The different therapeutic approaches available today, including pharmacotherapy, botulinum toxin injections, endoscopical dilatations, esophageal stents, peroral endoscopy myotomy and surgical treatment for achalasia (Figure ?(Figure6),6), all aim to treat the symptoms but are not capable of use as preventives or address the underlying pathology of the disease[8,74,75]. Table 1 Current treatment options in achalasia 9%). as suggested by observed correlations with other well-defined genetic syndromes such as Allgrove syndrome and multiple endocrine neoplasia type 2 B syndrome. Viral agents (herpes, varicella zoster) have also been proposed as causative and promoting factors. Unfortunately, the therapeutic approaches available today do not resolve the causes of the disease, and only target the consequential changes to the involved tissues, such as destruction of the LES, rather than restoring or modifying the underlying pathology. New therapies should aim to stop the disease at early stages, thereby preventing the consequential changes from developing and inhibiting permanent damage. This review focuses on the known characteristics of idiopathic achalasia that will help promote understanding its pathogenesis and improve therapeutic management to positively impact the patients quality Cyclamic Acid of life. enhancement of Treg function. This CD19+CD24hiCD38hi immature/transitional T1 B cell subset suppresses the differentiation of Th1 cells in an IL-10-dependent manner. Intriguingly, biopsies of myenteric plexus obtained from patients with achalasia showed a higher relative IL-10-producing B cell percentage than tissues from a control group (Figure ?(Figure44). Lastly, it is known that dendritic plasmacytoid regulatory cells (termed pDCregs) are a sub-population of immune cells Cyclamic Acid that express the indoleamine 2,3-dioxygenase (IDO) enzyme that is responsible for mediating tryptophan metabolism, which suppresses T effector cell activity and induces CD4+/CD25hi regulatory T cell polarization. IDO-mediated deprivation of tryptophan halts the proliferation of T cells at mid-G1 phase, which in concert with the pro-apoptotic activity of kynurenine leads to immune tolerance. IDO has a selective role in Th2 differentiation and is regulated positively during antigenic presentation and the functional complexing of CTLA-4/B7-1/B7-2 in lymphocytes and dendritic cells. In addition IDO contributes to the immune responses to pathogens, being up-regulated by circulating nucleic acids (from host and non-host genomes) through the activation of TLR4 and TLR9, and it contributes to adaptive immunity processes that subsequently modulate the inflammatory process. Patients with achalasia have shown a higher frequency of pDCregs in the myenteric plexus of esophageal tissue, as compared to control tissues (Figure ?(Figure44). Autoantibodies The observation of increased prevalence of circulating IgG antibodies against myenteric plexus in most patients with achalasia has led to the suggestion of a role for autoantibodies in the pathogenesis of this disease. Studies have also demonstrated a notable absence of anti-myenteric autoantibody in achalasia-free controls, patients with Hirschsprungs disease, esophageal cancer, peptic esophagitis, gastroesophageal reflux or myasthenia gravis[53-55]. Nonetheless, a study by Moses et al suggested that these circulatory antibodies are more likely the result of a nonspecific reaction to the disease process, rather than being the cause of the disease; this idea was supported by detection of similar antibodies in patients without achalasia. In accordance with the hypotheses, evidence of autoantibodies against myenteric neurons were detected in serum samples from patients with achalasia, especially in carriers of HLA DQA1*0103 and DQB1*0603 alleles. Recently, Kallel-Sellami et al, as well as our group, determined the levels of circulating anti-myenteric antibodies in serum from patients with achalasia; the measurements in both studies were carried out with the commercially available kit Neurology Mosaic 1 (Euroimmun, Leubeck, Germany) that involves a standard indirect immunofluorescence screening assay using frozen monkey nerves, cerebellum and intestinal tissue as antigenic substrates. The prevalence of nuclear Cyclamic Acid or cytoplasmic circulating antibodies against myenteric plexus in the sera from idiopathic achalasia patients was 63% and 100% 12% and 0% in the sera from healthy donors, respectively; moreover, most antibodies showed positive reaction in the nuclear and nucleolar compartments of cells in the myenteric plexus[6,30]. These two studies also analyzed the target antigens of circulating anti-myenteric autoantibodies by testing sera with the Neuronal Antigens Profile Plus RST kit (Euroimmun) that involves immunoblotting for a panel of individual neuronal antigens, including amphiphysin, CV2, PNMA2 (Ma-2/Ta), onconeuronal antigens (Ri, Yo, Hu), recoverin, SOX-1 and titin. A majority (69%) of the sera samples from the idiopathic achalasia patients CD36 reacted with PNMA2 (Ma2/Ta), and a few (8%) reacted with the recoverin antigen that is related to Sj?grens syndrome[6,30]. Other autoantibodies have been detected in serum from non-diabetic patients with achalasia, including glutamic acid descarboxylase-65 (GAD65) antibody, which showed a remarkably higher frequency compared to the control subjects (21% 2.5%). The enzyme GAD65 converts glutamic acid to gamma-aminobutyric acid, and is expressed in GABAergic nerve terminals in Cyclamic Acid the enteric nervous system. GAD65 antibodies are reportedly present in approximately 80% of patients with type I.