The Presence of Ganglionic Acetylcholine Receptor Antibodies in Sera from Patients with Functional Gastrointestinal Disorders: A Preliminary Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Cohort and Study Design
2.2. Luciferase Immunoprecipitation System (LIPS) Assay for Anti-gAChR Abs
2.3. Ethical Approval
2.4. Clinical Assessment
2.5. COMPASS
3. Results
Illustrative Cases
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Koloski, N.A.; Talley, N.J.; Boyce, P.M. Epidemiology and health care seeking in the functional GI disorders: A population-based study. Am. J. Gastroenterol. 2002, 97, 2290–2299. [Google Scholar] [CrossRef] [PubMed]
- Black, C.J.; Drossman, D.A.; Talley, N.J.; Ruddy, J.; Ford, A.C. Functional Gastrointestinal Disorders: Advances in Understanding and Management. Lancet 2020, 396, 1664–1674. [Google Scholar] [CrossRef] [PubMed]
- Vernino, S.; Low, P.A.; Fealey, R.D.; Stewart, J.D.; Farrugia, G.; Lennon, V.A. Autoantibodies to Ganglionic Acetylcholine Receptors in Autoimmune Autonomic Neuropathies. N. Engl. J. Med. 2000, 343, 847–855. [Google Scholar] [CrossRef] [PubMed]
- Wang, Z.; Low, P.A.; Jordan, J.; Freeman, R.; Gibbons, C.H.; Schroeder, C.; Sandroni, P.; Vernino, S. Autoimmune autonomic ganglionopathy: IgG effects on ganglionic acetylcholine receptor current. Neurology 2007, 68, 1917–1921. [Google Scholar] [CrossRef] [PubMed]
- Dhamija, R.; Tan, K.M.; Pittock, S.J.; Foxx–Orenstein, A.; Benarroch, E.; Lennon, V.A. Serologic profiles aiding the diagnosis of autoimmune gastrointestinal dysmotility. Clin. Gastroenterol. Hepatol. 2008, 6, 988–992. [Google Scholar] [CrossRef] [PubMed]
- Flanagan, E.P.; Saito, Y.A.; Lennon, V.A.; McKeon, A.; Fealey, R.D.; Szarka, L.A.; Murray, J.A.; Foxx-Orenstein, A.E.; Fox, J.C.; Pittock, S.J. Immunotherapy trial as diagnostic test in evaluating patients with presumed autoimmune gastrointestinal dysmotility. Neurogastroenterol. Motil. 2014, 26, 1285–1297. [Google Scholar] [CrossRef] [PubMed]
- Nakane, S.; Mukaino, A.; Ihara, E.; Ogawa, Y. Autoimmune gastrointestinal dysmotility: The interface between clinical immunology and neurogastroenterology. Immunol. Med. 2021, 44, 74–85. [Google Scholar] [CrossRef] [PubMed]
- Nakane, S.; Mukaino, A.; Higuchi, O.; Yasuhiro, M.; Takamatsu, K.; Yamakawa, M.; Watari, M.; Tawara, N.; Nakahara, K.-I.; Kawakami, A.; et al. A comprehensive analysis of the clinical characteristics and laboratory features in 179 patients with autoimmune autonomic ganglionopathy. J. Autoimmun. 2020, 108, 102403. [Google Scholar] [CrossRef] [PubMed]
- Nakane, S.; Higuchi, O.; Koga, M.; Kanda, T.; Murata, K.; Suzuki, T.; Kurono, H.; Kunimoto, M.; Kaida, K.-I.; Mukaino, A.; et al. Clinical features of autoimmune autonomic ganglionopathy and the detection of subunit-specific autoantibodies to the ganglionic acetylcholine receptor in Japanese patients. PLoS ONE 2015, 10, e0118312. [Google Scholar] [CrossRef]
- Burbelo, P.D.; Ching, K.H.; Klimavicz, C.M.; Iadarola, M.J. Antibody profiling by Luciferase Immunoprecipitation Systems (LIPS). J. Vis. Exp. 2009, 32, 1549. [Google Scholar]
- Burbelo, P.D.; Lebovitz, E.E.; Notkins, A.L. Luciferase immunoprecipitation systems for measuring antibodies in autoimmune and infectious diseases. Transl. Res. 2015, 165, 325–335. [Google Scholar] [CrossRef] [PubMed]
- Maeda, Y.; Migita, K.; Higuchi, O.; Mukaino, A.; Furukawa, H.; Komori, A.; Nakamura, M.; Hashimoto, S.; Nagaoka, S.; Abiru, S.; et al. Association between Anti-Ganglionic Nicotinic Acetylcholine Receptor (gAChR) Antibodies and HLA-DRB1 Alleles in the Japanese Population. PLoS ONE 2016, 11, e0146048. [Google Scholar] [CrossRef] [PubMed]
- Nakane, S.; Mukaino, A.; Higuchi, O.; Watari, M.; Maeda, Y.; Yamakawa, M.; Nakahara, K.; Takamatsu, K.; Matsuo, H.; Ando, Y. Autoimmune autonomic ganglionopathy: An update on diagnosis and treatment. Expert Rev. Neurother. 2018, 18, 953–965. [Google Scholar] [CrossRef] [PubMed]
- Mearin, F.; Lacy, B.E.; Chang, L.; Chey, W.D.; Lembo, A.J.; Simren, M.; Spiller, R. Bowel Disorders. Gastroenterology 2016, 150, 1393–1407. [Google Scholar]
- Drossman, D.A.; Hasler, W.L. Rome IV—Functional GI Disorders: Disorders of Gut-Brain Interaction. Gastroenterology 2016, 150, 1257–1261. [Google Scholar] [CrossRef] [PubMed]
- Sletten, D.M.; Suarez, G.A.; Low, P.A.; Mandrekar, J.; Singer, W. COMPASS 31: A Refined and Abbreviated Composite Autonomic Symptom Score. Mayo Clin. Proc. 2012, 87, 1196–1201. [Google Scholar] [CrossRef] [PubMed]
- Cortez, M.; Reddy, S.N.; Goodman, B.; Carter, J.; Wingerchuk, D. Autonomic symptom burden is associated with MS-related fatigue and quality of life. Mult. Scler. Relat. Disord. 2015, 4, 258–263. [Google Scholar] [CrossRef] [PubMed]
- Mukaino, A.; Minami, H.; Isomoto, H.; Hamamoto, H.; Ihara, E.; Maeda, Y.; Higuchi, O.; Okanishi, T.; Kokudo, Y.; Deguchi, K.; et al. Anti-ganglionic AChR antibodies in Japanese patients with motility disorders. J. Gastroenterol. 2018, 53, 1227–1240. [Google Scholar] [CrossRef] [PubMed]
- Koloski, N.; Jones, M.; Walker, M.M.; Veysey, M.; Zala, A.; Keely, S.; Holtmann, G.; Talley, N.J. Population based study: Atopy and autoimmune diseases are associated with functional dyspepsia and irritable bowel syndrome, independent of psychological distress. Aliment. Pharmacol. Ther. 2019, 49, 546–555. [Google Scholar] [CrossRef]
- Svedberg, P.; Johansson, S.; Wallander, M.; Hamelin, B.; Pedersen, N.L. Extra-intestinal manifestations associated with irritable bowel syndrome: A twin study. Aliment. Pharmacol. Ther. 2002, 16, 975–983. [Google Scholar] [CrossRef]
- De Giorgio, R.; Guerrini, S.; Barbara, G.; Stanghellini, V.; De Ponti, F.; Corinaldesi, R.; Moses, P.L.; Sharkey, K.A.; Mawe, G.M. Inflammatory neuropathies of the enteric nervous system. Gastroenterology 2004, 126, 1872–1883. [Google Scholar] [CrossRef] [PubMed]
- Kraneveld, A.D.; Rijnierse, A.; Nijkamp, F.P.; Garssen, J. Neuro-immune interactions in inflammatory bowel disease and irritable bowel syndrome: Future therapeutic targets. Eur. J. Pharmacol. 2008, 585, 361–374. [Google Scholar] [CrossRef] [PubMed]
- Burns, G.; Carroll, G.; Mathe, A.; Horvat, J.; Foster, P.; Walker, M.M.; Talley, N.J.; Keely, S. Evidence for Local and Systemic Immune Activation in Functional Dyspepsia and the Irritable Bowel Syndrome: A Systematic Review. Am. J. Gastroenterol. 2019, 114, 429–436. [Google Scholar] [CrossRef] [PubMed]
- Burns, G.L.; Bruce, J.K.; Minahan, K.; Mathe, A.; Fairlie, T.; Cameron, R.; Naudin, C.; Nair, P.M.; Potter, M.D.E.; Irani, M.Z.; et al. Type 2 and type 17 effector cells are increased in the duodenal mucosa but not peripheral blood of patients with functional dyspepsia. Front. Immunol. 2023, 13, 1051632. [Google Scholar] [CrossRef] [PubMed]
- De Giorgio, R.; Bovara, M.; Barbara, G.; Canossa, M.; Sarnelli, G.; De Ponti, F.; Stanghellini, V.; Tonini, M.; Cappello, S.; Pagnotta, E.; et al. Anti-HuD-induced neuronal apoptosis underlying paraneoplastic gut dysmotility. Gastroenterology 2003, 125, 70–79. [Google Scholar] [CrossRef] [PubMed]
- Pittock, S.J.; Lennon, V.A.; Dege, C.L.; Talley, N.J.; Locke, G.R., 3rd. Neural autoantibody evaluation in functional gastrointestinal disorders: A population-based case-control study. Dig. Dis. Sci. 2011, 56, 1452–1459. [Google Scholar] [CrossRef] [PubMed]
- Fan, W.; Fei, G.; Li, X.; Wang, X.; Hu, C.; Xin, H.; Sun, X.; Li, Y.; Wood, J.D.; Fang, X. 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. 2018, 30, e13457. [Google Scholar] [CrossRef] [PubMed]
- Fan, W.; Fang, X.; Hu, C.; Fei, G.; Xiao, Q.; Li, Y.; Li, X.; Wood, J.D.; Zhang, X. Multiple rather than specific autoantibodies were identified in irritable bowel syndrome with HuProt™ proteome microarray. Front. Physiol. 2022, 13, 1010069. [Google Scholar] [CrossRef] [PubMed]
- Bierła, J.B.; Cukrowska, B.; Skrzydło-Radomańska, B.; Prozorow-Król, B.; Kurzeja-Mirosław, A.; Cichoż-Lach, H.; Laskowska, K.; Sowińska, A.; Majsiak, E. The Occurrence of Gluten-Related Antibodies, Sensitization to Selected Food Allergens, and Antibodies against Intrinsic Factor in Adult Patients with Diarrhea-Predominant Irritable Bowel Syndrome. J. Pers. Med. 2023, 13, 1165. [Google Scholar] [CrossRef]
- Volter, F.; Fain, O.; Mathieu, E.; Thomas, M. Esophageal function and Sjögren’s syndrome. Dig. Dis. Sci. 2004, 49, 248–253. [Google Scholar] [CrossRef]
- Vernino, S.; Lindstrom, J.; Hopkins, S.; Wang, Z.; Low, P.A.; Muscle Study Group. Characterization of ganglionic acetylcholine receptor autoantibodies. J. Neuroimmunol. 2008, 197, 63–69. [Google Scholar] [CrossRef] [PubMed]
- Wang, Z.; Low, P.A.; Vernino, S. Antibody-mediated impairment and homeostatic plasticity of autonomic ganglionic synaptic transmission. Exp. Neurol. 2010, 222, 114–119. [Google Scholar] [CrossRef] [PubMed]
- Crisp, S.J.; Kullmann, D.M.; Vincent, A. Autoimmune synaptopathies. Nat. Rev. Neurosci. 2016, 17, 103–117. [Google Scholar] [CrossRef] [PubMed]
- Meeusen, J.W.; Haselkorn, K.E.; Fryer, J.P.; Kryzer, T.J.; Gibbons, S.J.; Xiao, Y.; Lennon, V.A. Gastrointestinal hypomotility with loss of enteric nicotinic acetylcholine receptors: Active immunization model in mice. Neurogastroenterol. Motil. 2013, 25, 84–88. [Google Scholar] [CrossRef] [PubMed]
- Lennon, V.A.; Ermilov, L.G.; Szurszewski, J.H.; Vernino, S. Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease. J. Clin. Invest. 2003, 111, 907–913. [Google Scholar] [CrossRef] [PubMed]
- Vernino, S.; Low, P.A.; Lennon, V.A. Experimental Autoimmune Autonomic Neuropathy. J. Neurophysiol. 2003, 90, 2053–2059. [Google Scholar] [CrossRef] [PubMed]
- Kobayashi, S.; Yokoyama, S.; Maruta, T.; Negami, M.; Muroyama, A.; Mitsumoto, Y.; Iwasa, K.; Yamada, M.; Yoshikawa, H. Autoantibody-induced internalization of nicotinic acetylcholine receptor α3 subunit exogenously expressed in human embryonic kidney cells. J. Neuroimmunol. 2013, 257, 102–106. [Google Scholar] [CrossRef] [PubMed]
- Yamakawa, M.; Nakane, S.; Ihara, E.; Tawara, N.; Ikeda, H.; Igarashi, Y.; Komohara, Y.; Takamatsu, K.; Ikeda, T.; Tomita, Y.; et al. A novel murine model of autoimmune dysautonomia by α3 nicotinic acetylcholine receptor immunization. Front. Neurosci. 2022, 16, 1006923. [Google Scholar] [CrossRef] [PubMed]
- Nakane, S.; Yamakawa, M.; Nakatsuji, Y. Autoantibodies against gAChR in humans and mouse models of autoimmune autonomic ganglionopathy. Clin. Exp. Neuroimmunol. 2024, 15, 16–23. [Google Scholar] [CrossRef]
- Hubball, A.W.; Lang, B.; Souza, M.A.; Curran, O.D.; Martin, J.E.; Knowles, C.H. Voltage-gated potassium channel (K(v) 1) autoantibodies in patients with chagasic gut dysmotility and distribution of K(v) 1 channels in human enteric neuromusculature (autoantibodies in GI dysmotility). Neurogastroenterol. Motil. 2012, 24, 719–728. [Google Scholar] [CrossRef]
- McMillan, H.J.; Srinivasan, J. Achalasia, chronic sensory neuropathy, and N-type calcium channel autoantibodies: Beneficial response to IVIG. Clin. J. Gastroenterol. 2010, 3, 78–82. [Google Scholar] [CrossRef] [PubMed]
- Hirano, I.; Pandolfino, J. Chronic intestinal pseudo-obstruction. Dig. Dis. 2000, 18, 83–92. [Google Scholar] [CrossRef] [PubMed]
- Srinivasan, S.; Wiley, J.W. New insights into neural injury, repair, and adaptation in visceral afferents and the enteric nervous system. Curr. Opin. Gastroenterol. 2000, 16, 78. [Google Scholar] [CrossRef]
- Goin, J.C.; Sterin–Borda, L.; Bilder, C.R.; Varrica, L.M.; Iantorno, G.; Ríos, M.C.; Borda, E. Functional implications of circulating muscarinic cholinergic receptor autoantibodies in chagasic patients with achalasia. Gastroenterology 1999, 117, 798–805. [Google Scholar] [CrossRef] [PubMed]
- Urriola, N.; Spies, J.M.; Blazek, K.; Lang, B.; Adelstein, S. A Flow Cytometric Assay to Detect Functional Ganglionic Acetylcholine Receptor Antibodies by Immunomodulation in Autoimmune Autonomic Ganglionopathy. Front. Immunol. 2021, 12, 705292. [Google Scholar] [CrossRef]
- Karagiorgou, K.; Dandoulaki, M.; Mantegazza, R.; Andreetta, F.; Furlan, R.; Lindstrom, J.; Zisimopoulou, P.; Chroni, E.; Kokotis, P.; Anagnostou, E.; et al. Novel Cell-Based Assay for Alpha-3 Nicotinic Receptor Antibodies Detects Antibodies Exclusively in Autoimmune Autonomic Ganglionopathy. Neurol.—Neuroimmunol. Neuroinflammation 2022, 9, 1162. [Google Scholar] [CrossRef]
Characteristics | FGID with gAChR Abs (n = 4) | FGID without gAChR Abs (n = 7) | p Value |
---|---|---|---|
Age (average, years) | 71.5 | 59.7 | 0.262 |
Sex, female (%) | 3 (75.0) | 5 (71.3) | 0.166 |
Mode of onset, chronic (%) | 4 (100.0) | 6 (85.7) | 0.788 |
Antecedent infection (%) | 0 (0.0) | 1 (14.3) | 0.788 |
Orthostatic hypotension (%) | 0 (0.0) | 2 (28.6) | 0.527 |
Orthostatic intolerance (%) | 1 (25.0) | 4 (57.1) | 0.412 |
Arrhythmia (%) | 0 (0.0) | 1 (14.3) | 0.788 |
Pupillary abnormality (%) | 0 (0.0) | 0 (0.0) | 1.000 |
Sicca (%) | 3 (75.0) | 0 (0.0) | 0.042 |
Coughing episode (%) | 0 (0.0) | 1 (14.3) | 0.788 |
Anhidrosis (%) | 1 (25.0) | 0 (0.0) | 0.788 |
Upper GI dysfunction (%) | 4 (100.0) | 7 (100.0) | 1.000 |
Lower GI dysfunction (%) | 4 (100.0) | 7 (100.0) | 1.000 |
Bladder dysfunction (%) | 2 (50.0) | 6 (85.7) | 0.412 |
Sexual dysfunction (%) | 0 (0.0) | 0 (0.0) | 1.000 |
Characteristics | FGID with gAChR Abs (n = 4) | FGID without gAChR Abs (n = 7) | p Value |
---|---|---|---|
COMPASS total score (average) | 16.5 | 20.8 | 0.455 |
COMPASS orthostatic intolerance score (average) | 3.0 | 8.7 | 0.294 |
COMPASS secretomotor score (%) | 2.6 | 0.4 | 0.114 |
COMPASS gastrointestinal score | 8.6 | 8.6 | 0.975 |
COMPASS bladder score | 1.4 | 3.1 | 0.185 |
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Nakane, S.; Mukaino, A.; Okumura, Y.; Hirosawa, H.; Higuchi, O.; Matsuo, H.; Kainuma, M.; Nakatsuji, Y. The Presence of Ganglionic Acetylcholine Receptor Antibodies in Sera from Patients with Functional Gastrointestinal Disorders: A Preliminary Study. J. Pers. Med. 2024, 14, 485. https://doi.org/10.3390/jpm14050485
Nakane S, Mukaino A, Okumura Y, Hirosawa H, Higuchi O, Matsuo H, Kainuma M, Nakatsuji Y. The Presence of Ganglionic Acetylcholine Receptor Antibodies in Sera from Patients with Functional Gastrointestinal Disorders: A Preliminary Study. Journal of Personalized Medicine. 2024; 14(5):485. https://doi.org/10.3390/jpm14050485
Chicago/Turabian StyleNakane, Shunya, Akihiro Mukaino, Yoshiaki Okumura, Hiroaki Hirosawa, Osamu Higuchi, Hidenori Matsuo, Mosaburo Kainuma, and Yuji Nakatsuji. 2024. "The Presence of Ganglionic Acetylcholine Receptor Antibodies in Sera from Patients with Functional Gastrointestinal Disorders: A Preliminary Study" Journal of Personalized Medicine 14, no. 5: 485. https://doi.org/10.3390/jpm14050485