Why does gluten cause an immune response?

Celiac disease (CD) may be considered the most common chronic inflammatory condition with an estimated incidence in Western Countries around one per cent. CD is an autoimmune pathology of the intestine caused by an abnormal immune response to dietary gluten that occurs in genetically susceptible individuals . The well known genetic factor is the HLA-DQ region at 6p21.3 which, contributes no more than 40% of the risk with the non-HLA genes seeming to be playing a stronger determinant of CD susceptibility

The immune response occurs when increased amounts of gluten peptides can enter the intestinal mucosa to initiate the inflammatory cascade. The actual mechanism by which the peptides are transported is still not clear, but may involve a faulty mechanisms with secretory IgA. (see references 3,4)

It currently appears that different gluten peptides are involved in the disease process in a different manner, some fragments being ‘toxic’ and others ‘immunogenic’. Those defined as ‘toxic’ are able to induce mucosal damage and those defined as ‘immunogenic’ are able to specifically stimulate HLA-DQ2- or DQ8.

Two pathways have been hypothesized to be triggered by these peptides: one is the direct effect on the epithelium that involves the innate immune response the non-specific immune system, the other represents the adaptive immune response involving CD4+ T cells in the lamina propria that recognize processed gluten antigenic detrminants.

Role of Zonulin in Inflammation

Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin isi a 47-kDa inflammatory protein that was discovered in 2000 by Alessio Fasano and his team at the University of Maryland School of Medicine. The protein helps regulate leakiness in the gut by opening and closing the spaces or "junctions" between cells in the lining of the digestive tract. Zonulin has been shown to be upregulated in several autoimmune diseases, including celiac disease (CD) and type 1 diabetes (T1D), in which TJ dysfunction seems to be the primary defect (see References 5,6)

It appears that gluten may be a strong trigger of zonulin in some individuals. And since no human can completely digest gluten, this may present a problem for some individuals who present a zonulin response to gluten. (See References 5,6) In additon Zonulin, is found in higher levels in the blood of both celiac and non-celiac gluten-sensitive individuals, 

Drug development 

Larazotide acetate, (Alba Therapuetics) is a drug currently in development that works by inhibiting zonulin, which has been shown to increase the permeability of the gut in celiac disease, allowing gluten particles to pass through to trigger inflammation, and gastrointestinal and other symptoms. Larazotide acetate is a novel agent that belongs to a new class of drugs called tight junction regulators. 

Site of damage in intestine 

The lining of the intestines have small areas called villi which project outward into the opening of the intestine. These structures help absorb nutrients. When people with celiac disease eat foods with gluten, their immune system reacts by damaging the villi. Because of the damage, the villi are unable to properly absorb iron, vitamins, and other nutrients.As a result, a number of symptoms and health problems may occur.

Gluten Inflammation in Other Diseases

According to Amy Meyers MD., If you have Lupus, Rheumatoid Arthritis, Hashimoto’s, Multiple Sclerosis, or any other autoimmune disease you should not be eating gluten.. "The bottom line is that if you have an autoimmune disease, or any inflammatory condition, you shouldn’t be eating gluten, period.."

According to Dr Meyers: "When your immune system is continuously creating inflammation in response to the gluten you’re eating, your leaky gut, and the microbes and toxins flooding your bloodstream, you develop chronic inflammation. Your immune system is now stressed and is less able to attack pathogens and invaders with precision. Instead, it begins indiscriminately sending wave after wave of attack in a desperate attempt to fight off the invaders. Eventually, your body’s own tissues end up on the receiving end of the attack, and you end up with an autoimmune disease..." read the full article Reference 7).

Readings and References

1-The immune recognition of gluten in coeliac disease

2-Current and Emerging Therapy for Celiac Disease

3-Intestinal permeability in coeliac disease: insight into mechanisms and relevance to pathogenesis.

4- Abnormal apical-to-basal transport of dietary ovalbumin by secretory IgA stimulates a mucosal Th1 response

5a-Zonulin, regulation of tight junctions, and autoimmune diseases

5b- The role of HLA DQ2 and DQ8 in dissecting celiac-like disease in common variable immunodeficiency.

6-Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

7-3 Important Reasons to Give Up Gluten If You Have an Autoimmune Disease

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