Multiple Sclerosis and Obesity: Possible Roles of Adipokines

Mediators of Inflammation

Volumn 2016, Issue , 2016, Pages

  Guerrero García, José De Jesús ^a,b   Carrera Quintanar, Lucrecia ^b   López Roa, Rocío Ivette ^b   Márquez Aguirre, Ana Laura ^c   Rojas Mayorquín, Argelia Esperanza ^b   Ortuño Sahagún, Daniel ^b  

^a INSTITUTO MEXICANO DEL SEGURO SOCIAL   (Mexico)

^b UNIVERSITY OF GUADALAJARA   (Mexico)

^c CENTRO DE INVESTIGACIÓN Y ASISTENCIA EN TECNOLOGÍA Y DISEÑO DEL ESTADO DE JALISCO   (Mexico)

Author keywords

[No Author keywords available]

Indexed keywords

ADIPOCYTOKINE; ADIPONECTIN; BIOLOGICAL MARKER; CHEMERIN; COMPLEMENT FACTOR D; FATTY ACID BINDING PROTEIN 4; LEPTIN; NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; OMENTIN; RESISTIN; TRANSCRIPTION FACTOR FOXP3; UNCLASSIFIED DRUG; VASPIN; INTERLEUKIN 17;

ADIPOCYTE; ADIPOSE DERIVED STEM CELL; ADIPOSE TISSUE; ASTROCYTE; AUTOIMMUNITY; CD4+ CD25+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CHRONIC INFLAMMATION; HUMAN; IMMUNE RESPONSE; IMMUNE SYSTEM; MEDIATOR RELEASE; MESENCHYMAL STEM CELL TRANSPLANTATION; MICROGLIA; MOLECULAR PATHOLOGY; MULTIPLE SCLEROSIS; NERVE CELL; NERVOUS TISSUE; NEUROIMMUNOLOGY; NEUROPATHOLOGY; NONHUMAN; OBESITY; OLIGODENDROGLIA; PHASE 2 CLINICAL TRIAL (TOPIC); REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE; TH1 CELL; TH17 CELL; TH2 CELL; ANIMAL; AUTOIMMUNE DISEASE; COMPLICATION; CYTOLOGY; DISEASE MODEL; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; INFLAMMATION; MESENCHYMAL STROMA CELL; METABOLISM; MOUSE; PATHOLOGY; PREVALENCE; RISK;

ADIPOCYTES; ADIPOKINES; ADIPONECTIN; ADIPOSE TISSUE; ANIMALS; ASTROCYTES; AUTOIMMUNE DISEASES; CD8-POSITIVE T-LYMPHOCYTES; COMPLEMENT FACTOR D; DISEASE MODELS, ANIMAL; ENCEPHALOMYELITIS, AUTOIMMUNE, EXPERIMENTAL; HUMANS; IMMUNE SYSTEM; INFLAMMATION; INTERLEUKIN-17; LEPTIN; MESENCHYMAL STROMAL CELLS; MICE; MICROGLIA; MULTIPLE SCLEROSIS; NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; OBESITY; OLIGODENDROGLIA; PREVALENCE; RESISTIN; RISK; TH1 CELLS; TH2 CELLS;

EID: 84990877532     PISSN: 09629351     EISSN: 14661861     Source Type: Journal    
DOI: 10.1155/2016/4036232     Document Type: Review

References (266)

1. L. Moroni, I. Bianchi, and A. Lleo, "Geoepidemiology, gender and autoimmune disease, " Autoimmunity Reviews, vol. 11, no. 6-7, pp. A386-A392, 2012.
2. M. Versini, P.-Y. Jeandel, E. Rosenthal, and Y. Shoenfeld, "Obesity in autoimmune diseases: not a passive bystander, " Autoimmunity Reviews, vol. 13, no. 9, pp. 981-1000, 2014.
3. WHO, "Overweight/obesity: overweight by country. Global Health Observatory Data Repository 2008-2013, " 2016, http://www. who. int/gho/ncd/risk factors/obesity text/en/.
4. E. Gremese, B. Tolusso, M. R. Gigante, and G. Ferraccioli, "Obesity as a risk and severity factor in rheumatic diseases (autoimmune chronic inflammatory diseases), " Frontiers in Immunology, vol. 5, article 576, 2014.
5. S. Overs, C. M. Hughes, J. K. Haselkorn, and A. P. Turner, "Modifiable comorbidities and disability in multiple sclerosis, " Current Neurology and Neuroscience Reports, vol. 12, no. 5, pp. 610-617, 2012.
6. R. Milo and A. Miller, "Revised diagnostic criteria of multiple sclerosis, " Autoimmunity Reviews, vol. 13, no. 4-5, pp. 518-524, 2014.
7. S. Schwarz and H. Leweling, "Multiple sclerosis and nutrition, " Multiple Sclerosis, vol. 11, no. 1, pp. 24-32, 2005.
8. R. L. Swank and B. B. Dugan, "effect of lowsaturated fat diet in early and late cases of multiple sclerosis, " The Lancet, vol. 336, no. 8706, pp. 37-39, 1990.
9. C. H. Marck, S. L. Neate, K. L. Taylor, T. J. Weiland, and G. A. Jelinek, "Prevalence of comorbidities, overweight and obesity in an international sample of people withmultiple sclerosis and associations with modifiable lifestyle factors, " PLoSONe, vol. 11, no. 2, Article ID e0148573, 2016.
10. A. Hedström, L. Alfredsson, and T. Olsson, "environmental factors and their interactions with risk genotypes in MS susceptibility, " Current Opinion in Neurology, vol. 29, no. 3, pp. 293-298, 2016.
11. H. Beltrán-Sánchez, M. O. Harhay, M. M. Harhay, and S. Mcelligott, "Prevalence and trends of metabolic syndrome in the adult U. S. population, 1999-2010, " Journal of the American College of Cardiology, vol. 62, no. 8, pp. 697-703, 2013.
12. J. N. Slawta, A. R. Wilcox, J. A. McCubbin, D. J. Nalle, S. D. Fox, and G. Anderson, "Health behaviors, body composition, and coronary heart disease risk in women with multiple sclerosis, " Archives of Physical Medicine and Rehabilitation, vol. 84, no. 12, pp. 1823-1830, 2003.
13. M. Markianos, M.-e. evangelopoulos, G. Koutsis, P. Davaki, and C. Sfagos, "Body mass index in multiple sclerosis: associations with CSF neurotransmitter metabolite levels, " ISRN Neurology, vol. 2013, Article ID 981070, 6 pages, 2013.
14. S. R. Khurana, A. M. Bamer, A. P. Turner et al., "The prevalence of overweight and obesity in veterans with multiple sclerosis, " American Journal of Physical Medicine and Rehabilitation, vol. 88, no. 2, pp. 83-91, 2009.
15. A. K. Hedström, T. Olsson, and L. Alfredsson, "High bodymass index before age 20 is associated with increased risk formultiple sclerosis in both men and women, " Multiple Sclerosis Journal, vol. 18, no. 9, pp. 1334-1336, 2012.
16. A. Langer-Gould, S. M. Brara, B. E. Beaber, and C. Koebnick, "Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome, " Neurology, vol. 80, no. 6, pp. 548-552, 2013.
17. K. L. Munger, J. Bentzen, B. Laursen et al., "Childhood body mass index and multiple sclerosis risk: A Long-Term Cohort Study, " Multiple Sclerosis Journal, vol. 19, no. 10, pp. 1323-1329, 2013.
18. K. L. Munger, T. Chitnis, and A. Ascherio, "Body size and risk of MS in two cohorts of US women, " Neurology, vol. 73, no. 19, pp. 1543-1550, 2009.
19. K. Wesnes, T. Riise, I. Casetta et al., "Body size and the risk of multiple sclerosis in Norway and Italy: the envIMS study, " Multiple Sclerosis Journal, vol. 21, no. 4, pp. 388-395, 2015.
20. R. A. Marrie, R. I. Horwitz, G. Cutter, T. Tyry, and T. Vollmer, "Association between comorbidity and clinical characteristics of MS, " Acta Neurologica Scandinavica, vol. 124, no. 2, pp. 135-141, 2011.
21. J. Cambil-Martí, N. Galiano-Castillo, E. Muñoz-Hellí et al., "Influence of body mass index on psychological and functional outcomes in patients with multiple sclerosis: a cross-sectional study, " Nutritional Neuroscience, vol. 19, no. 2, pp. 79-85, 2016.
22. K. L. Taylor, E. J. Hadgkiss, G. A. Jelinek et al., "Lifestyle factors, demographics and medications associated with depression risk in an international sample of people with multiple sclerosis, " BMC Psychiatry, vol. 14, article 327, 2014.
23. I. Wens, U. Dalgas, E. Stenager, and B. O. eijnde, "Risk factors related to cardiovascular diseases and the metabolic syndrome in multiple sclerosis-a systematic review, " Multiple Sclerosis Journal, vol. 19, no. 12, pp. 1556-1564, 2013.
24. S. R. Oliveira, A. N. Colado Simão, A. P. Kallaur et al., "Disability in patients with multiple sclerosis: influence of insulin resistance, adiposity, and oxidative stress, " Nutrition, vol. 30, no. 3, pp. 268-273, 2014.
25. R. A. Marrie, R. Rudick, R. Horwitz et al., "Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis, " Neurology, vol. 74, no. 13, pp. 1041-1047, 2010.
26. B. Weinstock-Guttman, R. Zivadinov, N. Mahfooz et al., "Serum lipidprofiles are associatedwithdisability andMRIoutcomes in multiple sclerosis, " Journal of Neuroinflammation, vol. 8, article 127, 2011.
27. S. R. Oliveira, A. P. Kallaur, A. N. C. Simão et al., "Oxidative stress in multiple sclerosis patients in clinical remission: association with the expanded disability status scale, " Journal of the Neurological Sciences, vol. 321, no. 1-2, pp. 49-53, 2012.
28. A. K. Hedstrom, T. Olsson, and L. Alfredsson, "Body mass index during adolescence, rather than childhood, is critical in determining MS risk, " Multiple Sclerosis Journal, vol. 22, no. 7, pp. 878-883, 2016.
29. L. E. Mokry, S. Ross, N. J. Timpson et al., "Obesity and multiple sclerosis: a mendelian randomization study, " PLoS Medicine, vol. 13, no. 6, Article ID e1002053, 2016.
30. S. Nishimura, I. Manabe, S. Takaki et al., "Adipose natural regulatory B cells negatively control adipose tissue inflammation, " Cell Metabolism, vol. 18, no. 5, pp. 759-766, 2013.
31. S. E. Shoelson, J. Lee, and A. B. Goldfine, "Inflammation and insulin resistance, "The Journal of Clinical Investigation, vol. 116, no. 7, pp. 1793-1801, 2006.
32. Å. Kraszula, A. Jasínska, M.-O. eusebio, P. Kuna, A. Glabínski, and M. Pietruczuk, "evaluation of the relationship between leptin, resistin, adiponectin and natural regulatory T cells in relapsing-remitting multiple sclerosis, " Neurologia i Neurochirurgia Polska, vol. 46, no. 1, pp. 22-28, 2012.
33. S. emamgholipour, S. M. eshaghi, A. Hossein-nezhad, K. Mirzaei, Z. Maghbooli, and M. A. Sahraian, "Adipocytokine profile, cytokine levels and Foxp3 expression in multiple sclerosis: a possible link to susceptibility and clinical course of disease, " PLoS ONe, vol. 8, no. 10, article e76555, 2013.
34. A. Hossein-Nezhad, F. N. Varzaneh, K. Mirzaei, S. emamgholipour, F. N. Varzaneh, and M. A. Sahraian, "A polymorphism in the resistin gene promoter and the risk of multiple sclerosis, " Minerva Medica, vol. 104, no. 4, pp. 431-438, 2013.
35. G. Matarese, P. B. Carrieri, A. La Cava et al., "Leptin increase in multiple sclerosis associates with reduced number of CD4+CD25regulatory T cells, " Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 14, pp. 5150-5155, 2005.
36. L. Piccio, C. Cantoni, J. G. Henderson et al., "Lack of adiponectin leads to increased lymphocyte activation and increased disease severity in a mouse model of multiple sclerosis, " european Journal of Immunology, vol. 43, no. 8, pp. 2089-2100, 2013.
37. U. Musabak, S. Demirkaya, G. Genç, R. S. Ilikci, and Z. Odabasi, "Serum adiponectin, TNF IL-12p70, and IL-13 levels in multiple sclerosis and the effects of different therapy regimens, " NeuroImmunoModulation, vol. 18, no. 1, pp. 57-66, 2011.
38. J. Tomalka-Kochanowska, B. Baranowska, E. Wolinska-Witort et al., "Plasma chemerin levels in patients with multiple sclerosis, " Neuroendocrinology Letters, vol. 35, no. 3, pp. 218-223, 2014.
39. S. Messina, D. Vargas-Lowy, A. Musallam et al., "Increased leptin and A-FABP levels in relapsing and progressive forms of MS, " BMC Neurology, vol. 13, article 172, 2013.
40. A. Shemer, D. erny, S. Jung, and M. Prinz, "Microglia plasticity during health and disease: an immunological perspective, " Trends in Immunology, vol. 36, no. 10, pp. 614-624, 2015.
41. J. Hu, H. He, Z. Yang et al., "Programmed death ligand-1 on microglia regulates Th1 differentiation via nitric oxide in experimental autoimmune encephalomyelitis, " Neuroscience Bulletin, vol. 32, no. 1, pp. 70-82, 2016.
42. M. A. Lynch, "The multifaceted profile of activated microglia, " Molecular Neurobiology, vol. 40, no. 2, pp. 139-156, 2009.
43. X. Fan, H. Zhang, Y. Cheng, X. Jiang, J. Zhu, and T. Jin, "Double roles of macrophages in human neuroimmune diseases and their animal models, " Mediators of Inflammation, vol. 2016, Article ID 8489251, 13 pages, 2016.
44. J. W. Peterson, L. Bö, S. Mörk, A. Chang, R. M. Ransohoff, and B. D. Trapp, "VCAM-1-positive microglia target oligodendrocytes at the border of multiple sclerosis lesions, " Journal of Neuropathology and experimental Neurology, vol. 61, no. 6, pp. 539-546, 2002.
45. R. Huizinga, B. J. van der Star, M. Kipp et al., "Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis, " Glia, vol. 60, no. 3, pp. 422-431, 2012.
46. L. A. N. Peferoen, D. Y. S. Vogel, K. Ummenthum et al., "Activation status of human microglia is dependent on lesion formation stage and remyelination in multiple sclerosis, " Journal of Neuropathology and experimental Neurology, vol. 74, no. 1, pp. 48-63, 2015.
47. á. C. Murphy, S. J. Lalor, M. A. Lynch, and K. H. G. Mills, "Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis, " Brain, Behavior, and Immunity, vol. 24, no. 4, pp. 641-651, 2010.
48. S. Chabot, F. P. Yong, D. M. Le, L. M. Metz, T. Myles, and V. W. Yong, "Cytokine production in T lymphocyte-microglia interaction is attenuated by glatiramer acetate: amechanism for therapeutic efficacy inmultiple sclerosis, "Multiple Sclerosis, vol. 8, no. 4, pp. 299-306, 2002.
49. M. Michels, L. G. Danieslki, A. Vieira et al., "CD40-CD40 ligand pathway is a major component of acute neuroinflammation and contributes to long-termcognitive dysfunction after sepsis, " Molecular Medicine, vol. 21, pp. 219-226, 2015.
50. G.-H. Schernthaner, H.-P. Kopp, K. Krzyzanowska, S. Kriwanek, R. Koppensteiner, and G. Schernthaner, "SolubleCD40L in patients with morbid obesity: significant reduction after bariatric surgery, " european Journal of Clinical Investigation, vol. 36, no. 6, pp. 395-401, 2006.
51. A. Chatzigeorgiou, M. Lyberi, G. Chatzilymperis, A. Nezos, and E. Kamper, "CD40/CD40L signaling and its implication in health and disease, " BioFactors, vol. 35, no. 6, pp. 474-483, 2009.
52. T. G. D'Aversa, K. M. Weidenheim, and J. W. Berman, "CD40-CD40L interactions induce chemokine expression by human microglia: implications for human immunodeficiency virus encephalitis andmultiple sclerosis, " American Journal of Pathology, vol. 160, no. 2, pp. 559-567, 2002.
53. J. Shijie, H. Takeuchi, I. Yawata et al., "Blockade of glutamate release from microglia attenuates experimental autoimmune encephalomyelitis in mice, "The Tohoku Journal of experimental Medicine, vol. 217, no. 2, pp. 87-92, 2009.
54. P. Werner, D. Pitt, and C. S. Raine, "Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyre and axonal damage, " Annals of Neurology, vol. 50, no. 2, pp. 169-180, 2001.
55. A. Gentile, F. De Vito, D. Fresegna et al., "exploring the role of microglia in mood disorders associated with experimental multiple sclerosis, " Frontiers in Cellular Neuroscience, vol. 9, article 243, 2015.
56. O. Butovsky, Y. Ziv, A. Schwartz et al., "Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells, "Molecular and Cellular Neuroscience, vol. 31, no. 1, pp. 149-160, 2006.
57. S. Columba-Cabezas, B. Serafini, E. Ambrosini et al., "Induction of macrophage-derived chemokine/CCL22 expression in experimental autoimmune encephalomyelitis and cultured microglia: implications for disease regulation, " Journal of Neuroimmunology, vol. 130, no. 1-2, pp. 10-21, 2002.
58. T. Magnus, B. Schreiner, T. Korn et al., "Microglial expression of the B7 family member B7 homolog 1 confers strong immune inhibition: implications for immune responses and autoimmunity in the CNS, " The Journal of Neuroscience, vol. 25, no. 10, pp. 2537-2546, 2005.
59. Y.-H. Jin, W. Hou, H. S. Kang, C.-S. Koh, and B. S. Kim, "The role of interleukin-6 in the expression of PD-1 and PDL-1 on central nervous system cells following infection with Theiler's murine encephalomyelitis virus, " Journal of Virology, vol. 87, no. 21, pp. 11538-11551, 2013.
60. A. Rogue, C. Spire, M. Brun, N. Claude, and A. Guillouzo, "Gene expression changes induced by PPARgammaagonists in animal and human liver, " PPAR Research, vol. 2010, Article ID 325183, 16 pages, 2010.
61. C. B. Duvanel, P. Honegger, H. Pershadsingh, D. Feinstein, and J.-M. Matthieu, "Inhibition of glial cell proinflammatory activities by peroxisome proliferator-activated receptor gamma agonist confers partial protection during antimyelin oligodendrocyte glycoprotein demyelination in vitro, " Journal of Neuroscience Research, vol. 71, no. 2, pp. 246-255, 2003.
62. B. H. Shamsi, C. Ma, S. Naqvi, and Y. Xiao, "effects of pioglitazone mediated activation of PPAR-γ on CIDeC and obesity related changes in mice, " PLoS ONe, vol. 9, no. 9, Article ID e106992, 2014.
63. D. Ortuño Sahagún, A. L. Márquez-Aguirre, S. Quintero-Fabián, R. I. López-Roa, and A. E. Rojas-Mayorquí, "Modulation of PPAR-γ by nutraceutics as complementary treatment for obesity-related disorders and inflammatory diseases, " PPAR Research, vol. 2012, Article ID 318613, 17 pages, 2012.
64. H. Su, W. B. Lau, and X.-L. Ma, "Hypoadiponectinaemia in diabetes mellitus type 2: molecular mechanisms and clinical significance, " Clinical and experimental Pharmacology and Physiology, vol. 38, no. 12, pp. 897-904, 2011.
65. P. D. Storer, J. Xu, J. Chavis, and P. D. Drew, "Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: implications for multiple sclerosis, " Journal of Neuroimmunology, vol. 161, no. 1-2, pp. 113-122, 2005.
66. C. Natarajan and J. J. Bright, "Peroxisome proliferatoractivated receptor-gamma agonists inhibit experimental allergic encephalomyelitis by blocking IL-12 production, IL-12 signaling and Th1 differentiation, " Genes & Immunity, vol. 3, no. 2, pp. 59-70, 2002.
67. A. Coste, J.-F. Louet, M. Lagouge et al., "The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α, " Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 44, pp. 17187-17192, 2008.
68. Y. Xiao, J. Xu, S. Wang et al., "Genetic ablation of steroid receptor coactivator-3 promotes PPAR-β-mediated alternative activation of microglia in experimental autoimmune encephalomyelitis, " Glia, vol. 58, no. 8, pp. 932-942, 2010.
69. W.-F. Wua, X.-J. Tana, Y.-B. Daia, V. Krishnan, M. Warner, and J.-Å. Gustafsson, "Targeting estrogen receptorin microglia and T cells to treat experimental autoimmune encephalomyelitis, " Proceedings of theNationalAcademy of Sciences of theUnited States of America, vol. 110, no. 9, pp. 3543-3548, 2013.
70. S. Dasgupta, M. Jana, X. Liu, and K. Pahan, "Myelin basic protein-primed T cells of female but not male mice induce nitric-oxide synthase and proinflammatory cytokines in microglia: implications for gender bias in multiple sclerosis, " The Journal of Biological Chemistry, vol. 280, no. 38, pp. 32609-32617, 2005.
71. G. Benedek, J. Zhang, S. Bodhankar et al., "estrogen induces multiple regulatory B cell subtypes and promotesM2 microglia and neuroprotection during experimental autoimmune encephalomyelitis, " Journal of Neuroimmunology, vol. 293, pp. 45-53, 2016.
72. L. Negrotto, M. F. Farez, and J. Correale, "Immunologic effects of metformin and pioglitazone treatment on metabolic syndrome and multiple sclerosis, " JAMA Neurology, vol. 73, no. 5, pp. 520-528, 2016.
73. P. B. Carrieri, F. Carbone, F. Perna et al., "Longitudinal assessment of immuno-metabolic parameters in multiple sclerosis patients during treatment with glatiramer acetate, " Metabolism: Clinical and experimental, vol. 64, no. 9, pp. 1112-1121, 2015.
74. H. Ouyang, J. Cheng, Y. Zheng, and J. Du, "Role of IL-31 in regulation of Th2 cytokine levels in patients with nasal polyps, " european Archives of Oto-Rhino-Laryngology, vol. 271, no. 10, pp. 2703-2709, 2014.
75. V. Sanna, A. Di Giacomo, A. La Cava et al., "Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses, " The Journal of Clinical Investigation, vol. 111, no. 2, pp. 241-250, 2003.
76. G. Frisullo, M. Mirabella, F. Angelucci et al., "The effect of disease activity on leptin, leptin receptor and suppressor of cytokine signalling-3 expression in relapsing-remittingmultiple sclerosis, " Journal ofNeuroimmunology, vol. 192, no. 1-2, pp. 174-183, 2007.
77. H. Hsuchou, P. K. Mishra, A. J. Kastin et al., "Saturable leptin transport across the BBB persists in eAe mice, " Journal of Molecular Neuroscience, vol. 51, no. 2, pp. 364-370, 2013.
78. S. Musio, B. Gallo, S. Scabeni et al., "A key regulatory role for histamine in experimental autoimmune encephalomyelitis: disease exacerbation in histidine decarboxylase-deficient mice, " Journal of Immunology, vol. 176, no. 1, pp. 17-26, 2006.
79. K. Chatzantoni, P. Papathanassopoulos, E. Gourzoulidou, and A. Mouzaki, "Leptin and its soluble receptor in plasma of patients suffering from remitting-relapsing multiple sclerosis (MS): in vitro effects of leptin on type-1 and type-2 cytokine secretion by peripheral blood mononuclear cells, T-cells and monocytes of MS patients, " Journal of Autoimmunity, vol. 23, no. 2, pp. 169-177, 2004.
80. S. Ouyang, H. Hsuchou, A. J. Kastin, P. K. Mishra, Y. Wang, and W. Pan, "Leukocyte infiltration into spinal cord of eAe mice is attenuated by removal of endothelial leptin signaling, " Brain, Behavior, and Immunity, vol. 40, pp. 61-73, 2014.
81. M. E. evangelopoulos, G. Koutsis, and M. Markianos, "Serum leptin levels in treatment-naive patients with clinically isolated syndrome or relapsing-remitting multiple sclerosis, " Autoimmune Diseases, vol. 2014, Article ID 486282, 6 pages, 2014.
82. R. F. Neuteboom, E. Verbraak, J. S. A. Voerman et al., "Serum leptin levels during pregnancy in multiple sclerosis, " Multiple Sclerosis, vol. 15, no. 8, pp. 907-912, 2009.
83. R. Martí, M. Hernández, C. Córdova, and M. L. Nieto, "Natural triterpenes modulate immune-inflammatory markers of experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis, " British Journal of Pharmacology, vol. 166, no. 5, pp. 1708-1723, 2012.
84. L. Piccio, J. L. Stark, and A. H. Cross, "Chronic calorie restriction attenuates experimental autoimmune encephalomyelitis, " Journal of Leukocyte Biology, vol. 84, no. 4, pp. 940-948, 2008.
85. A. P. Batocchi, M. Rotondi, M. Caggiula et al., "Leptin as a marker of multiple sclerosis activity in patients treated with interferon-beta, " Journal of Neuroimmunology, vol. 139, no. 1-2, pp. 150-154, 2003.
86. F. Angelucci, M. Mirabella, M. Caggiula et al., "evidence of involvement of leptin and IL-6 peptides in the action of interferon-beta in secondary progressive multiple sclerosis, " Peptides, vol. 26, no. 11, pp. 2289-2293, 2005.
87. E. eftekhari, M. etemadifar, A. ebrahimi, and S. Baradaran, "The relation between peptide hormones and sex hormone in patients with multiple sclerosis, " Iranian Journal of Neurology, vol. 12, no. 2, pp. 60-65, 2013.
88. V. De Rosa, C. Procaccini, A. La Cava et al., "Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis, " The Journal of Clinical Investigation, vol. 116, no. 2, pp. 447-455, 2006.
89. M. Rotondi, A. P. Batocchi, F. Coperchini et al., "Severe disability in patients with relapsing-remittingmultiple sclerosis is associated with profound changes in the regulation of leptin secretion, "NeuroImmunoModulation, vol. 20, no. 6, pp. 341-347, 2013.
90. Z.-L. Chen, D.-M. Wang, J.-F. Duan, S.-Q. Wen, Y.-F. Tang, and Z.-X. Li, "Leptin enhances the release of cytokines by peripheral blood mononuclear cells fromacutemultiple sclerosis patients, " Neuroscience Bulletin, vol. 22, no. 2, pp. 115-117, 2006.
91. G. Frisullo, F. Angelucci, M. Mirabella et al., "Leptin enhances the release of cytokines by peripheral blood mononuclear cells from relapsing multiple sclerosis patients, " Journal of Clinical Immunology, vol. 24, no. 3, pp. 287-293, 2004.
92. A. Hietaharju, H. Kuusisto, R. Nieminen, K. Vuolteenaho, I. elovaara, and E. Moilanen, "elevated cerebrospinal fluid adiponectin and adipsin levels in patients with multiple sclerosis: a Finnish co-twin study, " european Journal of Neurology, vol. 17, no. 2, pp. 332-334, 2010.
93. A. Schmid, A. Hochberg, M. Berghoff et al., "Quantification and regulation of adipsin in human cerebrospinal fluid (CSF), " Clinical endocrinology, vol. 84, no. 2, pp. 194-202, 2016.
94. K. L. Graham, B. A. Zabel, S. Loghavi et al., "Chemokinelike receptor-1 expression by central nervous system-infiltrating leukocytes and involvement in a model of autoimmune demyelinating disease, "The Journal of Immunology, vol. 183, no. 10, pp. 6717-6723, 2009.
95. R. Lande, V. Gafa, B. Serafini et al., "Plasmacytoid dendritic cells in multiple sclerosis: intracerebral recruitment and impaired maturation in response to interferon-β, " Journal ofNeuropathology and experimental Neurology, vol. 67, no. 5, pp. 388-401, 2008.
96. M. Assadi, H. Salimipour, S. Akbarzadeh et al., "Correlation of circulating omentin-1 with bone mineral density in multiple sclerosis: the crosstalk between bone and adipose tissue, " PLoS ONe, vol. 6, no. 9, Article ID e24240, 2011.
97. P. Connick, M. Kolappan, C. Crawley et al., "Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study, " The Lancet Neurology, vol. 11, no. 2, pp. 150-156, 2012.
98. M. Mohyeddin Bonab, M. Mohajeri, M. A. Sahraian et al., "evaluation of cytokines in multiple sclerosis patients treated withmesenchymal stem cells, " Archives ofMedical Research, vol. 44, no. 4, pp. 266-272, 2013.
99. B. Yamout, R. Hourani, H. Salti et al., "Bonemarrowmesenchymal stemcell transplantation in patients withmultiple sclerosis: a pilot study, " Journal of Neuroimmunology, vol. 227, no. 1-2, pp. 185-189, 2010.
100. D. Karussis, C. Karageorgiou, A. Vaknin-Dembinsky et al., "Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis, " Archives of Neurology, vol. 67, no. 10, pp. 1187-1194, 2010.
101. Y. J. Alderazi, S. W. Coons, and K. Chapman, "Catastrophic demyelinating encephalomyelitis after intrathecal and intravenous stem cell transplantation in a patient with multiple sclerosis, " Journal of Child Neurology, vol. 27, no. 5, pp. 632-635, 2012.
102. T. Zeis, L. enz, and N. Schaeren-Wiemers, "The immunomodulatory oligodendrocyte, " Brain Research, vol. 1641, pp. 139-148, 2016.
103. N. Scolding, R. Franklin, S. Stevens, C.-H. Heldin, A. Compston, and J. Newcombe, "Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis, " Brain, vol. 121, part 12, pp. 2221-2228, 1998.
104. J. M. Bin, S. Rajasekharan, T. Kuhlmann et al., "Full-length and fragmented netrin-1 in multiple sclerosis plaques are inhibitors of oligodendrocyte precursor cell migration, " The American Journal of Pathology, vol. 183, no. 3, pp. 673-680, 2013.
105. M. C. Sádaba, J. Tzartos, C. Paí et al., "Axonal and oligodendrocyte-localized IgM and IgG deposits in MS lesions, " Journal of Neuroimmunology, vol. 247, no. 1-2, pp. 86-94, 2012.
106. H. C. Wilson, N. J. Scolding, and C. S. Raine, "Co-expression of PDGF α receptor and NG2 by oligodendrocyte precursors in human CNS and multiple sclerosis lesions, " Journal of Neuroimmunology, vol. 176, no. 1-2, pp. 162-173, 2006.
107. N. Koning, D. F. Swaab, R. M. Hoek, and I. Huitinga, "Distribution of the immune inhibitory molecules CD200 and CD200R in the normal central nervous system and multiple sclerosis lesions suggests neuron-glia and glia-glia interactions, " Journal of Neuropathology and experimental Neurology, vol. 68, no. 2, pp. 159-167, 2009.
108. W. Lin, S. L. Bailey, H. Ho et al., "The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage, " The Journal of Clinical Investigation, vol. 117, no. 2, pp. 448-456, 2007.
109. W. Lin, Y. Lin, J. Li et al., "Oligodendrocyte-specific activation of PeRK signaling protects mice against experimental autoimmune encephalomyelitis, " The Journal of Neuroscience, vol. 33, no. 14, pp. 5980-5991, 2013.
110. Z. Liu and M. Chopp, "Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke, " Progress in Neurobiology, 2015.
111. A. H. Cross and G. Ku, "Astrocytes and central nervous system endothelial cells do not express B7-1 (CD80) or B7-2 (CD86) immunoreactivity during experimental autoimmune encephalomyelitis, " Journal of Neuroimmunology, vol. 110, no. 1-2, pp. 76-82, 2000.
112. J. Correale and M. F. Farez, "The role of astrocytes in multiple sclerosis progression, " Frontiers in Neurology, vol. 6, article 180, 2015.
113. A. Viehover, R. H. Miller, S.-K. Park, G. Fischbach, and T. Vartanian, "Neuregulin: an oligodendrocyte growth factor absent in active multiple sclerosis lesions, " Developmental Neuroscience, vol. 23, no. 4-5, pp. 377-386, 2001.
114. J.-Q. Liu, J. W. Carl Jr., P. S. Joshi et al., "CD24 on the resident cells of the central nervous system enhances experimental autoimmune encephalomyelitis, " Journal of Immunology, vol. 178, no. 10, pp. 6227-6235, 2007.
115. E. H. Tran, H. Hardin-Pouzet, G. Verge, and T. Owens, "Astrocytes and microglia express inducible nitric oxide synthase in mice with experimental allergic encephalomyelitis, " Journal of Neuroimmunology, vol. 74, no. 1-2, pp. 121-129, 1997.
116. M. Godíez-Rubí, A. E. Rojas-Mayorquí, and D. Ortuño-Sahagún, "Nitric oxide donors as neuroprotective agents after an ischemic stroke-related inflammatory reaction, " Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 297357, 16 pages, 2013.
117. G. Mallucci, L. Peruzzotti-Jametti, J. D. Bernstock, and S. Pluchino, "The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis, " Progress in Neurobiology, vol. 127-128, pp. 1-22, 2015.
118. C. Lucchinetti, W. Brück, J. Parisi, B. Scheithauer, M. Rodriguez, and H. Lassmann, "Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination, " Annals of Neurology, vol. 47, no. 6, pp. 707-717, 2000.
119. M. P. Murphy, "How mitochondria produce reactive oxygen species, " The Biochemical Journal, vol. 417, no. 1, pp. 1-13, 2009.
120. C. Wegner, M. M. esiri, S. A. Chance, J. Palace, and P. M. Matthews, "Neocortical neuronal, synaptic, and glial loss in multiple sclerosis, " Neurology, vol. 67, no. 6, pp. 960-967, 2006.
121. S. R. Choi, O. W. Howell, D. Carassiti et al., "Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis, " Brain, vol. 135, part 10, pp. 2925-2937, 2012.
122. Y. Liu, I. Teige, B. Birnir, and S. Issazadeh-Navikas, "Neuronmediated generation of regulatory T cells from encephalitogenic T cells suppresses eAe, " Nature Medicine, vol. 12, no. 5, pp. 518-525, 2006.
123. C. Severson and D. A. Hafler, "T-cells in multiple sclerosis, " Results and Problems in Cell Differentiation, vol. 51, pp. 75-98, 2010.
124. T. Naito, H. Tanaka, Y. Naoe, and I. Taniuchi, "Transcriptional control of T-cell development, " International Immunology, vol. 23, no. 11, pp. 661-668, 2011.
125. G. Martino and H.-P. Hartung, "Immunopathogenesis of multiple sclerosis: the role of T cells, " Current Opinion in Neurology, vol. 12, no. 3, pp. 309-321, 1999.
126. A. Compston and A. Coles, "Multiple sclerosis, " The Lancet, vol. 359, no. 9313, pp. 1221-1231, 2002.
127. J. D. J. Guerrero-García, V. A. Castañeda-Moreno, N. Torres-Carrillo et al., "Interleukin-17A levels vary in relapsingremitting multiple sclerosis patients in association with their age, treatment and the time of evolution of the disease, " NeuroImmunoModulation, vol. 23, no. 1, pp. 8-17, 2016.
128. L. De Riccardis, A. Rizzello, A. Ferramosca et al., "Bioenergetics profile of CD4T cells in relapsing remitting multiple sclerosis subjects, " Journal of Biotechnology, vol. 202, pp. 31-39, 2015.
129. M. Strachan-Whaley, S. Rivest, and V. W. Yong, "Interactions between microglia and T cells in multiple sclerosis pathobiology, " Journal of Interferon & Cytokine Research, vol. 34, no. 8, pp. 615-622, 2014.
130. Y. Okuda, M. Okuda, B. R. Apatoff, and D. N. Posnett, "The activation ofmemory CD4T cells andCD8T cells in patients withmultiple sclerosis, " Journal of the Neurological Sciences, vol. 235, no. 1-2, pp. 11-17, 2005.
131. L. Scandiuzzi, K. Ghosh, and X. Zang, "T cell costimulation and coinhibition: genetics and disease, " Discovery Medicine, vol. 12, no. 63, pp. 119-128, 2011.
132. S. Markovic-Plese, I. Cortese, K.-P. Wandinger, H. F. McFarland, and R. Martin, "CD4+CD28-costimulation-independent T cells in multiple sclerosis, "The Journal of Clinical Investigation, vol. 108, no. 8, pp. 1185-1194, 2001.
133. E. M. L. Oliveira, A. Bar-Or, A. I. Waliszewska et al., "CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls, " Journal of Autoimmunity, vol. 20, no. 1, pp. 71-81, 2003.
134. C. Scholz, K. T. Patton, D. E. Anderson, G. J. Freeman, and D. A. Hafler, "expansion of autoreactive T cells in multiple sclerosis is independent of exogenous B7 costimulation, " The Journal of Immunology, vol. 160, no. 3, pp. 1532-1538, 1998.
135. J.-B. Sun, T. Olsson, W.-Z. Wang et al., "Autoreactive T and B cells responding to myelin proteolipid protein in multiple sclerosis and controls, " european Journal of Immunology, vol. 21, no. 6, pp. 1461-1468, 1991.
136. J. Burns, B. Bartholomew, and S. Lobo, "Isolation ofmyelin basic protein-specific T cells predominantly from the memory T-cell compartment inmultiple sclerosis, " Annals of Neurology, vol. 45, no. 1, pp. 33-39, 1999.
137. Y. K. Chou, D. N. Bourdette, H. Offner et al., "Frequency of T cells specific for myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis, " Journal of Neuroimmunology, vol. 38, no. 1-2, pp. 105-113, 1992.
138. M. Chofflon, H. L. Weiner, C. Morimoto, and D. A. Hafler, "Decrease of suppressor inducer (CD4+2H4+) T cells in multiple sclerosis cerebrospinal fluid, " Annals of Neurology, vol. 25, no. 5, pp. 494-499, 1989.
139. C. A. Knosp and J. A. Johnston, "Regulation of CD4Tcell polarization by suppressor of cytokine signalling proteins, " Immunology, vol. 135, no. 2, pp. 101-111, 2012.
140. T. Renno, R. Zeine, J. M. Girard, S. Glllani, V. Dodelet, and T. Owens, "Selective enrichment of Th1 CD45RBlow CD4T cells in autoimmune infiltrates in experimental allergic encephalomyelitis, " International Immunology, vol. 6, no. 2, pp. 347-354, 1994.
141. B. Becher, B. G. Durell, and R. J. Noelle, "experimental autoimmune encephalitis and inflammation in the absence of interleukin-12, "The Journal of Clinical Investigation, vol. 110, no. 4, pp. 493-497, 2002.
142. H. S. Panitch, A. S. Haley, R. L. Hirsch, and K. P. Johnson, "exacerbations of multiple sclerosis in patients treated with gamma interferon, " The Lancet, vol. 329, no. 8538, pp. 893-895, 1987.
143. C. Rohowsky-Kochan, D. Molinaro, and S. D. Cook, "Cytokine secretion profile of myelin basic protein-specific T cells in multiple sclerosis, " Multiple Sclerosis, vol. 6, no. 2, pp. 69-77, 2000.
144. Y. Pan and Y. Chen, "Generation and characterization of smad7 conditional knockout mice, " in TGF-β Signaling, vol. 1344 of Methods in Molecular Biology, pp. 233-243, Springer, 2016.
145. I. Kleiter, J. Song, D. Lukas et al., "Smad7 in T cells drives T helper 1 responses in multiple sclerosis and experimental autoimmune encephalomyelitis, " Brain, vol. 133, no. 4, pp. 1067-1081, 2010.
146. A. Langer-Gould, R. Gupta, S. Huang et al., "Interferon-γ-producing T cells, pregnancy, and postpartum relapses of multiple sclerosis, " Archives of Neurology, vol. 67, no. 1, pp. 51-57, 2010.
147. R. A. Sosa and T. G. Forsthuber, "The critical role of antigenpresentation-induced cytokine crosstalk in the central nervous system in multiple sclerosis and experimental autoimmune encephalomyelitis, " Journal of Interferon & Cytokine Research, vol. 31, no. 10, pp. 753-768, 2011.
148. A. Roy and K. Pahan, "Myelin basic protein-primed T helper 2 cells suppress microglial activation via AlphaVBeta3 integrin: implications formultiple sclerosis, " Journal ofClinical&Cellular Immunology, vol. 7, article 158, 2013.
149. A. Miller, S. Shapiro, R. Gershtein et al., "Treatment of multiple sclerosis with copolymer-1 (Copaxone): implicating mechanisms of Th1 to Th2/Th3 immune-deviation, " Journal of Neuroimmunology, vol. 92, no. 1-2, pp. 113-121, 1998.
150. O. Neuhaus, C. Farina, A. Yassouridis et al., "Multiple sclerosis: comparison of copolymer-1-reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to Thelper 2 cells, " Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 13, pp. 7452-7457, 2000.
151. R. Furlan, A. Bergami, R. Lang et al., "Interferon-β treatment in multiple sclerosis patients decreases the number of circulating T cells producing interferon-γ and interleukin-4, " Journal of Neuroimmunology, vol. 111, no. 1-2, pp. 86-92, 2000.
152. R. Planas, I. Metz, Y. Ortiz et al., "Central role of Th2/Tc2 lymphocytes in pattern II multiple sclerosis lesions, " Annals of Clinical and Translational Neurology, vol. 2, no. 9, pp. 875-893, 2015.
153. T. McLaughlin, L.-F. Liu, C. Lamendola et al., "T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans, " Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 34, no. 12, pp. 2637-2643, 2014.
154. L. E. Harrington, R. D. Hatton, P. R. Mangan et al., "Interleukin 17-producing CD4effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages, " Nature Immunology, vol. 6, no. 11, pp. 1123-1132, 2005.
155. M. Noack and P. Miossec, "Th17 and regulatory T cell balance in autoimmune and inflammatory diseases, " Autoimmunity Reviews, vol. 13, no. 6, pp. 668-677, 2014.
156. V. Brucklacher-Waldert, K. Stuerner, M. Kolster, J. Wolthausen, and E. Tolosa, "Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis, " Brain, vol. 132, no. 12, pp. 3329-3341, 2009.
157. M. Montes, X. Zhang, L. Berthelot et al., "Oligoclonal myelinreactive T-cell infiltrates derived from multiple sclerosis lesions are enriched inTh17 cells, " Clinical Immunology, vol. 130, no. 2, pp. 133-144, 2009.
158. H. Kebir, K. Kreymborg, I. Ifergan et al., "Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation, " Nature Medicine, vol. 13, no. 10, pp. 1173-1175, 2007.
159. M. Kostic, T. Dzopalic, S. Zivanovic et al., "IL-17 and glutamate excitotoxicity in the pathogenesis of multiple sclerosis, " Scandinavian Journal of Immunology, vol. 79, no. 3, pp. 181-186, 2014.
160. S. Zhu and Y. Qian, "IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential, " Clinical Science, vol. 122, no. 11, pp. 487-511, 2012.
161. J. Zepp, L. Wu, and X. Li, "IL-17 receptor signaling and T helper 17-mediated autoimmune demyelinating disease, " Trends in Immunology, vol. 32, no. 5, pp. 232-239, 2011.
162. Y. K. Lee, H. Turner, C. L. Maynard et al., "Late developmental plasticity in the T Helper 17 lineage, " Immunity, vol. 30, no. 1, pp. 92-107, 2009.
163. K. S. Carbajal, Y. Mironova, J. T. Ulrich-Lewis et al., "Th cell diversity in experimental autoimmune encephalomyelitis and multiple sclerosis, " Journal of Immunology, vol. 195, no. 6, pp. 2552-2559, 2015.
164. L. Durelli, L. Conti, M. Clerico et al., "T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-β, " Annals of Neurology, vol. 65, no. 5, pp. 499-509, 2009.
165. V. S. Ramgolam and S. Markovic-Plese, "Interferon-beta inhibits Th17 cell differentiation in patients with multiple sclerosis, " endocrine, Metabolic & Immune Disorders-Drug Targets, vol. 10, no. 2, pp. 161-167, 2010.
166. X. Zhang and S. Markovic-Plese, "Interferon beta inhibits the Th17 cell-mediated autoimmune response in patients with relapsing-remitting multiple sclerosis, " Clinical Neurology and Neurosurgery, vol. 112, no. 7, pp. 641-645, 2010.
167. S. Winer, G. Paltser, Y. Chan et al., "Obesity predisposes to Th17 bias, " european Journal of Immunology, vol. 39, no. 9, pp. 2629-2635, 2009.
168. M. Ahmed and S. L. Gaffen, "IL-17 inhibits adipogenesis in part via C/eBPα, PPARγ and Krüppel-like factors, " Cytokine, vol. 61, no. 3, pp. 898-905, 2013.
169. C. T. Luo and M. O. Li, "Transcriptional control of regulatory T cell development and function, " Trends in Immunology, vol. 34, no. 11, pp. 531-539, 2013.
170. M. H. Nyirenda, E. Morandi, U. Vinkemeier et al., "TLR2 stimulation regulates the balance between regulatory T cell and Th17 function: a novel mechanism of reduced regulatory T cell function in multiple sclerosis, " Journal of Immunology, vol. 194, no. 12, pp. 5761-5774, 2015.
171. M. J. McGeachy, L. A. Stephens, and S. M. Anderton, "Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25regulatory cells within the central nervous system, " The Journal of Immunology, vol. 175, no. 5, pp. 3025-3032, 2005.
172. T. Schneider-Hohendorf, M.-P. Stenner, C. Weidenfeller et al., "Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients withmultiple sclerosis, " european Journal of Immunology, vol. 40, no. 12, pp. 3581-3590, 2010.
173. J. R. Huddlestone and M. B. A. Oldstone, "Suppressor T cells are activated in vivo in patients with multiple sclerosis coinciding with remission from acute attack, " Journal of Immunology, vol. 129, no. 3, pp. 915-917, 1982.
174. E. Kouchaki, M. Salehi, M. Reza Sharif, H. Nikoueinejad, and H. Akbari, "Numerical status of CD4+CD25+FoxP3and CD8+CD28 regulatory T cells in multiple sclerosis, " Iranian Journal of BasicMedical Sciences, vol. 17, no. 4, pp. 250-255, 2014.
175. P. Praksova, P. Stourac, J. Bednarik, E. Vlckova, Z. Mikulkova, and J. Michalek, "Immunoregulatory T cells in multiple sclerosis and the effect of interferon beta and glatiramer acetate treatment on T cell subpopulations, " Journal of the Neurological Sciences, vol. 319, no. 1-2, pp. 18-23, 2012.
176. M.-A. Bach, E. Tournier, F. Phan-Dinh-Tuy et al., "Deficit of suppressor t cells in active multiple sclerosis, " The Lancet, vol. 316, no. 8206, pp. 1221-1223, 1980.
177. D. DallaLibera, D. DiMitri, A. Bergami et al., "Tregulatory cells are markers of disease activity in multiple sclerosis patients, " PLoS ONe, vol. 6, no. 6, Article ID e21386, 2011.
178. J. Haas, M. Korporal, B. Balint, B. Fritzsching, A. Schwarz, and B. Wildemann, "Glatiramer acetate improves regulatory T-cell function by expansion of naive CD4+CD25+FOXP3+CD31Tcells in patients with multiple sclerosis, " Journal of Neuroimmunology, vol. 216, no. 1-2, pp. 113-117, 2009.
179. M. Chen, G. Chen, S. Deng, X. Liu, G. J. Hutton, and J. Hong, "IFN-β induces the proliferation of CD4+CD25+Foxp3regulatory T cells through upregulation of GITRL on dendritic cells in the treatment of multiple sclerosis, " Journal of Neuroimmunology, vol. 242, no. 1-2, pp. 39-46, 2012.
180. A. Namdar, B. Nikbin, M. Ghabaee, A. Bayati, and M. Izad, "effect of IFN-β therapy on the frequency and function of CD4+CD25regulatory T cells and Foxp3 gene expression in relapsing-remitting multiple sclerosis (RRMS): a preliminary study, " Journal of Neuroimmunology, vol. 218, no. 1-2, pp. 120-124, 2010.
181. F. Palavra, L. Almeida, A. F. Ambrósio, and F. Reis, "Obesity and brain inflammation: a focus on multiple sclerosis, " Obesity Reviews, vol. 17, no. 3, pp. 211-224, 2016.
182. L. Xu, Z. Xu, and M. Xu, "Glucocorticoid treatment restores the impaired suppressive function of regulatory T cells in patients with relapsing-remitting multiple sclerosis, " Clinical and experimental Immunology, vol. 158, no. 1, pp. 26-30, 2009.
183. G. Frisullo, V. Nociti, R. Iorio et al., "Glucocorticoid treatment reduces T-bet and pSTAT1 expression in mononuclear cells from relapsing remitting multiple sclerosis patients, " Clinical Immunology, vol. 124, no. 3, pp. 284-293, 2007.
184. C. Mammi, V. Marzolla, A. Armani et al., "A novel combined glucocorticoid-mineralocorticoid receptor selective modulator markedly prevents weight gain and fat mass expansion in mice fed a high-fat diet, " International Journal of Obesity, vol. 40, no. 6, pp. 964-972, 2016.
185. K. John, J. S. Marino, E. R. Sanchez, and T. D. Hinds Jr., "The glucocorticoid receptor: cause of or cure for obesity?" American Journal of Physiology-endocrinology and Metabolism, vol. 310, no. 4, pp. e249-e257, 2016.
186. D. Haghmorad, A. A. Amini, M. B. Mahmoudi, M. Rastin, M. Hosseini, and M. Mahmoudi, "Pregnancy level of estrogen attenuates experimental autoimmune encephalomyelitis in both ovariectomized and pregnant C57BL/6 mice through expansion of Treg and Th2 cells, " Journal of Neuroimmunology, vol. 277, no. 1-2, pp. 85-95, 2014.
187. C. Aristimuño, R. Teijeiro, L. Valor et al., "Sex-hormone receptors pattern on regulatory T-cells: clinical implications for multiple sclerosis, " Clinical and experimental Medicine, vol. 12, no. 4, pp. 247-255, 2012.
188. H. Offner, "Neuroimmunoprotective effects of estrogen and derivatives in experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis, " Journal of Neuroscience Research, vol. 78, no. 5, pp. 603-624, 2004.
189. H. Offner and M. Polanczyk, "A potential role for estrogen in experimental autoimmune encephalomyelitis and multiple sclerosis, " Annals of the New York Academy of Sciences, vol. 1089, pp. 343-372, 2006.
190. F. Lizcano and G. Guzmán, "estrogen deficiency and the origin of obesity during menopause, " BioMed Research International, vol. 2014, Article ID757461, 11 pages, 2014.
191. M. Salou, B. Nicol, A. Garcia, and D.-A. Laplaud, "Involvement of CD8T cells in multiple sclerosis, " Frontiers in Immunology, vol. 6, article 604, 2015.
192. S. Sinha, A. W. Boyden, F. R. Itani, M. P. Crawford, and N. J. Karandikar, "CD8T-cells as immune regulators of multiple sclerosis, " Frontiers in Immunology, vol. 6, article 619, 2015.
193. V. E. Maltby, M. C. Graves, R. A. Lea et al., "Genome-wide DNA methylation profiling of CD8T cells shows a distinct epigenetic signature to CD4T cells in multiple sclerosis patients, " Clinical epigenetics, vol. 7, article 118, 2015.
194. M. Bettini, K. Rosenthal, andB. D. evavold, "PathogenicMOGreactive CD8T cells require MOG-reactive CD4T cells for sustained CNS inflammation during chronic eAe, " Journal of Neuroimmunology, vol. 213, no. 1-2, pp. 60-68, 2009.
195. M. Camara, N. Beyersdorf, H. J. Fischer et al., "CD8T cell help is required for efficient induction of eAe in Lewis rats, " Journal of Neuroimmunology, vol. 260, no. 1-2, pp. 17-27, 2013.
196. M.-L. Chen, B.-S. Yan, Y. Bando, V. K. Kuchroo, and H. L. Weiner, "Latency-associated peptide identifies a novel CD4 +CD25 regulatory T cell subset with TGFβ-mediated function and enhanced suppression of experimental autoimmune encephalomyelitis, " Journal of Immunology, vol. 180, no. 11, pp. 7327-7337, 2008.
197. M.-L. Chen, B.-S. Yan, D. Kozoriz, and H. L. Weiner, "Novel CD8Treg suppress eAe by TGF-β-and IFN-γ-dependent mechanisms, " european Journal of Immunology, vol. 39, no. 12, pp. 3423-3435, 2009.
198. J. Correale and A. Villa, "Role of CD8CD25Foxp3regulatory T cells inmultiple sclerosis, " Annals of Neurology, vol. 67, no. 5, pp. 625-638, 2010.
199. G. Matarese, P. B. Carrieri, S. Montella, V. De Rosa, and A. La Cava, "Leptin as a metabolic link to multiple sclerosis, " Nature Reviews Neurology, vol. 6, no. 8, pp. 455-461, 2010.
200. M. Poggi, J. Jager, O. Paulmyer-Lacroix et al., "The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes, " Diabetologia, vol. 52, no. 6, pp. 1152-1163, 2009.
201. M. J. Neuparth, J. B. Proença, A. Santos-Silva, and S. Coimbra, "Adipokines, oxidized low-density lipoprotein, and Creactive protein levels in lean, overweight, and obese portuguese patients with type 2 diabetes, " ISRN Obesity, vol. 2013, Article ID 142097, 7 pages, 2013.
202. A. Nieva-Vazquez, R. Pérez-Fuentes, E. Torres-Rasgado, J. G. López-López, and J. R. Romero, "Serum resistin levels are associated with adiposity and insulin sensitivity in obese hispanic subjects, "Metabolic Syndrome and Related Disorders, vol. 12, no. 2, pp. 143-148, 2014.
203. X. Terra, T. Auguet, I. Quesada et al., "Increased levels and adipose tissue expression of visfatin inmorbidly obesewomen: the relationship with pro-inflammatory cytokines, " Clinical endocrinology, vol. 77, no. 5, pp. 691-698, 2012.
204. H. Münzberg and C. D. Morrison, "Structure, production and signaling of leptin, "Metabolism: Clinical and experimental, vol. 64, no. 1, pp. 13-23, 2015.
205. M. Otero, R. Lago, F. Lago et al., "Leptin, from fat to inflammation: old questions and new insights, " FeBS Letters, vol. 579, no. 2, pp. 295-301, 2005.
206. K. Wåhlen, E. Sjölin, and P. Löfgren, "Role of fat cell size for plasma leptin in a large population based sample, " experimental & Clinical endocrinology and Diabetes, vol. 119, no. 5, pp. 291-294, 2011.
207. C. Grunfeld, C. Zhao, J. Fuller et al., "endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters, " The Journal of Clinical Investigation, vol. 97, no. 9, pp. 2152-2157, 1996.
208. R. Faggioni, K. R. Feingold, and C. Grunfeld, "Leptin regulation of the immune response and the immunodeficiency of malnutrition, " The FASeB Journal, vol. 15, no. 14, pp. 2565-2571, 2001.
209. G. Fantuzzi and R. Faggioni, "Leptin in the regulation of immunity, inflammation, and hematopoiesis, " Journal of Leukocyte Biology, vol. 68, no. 4, pp. 437-446, 2000.
210. N. Iikuni, Q. L. K. Lam, L. Lu, G. Matarese, and A. La Cava, "Leptin and inflammation, " Current Immunology Reviews, vol. 4, no. 2, pp. 70-79, 2008.
211. I. S. Farooqi, G. Matarese, G. M. Lord et al., "Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency, " The Journal of Clinical Investigation, vol. 110, no. 8, pp. 1093-1103, 2002.
212. E. Papathanassoglou, K. el-Haschimi, X. C. Li, G. Matarese, T. Strom, and C. Mantzoros, "Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice, " The Journal of Immunology, vol. 176, no. 12, pp. 7745-7752, 2006.
213. C. Martí-Romero, J. Santos-Alvarez, R. Goberna, and V. Sánchez-Margalet, "Human leptin enhances activation and proliferation of human circulating T lymphocytes, " Cellular Immunology, vol. 199, no. 1, pp. 15-24, 2000.
214. V. De Rosa, C. Procaccini, G. Calì et al., "A key role of leptin in the control of regulatory T cell proliferation, " Immunity, vol. 26, no. 2, pp. 241-255, 2007.
215. Y. Zhao, R. Sun, L. You, C. Gao, and Z. Tian, "expression of leptin receptors and response to leptin stimulation of human natural killer cell lines, " Biochemical and Biophysical Research Communications, vol. 300, no. 2, pp. 247-252, 2003.
216. G. M. Lord, G. Matarese, J. K. Howard, S. R. Bloom, and R. I. Lechler, "Leptin inhibits the anti-CD3-driven proliferation of peripheral blood T cells but enhances the production of proinflammatory cytokines, " Journal of Leukocyte Biology, vol. 72, no. 2, pp. 330-338, 2002.
217. C. Lock, G. Hermans, R. Pedotti et al., "Gene-microarray analysis ofmultiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis, " Nature Medicine, vol. 8, no. 5, pp. 500-508, 2002.
218. Y. Yu, Y. Liu, F.-D. Shi, H. Zou, G. Matarese, and A. La Cava, "Cutting edge: leptin-induced RORγt expression in CD4T cells promotes Th17 responses in systemic lupus erythematosus, " The Journal of Immunology, vol. 190, no. 7, pp. 3054-3058, 2013.
219. J. Deng, Y. Liu, M. Yang et al., "Leptin exacerbates collageninduced arthritis via enhancement of Th17 cell response, " Arthritis & Rheumatism, vol. 64, no. 11, pp. 3564-3573, 2012.
220. A. Valerio, V. Ghisi, M. Dossena et al., "Leptin increases axonal growth cone size in developing mouse cortical neurons by convergent signals inactivating glycogen synthase kinase-3β, " The Journal of Biological Chemistry, vol. 281, no. 18, pp. 12950-12958, 2006.
221. J. Udagawa, R. Hashimoto, H. Suzuki et al., "The role of leptin in the development of the cerebral cortex in mouse embryos, " endocrinology, vol. 147, no. 2, pp. 647-658, 2006.
222. M. Galgani, C. Procaccini, V. De Rosa et al., "Leptin modulates the survival of autoreactive CD4T cells through the nutrient/energy-sensing mammalian target of rapamycin signaling pathway, " Journal of Immunology, vol. 185, no. 12, pp. 7474-7479, 2010.
223. D. Cipolletta, M. Feuerer, A. Li et al., "PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells, " Nature, vol. 486, no. 7404, pp. 549-553, 2012.
224. M. Feuerer, L. Herrero, D. Cipolletta et al., "Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affectmetabolic parameters, " Nature Medicine, vol. 15, no. 8, pp. 930-939, 2009.
225. S. Winer, Y. Chan, G. Paltser et al., "Normalization of obesityassociated insulin resistance through immunotherapy, " Nature Medicine, vol. 15, no. 8, pp. 921-929, 2009.
226. V. D. Longo and L. Fontana, "Calorie restriction and cancer prevention: metabolic and molecular mechanisms, " Trends in Pharmacological Sciences, vol. 31, no. 2, pp. 89-98, 2010.
227. A. I. esquifino, P. Cano, V. Jiménez, R. A. Cutrera, and D. P. Cardinali, "experimental allergic encephalomyelitis in male Lewis rats subjected to calorie restriction, " Journal of Physiology and Biochemistry, vol. 60, no. 4, pp. 245-252, 2004.
228. E. Toussirot, D. Binda, C. Gueugnon, and G. Dumoulin, "Adiponectin in autoimmune diseases, " Current Medicinal Chemistry, vol. 19, no. 32, pp. 5474-5480, 2012.
229. G. Fantuzzi, "Adiponectin in inflammatory and immunemediated diseases, " Cytokine, vol. 64, no. 1, pp. 1-10, 2013.
230. J. Thundyil, D. Pavlovski, C. G. Sobey, and T. V. Arumugam, "Adiponectin receptor signalling in the brain, " British Journal of Pharmacology, vol. 165, no. 2, pp. 313-327, 2012.
231. N. Ouchi and K. Walsh, "A novel role for adiponectin in the regulation of inflammation, " Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 7, pp. 1219-1221, 2008.
232. T. Yokota, K. Oritani, I. Takahashi et al., "Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages, " Blood, vol. 96, no. 5, pp. 1723-1732, 2000.
233. J. Yang, S.-C. Lin, G. Chen et al., "Adiponectin promotes monocyte-to-fibroblast transition in renal fibrosis, " Journal of the American Society of Nephrology, vol. 24, no. 10, pp. 1644-1659, 2013.
234. K. Makki, P. Froguel, and I. Wolowczuk, "Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines, " ISRN Inflammation, vol. 2013, Article ID 139239, 12 pages, 2013.
235. M. Y. Jung, H.-S. Kim, H.-J. Hong, B.-S. Youn, and T. S. Kim, "Adiponectin induces dendritic cell activation via PLCγ/JNK/NF-γB pathways, leading to Th1 and Th17 polarization, " Journal of Immunology, vol. 188, no. 6, pp. 2592-2601, 2012.
236. S. Arai, N. Maehara, Y. Iwamura et al., "Obesity-associated autoantibody production requires AIM to retain the immunoglobulin M immune complex on follicular dendritic cells, " Cell Reports, vol. 3, no. 4, pp. 1187-1198, 2013.
237. T. Miyazaki, Y. Hirokami, N. Matsuhashi, H. Takatsuka, and M. Naito, "Increased susceptibility of thymocytes to apoptosis in mice lacking AIM, a novelmurine macrophage-derived soluble factor belonging to the scavenger receptor cysteine-rich domain superfamily, "The Journal of experimental Medicine, vol. 189, no. 2, pp. 413-422, 1999.
238. M. Haluzik and D. Haluzikova, "The role of resistin in obesityinduced insulin resistance, " Current Opinion in Investigational Drugs, vol. 7, no. 4, pp. 306-311, 2006.
239. H. S. Jung, K.-H. Park, Y. M. Cho et al., "Resistin is secreted frommacrophages in atheromas and promotes atherosclerosis, " Cardiovascular Research, vol. 69, no. 1, pp. 76-85, 2006.
240. B. Gencer, R. Auer, N. de Rekeneire et al., "Association between resistin levels and cardiovascular disease events in older adults: the health, aging and body composition study, " Atherosclerosis, vol. 245, pp. 181-186, 2016.
241. Q. Huang, S.-S. Tao, Y.-J. Zhang et al., "Serum resistin levels in patients with rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis, " Clinical Rheumatology, vol. 34, no. 10, pp. 1713-1720, 2015.
242. C. M. Steppan, S. T. Bailey, S. Bhat et al., "The hormone resistin links obesity to diabetes, " Nature, vol. 409, no. 6818, pp. 307-312, 2001.
243. R. Nogueiras, R. Gallego, O. Gualillo et al., "Resistinis expressed in different rat tissues and is regulated in a tissue-and genderspecific manner, " FeBS Letters, vol. 548, no. 1-3, pp. 21-27, 2003.
244. B. A. Morash, E. Ur, G. Wiesner, J. Roy, and M. Wilkinson, "Pituitary resistin gene expression: effects of age, gender and obesity, " Neuroendocrinology, vol. 79, no. 3, pp. 149-156, 2004.
245. E. Badoer, S. Kosari, and M. J. Stebbing, "Resistin, an adipokine with non-generalized actions on sympathetic nerve activity, " Frontiers in Physiology, vol. 6, article 321, 2015.
246. J. Stastny, J. Bienertova-Vasku, and A. Vasku, "Visfatin and its role in obesity development, " Diabetes & Metabolic Syndrome, vol. 6, no. 2, pp. 120-124, 2012.
247. A. Fukuhara, M. Matsuda, M. Nishizawa et al., "Visfatin: a protein secreted by visceral fat that mimics the effects of insulin, " Science, vol. 307, no. 5708, pp. 426-430, 2005.
248. A. R. Moschen, A. Kaser, B. enrich et al., "Visfatin, an adipocytokine with proinflammatory and immunomodulating properties, " The Journal of Immunology, vol. 178, no. 3, pp. 1748-1758, 2007.
249. J. P. Bao, W. P. Chen, and L.-D. Wu, "Visfatin: a potential therapeutic target for rheumatoid arthritis, " The Journal of International Medical Research, vol. 37, no. 6, pp. 1655-1661, 2009.
250. M. R. Kazemi, C. M. McDonald, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold, "Adipocyte fatty acid-binding protein expression and lipid accumulation are increased during activation of murine macrophages by toll-like receptor agonists, " Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 6, pp. 1220-1224, 2005.
251. J. Jin, D.-Q. Peng, S.-G. Yuan et al., "Serum adipocyte fatty acid binding proteins and adiponectin in patientswith coronary artery disease: the significance of A-FABP/adiponectin ratio, " Clinica Chimica Acta, vol. 411, no. 21-22, pp. 1761-1765, 2010.
252. J. L. Miner, J. C. Byatt, C. A. Baile, and G. G. Krivi, "Adipsin expression and growth in rats as influenced by insulin and somatotropin, " Physiology & Behavior, vol. 54, no. 2, pp. 207-212, 1993.
253. J. C. Lo, S. Ljubicic, B. Leibiger et al., "Adipsin is an adipokine that improvescell function in diabetes, " Cell, vol. 158, no. 1, pp. 41-53, 2014.
254. R. Natarajan, S. Hagman, M. Hämälainen et al., "Adipsin is associated with multiple sclerosis: a follow-up study of adipokines, " Multiple Sclerosis International, vol. 2015, Article ID 371734, 9 pages, 2015.
255. F. Mariani and L. Roncucci, "Chemerin/chemR23 axis in inflammation onset and resolution, " Inflammation Research, vol. 64, no. 2, pp. 85-95, 2014.
256. V. Wittamer, J.-D. Franssen, M. Vulcano et al., "Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand fromhuman inflammatory fluids, "The Journal of experimental Medicine, vol. 198, no. 7, pp. 977-985, 2003.
257. K. L. Graham, J. V. Zhang, S. Lewén et al., "A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease, " PLoS ONe, vol. 9, no. 12, article e112925, 2014.
258. J.-Y. Zhou, L. Chan, and S.-W. Zhou, "Omentin: linking metabolic syndrome and cardiovascular disease, " Current Vascular Pharmacology, vol. 12, no. 1, pp. 136-143, 2014.
259. R.-Z. Yang, M.-J. Lee, H. Hu et al., "Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action, " American Journal of Physiology-endocrinology and Metabolism, vol. 290, no. 6, pp. e1253-e1261, 2006.
260. C. M. de Souza Batista, R.-Z. Yang, M.-J. Lee et al., "Omentin plasma levels and gene expression are decreased in obesity, " Diabetes, vol. 56, no. 6, pp. 1655-1661, 2007.
261. B.-S. Youn, N. Klöting, J. Kratzsch et al., "Serum vaspin concentrations in human obesity and type 2 diabetes, " Diabetes, vol. 57, no. 2, pp. 372-377, 2008.
262. J. D. Glenn and K. A. Whartenby, "Mesenchymal stem cells: emerging mechanisms of immunomodulation and therapy, " World Journal of Stem Cells, vol. 6, no. 5, pp. 526-539, 2014.
263. F. Yousefi, M. ebtekar, M. Soleimani, S. Soudi, and S. M. Hashemi, "Comparison of in vivo immunomodulatory effects of intravenous and intraperitoneal administration of adiposetissue mesenchymal stem cells in experimental autoimmune encephalomyelitis (eAe), " International Immunopharmacology, vol. 17, no. 3, pp. 608-616, 2013.
264. X. Zhang, A. C. Bowles, J. A. Semon et al., "Transplantation of autologous adipose stem cells lacks therapeutic efficacy in the experimental autoimmune encephalomyelitis model, " PLoS ONe, vol. 9, no. 1, article e85007, 2014.
265. C. Marin-Bañasco, M. Suardiaz García, I. Hurtado Guerrero et al., "Mesenchymal properties of SJL mice-stem cells and their efficacy as autologous therapy in a relapsing-remitting multiple sclerosis model, " Stem Cell Research & Therapy, vol. 5, no. 6, article 134, 2014.
266. A. L. Strong, A. C. Bowles, R. M. Wise et al., "Human adipose stromal/stem cells from obese donors show reduced efficacy in halting disease progression in the experimental autoimmune encephalomyelitis model of multiple sclerosis, " Stem Cells, vol. 34, no. 3, pp. 614-626, 2016.