Olfactory Dysfunction in CNS Neuroimmunological Disorders: a Review

  • Taekyun ShinEmail author
  • Jeongtae Kim
  • Meejung Ahn
  • Changjong Moon


Olfactory dysfunction is deeply associated with quality of human life in the aging population. Olfactory dysfunction is an occasional presymptomatic sign of neuroimmunological multiple sclerosis, neuromyelitis optica, and systemic lupus erythematosus. Olfaction is initially processed by olfactory receptor cells that capture odor molecules, and the signals are transmitted to the glomeruli in the olfactory bulbs via olfactory nerves and processed in the primary olfactory cortex in the brain. Damage to either the olfactory receptor cells or the olfactory bulb and primary olfactory cortex may influence olfactory functioning. A close link between neuroimmunological disorders and olfactory dysfunction has been reported in patients and animal models. This review summarizes the literature data concerning olfactory dysfunction in autoimmune diseases including multiple sclerosis, neuromyelitis optica, and systemic lupus erythematosus; animal models thereof; and inflammation in the olfactory bulb.


Autoimmune disease Olfactory dysfunction Multiple sclerosis Neuromyelitis optica Systemic lupus erythematosus 



Blood–brain barrier


Central nervous system


Cerebrospinal fluid


Experimental autoimmune encephalomyelitis


Myelin oligodendrocyte glycoprotein


Magnetic resonance imaging


Multiple sclerosis


Neuromyelitis optica


Olfactory bulb


Subarachnoid space


Systemic lupus erythematosus



This research was supported by the National Research Foundation of Korea (Grant Number, NRF-2017R1A2B4012487).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interests.


  1. 1.
    Huttenbrink KB, Hummel T, Berg D, Gasser T, Hahner A (2013) Olfactory dysfunction: common in later life and early warning of neurodegenerative disease. Dtsch Arztebl Int 110(1–2):1–7. PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Strous RD, Shoenfeld Y (2006) To smell the immune system: olfaction, autoimmunity and brain involvement. Autoimmun Rev 6(1):54–60. CrossRefPubMedGoogle Scholar
  3. 3.
    Durrant DM, Ghosh S, Klein RS (2016) The olfactory bulb: an immunosensory effector organ during neurotropic viral infections. ACS Chem Neurosci 7(4):464–469. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    van Riel D, Verdijk R, Kuiken T (2015) The olfactory nerve: a shortcut for influenza and other viral diseases into the central nervous system. J Pathol 235(2):277–287. CrossRefPubMedGoogle Scholar
  5. 5.
    Imamura F, Hasegawa-Ishii S (2016) Environmental toxicants-induced immune responses in the olfactory mucosa. Front Immunol 7:475. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Becker S, Pflugbeil C, Groger M, Canis M, Ledderose GJ, Kramer MF (2012) Olfactory dysfunction in seasonal and perennial allergic rhinitis. Acta Otolaryngol 132(7):763–768. CrossRefPubMedGoogle Scholar
  7. 7.
    Kaupp UB (2010) Olfactory signalling in vertebrates and insects: differences and commonalities. Nat Rev Neurosci 11(3):188–200. CrossRefPubMedGoogle Scholar
  8. 8.
    Dibattista M, Reisert J (2016) The odorant receptor-dependent role of olfactory marker protein in olfactory receptor neurons. J Neurosci 36(10):2995–3006. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mouret A, Murray K, Lledo PM (2009) Centrifugal drive onto local inhibitory interneurons of the olfactory bulb. Ann N Y Acad Sci 1170:239–254. CrossRefPubMedGoogle Scholar
  10. 10.
    Gottfried JA, Winston JS, Dolan RJ (2006) Dissociable codes of odor quality and odorant structure in human piriform cortex. Neuron 49(3):467–479. CrossRefPubMedGoogle Scholar
  11. 11.
    Mori K, Nagao H, Yoshihara Y (1999) The olfactory bulb: coding and processing of odor molecule information. Science 286(5440):711–715CrossRefPubMedGoogle Scholar
  12. 12.
    Murphy C, Schubert CR, Cruickshanks KJ, Klein BE, Klein R, Nondahl DM (2002) Prevalence of olfactory impairment in older adults. JAMA 288(18):2307–2312CrossRefPubMedGoogle Scholar
  13. 13.
    Doty RL, Kamath V (2014) The influences of age on olfaction: a review. Front Psychol 5:20. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ruan Y, Zheng XY, Zhang HL, Zhu W, Zhu J (2012) Olfactory dysfunctions in neurodegenerative disorders. J Neurosci Res 90(9):1693–1700. CrossRefPubMedGoogle Scholar
  15. 15.
    Doty RL (2017) Olfactory dysfunction in neurodegenerative diseases: is there a common pathological substrate? Lancet Neurol 16(6):478–488. CrossRefPubMedGoogle Scholar
  16. 16.
    Pimentel ML (2016) Olfactory dysfunction as a marker of multiple sclerosis progression. Arq Neuropsiquiatr 74(9):693–694. CrossRefPubMedGoogle Scholar
  17. 17.
    Bombini MF, Peres FA, Lapa AT, Sinicato NA, Quental BR, Pincelli ASM, Amaral TN, Gomes CC et al (2018) Olfactory function in systemic lupus erythematosus and systemic sclerosis. A longitudinal study and review of the literature. Autoimmun Rev 17(4):405–412. CrossRefPubMedGoogle Scholar
  18. 18.
    Lassmann H (2018) Multiple sclerosis pathology. Cold Spring Harbor Perspect Med 8(3).
  19. 19.
    Oukka M (2007) Interplay between pathogenic Th17 and regulatory T cells. Ann Rheum Dis 66(Suppl 3):iii87–iii90. PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Legroux L, Arbour N (2015) Multiple sclerosis and T lymphocytes: an entangled story. J NeuroImmune Pharmacol 10(4):528–546. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Lassmann H (2014) Mechanisms of white matter damage in multiple sclerosis. Glia 62(11):1816–1830. CrossRefPubMedGoogle Scholar
  22. 22.
    Lindner M, Klotz L, Wiendl H (2018) Mechanisms underlying lesion development and lesion distribution in CNS autoimmunity. J Neurochem 146:122–132. CrossRefPubMedGoogle Scholar
  23. 23.
    Mars LT, Saikali P, Liblau RS, Arbour N (2011) Contribution of CD8 T lymphocytes to the immuno-pathogenesis of multiple sclerosis and its animal models. Biochim Biophys Acta 1812(2):151–161. CrossRefPubMedGoogle Scholar
  24. 24.
    Doty RL, Li C, Mannon LJ, Yousem DM (1998) Olfactory dysfunction in multiple sclerosis. Relation to plaque load in inferior frontal and temporal lobes. Ann N Y Acad Sci 855:781–786CrossRefPubMedGoogle Scholar
  25. 25.
    Doty RL, Li C, Mannon LJ, Yousem DM (1999) Olfactory dysfunction in multiple sclerosis: relation to longitudinal changes in plaque numbers in central olfactory structures. Neurology 53(4):880–882CrossRefPubMedGoogle Scholar
  26. 26.
    Good KP, Tourbier IA, Moberg P, Cuzzocreo JL, Geckle RJ, Yousem DM, Pham DL, Doty RL (2017) Unilateral olfactory sensitivity in multiple sclerosis. Physiol Behav 168:24–30. CrossRefPubMedGoogle Scholar
  27. 27.
    Schmidt FA, Goktas O, Harms L, Bohner G, Erb K, Dahlslett B, Fleiner F (2011) Structural correlates of taste and smell loss in encephalitis disseminata. PLoS One 6(5):e19702. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Rhiannon JJ (2008) Systemic lupus erythematosus involving the nervous system: presentation, pathogenesis, and management. Clin Rev Allergy Immunol 34(3):356–360. CrossRefPubMedGoogle Scholar
  29. 29.
    Jafri K, Patterson SL, Lanata C (2017) Central nervous system manifestations of systemic lupus erythematosus. Rheum Dis Clin N Am 43(4):531–545. CrossRefGoogle Scholar
  30. 30.
    Engelhardt B, Carare RO, Bechmann I, Flugel A, Laman JD, Weller RO (2016) Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol 132(3):317–338. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Deng GM (2018) Pathogenesis of skin injury of systemic lupus erythematosus. Curr Rheumatol Rep 20(2):5. CrossRefPubMedGoogle Scholar
  32. 32.
    Khan SQ, Khan I, Gupta V (2018) CD11b activity modulates pathogenesis of lupus nephritis. Front Med 5:52. CrossRefGoogle Scholar
  33. 33.
    Tselios K, Urowitz MB (2017) Cardiovascular and pulmonary manifestations of systemic lupus erythematosus. Curr Rheumatol Rev 13(3):206–218. CrossRefPubMedGoogle Scholar
  34. 34.
    Dammacco R (2017) Systemic lupus erythematosus and ocular involvement: an overview. Clin Exp Med:135–149.
  35. 35.
    Bugala K, Mazurek A, Gryga K, Komar M, Kopec G, Musial J, Podolec P, Perricone C et al (2018) Influence of autoimmunity and inflammation on endothelial function and thrombosis in systemic lupus erythematosus patients. Clin Rheumatol 37:2087–2093. CrossRefPubMedGoogle Scholar
  36. 36.
    Plazak W, Pasowicz M, Kostkiewicz M, Podolec J, Tomkiewicz-Pajak L, Musial J, Podolec P (2011) Influence of chronic inflammation and autoimmunity on coronary calcifications and myocardial perfusion defects in systemic lupus erythematosus patients. Inflamm Res 60(10):973–980. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Sabbadini MG, Manfredi AA, Bozzolo E, Ferrario L, Rugarli C, Scorza R, Origgi L, Vanoli M et al (1999) Central nervous system involvement in systemic lupus erythematosus patients without overt neuropsychiatric manifestations. Lupus 8(1):11–19. CrossRefPubMedGoogle Scholar
  38. 38.
    Sanna G, Piga M, Terryberry JW, Peltz MT, Giagheddu S, Satta L, Ahmed A, Cauli A et al (2000) Central nervous system involvement in systemic lupus erythematosus: cerebral imaging and serological profile in patients with and without overt neuropsychiatric manifestations. Lupus 9(8):573–583. CrossRefPubMedGoogle Scholar
  39. 39.
    Appenzeller S, Pike GB, Clarke AE (2008) Magnetic resonance imaging in the evaluation of central nervous system manifestations in systemic lupus erythematosus. Clin Rev Allergy Immunol 34(3):361–366. CrossRefPubMedGoogle Scholar
  40. 40.
    Shin T, Kojima T, Tanuma N, Ishihara Y, Matsumoto Y (1995) The subarachnoid space as a site for precursor T cell proliferation and effector T cell selection in experimental autoimmune encephalomyelitis. J Neuroimmunol 56(2):171–178CrossRefPubMedGoogle Scholar
  41. 41.
    Shrestha B, Jiang X, Ge S, Paul D, Chianchiano P, Pachter JS (2017) Spatiotemporal resolution of spinal meningeal and parenchymal inflammation during experimental autoimmune encephalomyelitis. Neurobiol Dis 108:159–172. CrossRefPubMedGoogle Scholar
  42. 42.
    Shin T, Ahn M, Matsumoto Y (2012) Mechanism of experimental autoimmune encephalomyelitis in Lewis rats: recent insights from macrophages. Anat Cell Biol 45(3):141–148. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Louveau A, Da Mesquita S, Kipnis J (2016) Lymphatics in neurological disorders: a neuro-lympho-vascular component of multiple sclerosis and Alzheimer’s disease? Neuron 91(5):957–973. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Shin T, Matsumoto Y (2001) A quantitative analysis of CD45Rlow CD4+ T cells in the subarachnoid space of Lewis rats with autoimmune encephalomyelitis. Immunol Investig 30(1):57–64CrossRefGoogle Scholar
  45. 45.
    Matsumoto Y, Abe S, Tsuchida M, Hirahara H, Abo T, Shin T, Tanuma N, Kojima T et al (1996) Characterization of CD4-CD8- T cell receptor alpha beta + T cells appearing in the subarachnoid space of rats with autoimmune encephalomyelitis. Eur J Immunol 26(6):1328–1334. CrossRefPubMedGoogle Scholar
  46. 46.
    Shin T, Kang B, Tanuma N, Matsumoto Y, Wie M, Ahn M, Kang J (2001) Intrathecal administration of endothelin-1 receptor antagonist ameliorates autoimmune encephalomyelitis in Lewis rats. Neuroreport 12(7):1465–1468CrossRefPubMedGoogle Scholar
  47. 47.
    Zivadinov R, Zorzon M, Monti Bragadin L, Pagliaro G, Cazzato G (1999) Olfactory loss in multiple sclerosis. J Neurol Sci 168(2):127–130CrossRefPubMedGoogle Scholar
  48. 48.
    Atalar AC, Erdal Y, Tekin B, Yildiz M, Akdogan O, Emre U (2018) Olfactory dysfunction in multiple sclerosis. Mult Scler Relat Disord 21:92–96. CrossRefPubMedGoogle Scholar
  49. 49.
    Batur Caglayan HZ, Irkec C, Nazliel B, Akyol Gurses A, Capraz I (2016) Olfactory functioning in early multiple sclerosis: Sniffin’ sticks test study. Neuropsychiatr Dis Treat 12:2143–2147. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Schmidt FA, Fleiner F, Harms L, Bohner G, Erb K, Ludemann L, Dahlslett B, Goktas O (2011) Pathological changes of the chemosensory function in multiple sclerosis - an MRI study. Rofo 183(6):531–535. CrossRefPubMedGoogle Scholar
  51. 51.
    Lucassen EB, Turel A, Knehans A, Huang X, Eslinger P (2016) Olfactory dysfunction in multiple sclerosis: a scoping review of the literature. Mult Scler Relat Disord 6:1–9. CrossRefPubMedGoogle Scholar
  52. 52.
    Uecker FC, Olze H, Kunte H, Gerz C, Goktas O, Harms L, Schmidt FA (2017) Longitudinal testing of olfactory and gustatory function in patients with multiple sclerosis. PLoS One 12(1):e0170492. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Ciurleo R, Bonanno L, De Salvo S, Romeo L, Rifici C, Sessa E, D’Aleo G, Russo M et al (2018) Olfactory dysfunction as a prognostic marker for disability progression in multiple sclerosis: an olfactory event related potential study. PLoS One 13(4):e0196006. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Hawkes CH, Shephard BC, Kobal G (1997) Assessment of olfaction in multiple sclerosis: evidence of dysfunction by olfactory evoked response and identification tests. J Neurol Neurosurg Psychiatry 63(2):145–151CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Erb K, Bohner G, Harms L, Goektas O, Fleiner F, Dommes E, Schmidt FA, Dahlslett B et al (2012) Olfactory function in patients with multiple sclerosis: a diffusion tensor imaging study. J Neurol Sci 316(1–2):56–60. CrossRefPubMedGoogle Scholar
  56. 56.
    Tanik N, Serin HI, Celikbilek A, Inan LE, Gundogdu F (2015) Olfactory bulb and olfactory sulcus depths are associated with disease duration and attack frequency in multiple sclerosis patients. J Neurol Sci 358(1–2):304–307. CrossRefPubMedGoogle Scholar
  57. 57.
    Yaldizli O, Penner IK, Yonekawa T, Naegelin Y, Kuhle J, Pardini M, Chard DT, Stippich C et al (2016) The association between olfactory bulb volume, cognitive dysfunction, physical disability and depression in multiple sclerosis. Eur J Neurol 23(3):510–519. CrossRefPubMedGoogle Scholar
  58. 58.
    Goektas O, Schmidt F, Bohner G, Erb K, Ludemann L, Dahlslett B, Harms L, Fleiner F (2011) Olfactory bulb volume and olfactory function in patients with multiple sclerosis. Rhinology 49(2):221–226. PubMedCrossRefGoogle Scholar
  59. 59.
    Zorzon M, Ukmar M, Bragadin LM, Zanier F, Antonello RM, Cazzato G, Zivadinov R (2000) Olfactory dysfunction and extent of white matter abnormalities in multiple sclerosis: a clinical and MR study. Mult Scler 6(6):386–390. CrossRefPubMedGoogle Scholar
  60. 60.
    Schmidt FA, Maas MB, Geran R, Schmidt C, Kunte H, Ruprecht K, Paul F, Goktas O et al (2017) Olfactory dysfunction in patients with primary progressive MS. Neurol Neuroimmunol Neuroinflamm 4(4):e369. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Tepavcevic V, Lazarini F, Alfaro-Cervello C, Kerninon C, Yoshikawa K, Garcia-Verdugo JM, Lledo PM, Nait-Oumesmar B et al (2011) Inflammation-induced subventricular zone dysfunction leads to olfactory deficits in a targeted mouse model of multiple sclerosis. J Clin Invest 121(12):4722–4734. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Kim J, Choi Y, Ahn M, Jung K, Shin T (2018) Olfactory dysfunction in autoimmune central nervous system neuroinflammation. Mol Neurobiol.
  63. 63.
    Schmidt F, Goktas O, Jarius S, Wildemann B, Ruprecht K, Paul F, Harms L (2013) Olfactory dysfunction in patients with neuromyelitis optica. Mult Scler Int 2013:654501. PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    DeLuca GC, Joseph A, George J, Yates RL, Hamard M, Hofer M, Esiri MM (2015) Olfactory pathology in central nervous system demyelinating diseases. Brain Pathol 25(5):543–551. CrossRefPubMedGoogle Scholar
  65. 65.
    Zhang LJ, Zhao N, Fu Y, Zhang DQ, Wang J, Qin W, Zhang N, Wood K et al (2015) Olfactory dysfunction in neuromyelitis optica spectrum disorders. J Neurol 262(8):1890–1898. CrossRefPubMedGoogle Scholar
  66. 66.
    Li LM, Guo HY, Zhao N, Zhang LJ, Zhang N, Liu J, Yang L (2018) Comparison of olfactory function between neuromyelitis optica and multiple sclerosis. Int J Neurosci 128(8):772–777. CrossRefPubMedGoogle Scholar
  67. 67.
    Shoenfeld N, Agmon-Levin N, Flitman-Katzevman I, Paran D, Katz BS, Kivity S, Langevitz P, Zandman-Goddard G et al (2009) The sense of smell in systemic lupus erythematosus. Arthritis Rheum 60(5):1484–1487. CrossRefPubMedGoogle Scholar
  68. 68.
    Dos Passos GR, Oliveira LM, da Costa BK, Apostolos-Pereira SL, Callegaro D, Fujihara K, Sato DK (2018) MOG-IgG-associated optic neuritis, encephalitis, and myelitis: lessons learned from neuromyelitis optica spectrum disorder. Front Neurol 9:217. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Zvaifler NJ, Bluestein HG (1982) The pathogenesis of central nervous system manifestations of systemic lupus erythematosus. Arthritis Rheum 25(7):862–866CrossRefPubMedGoogle Scholar
  70. 70.
    Kapadia M, Stanojcic M, Earls AM, Pulapaka S, Lee J, Sakic B (2012) Altered olfactory function in the MRL model of CNS lupus. Behav Brain Res 234(2):303–311. CrossRefPubMedGoogle Scholar
  71. 71.
    Kapadia M, Zhao H, Ma D, Sakic B (2017) Sustained immunosuppression alters olfactory function in the MRL model of CNS lupus. J NeuroImmune Pharmacol 12(3):555–564. CrossRefPubMedGoogle Scholar
  72. 72.
    Attems J, Walker L, Jellinger KA (2014) Olfactory bulb involvement in neurodegenerative diseases. Acta Neuropathol 127(4):459–475. CrossRefPubMedGoogle Scholar
  73. 73.
    Meyer A, Wree A, Gunther R, Holzmann C, Schmitt O, Rolfs A, Witt M (2017) Increased regenerative capacity of the olfactory epithelium in Niemann-Pick disease type C1. Int J Mol Sci 18(4).
  74. 74.
    Seo Y, Kim HS, Kang I, Choi SW, Shin TH, Shin JH, Lee BC, Lee JY et al (2016) Cathepsin S contributes to microglia-mediated olfactory dysfunction through the regulation of Cx3cl1-Cx3cr1 axis in a Niemann-Pick disease type C1 model. Glia 64(12):2291–2305. CrossRefPubMedGoogle Scholar
  75. 75.
    Seo Y, Kim HS, Shin Y, Kang I, Choi SW, Yu KR, Seo KW, Kang KS (2014) Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann-Pick disease type C1 mice. Biochim Biophys Acta 1842(11):2193–2203. CrossRefPubMedGoogle Scholar
  76. 76.
    Hovakimyan M, Meyer A, Lukas J, Luo J, Gudziol V, Hummel T, Rolfs A, Wree A et al (2013) Olfactory deficits in Niemann-Pick type C1 (NPC1) disease. PLoS One 8(12):e82216. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Fleiner F, Dahlslett SB, Schmidt F, Harms L, Goektas O (2010) Olfactory and gustatory function in patients with multiple sclerosis. Am J Rhinol Allergy 24(5):e93–e97. CrossRefPubMedGoogle Scholar
  78. 78.
    Lutterotti A, Vedovello M, Reindl M, Ehling R, DiPauli F, Kuenz B, Gneiss C, Deisenhammer F et al (2011) Olfactory threshold is impaired in early, active multiple sclerosis. Mult Scler 17(8):964–969. CrossRefPubMedGoogle Scholar
  79. 79.
    Sokpor G, Abbas E, Rosenbusch J, Staiger JF, Tuoc T (2018) Transcriptional and epigenetic control of mammalian olfactory epithelium development. Mol Neurobiol.
  80. 80.
    Beites CL, Kawauchi S, Crocker CE, Calof AL (2005) Identification and molecular regulation of neural stem cells in the olfactory epithelium. Exp Cell Res 306(2):309–316. CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Veterinary Anatomy, College of Veterinary Medicine and Veterinary Medical Research InstituteJeju National UniversityJejuRepublic of Korea
  2. 2.Department of Veterinary Anatomy, College of Veterinary Medicine and BK21 Plus Project TeamChonnam National UniversityGwangjuRepublic of Korea

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