CELIAC DISEASE



Celiac disease (CeD) is one of the most common autoimmune disorders, affecting 1% of the population in the United States and Europe (3 million and 3.5 million people, respectively) and approximately 15 million individuals worldwide. CeD is emerging as a significant public health concern, as it is associated with increased co-morbidities and mortality, and has dramatically increased in prevalence during the past 50 years. Currently, there are no pharmacologic therapies available to treat this disease. The only management for CeD is to follow a gluten-free diet by eliminating foods that contain gluten. Unfortunately, the ability to maintain a strict gluten-free diet can be difficult, as many CeD patients reported being either accidentally or purposefully exposed to gluten-laden foods. For patients who do adhere to a strict gluten-free diet, up to 30 percent respond poorly. For these patients, therapeutic modalities beyond dietary modification would be beneficial.

Celiac disease is a T-cell mediated autoimmune disease of the small bowel, triggered by the ingestion of gluten-containing grains (e.g., wheat, barley, and rye) in genetically susceptible individuals. CeD is one of the few autoimmune disorders in which all the elements of autoimmunity are understood:

  • The triggering environmental factor: glutenin/gliadin, the active fractions of gluten
  • The route of passage into the body: the mucosa of the small intestine
  • A close genetic association: with HLA genes (DQ2 or DQ8), and
  • A highly specific humoral autoimmune response: auto-antibodies to tissue transglutaminase (anti-tTG), deamidated gliadin peptides (DGP), and endomysium (EMA).

While previously thought to be uncommon, the prevalence of CeD is approximately 1% of the general population. The 2004 NIH consensus conference on CeD confirmed that the prevalence in the United States alone is approximately 3 million people. The number of diagnosed patients will increase dramatically during the latter half of this decade, driven by broad based educational campaigns, NIH research funding and widely available blood screens for highly specific antibodies (anti-tTG, DGP, EMA).

The disease is highly variable with many non-intestinal manifestations and is frequently characterized by some or all of the following: chronic small bowel inflammation, fatty stools and malabsorption, osteoporosis, anemia, occurrence of other autoimmune diseases, neurological disorders and gastro-intestinal cancers. Symptoms may include chronic diarrhea, abdominal pain, muscle cramps, irritability, and painful skin rashes. Celiac disease patients that do not eliminate dietary gluten increase their chances of other diseases, such as concurrent autoimmune diseases and a 40-100 fold increase in gastrointestinal cancer. Celiac disease often presents with vague non-gastrointestinal symptoms. During the active phase, characteristic auto-antibodies recognizing tTG, deamidated gliadin peptides and endomysium are produced. Early in the disease, the tight junctions are opened and severe intestinal damage ensues. A biopsy of the small intestine, combined with auto-antibody and anti-tTG blood test, is the most accurate way to diagnose the illness.

There is no cure for celiac disease, and complete elimination of dietary gluten with a gluten-free diet is the only management of the disease. For most patients, strict dietary avoidance may heal the small intestine within 3 to 6 months and reduce the markers of autoimmunity (anti-tTG, DGP, and EMA). Several organizations have been formed to help patients meet the challenge of complete gluten avoidance. It is known that altered intestinal permeability (leaky gut) is a hallmark of CeD and tracks the severity of the disease. It is likely that leaky gut is both a cause and a consequence of the disease, facilitating transport of gluten which then triggers an inflammatory process, resulting in tight junction dysfunction (leak) which can be blocked by tight junction regulation.

Mechanism


Intestinal tight junctions control the passage of large molecules such as intact proteins, particles and cells through the paracellular space. This passive transport is known as intestinal paracellular permeability, and while it accounts for only 10 percent of total protein uptake it serves as the major portal for intact protein and antigen delivery into the body. Protein entry is in close proximity to the submucosal lymphocytes, which comprise 80 percent of immunoglobulin producing cells in the human body.

Increased intestinal paracellular permeability leads to antigen presentation for processing and antibody response. Tight junctions in other organs have a similar function: the regulation of paracellular transport. In the capillary endothelia of the blood brain barrier, tight junctions are the anatomical barrier interfacing blood and CNS.

Tight junction dysfunction has been implicated in a host of disease states, including a variety of autoimmune diseases. Ischemia - reperfusion injury also appears to be associated with tight junction dysfunction, while many cytokines, bacterial toxins, infections, and drugs have also been implicated in tight junction injury or destruction.