annals 1-2.qxd - Centrum Zdrowia Dziecka

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specific gliadin peptides that have been implicated in CD.
HLA-DQ molecules present on the surface of antigen presenting
cells (macrophages, dendritic cells), i.e. cells, which
catch the gliadin peptides and present them in association
with specific HLA-DQ receptors to T lymphocytes [43].
Gluten contains peptides presenting extremely high
affinity to DQ2 and DQ8 receptors [51]. These toxic peptides
are characterized by high glutamine content, i.e. the amino
acid which is a substrate for the enzyme – tissue transglutaminase
(tTG). tTG catalyzes deamination of glutamine into
glutamine acid. This reaction increases about 100-times
the affinity of toxic peptides, and is essential for significant
stimulation of gliadin-specific – T lymphocytes (Fig. 1). Activated
gliadin-specific T lymphocytes produce pro-inflammatory
cytokines responsible for histological changes in intestinal
mucosa [10, 11].
Fig. 1 Effector mechanisms of celiac disease – the activation of specific T
lymphocytes
Toxic peptides are present in wheat, barley and rye
[9]. Corn, rise and, as recently has been shown, pure oats do
not contain toxic peptides active in CD [23].
The recent reports by Shan et al. shows that digestion
of recombinant gliadin with gastric and pancreatic enzymes
in vitro produces the highly stable 33-mer peptide that is rich
in proline and glutamine, and which contains all known toxic
peptides [51]. This 33-mer peptide is resistant to brush
border enzymes, but it can be easily degestive by endopeptidases
coming from intestinal bacteria [51].
Findings showing that gut bacteria could deprive gliadin
peptides of toxicity open a new therapeutic possibility
with using probiotics, i.e. non-pathogenic bacteria regulating
gut microflora ecosystem. It is not excluded that bacterial endopeptidases
could be also used in preparation of non toxic
cereals [12].
HLA-DQ2 and -DQ8 are common in human population.
This haplotype is present in 20–30% of health controls,
suggesting that activation of pathological processes could be
influenced by other genes. It seems that HLA class I related
gene – the major histocompatibility complex class I chain-related
gene A (MICA) is an attractive candidate for better un-
derstanding of physiopathological mechanisms of CD [31].
MICA molecule is mainly expressed on the intestinal epithelium
and is recognized by T lymphocytes, CD8+ lymphocytes
and natural killer cells. The binding of MICA to cells induces
cytotoxic and inflammatory responses in the intestine.
Lopez-Vazquez et al. found an association of the MICA A5.1
allele with atypical form of CD. Up to 29% of patients with
atypical CD expressed A5.1 allele in comparison to 13% of
patients with typical CD and 7% of healthy population. The
mechanism by which atypical manifestations are triggered is
connected with the fact that MICA-A5.1 is responsible for secretion
of soluble form of MICA molecule. This protein reacts
with cytotoxic and pro-inflammatory lymphocytes and
inhibits their activation in intestine by MICA present in gut
epithelium.
Clinical symptoms
The classical clinical picture of childhood celiac disease consists
of prolonged diarrhea with failure to thrive, abdominal
distension, vomiting. Severe malnutrition and even cachexia
can occur when diagnosis is delayed. This type of presentation
has decreased in many European countries over the past
few decades. The factors responsible for this change might be
explained by the exclusion of gluten from the diet of babies
and promotion of natural feeding [14]. Studies performed in
United States on children with recognized CD showed that older
age of CD onset and atypical manifestations were results
of prolonged breast feeding [14]. On the other hand Swedish
observed that breast feeding decreased occurrence of CD in
children before 2 years of age, and high doses of gluten introduced
to the baby's diet independent on the age without protection
of breast milk increased the risk of CD [26]. Presented
results open the discussion on the period of introduction
of gluten to the infant diet. Experimental data show that oral
tolerance is developed only in early ontogeny, thus too late
administration of gluten to the diet could be responsible for
gluten intolerance. It seems that low amounts of gluten in the
diet before 6 months of life, but introduced during breast feeding
could prevent the development of CD [25]. However,
intake the gluten either before 3 month of life or under
7 month of life increased the risk of CD [46].
In Poland Szaflarska-Szczepanik observed the decreased
frequency of classical form of CD in children starting
from 1990 [55]. Children presented atypical symptoms, such
as low weight, short stature, anemia, abdominal pain. Ludvigsson
at al. reported similar tendency in children before
2 years old, in whom in addition, irritability and muscle wasting
were found [34].
Recently, increased frequency of CD reaching 3,4%
was found in patients with irritable bowel syndrome (IBS) [15,
53]. These patients tend to experience diarrhea, vomiting, recurrent
abdominal pain, constipation, nausea. Our studies also
showed high frequency of CD in children with IBS (1:60) [4].
Many symptomatic patients with newly diagnosed
CD initially present with non-gastrointestinal manifestations
of CD. Atypical symptoms of CD are presented in Table 1.