
74. Reindl M, Kuenz B, Berger T. B-cells and antibodies in MS. Results Probl Cell Differ 2010; 51: 99-113.
75. von Büdingen HC, Gulati M, Kuenzle S, Fischer K, Rupprecht TA, Goebels N. Clonally expanded plasma cells in the cerebrospinal fluid of patients with central nervous system autoimmune demyelination produce 'oligoclonal bands'. J Neuroimmunol 2010; 218: 134-139.
76. Ozawa K, Suchanek G, Breitschopf H, et al. Patterns of oligodendroglia pathology in multiple sclerosis. Brain 1994; 117: 1311-1322.
77. Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000; 47: 707-717.
78. Magliozzi R, Howell O, Vora A, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007; 130: 1089-1104.
79. Kinnunen T, Chamberlain N, Morbach H, et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest 2013; 123: 2737-2741.
80. Matsushita T, Yanaba K, Bouaziz JD, Fujimoto M, Tedder TF. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest 2008; 118: 3420-3430.
81. Shen P, Roch T, Lampropoulou V, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 2014; 507: 366-370.
82. Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002; 3: 944-950.
83. Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011; 378: 1779-1787.
84. Clarke LE, Barres BA. Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 2013; 14: 311-321.
85. Toft-Hansen H, Füchtbauer L, Owens T. Inhibition of reactive astrocytosis in established experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease. Glia 2011; 59: 166-176.
86. Mayo L, Trauger SA, Blain M, et al. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med 2014; 20: 1147-1156.
87. Timmermans S, Bogie JF, Vanmierlo T, et al. High fat diet exacerbates neuroinflammation in an animal model of multiple sclerosis by activation of the renin angiotensin system. J Neuroimmune Pharmacol 2013; 9: 209-217.
88. Kleinewietfeld M, Manzel A, Titze J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 2013; 496: 518-522.
89. Ochoa-Repáraz J, Kasper LH. Gut microbiome and the risk factors in central nervous system autoimmunity. FEBS Lett 2014; 588: 4214-4222.
90. Telesford K, Ochoa-Repáraz J, Kasper LH. Gut commensalism, cytokines, and central nervous system demyelination. J Interferon Cytokine Res 2014; 34: 605-614.
91. Berer K, Mues M, Koutroulos M, et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 2011; 479: 538-541.
92. Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2011; 108: 4615-4622.
93. Ochoa-Repáraz J, Mielcarz DW, Wang Y, et al. A polysaccharide from the human commensal Bacteroides fragilis protects against CNS demyelinating disease. Mucosal Immunol 2010; 3: 487-495.
94. Kuhlmann T, Lassmann H, Brück W. Diagnosis of inflammatory demyelination in biopsy specimens: a practical approach. Acta Neuropathol 2008; 115: 275-287.
95. Lassmann H. Mechanisms of white matter damage in multiple sclerosis. Glia 2014; 62: 1816-1830.
96. Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Brück W. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002; 125: 2202-2212.
97. De Stefano N, Narayanan S, Francis SJ, et al. Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability. Arch Neurol 2002; 59: 1565-1571.
98. Grigoriadis N, Ben-Hur T, Karussis D, Milonas I. Axonal damage in multiple sclerosis: a complex issue in a complex disease. Clin Neurol Neurosurg 2004; 106: 211-217.
99. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278-285.
100. Mahad DJ, Ziabreva I, Campbell G, et al. Mitochondrial changes within axons in multiple sclerosis. Brain 2009; 132: 1161-1174.
101. Brex PA, Jenkins R, Fox NC, et al. Detection of ventricular enlargement in patients at the earliest clinical stage of MS. Neurology 2000; 54: 1689-1691.
102. Dalton CM, Brex PA, Jenkins R, et al. Progressive ventricular enlargement in patients with clinically isolated syndromes is associated with the early development of multiple sclerosis. J Neurol Neurosurg Psychiatry 2002; 73: 141-147.
103. De Stefano N, Airas L, Grigoriadis N, et al. Clinical relevance of brain volume measures in multiple sclerosis. CNS Drugs 2014; 28: 147-156.
104. Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005; 128: 2705-2712.
105. Bø L, Vedeler CA, Nyland HI, Trapp BD, Mørk SJ. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 2003; 62: 723-732.
106. Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, Revesz T. Cortical lesions in multiple sclerosis. Brain 1999; 122: 17-26.
107. Lassmann H. Multiple sclerosis: lessons from molecular neuropathology. Exp Neurol 2014; 262: 2-7.
108. Haider L, Simeonidou C, Steinberger G, et al. Multiple sclerosis deep grey matter: the relation between demyelination, neurodegeneration, inflammation and iron. J Neurol Neurosurg Psychiatry 2014; 85: 1386-1395.
109. Siffrin V, Vogt J, Radbruch H, Nitsch R, Zipp F. Multiple sclerosis - candidate mechanisms underlying CNS atrophy. Trends Neurosci 2010; 33: 202-210.
110. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 2004; 14: 164-174.
111. Carroll WM. Clinical trials of multiple sclerosis therapies: improvements to demonstrate long-term patient benefit. Mult Scler 2009; 15: 951-958.
112. Weissert R. The immune pathogenesis of multiple sclerosis. J Neuroimmune Pharmacol 2013; 8: 857-866.
113. Ali R, Nicholas RS, Muraro PA. Drugs in development for relapsing multiple sclerosis. Drugs 2013; 73: 625-650.
114. Grigoriadis N, Grigoriadis S, Polyzoidou E, Milonas I, Karussis D. Neuroinflammation in multiple sclerosis: evidence for autoimmune dysregulation, not simple autoimmune reaction. Clin Neurol Neurosurg 2006; 108: 241-244.
115. Groves A, Kihara Y, Chun J. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J Neurol Sci 2013; 328: 9-18.
116. Havari E, Turner MJ, Campos-Rivera J, et al. Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro. Immunology 2014; 141: 123-131.
117. Zhang X, Tao Y, Chopra M, et al. Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis. J Immunol 2013; 191: 5867-5874.
118. Wiendl H, Kieseier B. Multiple sclerosis: reprogramming the immune repertoire with alemtuzumab in MS. Nat Rev Neurol 2013; 9: 125-126.