The clinical importance of autoantibodies against the ganglionic acetylcholine receptor (gAChR) remains to be fully elucidated. We aimed to identify the clinical characteristics of autoimmune autonomic ganglionopathy (AAG) in patients with gAChR autoantibodies. For this cohort investigation, serum samples were obtained from patients with AAG between 2012 and 2018 in Japan. We measured the levels of autoantibodies against gAChRα3 and gAChRβ4 and evaluated clinical features, as well as assessing the laboratory investigation results among the included patients. A total of 179 patients tested positive for antibodies, including 116 gAChRα3-positive, 13 gAChRβ4-positive, and 50 double antibody-positive patients. Seropositive AAG patients exhibited widespread autonomic dysfunction. Extra-autonomic manifestations including sensory disturbance, central nervous system involvement, endocrine disorders, autoimmune diseases, and tumours were present in 118 patients (83%). We observed significant differences in the frequencies of several autonomic and extra-autonomic symptoms among the three groups. Our 123I-metaiodobenzylguanidine myocardial scintigraphy analysis of the entire cohort revealed that the heart-to-mediastinum ratio had decreased by 80%. The present study is the first to demonstrate that patients with AAG who are seropositive for anti-gAChRβ4 autoantibodies exhibit unique autonomic and extra-autonomic signs. Decreased cardiac uptake occurred in most cases, indicating that 123I- metaiodobenzylguanidine myocardial scintigraphy may be useful for monitoring AAG. Therefore, our findings indicate that gAChRα3 and gAChRβ4 autoantibodies cause functional changes in postganglionic fibres in the autonomic nervous system and extra-autonomic manifestations in seropositive patients with AAG.

BACKGROUND: The existence of several autoantibodies suggests an autoimmune basis for gastrointestinal (GI) dysmotility. Whether GI motility disorders are features of autoimmune autonomic ganglionopathy (AAG) or are related to circulating anti-ganglionic acetylcholine receptor (gAChR) antibodies (Abs) is not known. The aim of this study was to determine the associations between autonomic dysfunction, anti-gAChR Abs, and clinical features in patients with GI motility disorders including achalasia and chronic intestinal pseudo-obstruction (CIPO).
METHODS: First study: retrospective cohort study and laboratory investigation. Samples from 123 patients with seropositive AAG were obtained between 2012 and 2017. Second study: prospective study. Samples from 28 patients with achalasia and 14 patients with CIPO were obtained between 2014 and 2016, and 2013 and 2017, respectively. In the first study, we analyzed clinical profiles of seropositive AAG patients. In the second study, we compared clinical profiles, autonomic symptoms, and results of antibody screening between seropositive, seronegative achalasia, and CIPO groups.
RESULTS: In the first study, we identified 10 patients (8.1%) who presented with achalasia, or gastroparesis, or paralytic ileus. In the second study, we detected anti-gAChR Abs in 21.4% of the achalasia patients, and in 50.0% of the CIPO patients. Although patients with achalasia and CIPO demonstrated widespread autonomic dysfunction, bladder dysfunction was observed in the seropositive patients with CIPO as a prominent clinical characteristic of dysautonomia.
CONCLUSIONS: These results demonstrate a significant prevalence of anti-gAChR antibodies in patients with achalasia and CIPO. Anti-gAChR Abs might mediate autonomic dysfunction, contributing to autoimmune mechanisms underlying these GI motility disorders.

  The nervous system and the immune system are two major systems in human body. Although it was revealed these two systems correlated, the control of immune cell dynamics by the nervous system has come to draw a lot of attention at the present time. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in several animal models. One well-characterized cytokine-inhibiting mechanism, termed the \"inflammatory reflex\", is dependent upon vagus nerve stimulation that inhibits cytokine production and attenuates the inflammation. And the mechanism for controlling lymphocyte trafficking becomes clear, and molecular basis of immune regulation by the nervous system was reported. On the other hand, the nervous system is protected from the invasion of harmful agents by the barrier. However, there are neuroimmunological disorders, which is associated with autoimmunity, tumor immunity, and infection immunity. Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to widespread autonomic manifestations, in which autoantibodies to ganglionic nicotinic acetylcholine receptors play a central role. Previously, we elucidated the prevalence of extra-autonomic manifestations in patients with AAG. It is necessary to establish the new systems for the detection of autoantibodies to other subunits of acetylcholine receptor.