Understanding the molecular basis of celiac disease: What genetic studies reveal

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    Understanding the molecular basis of celiac disease: What geneticstudies reveal


    Complex Genetics Section, Department of Biomedical Genetics, UMC Utrecht, The Netherlands

    AbstractCeliac disease (CD) is characterized by a chronic immune reaction in the small intestine to the gluten proteins that arepresent in a (Western) daily diet. Besides the well known involvement of the HLA class II histocompatibility antigen (HLA)-DQ2.5 and -DQ8 heterodimers (encoded by particular combinations of the HLA-DQA1 and -DQB1 gene) in CD and theminor contribution of the CTLA-4 gene, recently the myosin IXB (MYO9B) gene has also been found to be geneticallyassociated. This review covers the general aspects of CD as well as current insight into important molecular aspects. Weevaluate the role of susceptibility genes in CD by following gluten along its path from ingestion to uptake in the body, whichleads us through the three aspects of CDs pathology. The first is the presence of gluten in the lumen of the intestine, whereit is broken down by several enzymes. The second is the intestinal barrier through which gluten peptides pass. The third isthe reaction of the immune system in response to gluten peptides, in which both the innate and the adaptive immunesystems play a role. Our main conclusion, based on the current genetic and functional studies, is that we should look forcausal genes in the barrier function as well as in the immune systems.

    Key words: Adaptive immunity, Celiac disease, CTLA-4, gluten, HLA-DQ, intestinal barrier, MYO9B, myosin IXB,innate immunity, tissue transglutaminase


    An inflammatory disorder in response to gluten

    Celiac disease (CD) is characterized by a chronic

    immune reaction in the small intestine to the gluten

    proteins that are present in a (Western) daily diet.

    Gluten proteins are storage proteins present in

    wheat, barley and rye, and are needed to maintain

    the processing quality of food derivates such as

    bread, pasta, and cookies; they are also widely used

    to bind and thicken sauces. CD mostly occurs in

    Westernized populations where gluten-derived pro-

    ducts form a large part of the diet. The involvement

    of the HLA-DQ2.5 and -DQ8 heterodimers

    (encoded by particular combinations of the HLA-

    DQA1 and -DQB1 gene) in CD is well known since

    most of the patients carry these molecules.

    This review covers the current insight into

    important aspects of CD and evaluates the role of

    susceptibility genes in CD by following the gluten

    molecules from the lumen of the small intestine,

    passing through the epithelial barrier of the intestine

    and eliciting the immune response (see also

    Figure 1).

    General overview of CD

    Clinical features and treatment

    Until recently CD was considered to be a pediatric

    intestinal disorder, seen mostly in young children

    who had just started a gluten-containing diet.

    The intestinal problems seen in CD patients

    comprise chronic diarrhea, growth retardation,

    weight loss, abdominal pain, vomiting, bloating,

    distention, and constipation (reviewed in Rewers et

    al.) (1). CD is now being recognized more and more

    in older patients who do not present with all the

    clinical features or who are developing more of these

    features at a later age. Their symptoms are more

    systemic, and the disease is now more likely to

    present as a multiorgan disorder, including bone

    problems, ataxia, carditis, reproductive problems

    and skin manifestations like dermatitis herpetiformis

    Correspondence: Professor Cisca Wijmenga, Complex Genetics Section, Stratenum 2.117, Department of Biomedical Genetics, University Medical Centre

    Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands. Fax: +31-30 253 8479. E-mail: t.n.wijmenga@med.uu.nl

    Annals of Medicine. 2006; 38: 578591

    ISSN 0785-3890 print/ISSN 1365-2060 online # 2006 Taylor & FrancisDOI: 10.1080/07853890600989054
















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  • (2). These older patients may present with either

    active or silent CD (reviewed in Dewar et al.) (2).

    The more systemic presentation of active CD leads

    to these patients not always being recognized or

    properly diagnosed. The silent cases are unaware of

    their disease due to a lack of symptoms, or they may

    have only vague symptoms which often remain

    undiagnosed. They are mostly identified during the

    screening of large populations to determine pre-

    valence, or of other risk groups like index patients

    family members.

    Over the last 25 years it was observed that the

    frequency of patients presenting with diarrhea at

    diagnosis has gradually dropped from 91% to 37%

    (3). The duration of symptoms before diagnosis has

    also decreased, from 11 years to 4 years, nonetheless

    this is just the average duration and 4 years is still a

    long period, meaning that there are many patients

    who have remained undiagnosed for a long time.

    The only existing treatment for CD is a life-long

    gluten-free diet (GFD), which reverses the damage

    in the intestine so that the Marsh III stage (Marsh

    stages, see diagnosis and Table I) gradually changes

    to a Marsh 0 stage, the clinical symptoms disappear,

    and the risk of complications diminishes. The

    normalization in the intestine is slower in adults

    than in young children, who often reach the Marsh 0

    stage in a few months, while adults may take up to a

    few years (4).

    Features observed in CD patients are an impaired

    intestinal barrier, less regular tight junctions and

    altered sugar absorption ratios. These features are

    mostly seen in patients on a gluten-containing diet,

    although the functionality of the intestinal barrier

    does not recover completely in patients on a gluten-

    free diet who regain a normalized intestine (57).

    Patients with dermatitis herpetiformis (DH, dis-

    cussed below) who show no histological damage in

    the intestine may also have an impaired intestinal

    barrier (8).

    One of the systemic manifestations of CD is DH

    generally seen as a cutaneous manifestation of CD

    (reviewed in Zone et al.) (9). Most DH patients have

    varying degrees of lesions in the small intestine and

    react to gluten. DH and CD run in families and

    often co-occur in individuals. The best treatment is a

    gluten-free diet, although most patients only treat

    their skin problems using medicine and neglect the

    underlying intestinal problems caused by gluten.

    A small proportion (v7%) of CD patients do not

    respond to a strict GFD (4). This group of

    CD patients (generally referred to as refractory CD

    (RCD) patients) is split into RCD type I and RCD

    type II patients and was defined by Daum et al. as

    individuals with a persisting villous atrophy with

    crypt hyperplasia and increased intraepithelial lym-

    phocytes (IEL) in spite of being on a strict GFD for

    more than 12 months, or those whose severe and

    persisting symptoms necessitate intervention inde-

    pendent of the duration of their GFD (10). The

    RCD type II group (v0.3% of the total CD

    population) shows abnormal IELs, with abnormal

    surface markers in small intestinal biopsies, like the

    expression of intracytoplasmic CD3e and the lack of

    several classical T cell markers, e.g. CD8 and CD4.

    Key messages

    N Gluten proteins are resistant to enzymaticbreakdown, leading to peptides that may

    evoke an immune response in genetically

    susceptible individuals.

    N The intestinal barrier is impaired in celiacdisease patients and this affects its protective

    function against pathogens and the selective

    uptake of nutrients. Myosin IXB was found

    to be genetically involved in the impaired


    N Both the innate and the adaptive immuneresponse play a role in celiac disease and the

    genetic involvement of the HLA-DQ2.5 and

    -DQ8 molecules as well as the CTLA-4 gene

    has been shown.


    ASCA anti-Saccharomyces cerevisiae


    CARD caspase recruitment domain

    CD celiac disease

    DH dermatitis herpetiformis

    RCD refractory CD

    EATL enteropathy-associated T cell


    RR relative risk

    MYO9B myosin IXB

    CTLA-4 cytotoxic T lymphocyte-

    associated 4

    PREP prolyl endopeptidase

    PGPEPI pyroglutamyl-peptidase I

    tTG tissue transglutaminase

    IBD inflammatory bowel disorders


    alias MLCK

    myosin light chain kinase

    ROCK Rho kinase

    TNF tumor necrosis factor

    MICA MHC class I polypeptide-related

    chain A

    IEL intraepithelial lymphocytes

    A clearer view of celiac disease 579
















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  • A proportion of this group develops enteropathy-

    associated T cell lymphoma (EATL).

    CD also co-occurs with other autoimmune dis-

    orders in families and in pat