Mechanisms of Celiac Disease

Celiac disease is a serious autoimmune disorder in which the ingestion of gluten triggers an immune response that damages the lining of the small intestine. This damage impairs the intestine’s ability to absorb food nutrients, leading to gastrointestinal and systemic symptoms.

Figure 1: Diagram of the mechanisms of celiac disease.⁷

Immune Response to Gluten

1. Role of Gluten Proteins

Gluten is a complex mixture of many distinct proteins, mainly gliadin and glutenin. These proteins include secalin in rye, hordein in barley, and avenins in oats.¹ Gliadin, which is mainly found in wheat, contains specific peptide sequences that are resistant to gastrointestinal digestion, leading to their accumulation and exposure in the immune system.¹

2. Activation of Immune Cells

In individuals with celiac disease, gluten consumption triggers an abnormal immune response that occurs in the small intestine. The development of celiac disease includes a combination of the antigen gluten, the association of celiac disease with a human leukocyte antigen (HLA), the deamidation of gluten peptides by the enzyme transglutaminase 2 (TG2) producing peptides that bind strongly to the predisposing HLA-DQ2 or HLA-DQ8 molecules, and the result of an unrestrained T cell response, a type of white blood cell involved in immune responses.² In genetically susceptible individuals, these gluten peptides are recognized as foreign antigens, leading to the activation and proliferation of gluten-specific T cells.²

Figure 2. Cytokine release in celiac disease.⁸

3. Cytokine Release and Inflammation

T cell immunity significantly contributes to the disease’s inflammatory process. This process starts with the loss of tolerance to gluten, leading to the activation of HLA-DQ2 or HLA-DQ8 restricted anti-gluten inflammatory CD4⁺ T cells.² These T cells secrete proinflammatory cytokines, triggering the cytotoxic intraepithelial CD8⁺ lymphocytes to kill intestinal epithelial cells.² These cytokines contribute to the recruitment and activation of other immune cells, leading to an inflammatory cascade in the small intestine.

Damage to Intestinal Villi

Figure 3. Comparison between a normal mucosa and a mucosa with celiac disease.¹⁰

1. Disruption of Intestinal Barrier

Epithelial barriers are essential to maintain multicellular organisms well-compartmentalized and protected from the external environment. In the intestine, the epithelial layer balances nutrients and prevents microorganisms and antigens.³ In celiac disease, the molecular structures and function of tight junctions are disrupted and are not entirely recovered even after treatment with a gluten-free diet. The culprit is zonulin, the regulator of tight junction permeability, which appears to be augmented in autoimmune conditions associated with TJ dysfunction, including celiac disease.³ This disruption allows gluten peptides and other antigens to penetrate the epithelial layer and enter the lamina propria, the underlying tissue layer of the intestinal mucosa.

2. Activation of Transglutaminase Enzymes

Within the lamina propria, tissue transglutaminase (tTG) is a calcium-dependent enzyme that modifies proteins and is released from cells during inflammation.⁴ In celiac disease, tTG enhances the immunostimulatory effect of gluten and is a target autoantigen in the immune response.⁴ As gliadin peptides are excellent substrates for tTG, the negatively charged peptides have a much higher connection for the HLA-DQ2 and HLA-DQ8 molecules, which is why the action of tTG is a critical step in the pathogenesis of celiac disease.⁴

Figure 4. Comparison of a typical small intestine to a small intestine with celiac disease.⁹

3. Immune-Mediated Damage

The activation of gluten-specific T cells and the release of pro-inflammatory cytokines all contribute to the destruction of intestinal epithelial cells and the flattening of intestinal villi. This damage impairs the small intestine’s absorptive function, leading to nutrient malabsorption and nutritional deficiencies.

Systematic Effects

1. Symptoms

While celiac disease primarily affects the gastrointestinal tract, it can also manifest with extraintestinal symptoms affecting other organ systems. Anemia, osteoporosis, herpetiformis, oral ulcers, joint pain, and elevated liver enzymes are some extraintestinal symptoms celiac disease can also provoke.⁶ Intestinal damage can also cause common symptoms such as diarrhea, fatigue, weight loss, bloating, or anemia due to malabsorption of nutrients.

2. Association with Other Autoimmune Disorders

As celiac disease is an autoimmune disorder, people with one autoimmune disorder are prone to getting other autoimmune disorders. The most common autoimmune disorders associated with celiac disease include thyroid disease and type 1 diabetes.⁵ Other severe conditions and some types of cancers are also associated with celiac disease, and following a strict gluten-free diet is the best way to decrease cancer risk.

Management of Celiac Disease

It is estimated that up to 1% of Americans have celiac disease, with 83% undiagnosed or misdiagnosed.¹¹ Diagnosing for celiac disease involves a combination of clinical evaluation, serological testing for specific antibodies, and confirmation through a biopsy. Blood tests, such as tTG and EMA antibodies, can detect the presence of antibodies associated with celiac disease.

The only current treatment for celiac disease is a strict gluten-free diet. A gluten-free diet can help alleviate symptoms, promote intestinal healing, and prevent long-term conditions associated with untreated celiac disease.

Celiac disease is a complex autoimmune disorder characterized by an abnormal immune response to gluten, leading to inflammation and damage to the small intestine’s lining. Understanding the mechanisms, symptoms, and diagnosis is crucial for early detection, effective treatment, and an improved quality of life for individuals with this chronic condition.

Works Cited

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