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WORLD GASTROENTEROLOGY NEWS JULY 2019
Editorial | Expert Point of View | WCOG 2019 | WDHD News | WGO & WGOF News | WGO Global Guidelines | Calendar of Events
Achalasia: New Insights in Pathophysiology
Janette Furuzawa-Carballeda, MSc, PhD
Department of Immunology and Rheumatology
Instituto Nacional de Ciencias Médicas y Nutrición “Salvador
Zubirán”.
Gonzalo Torres-Villalobos, MD, PhD
Department of Surgery and Experimental Surgery
Instituto Nacional de Ciencias Médicas y Nutrición “Salvador
Zubirán”.
Miguel A. Valdovinos, MD
Department of Gastroenterology
Instituto Nacional de Ciencias Médicas y Nutrición “Salvador
Zubirán”.
Achalasia is an uncommon major
esophageal motility disorder characterized
by loss of esophageal peristalsis
and incomplete relaxation of the
lower esophageal sphincter (LES). The
primary cause of achalasia is thought
to be a loss of neurons in the myenteric
plexus of the distal esophagus
and LES. New findings in molecular
pathology in patients with achalasia
have suggested the hypothesis that
achalasia is an autoimmune disorder.
In this review we will focus on the
evaluation of the several aspects that
suggests that achalasia is an autoimmune
inflammatory disease, including:
1. Evidence that the pathology is
preceded by a viral infection;
2. Chronic inflammatory infiltrates,
predominantly enriched in lymphocytes
that damage the ganglion
cells of the myenteric plexus of the
LES;
3. The presence of organ-specific
autoantibodies;
4. The association of achalasia with
well-established autoimmune
diseases;
5. Genetic factors and polymorphisms
that might play a role in
the development and progression
of achalasia; and
6. The improvement of achalasia
symptoms with immunosuppressive
agents.
Infections
It has been hypothesized that the
infectious agent represents the trigger
of an immune reaction in the
myenteric plexus. This immune
response eventually overcomes the
infectious insult, but only in genetically
predispose individuals may create
susceptibility to this disease and the
damage of ganglion cells. Several
studies have suggested that a chronic
latent or active neurotrophic viral
or bacterial infections are associated
with achalasia. The proposed virus
candidates have included HSV-1, JC
virus, bornavirus, VZV, measles, and
HPV.1 An epidemiological study and
genotype-phenotype analysis demonstrated
that patients with achalasia
were frequently affected by viral
infections, especially by VZV, before
achalasia onset, and that pregnancy
may stimulate the disease in females
who are carriers of the HLA-DQβ1
insertion.2 Achalasia patients have a
significantly higher rate of oligoclonal
CD3+/CD8+ lymphocytic infiltrates
in LES than healthy controls, and a
deprived release of Th1-type cytokines
(IFN-Γ and IL-2) that may contribute
to establish the neuronal damage and
the HSV-1 latent state.1 Moreover,
HSV-1 DNA (viral infection), RNA
(active replication), and virus has been
detected in LES tissue from achalasia
patients by PCR, RT-PCR, and
immunohistochemistry, but not in
control tissue.2
Inflammation
Inflammatory infiltrates of varying
intensity around myenteric neurons
have been found in achalasia patients,
contrasting with the non-infiltrate
findings of control groups with
normal myenteric plexus.3,4 The
characterization of the intraganglionic
infiltrate showed a predominance of
CD3+, CD4+, CD25+ and CD8+
T lymphocytes, as well as CD20+ B
cells and eosinophils but to a lesser
degree, with detection of occasional
plasma cells along the nerve fascicles
and around the ganglion cells.5
Functional contact of mast cells with
interstitial cells of Cajal (ICC) has
recently associated with nitrergic
nerves, S-100-positive cells, ICC and