The etiology of achalasia: An immune‐dominant disease

Abstract

There is accumulating evidence suggesting that an autoimmune component is involved in esophageal achalasia. An increase in immune cells, cytokines, chemokines, and autoimmune antibodies in serum and infiltration of immune cells in tissues support the view that immune-mediated inflammation is a crucial pathogenesis of inhibitory neuron degeneration in the lower esophageal sphincter. Infection of viruses such as the herpes virus family has been suspected of provoking the autoimmune reaction. Meanwhile, previous reports on immunogenetics have proposed that specific risk alleles on the human leukocyte antigen complex define the susceptible population to achalasia. In this study we reviewed current knowledge regarding the immune-related factors of achalasia, including immunology, viral infection and immunogenetic variations. K E Y W O R D S autoimmune diseases, esophageal achalasia, histocompatibility antigens class II, immunology, viruses 1 | INTRODUCTION Esophageal achalasia is a motility disorder that presents with symptoms including dysphagia, regurgitation, chest pain, and weight loss. It is clinically subclassified into three types based on different manifestations in high-resolution manometry: type I achalasia is the classical achalasia with no pressurization; in type II achalasia there is compression of over 30 mmHg in the distal esophagus; while type III achalasia can be diagnosed when two or more spastic contractions are observed. 1 The pathophysiology of this disease is a loss of peristalsis and inadequate relaxation of the lower esophageal sphincter (LES), which results from gradual disappearance of the myenteric neurons. Previous histological studies have found the loss of inhibitory enteric neurons in the esophageal tissues of patients with achalasia. 2 In the nervous system, these types of neurons contain nitric oxide and vasoactive intestinal polypeptide, which are responsible for this process. 7 Achalasia was recognized as a degenerative disease of the myenteric plexus. 8 About three decades ago studies on achalasia revealed inflammatory cell infiltration in the myenteric ganglia. 9 Later reports have demonstrated that the pathogenesis of achalasia is associated with immunology, viral infection, and host genetics. It turns out that immunology is potentially the crucial factor, and viral infection may trigger the disordered immune reaction in specific patients with an immunogenetic variation. In this review, we focused on all the *These three authors contributed equally to this work.

Autoimmune and viral risk factors are associated with achalasia: A case‐control study

“…Given that neural degeneration in the esophageal myenteric plexus, 12 some have postulated that an upstream viral insult coupled with an aberrant immune system response may be responsible for causing this damage 13,14 . This connection implicates infectious and autoimmune diseases as potential drivers of achalasia pathogenesis 15‐17 . Existing studies examining the association between these diseases with achalasia have demonstrated a positive relationship, though they are limited by small sample sizes and control selection that is not directly sampled from the underlying source population that gave rise to the cases 18,19 .…”

“…13,14 This connection implicates infectious and autoimmune diseases as potential drivers of achalasia pathogenesis. [15][16][17] Existing studies examining the association between these diseases with achalasia have demonstrated a positive relationship, though they are limited by small sample sizes and control selection that is not directly sampled from the underlying source population that gave rise to the cases. 18,19 Such designs have high risk of bias.…”

RNA-sequencing reveals molecular and regional differences in the esophageal mucosa of achalasia patients

“…Interestingly, a possible association between achalasia, the destruction of myenteric neurons and viral infection has been proposed, indicating a possible association between achalasia and viral infection. Potential viruses associated with achalasia include herpes simplex virus (HSV)-1, varicella-zoster virus (VZV), measles, mumps, and human immunodeficiency virus (HIV) 32 . Among the up-regulated genes associated to viral response was IFNε , a unique member of the type I interferon family which plays crucial role in innate and adaptive responses to viral infection 33 .…”

Diagnosis and Management of Achalasia: Updates of the Last Two Years

“…Additionally, other studies have addressed the emerging role of proinflammatory cytokines (interleukin (IL)-22, IL-17, interferon-gamma, IL-6, and tumor necrosis factor alpha) that were overexpressed in achalasia patients compared with controls [23,25]. However, still more studies are needed to explore the dominant immune cells and cytokines that trigger the development of achalasia and to determine the underlying trigger for the activation of those immune cells and pathways [26]. Still, an underlying viral infection is an acknowledged and reported factor behind achalasia development [27,28].…”