The Immunopathophysiology of Multiple Sclerosis

Neurologic Clinics

Volumn 29, Issue 2, 2011, Pages 257-278

  Wu, Gregory F ^a   Alvarez, Enrique ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Demyelination; Multiple sclerosis; Neuroimmunology; Pathogenesis

Indexed keywords

INTERLEUKIN 17;

B LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL MIGRATION; CYTOKINE PRODUCTION; DEMYELINATION; HUMAN; IMMUNOPATHOGENESIS; MULTIPLE SCLEROSIS; NEUROIMMUNOLOGY; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REMYELINIZATION; REVIEW;

ANIMALS; ANTIGEN-PRESENTING CELLS; AXONS; BRAIN; CYTOKINES; HUMANS; LEUKOCYTES; LYMPHOCYTES; MODELS, BIOLOGICAL; MULTIPLE SCLEROSIS; NEURONS;

EID: 79952832197     PISSN: 07338619     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ncl.2010.12.009     Document Type: Review

References (141)

1. 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 1953, 129:2006.
2. Goverman J. Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 2009, 9:393.
3. Charcot J.M. Lecons sur les maladies du systeme nerveux faites a la salpetriere 1872, A. Delahaye, Paris.
4. Compston A., McDonald I.R., Noseworthy J., et al. McAlpine's multiple sclerosis 2006, Churchill Livingstone, Philadelphia.
5. Frohman E.M., Racke M.K., Raine C.S. Multiple sclerosis-the plaque and its pathogenesis. N Engl J Med 2006, 354:942.
6. Greenfield J.G., Love S., Louis D.N., et al. Greenfield's neuropathology 2008, Hodder Arnold, London. 8th edition.
7. Perry A., Brat D.J. Practical surgical neuropathology: a diagnostic approach 2010, Churchill Livingstone/Elsevier, Philadelphia.
8. Henderson A.P., Barnett M.H., Parratt J.D., et al. Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Ann Neurol 2009, 66:739.
9. Trapp B.D., Peterson J., Ransohoff R.M., et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998, 338:278.
10. Lassmann H., Bruck W., Lucchinetti C., et al. Remyelination in multiple sclerosis. Mult Scler 1997, 3:133.
11. Wilson H.C., Scolding N.J., Raine C.S. Co-expression of PDGF alpha receptor and NG2 by oligodendrocyte precursors in human CNS and multiple sclerosis lesions. J Neuroimmunol 2006, 176:162.
12. Lucchinetti C.F., Bruck W., Lassmann H. Evidence for pathogenic heterogeneity in multiple sclerosis. Ann Neurol 2004, 56:308.
13. Keegan M., Konig F., McClelland R., et al. Relation between humoral pathological changes in multiple sclerosis and response to therapeutic plasma exchange. Lancet 2005, 366:579.
14. Raine C.S. Multiple sclerosis: classification revisited reveals homogeneity and recapitulation. Ann Neurol 2008, 63:1.
15. Barnett M.H., Prineas J.W. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 2004, 55:458.
16. Breij E.C., Brink B.P., Veerhuis R., et al. Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol 2008, 63:16.
17. Baker R.W., Thompson R.H., Zilkha K.J. Fatty-acid composition of brain lecithins in multiple sclerosis. Lancet 1963, 1:26.
18. Suzuki K., Kamoshita S., Eto Y., et al. Myelin in multiple sclerosis. Composition of myelin from normal-appearing white matter. Arch Neurol 1973, 28:293.
19. Ceccarelli A., Rocca M.A., Falini A., et al. Normal-appearing white and grey matter damage in MS. A volumetric and diffusion tensor MRI study at 3.0 Tesla. J Neurol 2007, 254:513.
20. Filippi M., Campi A., Dousset V., et al. A magnetization transfer imaging study of normal-appearing white matter in multiple sclerosis. Neurology 1995, 45:478.
21. Zivadinov R., Stosic M., Cox J.L., et al. The place of conventional MRI and newly emerging MRI techniques in monitoring different aspects of treatment outcome. J Neurol 2008, 255(Suppl 1):61.
22. Allen I.V., McQuaid S., Mirakhur M., et al. Pathological abnormalities in the normal-appearing white matter in multiple sclerosis. Neurol Sci 2001, 22:141.
23. Kutzelnigg A., Lucchinetti C.F., Stadelmann C., et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005, 128:2705.
24. Moore G.R., Laule C., Mackay A., et al. Dirty-appearing white matter in multiple sclerosis: preliminary observations of myelin phospholipid and axonal loss. J Neurol 1802, 255:2008.
25. Geurts J.J., Pouwels P.J., Uitdehaag B.M., et al. Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. Radiology 2005, 236:254.
26. Gilmore C.P., Donaldson I., Bo L., et al. Regional variations in the extent and pattern of grey matter demyelination in multiple sclerosis: a comparison between the cerebral cortex, cerebellar cortex, deep grey matter nuclei and the spinal cord. J Neurol Neurosurg Psychiatry 2009, 80:182.
27. Peterson J.W., Bo L., Mork S., et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001, 50:389.
28. Amato M.P., Portaccio E., Goretti B., et al. Association of neocortical volume changes with cognitive deterioration in relapsing-remitting multiple sclerosis. Arch Neurol 2007, 64:1157.
29. Brink B.P., Veerhuis R., Breij E.C., et al. The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions. J Neuropathol Exp Neurol 2005, 64:147.
30. van Horssen J., Brink B.P., de Vries H.E., et al. The blood-brain barrier in cortical multiple sclerosis lesions. J Neuropathol Exp Neurol 2007, 66:321.
31. Bo L. The histopathology of grey matter demyelination in multiple sclerosis. Acta Neurol Scand Suppl 2009, 189:51.
32. Bo L., Vedeler C.A., Nyland H.I., et al. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 2003, 62:723.
33. 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.
34. 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.
35. Pette M., Fujita K., Wilkinson D., et al. Myelin autoreactivity in multiple sclerosis: recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of multiple-sclerosis patients and healthy donors. Proc Natl Acad Sci U S A 1990, 87:7968.
36. Valli A., Sette A., Kappos L., et al. Binding of myelin basic protein peptides to human histocompatibility leukocyte antigen class II molecules and their recognition by T cells from multiple sclerosis patients. J Clin Invest 1993, 91:616.
37. Greer J.M., Csurhes P.A., Cameron K.D., et al. Increased immunoreactivity to two overlapping peptides of myelin proteolipid protein in multiple sclerosis. Brain 1997, 120(Pt 8):1447.
38. Zhang J., Markovic-Plese S., Lacet B., et al. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 1994, 179:973.
39. de Rosbo N.K., Kaye J.F., Eisenstein M., et al. The myelin-associated oligodendrocytic basic protein region MOBP15-36 encompasses the immunodominant major encephalitogenic epitope(s) for SJL/J mice and predicted epitope(s) for multiple sclerosis-associated HLA-DRB1*1501. J Immunol 2004, 173:1426.
40. Bajramovic J.J., Plomp A.C., Goes A., et al. Presentation of alpha B-crystallin to T cells in active multiple sclerosis lesions: an early event following inflammatory demyelination. J Immunol 2000, 164:4359.
41. Derfuss T., Parikh K., Velhin S., et al. Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc Natl Acad Sci U S A 2009, 106:8302.
42. Berthelot L., Laplaud D.A., Pettre S., et al. Blood CD8+ T cell responses against myelin determinants in multiple sclerosis and healthy individuals. Eur J Immunol 2008, 38:1889.
43. Hellings N., Baree M., Verhoeven C., et al. T-cell reactivity to multiple myelin antigens in multiple sclerosis patients and healthy controls. J Neurosci Res 2001, 63:290.
44. Bielekova B., Sung M.H., Kadom N., et al. Expansion and functional relevance of high-avidity myelin-specific CD4+ T cells in multiple sclerosis. J Immunol 2004, 172:3893.
45. Han M.H., Hwang S.I., Roy D.B., et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 2008, 451:1076.
46. Kanter J.L., Narayana S., Ho P.P., et al. Lipid microarrays identify key mediators of autoimmune brain inflammation. Nat Med 2006, 12:138.
47. Lock C., Hermans G., Pedotti R., et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 2002, 8:500.
48. Chabas D., Baranzini S.E., Mitchell D., et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001, 294:1731.
49. Lanz T.V., Ding Z., Ho P.P., et al. Angiotensin II sustains brain inflammation in mice via TGF-beta. J Clin Invest 2010, 120:2782.
50. Munz C., Lunemann J.D., Getts M.T., et al. Antiviral immune responses: triggers of or triggered by autoimmunity?. Nat Rev Immunol 2009, 9:246.
51. Sospedra M., Martin R. Immunology of multiple sclerosis. Annu Rev Immunol 2005, 23:683.
52. Salvetti M., Giovannoni G., Aloisi F. Epstein-Barr virus and multiple sclerosis. Curr Opin Neurol 2009, 22:201.
53. Talbot P.J., Paquette J.S., Ciurli C., et al. Myelin basic protein and human coronavirus 229E cross-reactive T cells in multiple sclerosis. Ann Neurol 1996, 39:233.
54. Tejada-Simon M.V., Zang Y.C., Hong J., et al. Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis. Ann Neurol 2003, 53:189.
55. Steinman L. Antigen-specific therapy of multiple sclerosis: the long-sought magic bullet. Neurotherapeutics 2007, 4:661.
56. Bar-Or A., Vollmer T., Antel J., et al. Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial. Arch Neurol 2007, 64:1407.
57. Dolgin E. The inverse of immunity. Nat Med 2010, 16:740.
58. Miossec P., Korn T., Kuchroo V.K. Interleukin-17 and type 17 helper T cells. N Engl J Med 2009, 361:888.
59. Cua D.J., Sherlock J., Chen Y., et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003, 421:744.
60. Langrish C.L., Chen Y., Blumenschein W.M., et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005, 201:233.
61. Mangan P.R., Harrington L.E., O'Quinn D.B., et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006, 441:231.
62. Reboldi A., Coisne C., Baumjohann D., et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 2009, 10:514.
63. Kroenke M.A., Carlson T.J., Andjelkovic A.V., et al. IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med 2008, 205:1535.
64. Haak S., Croxford A.L., Kreymborg K., et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest 2009, 119:61.
65. Brucklacher-Waldert V., Stuerner K., Kolster M., et al. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain 2009, 132:3329.
66. 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.
67. Tzartos J.S., Friese M.A., Craner M.J., et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 2008, 172:146.
68. Kebir H., Kreymborg K., Ifergan I., et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med 2007, 13:1173.
69. Spolski R., Leonard W.J. Cytokine mediators of Th17 function. Eur J Immunol 2009, 39:658.
70. Ramgolam V.S., Sha Y., Jin J., et al. IFN-beta inhibits human Th17 cell differentiation. J Immunol 2009, 183:5418.
71. Axtell R.C., de Jong B.A., Boniface K., et al. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med 2010, 16:406.
72. Koike F., Satoh J., Miyake S., et al. Microarray analysis identifies interferon beta-regulated genes in multiple sclerosis. J Neuroimmunol 2003, 139:109.
73. Du C., Liu C., Kang J., et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol 2009, 10:1252.
74. O'Connor W., Zenewicz L.A., Flavell R.A. The dual nature of T(H)17 cells: shifting the focus to function. Nat Immunol 2010, 11:471.
75. Baranzini S.E., Jeong M.C., Butunoi C., et al. B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J Immunol 1999, 163:5133.
76. Owens G.P., Burgoon M.P., Anthony J., et al. The immunoglobulin G heavy chain repertoire in multiple sclerosis plaques is distinct from the heavy chain repertoire in peripheral blood lymphocytes. Clin Immunol 2001, 98:258.
77. Warren K.G., Catz I. Autoantibodies to myelin basic protein within multiple sclerosis central nervous system tissue. J Neurol Sci 1993, 115:169.
78. Wucherpfennig K.W., Catz I., Hausmann S., et al. Recognition of the immunodominant myelin basic protein peptide by autoantibodies and HLA-DR2-restricted T cell clones from multiple sclerosis patients. Identity of key contact residues in the B-cell and T-cell epitopes. J Clin Invest 1997, 100:1114.
79. O'Connor K.C., Appel H., Bregoli L., et al. Antibodies from inflamed central nervous system tissue recognize myelin oligodendrocyte glycoprotein. J Immunol 1974, 175:2005.
80. Genain C.P., Cannella B., Hauser S.L., et al. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 1999, 5:170.
81. Barnett M.H., Parratt J.D., Cho E.S., et al. Immunoglobulins and complement in postmortem multiple sclerosis tissue. Ann Neurol 2009, 65:32.
82. Franciotta D., Salvetti M., Lolli F., et al. B cells and multiple sclerosis. Lancet Neurol 2008, 7:852.
83. Avasarala J.R., Cross A.H., Trotter J.L. Oligoclonal band number as a marker for prognosis in multiple sclerosis. Arch Neurol 2001, 58:2044.
84. von Budingen H.C., Harrer M.D., Kuenzle S., et al. Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin-specific antibodies. Eur J Immunol 2008, 38:2014.
85. Lambracht-Washington D., O'Connor K.C., Cameron E.M., et al. Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B cells from patients with relapsing remitting MS. J Neuroimmunol 2007, 186:164.
86. Owens G.P., Bennett J.L., Lassmann H., et al. Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Ann Neurol 2009, 65:639.
87. Villar L.M., Sadaba M.C., Roldan E., et al. Intrathecal synthesis of oligoclonal IgM against myelin lipids predicts an aggressive disease course in MS. J Clin Invest 2005, 115:187.
88. Bosca I., Magraner M.J., Coret F., et al. The risk of relapse after a clinically isolated syndrome is related to the pattern of oligoclonal bands. J Neuroimmunol 2010, 226:143.
89. Bosca I., Villar L.M., Coret F., et al. Response to interferon in multiple sclerosis is related to lipid-specific oligoclonal IgM bands. Mult Scler 2010, 16:810.
90. Mathey E.K., Derfuss T., Storch M.K., et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med 2007, 204:2363.
91. Reindl M., Khalil M., Berger T. Antibodies as biological markers for pathophysiological processes in MS. J Neuroimmunol 2006, 180:50.
92. Hauser S.L., Waubant E., Arnold D.L., et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008, 358:676.
93. Cross A.H., Stark J.L., Lauber J., et al. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 2006, 180:63.
94. Bar-Or A., Fawaz L., Fan B., et al. Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS?. Ann Neurol 2010, 67:452.
95. Fillatreau S., Sweenie C.H., McGeachy M.J., et al. B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002, 3:944.
96. Prineas J.W. Multiple sclerosis: presence of lymphatic capillaries and lymphoid tissue in the brain and spinal cord. Science 1979, 203:1123.
97. Serafini B., Rosicarelli B., Magliozzi R., et al. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 2004, 14:164.
98. Kooi E.J., Geurts J.J., van Horssen J., et al. Meningeal inflammation is not associated with cortical demyelination in chronic multiple sclerosis. J Neuropathol Exp Neurol 2009, 68:1021.
99. Serafini B., Rosicarelli B., Franciotta D., et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med 2007, 204:2899.
100. Ransohoff R.M., Kivisakk P., Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 2003, 3:569.
101. Daneman R., Rescigno M. The gut immune barrier and the blood-brain barrier: are they so different?. Immunity 2009, 31:722.
102. Piccio L., Rossi B., Scarpini E., et al. Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric G(i)-linked receptors. J Immunol 1940, 168:2002.
103. Holman D.W., Klein R.S., Ransohoff R.M. The blood-brain barrier, chemokines and multiple sclerosis. Biochim Biophys Acta 2011, 1812(2):220-230.
104. Yednock T.A., Cannon C., Fritz L.C., et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 1992, 356:63.
105. Polman C.H., O'Connor P.W., Havrdova E., et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006, 354:899.
106. Rudick R.A., Stuart W.H., Calabresi P.A., et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006, 354:911.
107. del Pilar Martin M., Cravens P.D., Winger R., et al. Decrease in the numbers of dendritic cells and CD4+ T cells in cerebral perivascular spaces due to natalizumab. Arch Neurol 2008, 65:1596.
108. Cayrol R., Wosik K., Berard J.L., et al. Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system. Nat Immunol 2008, 9:137.
109. Steinman L. A molecular trio in relapse and remission in multiple sclerosis. Nat Rev Immunol 2009, 9:440.
110. McCandless E.E., Piccio L., Woerner B.M., et al. Pathological expression of CXCL12 at the blood-brain barrier correlates with severity of multiple sclerosis. Am J Pathol 2008, 172:799.
111. Pashenkov M., Teleshova N., Kouwenhoven M., et al. Elevated expression of CCR5 by myeloid (CD11c+) blood dendritic cells in multiple sclerosis and acute optic neuritis. Clin Exp Immunol 2002, 127:519.
112. Teleshova N., Pashenkov M., Huang Y.M., et al. Multiple sclerosis and optic neuritis: CCR5 and CXCR3 expressing T cells are augmented in blood and cerebrospinal fluid. J Neurol 2002, 249:723.
113. Chastain E.M., Duncan D.S., Rodgers J.M., et al. The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta 2011, 1812(2):265-274.
114. Slavin A.J., Soos J.M., Stuve O., et al. Requirement for endocytic antigen processing and influence of invariant chain and H-2M deficiencies in CNS autoimmunity. J Clin Invest 2001, 108:1133.
115. Tompkins S.M., Padilla J., Dal Canto M.C., et al. De novo central nervous system processing of myelin antigen is required for the initiation of experimental autoimmune encephalomyelitis. J Immunol 2002, 168:4173.
116. Becher B., Bechmann I., Greter M. Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain. J Mol Med 2006, 84:532.
117. Greter M., Heppner F.L., Lemos M.P., et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 2005, 11:328.
118. Bartholomaus I., Kawakami N., Odoardi F., et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 2009, 462:94.
119. Aloisi F., Ria F., Adorini L. Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes. Immunol Today 2000, 21:141.
120. Lassmann H., Bruck W., Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 2001, 7:115.
121. Heppner F.L., Greter M., Marino D., et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 2005, 11:146.
122. McMahon E.J., Bailey S.L., Castenada C.V., et al. Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat Med 2005, 11:335.
123. Ortler S., Leder C., Mittelbronn M., et al. B7-H1 restricts neuroantigen-specific T cell responses and confines inflammatory CNS damage: implications for the lesion pathogenesis of multiple sclerosis. Eur J Immunol 2008, 38:1734.
124. Gabrilovich D.I., Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009, 9:162.
125. Zhu B., Bando Y., Xiao S., et al. CD11b+Ly-6C(hi) suppressive monocytes in experimental autoimmune encephalomyelitis. J Immunol 2007, 179:5228.
126. Piccio L., Buonsanti C., Cella M., et al. Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain 2008, 131:3081.
127. Ferguson B., Matyszak M.K., Esiri M.M., et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997, 120(Pt 3):393.
128. Kuhlmann T., Lingfeld G., Bitsch A., et al. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002, 125:2202.
129. Kornek B., Storch M.K., Weissert R., et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 2000, 157:267.
130. Tallantyre E.C., Bo L., Al-Rawashdeh O., et al. Clinico-pathological evidence that axonal loss underlies disability in progressive multiple sclerosis. Mult Scler 2010, 16:406.
131. Medana I., Martinic M.A., Wekerle H., et al. Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am J Pathol 2001, 159:809.
132. Neumann H., Medana I.M., Bauer J., et al. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci 2002, 25:313.
133. Smith K.J., Lassmann H. The role of nitric oxide in multiple sclerosis. Lancet Neurol 2002, 1:232.
134. Fernandez M., Montalban X., Comabella M. Orchestrating innate immune responses in multiple sclerosis: molecular players. J Neuroimmunol 2010, 225(1-2):5-12.
135. Sloane J.A., Batt C., Ma Y., et al. Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2. Proc Natl Acad Sci U S A 2010, 107:11555.
136. Mahad D.J., Ziabreva I., Campbell G., et al. Mitochondrial changes within axons in multiple sclerosis. Brain 2009, 132:1161.
137. Pitt D., Werner P., Raine C.S. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 2000, 6:67.
138. Rovaris M., Gambini A., Gallo A., et al. Axonal injury in early multiple sclerosis is irreversible and independent of the short-term disease evolution. Neurology 2005, 65:1626.
139. Burkholder B.M., Osborne B., Loguidice M.J., et al. Macular volume determined by optical coherence tomography as a measure of neuronal loss in multiple sclerosis. Arch Neurol 2009, 66:1366.
140. Clements R.J., McDonough J., Freeman E.J. Distribution of parvalbumin and calretinin immunoreactive interneurons in motor cortex from multiple sclerosis post-mortem tissue. Exp Brain Res 2008, 187:459.
141. Nave K.A., Trapp B.D. Axon-glial signaling and the glial support of axon function. Annu Rev Neurosci 2008, 31:535.