Detecting gastrointestinal manifestations in patients with systemic sclerosis using anti-gAChR antibodies

Abstract

Background: Patients with systemic sclerosis (SSc) complicated by gastrointestinal dysmotility are difficult to treat and have high mortality. To clarify the pathogenesis of gastrointestinal manifestations, we aimed to demonstrate the association among the clinical features of SSc, the serological markers, the autoantibodies against nicotinic acetylcholine receptor at autonomic ganglia (gAChR). Methods: Fifty patients were enrolled and divided into two groups according to the presence or absence of gastrointestinal manifestations, and the characteristics were analyzed between these two groups. We measured biomarkers and the autoantibodies against two gAChRα3 and β4 subunits to test sera samples. Furthermore, patients were classified based on the presence or absence of anti-gAChR autoantibodies, and their clinical features were compared. Results: In patients with SSc and gastrointestinal manifestations, digital ulcers were more frequent (p = 0.050) and VEGF expression was significantly higher (p = 0.038). Seven subjects with SSc were seropositive for α3 subunit, whereas one patient was seropositive for β4 subunit. The mean level of anti-gAChRα3 autoantibodies in SSc patients with gastrointestinal manifestations was significantly higher than that in SSc patients without gastrointestinal manifestations (p = 0.001). The group of patients with SSc and gAChR autoantibodies had significantly higher endostatin levels (p = 0.046).Conclusions: This study is the first to demonstrate that clinical characteristics of SSc patients with seropositivity for gAChR autoantibodies. Patients with SSc have circulating autoantibodies against gAChR, which may contribute to gastrointestinal manifestations associated with this disease, suggesting that gAChR-mediated autonomic neurotransmission may provide a pathomechanism for gastrointestinal dysmotility in SSc.

Autoimmune gastrointestinal dysmotility: the interface between clinical immunology and neurogastroenterology

“…GI disorders have been reported in a wide variety of systemic autoimmune diseases. Recently, we attempted to understand the pathogenesis of GI manifestations in SSc, as it is well known that SSc frequently affects the GI functions [43]. The patients with SSc often suffer from esophageal absent contractility, severe gastroesophageal reflux disease, IPO and malabsorption with the complaints of dysphasia, heartburn, vomiting, abdominal fullness, constipation and diarrhea.…”

“…Previous studies have demonstrated that GI dysmotility in SSc was associated with circulating AAbs against the muscarinic AChRs, RNPC3, U1 snRNP, U3 snRNP, signal recognition particle, Ku, and myenteric neurons [40,[44][45][46][47][48][49][50][51][52]. We have reported the clinical characteristics of SSc patients with seropositivity for the anti-gAChR AAbs, and have analyzed the relationship among gAChR Abs, several biomarkers, and GI manifestations in SSc [43]. In AGID, including ARD-related GI dysmotility, the connection between the presence of these AAbs and the specific interference in synaptic transmission in the plexus ganglia of the ENS should be determined.…”

Dysphagia, reflux and related sequelae due to altered physiology in scleroderma

“…Vascular damage to the vasa nervorum is important in the development of this dysfunction[ 9 ]. Autoantibodies against nicotinic acetylcholine receptor at autonomic ganglia (gAChR) may also play a role in GI autonomic dysfunction, as anti-gAChRα3 autoantibodies were significantly higher in patients with SSc GI disease than in SSc patients without GI manifestations[ 10 ]. Anti-muscarinic-3 receptor autoantibodies may also contribute by inhibiting contraction of smooth muscle cells[ 11 ].…”

The role of the cholinergic anti‐inflammatory pathway in autoimmune rheumatic diseases

“…104 α7nAChR can express in several cells of the skin, 105,106 and among these cutaneous cells, the dermal fibroblast is the most important as it meditates the production of collagen and TGF-β and contraction of the surrounding extracellular matrix; α7nAChR agonists can repress TGF-β-mediated responses in dermal fibroblasts, 105 perhaps this is another way in which nicotine can improve the symptoms of SSc. Apart from α7nAChR, anti-ganglionic (nicotinic) acetylcholine receptor (gAChR) antibodies, particularly anti-gAChRα3 and β4 antibodies, were also detected in the sera of SSc patients, 107 and the average level of anti-gAChRα3 Abs in the SSc patients with GI manifestations was much higher than that in the SSc without GI symptoms, 108 so the presence of gAChR antibodies may be the sole cause of SSc intestinal symptom and immune imbalance.…”