Introductory Chapter: Celiac Disease - Now and Then

1. Introduction

Celiac disease, in one sentence, can probably be defined as a complex autoimmune disorder triggered by gluten ingestion in people carrying the HLA-DQ2 or HLA-DQ8 gene. The most common symptom associated with the disease is diarrhea after eating gluten-containing food, such as wheat, rye, or barley products. The earliest documentation about the celiac disease can be traced back to the 2nd century AD and it was written by a Greek physician named Aretaeus the Cappadocian [1]. He used the Greek word “koiliakos” or “coeliacs” to call it, meaning abdomen discomfort. He said in English translation: “If the stomach be irretentive of food and if it passes through undigested and crude, and nothing ascends into the body, we call such persons coeliacs”. He also identified the connection between the illness and eating bread and learned that fasting was helpful to reduce the symptoms. This knowledge was elaborated 1700 years later by a British doctor, Samuel Jones Gee, in his lecture entitled “On the Celiac Affection” [2]. He revealed the fact that celiac disease could affect not only children but also adults, but mostly children under 5 years old. If the patient must eat bread, he suggested, “Bread cut thin and well toasted on both sides … But if the patient can be cured at all, it must be by means of diet”. This is consistent with our knowledge today. A more interesting description about the celiac disease was found in the three lectures given by Professor George F. Still at the Royal College of Physicians of London [3], who vividly pictured his observation of the sick children: “What appears to be an infant little more than 12 months old … it is at least a year or two older, perhaps three or four years older, than its appearance would suggest”. Now we know that this is due to malnutrition associated with such eating disorders. Another important discovery was made by Dicke, a Dutch pediatrician, who noticed that celiac disease almost vanished in the Netherlands during World War II when bread was on a serious scarcity, but it came back quickly when the Swedish airplanes dropped bread to the region. Later, he figured out that it was gluten that made people sick [4]. Starting from the mid-20th century, people have been developing various endoscopic tools to reach into the duodenum or even further down into the small intestine to obtain tissue samples for pathological analysis. This technology significantly accelerated our understanding of the pathogenesis of the celiac disease [5]. Later on, gluten antibodies were discovered in patients with celiac disease and their diagnostic value was soon recognized in the medical community [6]. This work built the foundation for serological detection of celiac disease today. From the 70s, people started to look for the possible genetic reasons for celiac disease, and soon a connection with HLA-DQ2 and HLA-DQ8 expression was found [7, 8]. After the 90s, our current concept of celiac disease was gradually formed: this is an autoimmune disorder that can be triggered by gluten ingestion in people with a DQ2 or DQ8 genetic background.

Looking back the history, our understanding of celiac disease has experienced such path: presentations of the disease (ancient time till 19th century) – identification of gluten as the cause (mid-20th century) – pathology of the disease (the 50-the 60s) – immunology of the disease (the 60–70s) – genetics of the disease (the 70–80s) – current concept of the disease (after the 90s).

2. Pathogenesis of celiac disease

Gluten is a common name for the viscoelastic proteins present in various grains, such as gliadin from wheat, hordein from barley, and secaline from rye. The main amino acids of these proteins are glutamine and proline (or collectively called prolamine), which makes them resistant to proteolytic enzymes of the human gut. Using gliadin as an example, gliadin contains 35% glutamine and 15% proline and can only be broken down to oligopeptides of 20–50 amino acids in the human intestine. For the majority of people, these peptides remain in the lumen of the intestine and eventually are expelled out from the body, but for those individuals who carry HLA-DQ2/DQ8 genes, they can bind to the chemokine receptor CXCR3 on the intestinal epithelial cells to induce zonulin overexpression. Zonulin in structure is similar to the zona occludens toxin from Vibrio cholera and has the function to disassemble the tight junctions between epithelial cells via protease activated receptor 2/EGFR pathway. This allows the half-digested gluten peptides to pass through the mucosal barrier and reach the lamina propria [9]. Gluten peptides can also reach the lamina propria through the epithelial cells using IgA/CD71 channels. Once getting into the lamina propria, these peptides are deamidated by tissue transglutaminase 2 (tTG2), converting glutamine to glutamate, which makes them easier to be taken up by HLA-DQ2 and –DQ8 bearing antigen-presenting cells. This triggers the generation of gluten-specific CD4+ T lymphocytes [10]. Upon gluten stimulation, these gluten-specific T cells start to produce a lot of pro-inflammatory cytokines, including interleukin (IL)-15, IL-21, and interferon-γ. IL-15 stimulates CD8+ T cells to migrate to the epithelial layer to attack the epithelial cells, causing villous atrophy, a hallmark of celiac disease [11]. Gluten-specific T cells also promote the activation of B cells, which develop into plasma cells, producing the autoantibodies against tTG2, which is used nowadays as the biomarker in serological tests for celiac disease [12].

Although all of the celiac disease patients are either DQ2 or DQ8 positive, only 1–3% of the people with such genetic background develop the disease [13, 14], indicating that other factors must be involved. Microbial infection in the duodenum has been postulated to play a role. For instance, Pseudomonas aeruginosa, a bacteria that is commonly found in the duodenum of celiac disease patients, produces elastases that can degrade the gluten into highly immunogenic peptides [15]. Other factors that have been investigated for their possible contributions to the onset of celiac disease include (1) time and amount of gluten consumption in infants [16, 17, 18], (2) virus infection [19, 20], (3) H. pylori eradication [21, 22], (4) maternal gluten consumption [23], (5) maternal C-section [24, 25, 26], (6) maternal iron deficiency [27, 28], (7) summer birth [29, 30, 31], (8) maternal high education [32], (9) maternal non-smoking [33], (10) high socio-economic status [34, 35], (11) geographic locations [36, 37, 38], (12) Vitamin D deficiency [39], (13) antibiotic use in childhood [40], and (14) PPI use [41]. However, none of these factors are sufficient to solve the puzzle completely. It seems that each one of these factors plays a part but they (at least some of them) must work together to trigger the intestinal allergy to gluten and the subsequent clinical manifestations of celiac disease.

While many years of effort has been made, the pathogenesis of celiac disease still remains as a mystery today.

3. Current therapeutic strategies for celiac disease

Since celiac disease is troubling at least 1% of the world population, people have been actively searching for therapeutic solutions to control the disease. The effort has been focusing on each key component in the entire pathogenic process, which can be classified into the following five categories.

3.1 Reduction of gluten immunogenicity

The simplest way that one can think of to cure celiac disease is to stop eating all gluten-containing food. Without the trigger, the disease of course will never occur. Believe it or not, this is the most effective method thus far to treat celiac disease – a gluten-free diet. However, wheat products have been the main component of our daily meals for thousands of years, not only for the Western world but also for the Orientals. The only difference between the western bread and the eastern bread is that the former is baked and the latter is steamed. Quitting such a lifestyle for most people is hard to do. For this reason, scientists have been trying to engineer wheat genetically so that it will produce flour containing less or not all gluten without losing much of the original gastronomic properties. Unfortunately, this has not been very successful so far [42, 43].

3.2 Prevention of gluten degradation

The idea is to use synthetic polymers or specific antibodies to sequester gluten in the gut so that it would not be degraded into an immunogen. BL-7010 is such a polymer. In vitro analyses as well as animal studies all showed promising results, including no toxicity [44], gluten selectivity [45], and villous protection [46]. Now its clinical trials are underway. Using antibodies to seize gluten in the intestine has also gained encouraging results. AGY is an IgY antibody generated from chicken eggs against gluten. Taking AGY capsules has been shown capable to reduce gliadin absorption from 42.8% to 0.7% in an animal study [47]. A clinical trial with AGY also obtained effectiveness [48].

3.3 Prevention of gluten peptides entering intestinal mucosa

The next target is intestinal epithelial integrity. The majority of gluten peptides get to the lamina propria through para-cellular space, which is sealed by tight junctions in healthy individuals. Overexpression of zonulin triggered by gluten stimulation in DQ2/DQ8 carriers causes a collapse of the tight junctions. Therefore, if mucosal permeability is restricted, gluten peptides will largely remain in the intestinal lumen. Larazotide acetate is an octa-peptide developed against zonulin. Phase I and II clinical trials all showed substantial improvement in clinical symptoms, although some patients had some minor side-effect, such as headache and urinary infections [49, 50, 51, 52].

3.4 Inhibition of tissue transglutaminase

As mentioned above, the immunogenicity of gluten peptides in celiac disease patients is largely dependent on their deamidation by tTG-2. Therefore, inhibition of tTG-2 activity would reduce the amount of immunogen production. Because tTG-2 activation also contributes to several other diseases, such as Parkinson’s, Alzheimer’s, Huntington’s, and even some cancers, a great effort has been put in to develop tTG-2 inhibitors. An animal study has shown some encouraging results using this strategy in the treatment of celiac disease. A phase II clinical trial has been initiated.

3.5 Prevention of immune reaction

Celiac disease is an autoimmune disorder. The therapeutic strategies discussed above all intend to stop gluten from becoming an immunogen. The last approach is targeting the immune reaction assuming the four strategies above all failed. This includes using chemical blockers to mask the active sites of DQ2, using immunodominant gluten peptides to vaccinate DQ2/DQ8 carriers, transplanting special bacteria that are capable to produce nontoxic gluten in the human gut, using steroids, etc. Many such products will be out soon.