Esophageal achalasia (EA) is a primary motility disorder characterized by insufficient lower esophageal sphincter relaxation and loss of esophageal peristalsis.¹ Specifically, it is a neuromuscular disorder characterized by degenerative changes of the myenteric plexus that result in selective nerve ending loss.² However, these findings are close to a phenomenological snapshot of the pathophysiology, and the precise underlying mechanisms of EA have remained unknown. Therefore, most treatments are still palliative. A study published in this issue, Yao et al,³ however, has shed new light on the role of the immune system in this disorder, offering valuable insights that may pave the way for more effective treatments. In this study, researchers investigated the immunological aspects of EA, such as the phenotype of peripheral leukocytes, gene expression profiles, and the immune cell infiltration in the lower esophageal sphincter in a cohort of 76 EA patients and 50 age-matched healthy controls. The findings of this study revealed a complex interplay of immune components in EA. In peripheral blood, significant alterations were observed in EA patients compared to healthy controls. Neutrophils, the primary responders in innate immunity, were found to be more abundant in EA patients.⁴ This discovery highlights their potential role in driving inflammation and tissue damage in the esophagus, aligning with observations in other autoimmune and neurodegenerative diseases. Conversely, T cells, essential components of adaptive immunity, exhibited a complex pattern in EA. While the percentage of CD8+ cytotoxic T cells was higher in EA patients, the percentage of total T cells was decreased. This shift may reflect a compensatory mechanism due to the elevated neutrophil count. Furthermore, regulatory T cells showed a marked increase in EA patients, suggesting an attempt to modulate the immune response in the esophagus. Eosinophilic infiltration is a known characteristic of EA, with eosinophils accumulating in the lower esophageal sphincter. Surprisingly, this study revealed a reduction in peripheral eosinophil counts in EA patients, particularly in those with severe symptoms. This discrepancy between local and systemic eosinophil levels suggests a complex relationship between tissue-specific immune responses and peripheral immune regulation. To gain further insights into the molecular mechanisms underlying EA, the researchers conducted RNA sequencing of peripheral blood mononuclear cells. This analysis identified 170 differentially expressed genes (DEGs) associated with EA. These DEGs were linked to various immune-related processes, including humoral immune responses, lymphocyte-mediated immunity, and complement activation. Functional enrichment analysis revealed that these DEGs were involved in critical biological processes such as leukocyte migration, synapse pruning, and cell chemotaxis. Moreover, the Kyoto Encyclopedia of Genes and Genomespathway analysis pointed to the involvement of pathways related to complement cascades, cytokine-cytokine receptor interactions, and autoimmune diseases.

A network-based analysis identified several hub genes, including IL-6, toll-like receptor 2, IL-1β, TNF, complement C3, complement C1q B chain, and complement C1q A chain. These hub genes were associated with inflammatory processes and immune regulation. IL-6 and IL-1β, in particular, were upregulated in EA patients, suggesting their potential as key players in the pathogenesis of the disorder.

This comprehensive study illuminates the intricate immune dysregulation observed in EA. Neutrophils, T cells, eosinophils, and various cytokines all play pivotal roles in shaping the disease’s immunological landscape. These findings open new avenues for research into the molecular and cellular mechanisms driving EA. Understanding the immune components involved in EA pathogenesis offers hope for the development of targeted therapies. Modulating specific immune responses, such as neutrophil activity and T cell regulation, may hold promise for managing this challenging condition. Additionally, investigating the potential of hub genes, particularly IL-6 and IL-1β, as therapeutic targets could lead to innovative treatment strategies. Therefore, EA may eventually yield to the advances of immunology, bringing relief to countless individuals who suffer from this condition.

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