Search Results (4)

Background/Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition with not fully understood causes, though evidence points to immune system involvement and possible autoimmunity. ME/CFS could be triggered by various infectious pathogens, like SARS-CoV-2; furthermore, a subset of the post-COVID-19 condition (PCC) patients fulfill the diagnostic criteria of ME/CFS. According to the Canadian Consensus Criteria (CCC), the presence of specific symptoms such as fatigue, post-exertional malaise, sleep dysfunction, pain, neurological/cognitive manifestations, and symptoms from at least two of the following categories lead to the diagnosis of ME/CFS: autonomic, neuroendocrine, and immune manifestation. In this study, the patient selection was based on the identification of ME/CFS patients with elevated autoantibodies, regardless of the triggering factor of their condition. Methods: The aim of this study was to identify ME/CFS patients among long COVID patients with elevated autoantibodies. In seven cases, plasmapheresis (PE) and intravenous immunoglobulins (IVIGs) with repetitive autoantibody measurements were applied: four PE sessions on days 1, 5, 30, and 60, and a low-dose IVIG therapy after each treatment. Antibodies were measured before the first PE and two weeks after the last PE session. To monitor clinical outcomes, the following somatic and psychometric follow-up assessments were conducted before the first PE, 2 weeks after the second, and 2 weeks after the last PE: the Schellong test, ISI (insomnia), FSS (fatigue), HADS (depression and anxiety), and EQ-5D-5L (quality of life) questionnaires. Results: There was a negative association between both the β2-adrenergic and M3-muscarinic receptor autoantibody concentration and the quality of life measurements assessed with the EQ-5D-5L questionnaire. Per 1 U/mL increase in the concentration levels of β2-adrenergic receptor antibodies or M3-muscarinic acetylcholine receptor antibodies, the EQ-5D-5L index score [−0.59 to 1] decreased by 0.01 (0.63%) or 0.02 (1.26%), respectively. There were no significant associations between the ISI, HADS, and FSS questionnaires and the β1-adrenergic and M4-muscarinic receptor antibodies titers. Conclusions: After a thorough selection of patients with present autoantibodies, this pilot study found negative associations concerning autoantibody concentration and somatic, as well as psychological wellbeing. To validate these promising feasibility study results—indicating the potential therapeutic potential of antibody-lowering methods—further investigation with larger sample sizes is needed. Full article

Systemic sclerosis (SSc) is a multifaceted connective tissue disease whose aetiology remains largely unknown. Autoimmunity is thought to play a pivotal role in the development of the disease, but the direct pathogenic role of SSc-specific autoantibodies remains to be established. The recent discovery of functional antibodies targeting G-protein-coupled receptors (GPCRs), whose presence has been demonstrated in different autoimmune conditions, has shed some light on SSc pathogenesis. These antibodies bind to GPCRs expressed on immune and non-immune cells as their endogenous ligands, exerting either a stimulatory or inhibitory effect on corresponding intracellular pathways. Growing evidence suggests that, in SSc, the presence of anti-GPCRs antibodies correlates with specific clinical manifestations. Autoantibodies targeting endothelin receptor type A (ETAR) and angiotensin type 1 receptor (AT1R) are associated with severe vasculopathic SSc-related manifestations, while anti-C-X-C motif chemokine receptors (CXCR) antibodies seem to be predictive of interstitial lung involvement; anti-muscarinic-3 acetylcholine receptor (M3R) antibodies have been found in patients with severe gastrointestinal involvement and anti-protease-activated receptor 1 (PAR1) antibodies have been detected in patients experiencing scleroderma renal crisis. This review aims to clarify the potential pathogenetic significance of GPCR-targeting autoantibodies in SSc, focusing on their associations with the different clinical manifestations of scleroderma. An extensive examination of functional autoimmunity targeting GPCRs might provide valuable insights into the underlying pathogenetic mechanisms of SSc, thus enabling the development of novel therapeutic strategies tailored to target GPCR-mediated pathways. Full article

Background: Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) constitute rare chronic inflammatory biliary diseases which likely comprise genetic, environmental and autoimmune factors. Specific inhibitory (auto-) antibodies against the muscarinic acetylcholine receptor type 3 (mAChR3 auto-ab) may contribute to the pathogenesis of chronic biliary inflammation by modulating mAChR3− mediated signaling. Aims: The aim of this study was to analyze the prevalence and relevance of inhibitory mAChR3 auto-ab (mAChR3inh+ auto-ab) in a large cohort of PBC patients from two independent tertiary centers in Berlin and Leipzig in comparison to a large PSC cohort. Baseline parameters and response rates to standard treatment with ursodeoxycholic acid (UDCA) were characterized with respect to the individual mAChR3 auto-ab status. Methods: In total, the study population comprised 437 PBC patients, 187 PSC patients and 80 healthy controls. Clinical and laboratory baseline characteristics were retrieved from medical records. The response to ursodeoxycholic acid (UDCA) therapy after 12 months of treatment was available in 176 PBC and 45 PSC patients. Results: The prevalence of mAChR3inh+ auto-ab was significantly higher among PBC patients (11.2%, 49/437; p = 0.008 vs. healthy controls) and PSC patients (33.6%, 63/187; p < 0.0001 vs. healthy controls) compared to healthy controls (2.5%, 2/80), respectively. PBC patients with mAChR3inh+ auto-ab exhibited significantly higher levels of alkaline phosphatase (ALP) and bilirubin, which constitute established parameters for PBC risk stratification. Moreover, mAChR3inh+ PBC patients tended to show decreased response rates to UDCA therapy compared to PBC patients without mAChR3inh+ auto-ab (mAChR3− PBC). In contrast, PSC patients with mAChR3inh+ auto-ab showed no significant differences in laboratory findings compared to mAChR3 auto-ab negative (mAChR3−) PSC patients. Conclusion: MAChR3inh+ auto-ab might be involved in the pathogenesis and treatment response of chronic biliary inflammation in patients with PBC but not in patients with PSC. Full article

Arecoline is the primary alkaloid in betel nuts, which are known as a risk factor for oral submucosal fibrosis and oral cancer. Lung cancer is a severe type of carcinoma with high cell motility that is difficult to treat. However, the detailed mechanisms of the correlation between Arecoline and lung cancer are not fully understood. Here, we investigated the effect of Arecoline on migration in lung cancer cell lines and its potential mechanism through the muscarinic acetylcholine receptor 3 (mAChR3)-triggered EGFR/Src/FAK pathway. Our results indicate that different concentrations of Arecoline treatment (10 µM, 20 µM, and 40 µM) significantly increased the cell migration ability in A549 and CL1-0 cells and promoted the formation of the filamentous actin (F-actin) cytoskeleton, which is a crucial element for cell migration. However, migration of H460, CL1-5, and H520 cell lines, which have a higher migration ability, was not affected by Arecoline treatment. The EGFR/c-Src/Fak pathway, which is responsible for cell migration, was activated by Arecoline treatment, and a decreased expression level of E-cadherin, which is an epithelial marker, was observed in Arecoline-treated cell lines. Blockade of the EGFR/c-Src/Fak pathway with the inhibitors of EGFR (Gefitinib) or c-Src (Dasatinib) significantly prevented Arecoline-promoted migration in A549 cells. Gefitinib or Dasatinib treatment significantly disrupted the Arecoline-induced localization of phospho-Y576-Fak during focal adhesion in A549 cells. Interestingly, Arecoline-promoted migration in A549 cells was blocked by a specific mAChR3 inhibitor (4-DAMP) or a neutralizing antibody of matrix metalloproteinase (MMP7 or Matrilysin). Taken together, our findings suggest that mAChR3 might play an essential role in Arecoline-promoted EGFR/c-Src/Fak activation and migration in an A549 lung cancer cell line. Full article