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WORLD GASTROENTEROLOGY NEWS JULY 2019
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neuronal degeneration in achalasia.
The number of mast cells was higher
in type I achalasia than type III. Additionally,
patients with a history of
autoimmune disease or viral infection
had greater mast cell infiltration in
the LES muscle. Mast cells express
the 3-O-sulphated heparan sulphate
receptor that mediates the entry of
HSV-1 but not HSV-2.4
Serum profile studies has established
that elevated concentrations of
proinflammatory cytokines (IL-22,
IL-23, IL-17, TNF-α, IL-6, IFN-γ,
and IL-12), C4B5, C3, cyclin-dependent
kinase 5, α2-macroglobulin
and anti-GAD65 antibodies are
up-regulated in achalasia patients, as
compared with controls, supporting
the hypothesis of immune-mediated
reponse.6,7
A significantly increased ratios
of MMP-9/MMP-2 and activated
MMP-9/proMMP-9 in sera of achalasia
patients has been determined
compared with controls. Moreover,
extensive damage within the plexus
was found in the tissues with more
MMP-9-expressing cells. Additionally,
achalasia-associated autoantigens
PNMA2, GAD65, VIP and Ri are
substrates of MMP-9. Thus MMP-9
may contribute to the pathogenesis by
cleaving achalasia-associated autoantigens
into remnant epitopes generating
autoimmunity (REGA paradigm).8
An increased in some proinflammatory/
profibrogenic tissue and
circulating CD4+ T cell subsets
(Th22, Th17, Th2 and Th1) have
been characterized in patients with
achalasia compared with controls.2,3
Furthermore, patients with achalasia
have also shown a higher frequency
of immune regulatory cells in the
myenteric plexus of esophageal tissue,
as compared to controls. 2,3 The
concomitant presence of inflammatory
and regulatory cells suggests that
the proinflammatory and regulatory
balance favors the former with the
incapacity of the latter in trying to
maintain homeostasis and avoid tissue
damage.
Ganglion cell loss
Achalasia is known to be caused by
the reduction of ICC but most importantly
to a selective loss of inhibitory
ganglion in the myenteric plexus of
the esophagus, which is associated
with a decrease of nNOS, VIP, neural
proteins, S-100, substance P and
PGP9.5. The imbalance produced by
loss of VIP and NO-secreting neurons
as a result of the progressive destruction
of myenteric ganglion cells and
the occurrence of neural fibrosis
would lead to the classic subtype of
achalasia.4
An underpinning pathogenic
mechanism in the early stage of
achalasia is the esophageal myenteric
immune-mediated response, inflammatory
state accompanied by T cell
infiltration, neuritis, ganglionitis and
neuronal degeneration with only mild
to severe fibrosis in the smooth muscle
layer. Moreover, achalasia patients
have shown increased deposits of the
complement complex C5b-C9, C9
and of IgM within or proximal to
ganglion cells of myenteric plexus.6
Autoantibodies
Antinuclear antibodies (ANAs) are
present in 56-68% of the patients
with achalasia. The most prevalent
pattern observed is speckled, followed
by nucleolar, homogeneous
and NuMA-1. Moreover, unusual
staining patterns in the nuclei, such
as the nuclear mitotic apparatus, and
cytoplasmic staining as in anti-Jo-1
positive polymyositis/dermatomyositis,
and antimitochondrial antibodies
have been determined.2,3,9,10
The increased prevalence of
circulating IgG antibodies against
cytoplasm and nucleus of neuronal
cells from myenteric plexus in most
patients with achalasia compared
with GERD, Hirschsprung’s disease,
esophageal cancer, peptic esophagitis,
or myasthenia gravis has led to the
suggestion of a key role for autoantibodies
in the etiopathogenesis of the
disease. However, their precise role is
still unclear. Nonetheless, serum from
patients with achalasia can reproduce
functional and phenotypic changes of
the disease in normal tissues.9
Nuclear, nucleolar or cytoplasmic
circulating myenteric anti-plexus antibodies
were detected in 54.3-100%
of serum samples from patients with
achalasia versus 7.5-12% of healthy
subjects, especially in carriers of HLA
DQA1*0103 and DQB1*0603 alleles
(OR=3.17 and OR=5.82, respectively).
The target antigens of circulating
anti-myenteric autoantibodies are
PNMA2 and GAD65 (69%-80%),
recoverin (8%) and none with Hu,
CDR-62 (Yo), Nova-1 (Ri), SOX-1,
titina or amphiphysin.2,3
Autoimmunity and inflammatory
diseases comorbidity
Autoimmune diseases often occur in
association with one another, either
involving a single individual or within
a family sharing autoimmune diseases,
and the presence of autoantibodies
without disease. Compared with the
general population, patients with
achalasia are 3.6-times more likely to
have autoimmune diseases, including
uveitis (RR=259), Sjögren’s syndrome
(RR=37), systemic lupus erythematosus
(RR=43), type I diabetes
(RR=5.4), hypothyroidism (RR=8.5),
rheumatoid arthritis (RR=2.4),
scleroderma, ankylosing spondylitis,
myasthenia gravis, Guillain-Barre
syndrome, autoimmune acquired
hemophilia A, polyglandular autoimmune
syndrome type II, psoriasis and
asthma. Intriguingly, the younger
population of patients with achalasia
was shown to have a higher prevalence
of autoimmune comorbidities (RR =
3.3), compared with an older population
of patients with achalasia.11
A recent cross-sectional study of 114
patients with achalasia showed that
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