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

Figure 8

Proposed model of achalasia pathophysiology. (1) Active or latent infectious insult in achalasia is strongly suggested by several studies. Some neurotropic viruses such as the herpes family of viruses have predilection for squamous epithelium and may cause ganglion cell damage that is limited to the esophagus. (2) Some individuals with genetic predisposition will develop an aggressive inflammatory response. (3) At very early stage of the disease, it is possible that inflammatory infiltrates may be predominantly composed of Th1, Th2, and regulatory cell subsets (Tregs, Bregs, and plasmacytoid dendritic cells (pDCs)). (4) Repair of tissue after injury requires orchestrated coordination of several cell types and biosynthetic processes and is coordinated by an interacting group of pro- and anti-inflammatory cytokines, fibrous extracellular matrix (ECM) proteins to replace lost or damaged tissue, and products of metabolism such as oxygen radicals. The most prominent profibrogenic cytokines are TGFβ, IL-4, and IL-13. ECM also mediates cellular crosstalk and does so in two ways. Newly deposited ECM is then rebuilding over time to emulate normal tissue. Matrix proteinases and their inhibitors (TIMPs) also are important, both during wound repair, tissue remodeling, and fibrosis. (2′, 5) If steps 1–4 happen repeatedly, chronic infection, only those individuals with genetic predisposition to develop a long-lasting autoinflammatory response will progress to develop the disease (loss of peripheral tolerance). Thus, autoinflammatory infiltrates are predominantly composed of Th22, Th17, and regulatory subpopulations. (6) Degeneration and significant loss of nerve fibers, associated with autoinflammatory infiltrates of the myenteric plexus, provide evidence of an immune mediated destruction of the inhibitory neurons, not only by necrosis but also by apoptosis (Fas/FasL overexpression). (7) Autoimmune etiology of achalasia is further supported by the presence of anti-myenteric autoantibodies in sera. (8) Pathophysiologically, achalasia is cause by autoinflammation, degeneration of nerves in the esophagus, plexitis, abnormalities in microvasculature, ganglionitis, and finally by the loss of inhibitory ganglion in the myenteric plexus.