Abstract
The sense of smell is an ancient sensory modality vital for sampling and perceiving the chemical composition of surrounding environments. Olfaction involves a pathway of biochemical and electrophysiological processes, which allows the conversion of molecular information into sensations. Disturbances in the olfactory function have been investigated mainly in neurological/neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases; impaired sense of smell has been associated with depressed mood. Only recently, smell capability was tested in other diseases, particularly autoimmune diseases. Shoenfeld and colleagues opened this chapter showing that patients affected with systemic lupus erythematosus (SLE) have disturbances in their olfactory functions and revealed its association with neuropsychiatric manifestations of the disease. This evidence was confirmed in experimental models and replicated in other SLE populations. The connection between autoimmunity and the sense of smell was lately emphasized by studies on patients with Sjögren’s syndrome and in patients with other autoimmune/immune-mediated diseases, such as polydermatomyositis, recurrent spontaneous abortion, and hereditary angioedema. Genetic susceptibility and hormonal and environmental factors may play a role in these conditions. Olfactory receptor gene clusters are located in proximity to key locus of susceptibility for autoimmune diseases such as the major histocompatibility complex, suggesting not only a physic linkage, but a functional association. Nonetheless, gender- and hormone-mediated effects are fundamental in the development of autoimmune diseases. The different connections between smell and autoimmunity, genes and hormones may suggest that this is another tessera of a mosaic which is waiting the answer of Oedipus.
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References
Hasin-Brumshtein Y, Lancet D, Olender T (2009) Human olfaction: from genomic variation to phenotypic diversity. Trends Genet 25(4):178–184
Swedenborg E, Sewall F (1887) The sense of smell. The soul or rational psychology, 3rd edn. The New Church Press, New York, USA, pp 40–45
Gelstein S, Yeshurun Y, Rozenkrantz L, Shushan S, Frumin I, Roth Y, Sobel N (2011) Human tears contain a chemosignal. Science 331(6014):226–230
Aschenbrenner K, Hummel C, Teszmer K, Krone F, Ishimaru T, Seo HS, Hummel T (2008) The influence of olfactory loss on dietary behaviors. Laryngoscope 118(1):135–144
Strous RD, Shoenfeld Y (2006) To smell the immune system: olfaction, autoimmunity and brain involvement. Autoimmun Rev 6(1):54–60
Menini A, Lagostena L, Boccaccio A (2004) Olfaction: from odorant molecules to the olfactory cortex. News Physiol Sci 19:101–104
Cleland TA, Linster C (2003) Central olfactory structures. In: Doty RL (ed) Handbook of olfaction and gestation. Marcel Dekker, New York, pp 165–180
Hawkes CH, Doty RL (2009) The neurology of olfaction. Cambridge University Press, Cambridge
Doty RL (2012) Olfaction in Parkinson’s disease and related disorders. Neurobiol Dis 46(3):527–552
Mombaerts P (2004) Love at first smell—the 2004 Nobel Prize in Physiology or Medicine. N Engl J Med 351(25):2579–2580
Glusman G, Yanai I, Rubin I, Lancet D (2001) The complete human olfactory subgenome. Genome Res 11(5):685–702
Holley A, Duchamp A, Revial MF, Juge A (1974) Qualitative and quantitative discrimination in the frog olfactory receptors: analysis from electrophysiological data. Ann N Y Acad Sci 237:102–114
Sicard G, Holley A (1984) Receptor cell responses to odorants: similarities and differences among odorants. Brain Res 292(2):283–296
Johnson BA, Leon M (2007) Chemotopic odorant coding in a mammalian olfactory system. J Comp Neurol 503(1):1–34
Cleland TA, Linster C (2003) Central olfactory structures. In: Doty RL (ed) Handbook of olfaction and gustation. Marcel Dekker, New York, pp 165–180
Doherty PC (2003) On the nose: shared themes for the sensory and immune self. Nat Immunol 4:1043–2045
Menzel R, Giurfa M (2001) Cognitive architecture of a mini-brain: the honeybee. Trends Cogn Sci 5(2):62–71
Song C, Leonard BE (2005) The olfactory bulbectomised rat as a model of depression. Neurosci Biobehav Rev 29(4–5):627–647
Song C (2002) The effect of thymectomy and IL-1 on memory: implications for the relationship between immunity and depression. Brain Behav Immun 16(5):557–568
Schiffman SS, Miletic ID (1999) Effect of taste and smell on secretion rate of salivary IgA in elderly and young persons. J Nutr Health Aging 3(3):158–164
Alobid I, Guilemany JM, Mullol J (2004) Nasal manifestations of systemic illnesses. Curr Allergy Asthma Rep 4(3):208–216
Doty RL, Laing DG (2003) Psychophysical measurement of olfactory function, including odorant mixture assessment. In: Doty RL (ed) Handbook of olfaction and gustation. Marcel Dekker, New York, pp 203–228
Wang J, You H, Liu JF, Ni DF, Zhang ZX, Guan J (2011) Association of olfactory bulb volume and olfactory sulcus depth with olfactory function in patients with Parkinson disease. AJNR Am J Neuroradiol 32(4):677–681
Toledano A, Borromeo S, Luna G, Molina E, Solana AB, García-Polo P, Hernández JA, Alvarez-linera J (2012) Objective assessment of olfactory function using functional magnetic resonance imaging. Acta Otorrinolaringol Esp 63(4):280–285
Doty RL, Shaman P, Applebaum SL, Giberson R, Siksorski L, Rosenberg L (1984) Smell identification ability: changes with age. Science 226(4681):1441–1443
Hummel T, Barz S, Lötsch J, Roscher S, Kettenmann B, Kobal G (1996) Loss of olfactory function leads to a decrease of trigeminal sensitivity. Chem Senses 21(1):75–79
Negoias S, Croy I, Gerber J, Puschmann S, Petrowski K, Joraschky P, Hummel T (2010) Reduced olfactory bulb volume and olfactory sensitivity in patients with acute major depression. Neuroscience 169(1):415–421
Licznerski P, Duman RS (2012) Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression. Neuroscience. doi:10.1016/j.neuroscience.2012.09.057
Machado DG, Cunha MP, Neis VB, Balen GO, Colla AR, Grando J, Brocardo PS, Bettio LE, Dalmarco JB, Rial D, Prediger RD, Pizzolatti MG, Rodrigues AL (2012) Rosmarinus officinalis L. hydroalcoholic extract, similar to fluoxetine, reverses depressive-like behavior without altering learning deficit in olfactory bulbectomized mice. J Ethnopharmacol 143(1):158–169
Quidé Y, Witteveen AB, El-Hage W, Veltman DJ, Olff M (2012) Differences between effects of psychological versus pharmacological treatments on functional and morphological brain alterations in anxiety disorders and major depressive disorder: a systematic review. Neurosci Biobehav Rev 36(1):626–644
Drevets WC (2000) Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Prog Brain Res 126:413–431, Review
Hoexter MQ, Dougherty DD, Shavitt RG, D’Alcante CC, Duran FL, Lopes AC, Diniz JB, Batistuzzo MC, Evans KC, Bressan RA, Busatto GF, Miguel EC (2012). Differential prefrontal gray matter correlates of treatment response to fluoxetine or cognitive–behavioral therapy in obsessive-compulsive disorder. Eur Neuropsychopharmacol (epub ahead of print)
Burón E, Bulbena A (2012) Olfaction in affective and anxiety disorders: a review of the literature. Psychopathology (epub ahead of print)
Segalàs C, Labad J, Alonso P, Real E, Subirà M, Bueno B, Jiménez-Murcia S, Menchón JM (2011) Olfactory identification and discrimination in obsessive-compulsive disorder. Depress Anxiety 28(10):932–940
Barnett R, Maruff P, Purcell R, Wainwright K, Kyrios M, Brewer W, Pantelis C (1999) Impairment of olfactory identification in obsessive-compulsive disorder. Psychol Med 29(5):1227–1233
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
Benkler M, Agmon-Levin N, Shoenfeld Y (2009) Parkinson's disease, autoimmunity, and olfaction. Int J Neurosci 119(12):2133–2143
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 855:781–786
Franklin RJ, Barnett SC (2000) Olfactory ensheathing cells and CNS regeneration: the sweet smell of success? Neuron 28(1):15–18
Dahlslett SB, Goektas O, Schmidt F, Harms L, Olze H, Fleiner F (2012) Psychophysiological and electrophysiological testing of olfactory and gustatory function in patients with multiple sclerosis. Eur Arch Otorhinolaryngol 269(4):1163–1169
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
Lutterotti A, Vedovello M, Reindl M, Ehling R, DiPauli F, Kuenz B, Gneiss C, Deisenhammer F, Berger T (2011) Olfactory threshold is impaired in early, active multiple sclerosis. Mult Scler 17(8):964–969
Gatto M, Zen M, Ghirardello A, Bettio S, Bassi N, Iaccarino L, Punzi L, Doria A (2012) Emerging and critical issues in the pathogenesis of lupus. Autoimmun Rev S1568-9972(12):00213–00213
Brooks WH (2012) Mechanisms and pathophysiology of autoimmune disease. Clin Rev Allergy Immunol 42(1):1–4
Sciascia S, Bertolaccini ML, Baldovino S, Roccatello D, Khamashta MA, Sanna G (2012) Central nervous system involvement in systemic lupus erythematosus: overview on classification criteria. Autoimmun Rev (epub ahead of print)
Greenwood DL, Gitlits VM, Alderuccio F, Sentry JW, Toh BH (2002) Autoantibodies in neuropsychiatric lupus. Autoimmunity 35(2):79–86
Conti F, Alessandri C, Perricone C, Scrivo R, Rezai S, Ceccarelli F, Spinelli FR, Ortona E, Marianetti M, Mina C, Valesini G (2012) Neurocognitive dysfunction in systemic lupus erythematosus: association with antiphospholipid antibodies, disease activity and chronic damage. PLoS One 7(3):e33824
Hanly JG, Urowitz MB, Su L, Bae SC, Gordon C, Clarke A, Bernatsky S, Vasudevan A, Isenberg D, Rahman A, Wallace DJ, Fortin PR, Gladman D, Romero-Diaz J, Sanchez-Guerrero J, Dooley MA, Bruce I, Steinsson K, Khamashta M, Manzi S, Ramsey-Goldman R, Sturfelt G, Nived O, van Vollenhoven R, Ramos-Casals M, Aranow C, Mackay M, Kalunian K, Alarcón GS, Fessler BJ, Ruiz-Irastorza G, Petri M, Lim S, Kamen D, Peschken C, Farewell V, Thompson K, Theriault C, Merrill JT (2011) Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus. Ann Rheum Dis 70(10):1726–1732
Katzav A, Solodeev I, Brodsky O, Chapman J, Pick CG, Blank M, Zhang W, Reichlin M, Shoenfeld Y (2007) Induction of autoimmune depression in mice by anti-ribosomal P antibodies via the limbic system. Arthritis Rheum 56(3):938–948
Katzav A, Ben-Ziv T, Chapman J, Blank M, Reichlin M, Shoenfeld Y (2008) Anti-P ribosomal antibodies induce defect in smell capability in a model of CNS -SLE (depression). J Autoimmun 31(4):393–398
Shoenfeld Y (2007) To smell autoimmunity: anti-P-ribosomal autoantibodies, depression, and the olfactory system. J Autoimmun 28(2–3):165–169
Blank M, Shoenfeld Y (2008) The story of the 16/6 idiotype and systemic lupus erythematosus. Isr Med Assoc J 10(1):37–39
Shoenfeld N, Agmon-Levin N, Flitman-Katzevman I, Paran D, Katz BS, Kivity S, Langevitz P, Zandman-Goddard G, Shoenfeld Y (2009) The sense of smell in systemic lupus erythematosus. Arthritis Rheum 60(5):1484–1487
Weber JC, Alt M, Blaison G, Welsch M, Martin T, Pasquali JL (1996) Changes in taste and smell caused by hydroxychloroquine. Presse Med 25(5):213
Henkin RI, Talal N, Larson AL, Mattern CF (1972) Abnormalities of taste and smell in Sjogren’s syndrome. Ann Intern Med 76(3):375–383
Rasmussen N, Brofeldt S, Manthorpe R (1986) Smell and nasal findings in patients with primary Sjögren’s syndrome. Scand J Rheumatol Suppl 61:142–145
Kamel UF, Maddison P, Whitaker R (2009) Impact of primary Sjogren’s syndrome on smell and taste: effect on quality of life. Rheumatology (Oxford) 48(12):1512–1514
Takano K, Yamamoto M, Kondo A, Takahashi H, Himi T (2011) A clinical study of olfactory dysfunction in patients with Mikulicz’s disease. Auris Nasus Larynx 38(3):347–351
Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L, Bucher C, Castaldo AJ, Cicardi M, Davis AE, De Carolis C, Drouet C, Duponchel C, Farkas H, Fáy K, Fekete B, Fischer B, Fontana L, Füst G, Giacomelli R, Gröner A, Hack CE, Harmat G, Jakenfelds J, Juers M, Kalmár L, Kaposi PN, Karádi I, Kitzinger A, Kollár T, Kreuz W, Lakatos P, Longhurst HJ, Lopez-Trascasa M, Martinez-Saguer I, Monnier N, Nagy I, Németh E, Nielsen EW, Nuijens JH, O'grady C, Pappalardo E, Penna V, Perricone C, Perricone R, Rauch U, Roche O, Rusicke E, Späth PJ, Szendei G, Takács E, Tordai A, Truedsson L, Varga L, Visy B, Williams K, Zanichelli A, Zingale L (2004) Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 114(3 Suppl):S51–S131
Khan S, Tarzi MD, Doré PC, Sewell WA, Longhurst HJ (2007) Secondary systemic lupus erythematosus: an analysis of 4 cases of uncontrolled hereditary angioedema. Clin Immunol 123(1):14–17
Perricone C, Agmon-Levin N, Shoenfeld N, de Carolis C, Guarino MD, Gigliucci G, Milana I, Novelli L, Valesini G, Perricone R, Shoenfeld Y (2011) Evidence of impaired sense of smell in hereditary angioedema. Allergy 66(1):149–154
Buettner JA, Glusman G, Ben-Arie N, Ramos P, Lancet D, Evans GA (1998) Organization and evolution of olfactory receptor genes on human chromosome 11. Genomics 53:56–68
McConnell RJ, Menendez CE, Smith FR, Henkin RI, Rivlin RS (1975) Defects of taste and smell in patients with hypothyroidism. Am J Med 59(3):354–364
Beard MD, Mackay-Sim A (1987) Loss of sense of smell in adult, hypothyroid mice. Brain Res 433(2):181–189
Eschler DC, Hasham A, Tomer Y (2011) Cutting edge: the etiology of autoimmune thyroid diseases. Clin Rev Allergy Immunol 41(2):190–197
Doty RL, Cameron EL (2009) Sex differences and reproductive hormone influences on human odor perception. Physiol Behav 97(2):213–228, Epub 2009 Mar 9. Review. Erratum in: Physiol Behav. 2009 Oct 19;98(4):517
Noferi G, Giudizi S (1946) Le variazioni della sensibilita gustativa in particolari situazioni fisiologiche ed in alcuni stati morbosi. Nota IV. Le variazioni della soglia gustativa per l'acido e della soglia olfattiva per l'odore limone durante la gravidanza. Riv Clin Med 5(Suppl 1):89–100
Luvara A, Murizi M (1961) Ricerche di olfattometria in gravidanze. Boll Malatt Orecchio Gola Naso 79:367–375
Perricone C, de Carolis C, Perricone R (2012) Pregnancy and autoimmunity: a common problem. Best Pract Res Clin Rheumatol 26(1):47–60
De Carolis C, Perricone C, Perricone R (2010) NK cells, autoantibodies, and immunologic infertility: a complex interplay. Clin Rev Allergy Immunol 39(3):166–175
Shoenfeld Y, Tincani A, Gershwin ME (2012) Sex gender and autoimmunity. J Autoimmun 38(2–3):J71–J73
Pollard KM (2012) Gender differences in autoimmunity associated with exposure to environmental factors. J Autoimmun 38(2–3):J177–J186
Quintero OL, Amador-Patarroyo MJ, Montoya-Ortiz G, Rojas-Villarraga A, Anaya JM (2012) Autoimmune disease and gender: plausible mechanisms for the female predominance of autoimmunity. J Autoimmun 38(2–3):J109–J119
Borchers AT, Gershwin ME (2012) Sociological differences between women and men: implications for autoimmunity. Autoimmun Rev 11(6–7):A413–A421
Nussinovitch U, Shoenfeld Y (2012) The role of gender and organ specific autoimmunity. Autoimmun Rev 11(6–7):A377–A385
Larsen CE, Alper CA (2004) The genetics of HLA-associated disease. Curr Opin Immunol 16(5):660–667
Arakawa H, Cruz S, Deak T (2011) From models to mechanisms: odorant communication as a key determinant of social behavior in rodents during illness-associated states. Neurosci Biobehav Rev 35(9):1916–1928
Havlicek J, Roberts SC (2009) MHC-correlated mate choice in humans: a review. Psychoneuroendocrinology 34(4):497–512
Ortega-Hernandez OD, Kivity S, Shoenfeld Y (2009) Olfaction, psychiatric disorders and autoimmunity: is there a common genetic association? Autoimmunity 42(1):80–88
Drickamer LC (1988) Long-term effects of accelerated or delayed sexual maturation on reproductive output in wild female house mice (Mus musculus). J Reprod Fertil 83(1):439–445
Santos PS, Schinemann JA, Gabardo J, Bicalho MG (2005) New evidence that the MHC influences odor perception in humans: a study with 58 Southern Brazilian students. Horm Behav 47(4):384–388
Jahromi MM (2012) Haplotype specific alteration of diabetes MHC risk by olfactory receptor gene polymorphism. Autoimmun Rev 12(2):270–274
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This work was supported by grants from the ASR ONLUS, Rome, Italy. Funding source had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
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Perricone, C., Shoenfeld, N., Agmon-Levin, N. et al. Smell and Autoimmunity: A Comprehensive Review. Clinic Rev Allerg Immunol 45, 87–96 (2013). https://doi.org/10.1007/s12016-012-8343-x
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DOI: https://doi.org/10.1007/s12016-012-8343-x