Achalasia—An Autoimmune Inflammatory Disease: A Cross-Sectional Study

Abstract

Idiopathic achalasia is a disease of unknown etiology. The loss of myenteric plexus associated with inflammatory infiltrates and autoantibodies support the hypothesis of an autoimmune mechanism. Thirty-two patients diagnosed by high-resolution manometry with achalasia were included. Twenty-six specimens from lower esophageal sphincter muscle were compared with 5 esophagectomy biopsies (control). Immunohistochemical (biopsies) and flow cytometry (peripheral blood) analyses were performed. Circulating anti-myenteric autoantibodies were evaluated by indirect immunofluorescence. Herpes simplex virus-1 (HSV-1) infection was determined by in situ hybridization, RT-PCR, and immunohistochemistry. Histopathological analysis showed capillaritis (51%), plexitis (23%), nerve hypertrophy (16%), venulitis (7%), and fibrosis (3%). Achalasia tissue exhibited an increase in the expression of proteins involved in extracellular matrix turnover, apoptosis, proinflammatory and profibrogenic cytokines, and Tregs and Bregs versus controls (P < 0.001). Circulating Th22/Th17/Th2/Th1 percentage showed a significant increase versus healthy donors (P < 0.01). Type III achalasia patients exhibited the highest inflammatory response versus types I and II. Prevalence of both anti-myenteric antibodies and HSV-1 infection in achalasia patients was 100% versus 0% in controls. Our results suggest that achalasia is a disease with an important local and systemic inflammatory autoimmune component, associated with the presence of specific anti-myenteric autoantibodies, as well as HSV-1 infection.

Mucosally Expressed Cytokines are Associated with the Esophageal Motility Function

“…Helper T (Th) cells play an important role in the immune response and Th cells are generally divided into 3 major subsets: Th1, Th2, and Th17 [4-6]. More recently, the Th2 and Th17 cell subsets were reported to be associated with achalasia [7]. …”

Mast cell infiltration associated with loss of interstitial cells of Cajal and neuronal degeneration in achalasia

“…Recent evidence suggests that inhibitory neuronal degeneration in Auerbach's nerve plexus is the primary morphologic feature . Genetic susceptibility, viral infection, and autoimmunity have also been reported to be associated with development of the disease . Among these, autoimmune‐mediated inflammation has been considered to play an important role in neuronal degeneration.…”

“…Another study found oligoclonal lymphocytic infiltration in the myenteric plexus of patients with achalasia, which reacted to HSV‐1 antigens . Reported potential etiologic viral candidates include varicella zoster, measles, bornavirus, and HPV . Therefore, it has been hypothesized that neuronal degeneration in achalasia results from an aberrant autoimmune‐mediated inflammatory reaction, which may be triggered by viral infection in patients with potential hereditary susceptibility in the immunogenetic system …”

“…Control specimens were obtained from 20 age‐matched patients at the same site of the esophagus who underwent surgery for esophageal or stomach neoplasms (without invasion of the cardia). This strategy for obtaining control specimens has been widely used in previous studies . To obtain control tissues that were as normal as possible, the tissues were taken from the uninvolved high‐pressure zone of the LES, and we only included patients who received no chemotherapy or radiotherapy before surgery.…”

“…This strategy for obtaining control specimens has been widely used in previous studies. [17][18][19] To obtain control tissues that were as normal as possible, the tissues were taken from the uninvolved high-pressure zone of the LES, and we only included patients who received no chemotherapy or radiotherapy before surgery.…”