Abstract
Anti-neuronal autoantibodies can lead to subacute gastrointestinal dysmotility, presenting with various symptoms typical of intestinal pseudoobstruction, achalasia, gastroparesis, or slow intestinal transit, among others. Such autoantibodies may be produced in response to a remote tumor and accelerate the diagnosis of malignancy, but in other cases they appear without an identifiable underlying cause. One example is the type I anti-neuronal nuclear antibody (ANNA-1 otherwise known as anti-Hu), which is usually linked to small cell–lung carcinoma. Anti-Hu can directly activate enteric neurons and visceral sensory nerve fibers and has a cytotoxic effect. Various other anti-neuronal antibodies have been described, targeting different ion channels or receptors on nerve cells of the central or the enteric nervous system. Autoimmune processes targeting enteric neurons may also play a role in more common disorders such as esophageal achalasia, celiac disease, or multiple sclerosis. Furthermore, anti-enteric neuronal antibodies have been found more abundant in the common functional gastrointestinal disorder, irritable bowel syndrome (IBS), than in controls. The pathogenesis of IBS is very complex, involving the release of various mediators from immune cells in the gut wall. Products of mast cells, such as histamine and tryptase, excite visceral afferents and enteric neurons, which may contribute to symptoms like abdominal pain and disturbed motility. Elevated serine- and cysteine-protease activity in stool of IBS-D and IBS-C patients, respectively, can be a factor leading to leaky gut and visceral hypersensitivity. More knowledge on these mediators in IBS may facilitate the development of novel diagnostic methods or therapies.
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Annaházi A, Ferrier L, Bézirard V, Lévêque M, Eutamène H, Ait-Belgnaoui A, Coëffier M, Ducrotté P, Róka R, Inczefi O, Gecse K, Rosztóczy A, Molnár T, Ringel-Kulka T, Ringel Y, Piche T, Theodorou V, Wittmann T, Bueno L (2013) Luminal cysteine-proteases degrade colonic tight junction structure and are responsible for abdominal pain in constipation-predominant IBS. Am J Gastroenterol 108:1322–1331. https://doi.org/10.1038/ajg.2013.152
Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW, Collins SM, Corinaldesi R (2004) Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126:693–702. https://doi.org/10.1053/j.gastro.2003.11.055
Boronat A, Gelfand JM, Gresa-Arribas N, Jeong H-Y, Walsh M, Roberts K, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R, Graus F, Rudy B, Dalmau J (2013) Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol 73:120–128. https://doi.org/10.1002/ana.23756
Bruley des Varannes S, Chevalier J, Pimont S, Le Neel J-C, Klotz M, Schafer K-H, Galmiche J-P, Neunlist M (2006) Serum from achalasia patients alters neurochemical coding in the myenteric plexus and nitric oxide mediated motor response in normal human fundus. Gut 55:319–326. https://doi.org/10.1136/gut.2005.070011
Buhner S, Li Q, Vignali S, Barbara G, De Giorgio R, Stanghellini V, Cremon C, Zeller F, Langer R, Daniel H, Michel K, Schemann M (2009) Activation of human enteric neurons by supernatants of colonic biopsy specimens from patients with irritable bowel syndrome. Gastroenterology 137:1425–1434. https://doi.org/10.1053/j.gastro.2009.07.005
Buhner S, Li Q, Berger T, Vignali S, Barbara G, De Giorgio R, Stanghellini V, Schemann M (2012) Submucous rather than myenteric neurons are activated by mucosal biopsy supernatants from irritable bowel syndrome patients. Neurogastroenterol Motil 24:1134–e572. https://doi.org/10.1111/nmo.12011
Buhner S, Braak B, Li Q, Kugler EM, Klooker T, Wouters M, Donovan J, Vignali S, Mazzuoli-Weber G, Grundy D, Boeckxstaens G, Schemann M (2014) Neuronal activation by mucosal biopsy supernatants from irritable bowel syndrome patients is linked to visceral sensitivity. Exp Physiol 99:1299–1311. https://doi.org/10.1113/expphysiol.2014.080036
Buhner S, Barki N, Greiter W, Giesbertz P, Demir IE, Ceyhan GO, Zeller F, Daniel H, Schemann M (2017) Calcium imaging of nerve-mast cell signaling in the human intestine. Front Physiol 8:971. https://doi.org/10.3389/fphys.2017.00971
Buhner S, Hahne H, Hartwig K, Li Q, Vignali S, Ostertag D, Meng C, Hörmannsperger G, Braak B, Pehl C, Frieling T, Barbara G, De Giorgio R, Demir IE, Ceyhan GO, Zeller F, Boeckxstaens G, Haller D, Kuster B, Schemann M (2018) Protease signaling through protease activated receptor 1 mediate nerve activation by mucosal supernatants from irritable bowel syndrome but not from ulcerative colitis patients. PLoS One 13:e0193943. https://doi.org/10.1371/journal.pone.0193943
Caio G, De Giorgio R, Venturi A, Giancola F, Latorre R, Boschetti E, Serra M, Ruggeri E, Volta U (2015) Clinical and immunological relevance of anti-neuronal antibodies in celiac disease with neurological manifestations. Gastroenterol Hepatol Bed Bench 8:146–152
Cenac N, Andrews CN, Holzhausen M, Chapman K, Cottrell G, Andrade-Gordon P, Steinhoff M, Barbara G, Beck P, Bunnett NW, Sharkey KA, Ferraz JGP, Shaffer E, Vergnolle N (2007) Role for protease activity in visceral pain in irritable bowel syndrome. J Clin Invest 117:636–647. https://doi.org/10.1172/JCI29255
Cheng L, Luo QQ, Chen SL (2021) The role of intestinal mast cell infiltration in irritable bowel syndrome. J Dig Dis 22:143–151. https://doi.org/10.1111/1751-2980.12971
Chia YW, Gill KP, Jameson JS, Forti AD, Henry MM, Swash M, Shorvon PJ (1996) Paradoxical puborectalis contraction is a feature of constipation in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 60:31–35. https://doi.org/10.1136/jnnp.60.1.31
De Giorgio R, Bovara M, Barbara G, Canossa M, Sarnelli G, De Ponti F, Stanghellini V, Tonini M, Cappello S, Pagnotta E, Nobile-Orazio E, Corinaldesi R (2003) Anti-HuD-induced neuronal apoptosis underlying paraneoplastic gut dysmotility. Gastroenterology 125:70–79. https://doi.org/10.1016/s0016-5085(03)00664-4
Dhamija R, Tan KM, Pittock SJ, Foxx–Orenstein A, Benarroch E, Lennon VA (2008) Serologic profiles aiding the diagnosis of autoimmune gastrointestinal dysmotility. Clin Gastroenterol Hepatol 6:988–992. https://doi.org/10.1016/j.cgh.2008.04.009
Fan W, Fei G, Li X, Wang X, Hu C, Xin H, Sun X, Li Y, Wood JD, Fang X (2018) Sera with anti-enteric neuronal antibodies from patients with irritable bowel syndrome promote apoptosis in myenteric neurons of guinea pigs and human SH-Sy5Y cells. Neurogastroenterol Motil 30:e13457. https://doi.org/10.1111/nmo.13457
Frieling T, Kreysel C, Blank M, Müller D, Melchior I, Euler P, Kuhlbusch-Zicklam R, Haarmeier T, Schemann M (2020) Autoimmune encephalitis and gastrointestinal dysmotility: achalasia, gastroparesis, and slow transit constipation. Z Gastroenterol 58:975–981. https://doi.org/10.1055/a-1233-2190
Gecse K, Róka R, Ferrier L, Leveque M, Eutamene H, Cartier C, Ait-Belgnaoui A, Rosztóczy A, Izbéki F, Fioramonti J, Wittmann T, Bueno L (2008) Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity. Gut 57:591–599. https://doi.org/10.1136/gut.2007.140210
Klooker TK, Braak B, Koopman KE, Welting O, Wouters MM, van der Heide S, Schemann M, Bischoff SC, van den Wijngaard RM, Boeckxstaens GE (2010) The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut 59:1213–1221. https://doi.org/10.1136/gut.2010.213108
Kraichely RE, Farrugia G, Pittock SJ, Castell DO, Lennon VA (2010) Neural autoantibody profile of primary achalasia. Dig Dis Sci 55:307–311. https://doi.org/10.1007/s10620-009-0838-9
Lennon VA, Sas DF, Busk MF, Scheithauer B, Malagelada JR, Camilleri M, Miller LJ (1991) Enteric neuronal autoantibodies in pseudoobstruction with small-cell lung carcinoma. Gastroenterology 100:137–142. https://doi.org/10.1016/0016-5085(91)90593-a
Levinthal DJ, Rahman A, Nusrat S, O’Leary M, Heyman R, Bielefeldt K (2013) Adding to the burden: gastrointestinal symptoms and syndromes in multiple sclerosis. Mult Scler Int 2013:319201. https://doi.org/10.1155/2013/319201
Li Q, Michel K, Annahazi A, Demir IE, Ceyhan GO, Zeller F, Komorowski L, Stöcker W, Beyak MJ, Grundy D, Farrugia G, De Giorgio R, Schemann M (2016) Anti-Hu antibodies activate enteric and sensory neurons. Sci Rep 6:38216. https://doi.org/10.1038/srep38216
Lütt A, Michel K, Krüger D, Volz MS, Nassir M, Schulz E, Poralla L, Tangermann P, Bojarski C, Höltje M, Teegen B, Stöcker W, Schemann M, Siegmund B, Prüss H (2018) High prevalence and functional effects of serum antineuronal antibodies in patients with gastrointestinal disorders. Neurogastroenterol Motil 30:e13292. https://doi.org/10.1111/nmo.13292
Meira de-Faria F, Casado-Bedmar M, MÃ¥rten Lindqvist C, Jones MP, Walter SA, Keita Ã…V (2021) Altered interaction between enteric glial cells and mast cells in the colon of women with irritable bowel syndrome. Neurogastroenterol Motil. https://doi.org/10.1111/nmo.14130
Ostertag D, Buhner S, Michel K, Pehl C, Kurjak M, Götzberger M, Schulte-Frohlinde E, Frieling T, Enck P, Phillip J, Schemann M (2015) Reduced responses of submucous neurons from irritable bowel syndrome patients to a cocktail containing histamine, serotonin, TNFα, and tryptase (IBS-cocktail). Front Neurosci 9:465. https://doi.org/10.3389/fnins.2015.00465
Ostertag D, Annahazi A, Krueger D, Michel K, Demir IE, Ceyhan GO, Zeller F, Schemann M (2017) Tryptase potentiates enteric nerve activation by histamine and serotonin: relevance for the effects of mucosal biopsy supernatants from irritable bowel syndrome patients. Neurogastroenterol Motil 29. https://doi.org/10.1111/nmo.13070
Piepgras J, Höltje M, Michel K, Li Q, Otto C, Drenckhahn C, Probst C, Schemann M, Jarius S, Stöcker W, Balint B, Meinck H-M, Buchert R, Dalmau J, Ahnert-Hilger G, Ruprecht K (2015) Anti-DPPX encephalitis: pathogenic effects of antibodies on gut and brain neurons. Neurology 85:890–897. https://doi.org/10.1212/WNL.0000000000001907
Róka R, Rosztóczy A, Leveque M, Izbéki F, Nagy F, Molnár T, Lonovics J, Garcia-Villar R, Fioramonti J, Wittmann T, Bueno L (2007) A pilot study of fecal serine-protease activity: a pathophysiologic factor in diarrhea-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol 5:550–555. https://doi.org/10.1016/j.cgh.2006.12.004
Sanchez-Ruiz M, Brunn A, Montesinos-Rongen M, Rudroff C, Hartmann M, Schlüter D, Pfitzer G, Deckert M (2019) Enteric murine ganglionitis induced by autoimmune CD8 T cells mimics human gastrointestinal dysmotility. Am J Pathol 189:540–551. https://doi.org/10.1016/j.ajpath.2018.11.016
Schäfer KH, Klotz M, Mergner D, Mestres P, Schimrigk K, Blaes F (2000) IgG-mediated cytotoxicity to myenteric plexus cultures in patients with paraneoplastic neurological syndromes. J Autoimmun 15:479–484. https://doi.org/10.1006/jaut.2000.0454
Spear ET, Holt EA, Joyce EJ, Haag MM, Mawe SM, Hennig GW, Lavoie B, Applebee AM, Teuscher C, Mawe GM (2018) Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neurogastroenterol Motil 30:e13349. https://doi.org/10.1111/nmo.13349
Stavely R, Abalo R, Nurgali K (2020) Targeting enteric neurons and plexitis for the management of inflammatory bowel disease. Curr Drug Targets 21:1428–1439. https://doi.org/10.2174/1389450121666200516173242
Tooth D, Garsed K, Singh G, Marciani L, Lam C, Fordham I, Fields A, Banwait R, Lingaya M, Layfield R, Hastings M, Whorwell P, Spiller R (2014) Characterisation of faecal protease activity in irritable bowel syndrome with diarrhoea: origin and effect of gut transit. Gut 63:753–760. https://doi.org/10.1136/gutjnl-2012-304042
Volta U, Giorgio RD, Petrolini N, Stanghellini V, Barbara G, Granito A, Ponti FD, Corinaldesi R, Bianchi FB (2002) Clinical findings and anti-neuronal antibodies in coeliac disease with neurological disorders. Scand J Gastroenterol 37:1276–1281. https://doi.org/10.1080/003655202761020542
Wood JD, Liu S, Drossman DA, Ringel Y, Whitehead WE (2012) Anti-enteric neuronal antibodies and the irritable bowel syndrome. J Neurogastroenterol Motil 18:78–85. https://doi.org/10.5056/jnm.2012.18.1.78
Wouters MM, Balemans D, Van Wanrooy S, Dooley J, Cibert-Goton V, Alpizar YA, Valdez-Morales EE, Nasser Y, Van Veldhoven PP, Vanbrabant W, Van der Merwe S, Mols R, Ghesquière B, Cirillo C, Kortekaas I, Carmeliet P, Peetermans WE, Vermeire S, Rutgeerts P, Augustijns P, Hellings PW, Belmans A, Vanner S, Bulmer DC, Talavera K, Vanden Berghe P, Liston A, Boeckxstaens GE (2016) Histamine receptor H1-mediated sensitization of TRPV1 mediates visceral hypersensitivity and symptoms in patients with irritable bowel syndrome. Gastroenterology 150:875–887.e9. https://doi.org/10.1053/j.gastro.2015.12.034
Wunsch M, Jabari S, Voussen B, Enders M, Srinivasan S, Cossais F, Wedel T, Boettner M, Schwarz A, Weyer L, Göcer O, Schroeter M, Maeurer M, Woenckhaus M, Pollok K, Radbruch H, Klotz L, Scholz C-J, Nickel J, Friebe A, Addicks K, Ergün S, Lehmann PV, Kuerten S (2017) The enteric nervous system is a potential autoimmune target in multiple sclerosis. Acta Neuropathol 134:281–295. https://doi.org/10.1007/s00401-017-1742-6
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Annaházi, A., Schemann, M. (2022). Contribution of the Enteric Nervous System to Autoimmune Diseases and Irritable Bowel Syndrome. In: Spencer, N.J., Costa, M., Brierley, S.M. (eds) The Enteric Nervous System II. Advances in Experimental Medicine and Biology, vol 1383. Springer, Cham. https://doi.org/10.1007/978-3-031-05843-1_1
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