Celiac Disease: Molecular Insight and Future Challenges
Navneet Singh Deora*
Ingredients Innovation and Research, Jubilant Foodworks, India
Received date: 27 Aug 2017; Accepted date: 27 Oct 2017; Published date:
02 Nov 2017
*Corresponding author: Navneet Singh Deora, Ingredients Innovation and
Research, Jubilant Foodworks, India; E-mail: email@example.com
CD is an autoimmune enteropathy resulting in lifelong immune disorder of the small intestine where inflammation is triggered by ingestion
of gliadin fraction of wheat gluten and similar alcohol-soluble proteins (prolamines) of barley and rye in genetically susceptible subjects.
In current situation, there is an urgent need for the development of non-dietary therapies by multidisciplinary research direction involving
collaborative efforts between biologist, engineers, chemist and clinicians. This can be achieved by molecular understanding of gluten-induced
pathogenesis in CD. Over the past decades, three pathogenically critical molecules - gluten, TG2, and HLA-DQ2 - have served as focal points
of interest. This mini review summarizes current understanding about the CD from the molecular basis and address future challenges.
Celiac disease (CD) is a multifactorial and polygenic disorder that
is caused by an immune response to ingested cereal gluten proteins of
wheat (gliadins and glutenins), barley (hordeins), and rye (secalins)
[1,2] CD is increasingly considered a systemic disorder although the
main pathological lesion is located in the proximal small intestine. In the
most developed lesion, there is loss of intestinal villi and infiltration of
mononuclear cells, both in the epithelium and the lamina propria.
In normal physiological conditions, enzymes (gastric, pancreatic
and small intestinal brush-border enzymes) digest and convert dietary
proteins into amino acids and small peptides. In terms of CD, toxic
peptides are rich in the proline content consequently they are more
resistant to digestion and non-digested peptides (proline and glutamine
rich fragments) accumulate in the small intestine. These peptides are
referred to as toxic/immunogenic peptides. The pathological conditions
associated with CD begin with the alteration of the barrier function of the
intestinal mucosa, allowing dietary gluten peptides to reach the immune
system. This suggests that CD is the result of an inappropriate T cellmediated
immune response against ingested gluten.
In addition, patients ingesting gluten also have circulating diseasespecific
autoantibodies derived from B cells that recognize the enzyme
transglutaminase 2 (TG2) as well its product and complexes [3-5].
Strikingly, both the intestinal lesions and the autoantibodies are reversibly
dependent on oral gluten exposure . A molecular understanding of
gluten-induced pathogenesis will therefore likely provide new insights
into how the intestinal epithelium and its underlying immune system
interact with each other with implications beyond CD. Figure 1 below
shows flow diagram of gluten-induced pathogenesis leading to tissue
damage in CD.
In the context of CD, three pathogenically critical molecules - gluten,
TG2, and HLA-DQ2 (Figure 2) - have served as focal points for intensive
collaborative efforts between biologists, chemists, engineers, and
It is comprised of a number of homologous proteins called gliadins
and glutenins in wheat, hordeins in barley, and secalins in rye. Each of
these proteins harbors multiple disease-specific T-cell epitopes. These
epitopes have relatively higher abundance of Pro and Gln residues. As
a consequence, the concentration of certain antigenic peptides builds
up in the upper intestinal lumen after ingestion of dietary gluten. This
proteolytic resistance of gluten causes HLA-DQ2 mediated inflammatory
T cell response in certain individuals with genetic background. Decoding
Figure 1: Showing flow diagram of gluten-induced pathogenesis
leading to tissue damage (Adapted from )
Figure 2: Clinicians, biologists, chemists. Principal autoantigen &
Pathogenically critical molecules in the area of CD and research
collaboration (Adapted from )
this fundamental characteristic will consequently support the interface
of chemistry-immunology. Advances has further supported the
discovery, scale up, and ongoing clinical development of latiglutenase,
an experimental oral enzyme therapy comprised of a fixed dose mixture
of two proteases . More recently, a monoclonal antibody capable of
sensitively and specifically detecting a protease-resistant and highly
immunogenic gluten peptide has been commercialized, and subsequently
used to develop assays for detecting inadvertent gluten consumption,
thereby highlighting a potentially practical means for improved dietary
compliance by CD patients . The current dietary compliance for
gluten-free products is limited to maximum 20 ppm set by the European
Transglutaminase 2 (TG2)
It is a non-essential ubiquitous protein in mammals. Its relationship
to CD pathogenesis became evident in the last two decade mainly due to
two major findings. Firstly, TG2 was identified as the principal antigen
recognized by disease-specific auto antibodies in the serum of patients
with active CD. Secondly, it was observed that, in order for the T cell
epitopes from gluten to be recognized as high affinity ligands by HLADQ2,
they must undergo post-translational modifications at selected Gln
residues via TG2-catalyzed deamidation.
However it is to be noted that the relationship between these two in
terms of mechanism currently remains to be fully established. However,
together they laid the hypothesis that pre-systemic inhibition of TG2 in
the small intestine may represent a viable non-dietary modality for CD
therapy. A number of investigators have independently lead inhibitors
against this cysteine protease-like enzyme. However, identification of
appropriate cellular and animal models for pharmacological evaluation
of these inhibitors is challenging and needs further research. However,
an unexpected finding that enabled progress in this regard was the
observation that an allosteric disulfide bond maintains extracellular
TG2 in a catalytically inactive state in the intestine . This in turn
led to a search for molecular factors capable of inducing TG2 activity. A
growing number of inflammatory signals have been identified that induce
extracellular TG2 activity in the small intestine although their relevance
to CD remains to be definitively established.
In past two decades, the role of gluten and HLA-DQ2 (or infrequently
HLA-DQ8) as the most important environmental and genetic causes
has been understood to some extend . It is also understood that
other genetic and environmental factors can play significant roles in
the onset of CD. Recent studies also suggest that in celiac patients,
multiple gluten-related immunogenic pathways are dependent on
microbial transglutaminase . Recent studies suggest that microbial
transglutaminase is a potential inducer of tight junction permeability, and
many characteristics of tissue transglutaminase, if imitated by microbial
transglutaminase, may have devastating effects on the celiac population
. Nonetheless, any of these genetic clues could present an entirely new
window into the onset, severity, or clinical heterogeneity of CD. With
respect to environmental factors beyond dietary gluten, the list of potential
culprits is seemingly endless. Perhaps the most significant translational
advances in the foreseeable future will likely be the development of
prototypical animal models for CD.
Recent studies have shown that the new insight into the pathogenesis
of CD is shifting toward an important role of B-cells in addition to
CD4+ T-cells . Current knowledge about the host microbiome
characterization and the better understanding of toxic peptides at
molecular and structural level had added new and relevant information
to better understand the mechanism that could initiate the CD4+-T-cells
response and induce the loss of oral tolerance to the gluten. Overall, these
results are of potential consequences for therapeutic approaches targeting
on plasma-cell depletion and on modified propyl-endopeptidase enzymes
. Amongst human autoimmune diseases, the environmental trigger
has been identified and characterized chemically [1,16]. As referred to
our earlier discussion, T cell epitopes in gluten have also been extensively
characterized, however the mechanism by which they gain access to
sub-epithelial antigen presenting cells is not fully understood [11,17,18].
This is a key area of interest so as to further develop insight about CD.
Elucidation of the mechanism will allow researcher to understand the
process for the transport of intact peptides from the gut lumen to the
subepithelial vasculature. This would definitely have broader physiological
implications beyond CD.
In conclusion, notwithstanding the fact that CD remains an example
of a lifelong chronic disorder for which no drug therapies are available,
it has been a vivid example of the power of collaborative research at the
chemistry-biology interface. One can only hope that, over the next decade,
the celiac patient will start to reap the benefits of the scientific advances
that have emerged as a result of this collaborative spirit.
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