The Immunology of Immediate and Delayed Hypersensitivity Reaction to Gluten

Abstract

The immunology of gluten hypersensitivity and celiac disease has been pursued with significant interest in the past 20 years. For the prevention of systemic diseases, most pathogens that gain entry into our bodies must be met with an effective immune response, yet in the gastrointestinal tract it is equally important that commensal bacteria and a diverse collection of dietary proteins and peptides be recognized without eliciting an active immune response or constant activation of the inflammatory pathway. This phenomenon of hyporesponsiveness to food antigens is known as oral tolerance. This oral tolerance to dietary antigens is maintained by three different mechanisms: anergy, cell deletion and immune suppression. However, in the presence of mechanical/chemical stressors and infections, this tolerance may break down, and gut associated lymphoid tissues (GALT) will react to different luminal antigens. The reaction of GALT to these antigens may lead to the production of pro-inflammatory cytokines, opening of tight junctions, entry of undigested antigens into the circulation, and the subsequent production of IgA, IgG, IgM and IgE antibodies in blood and secretory components. Like any other food hypersensitivity reaction, gluten sensitivity can be divided into immediate and delayed hypersensitivities. In this review an attempt is made first to differentiate immediate hypersensitivity to gliadin, mediated by IgE, from delayed hypersensitivity, which is mediated by IgA and IgG. Furthermore, we attempt to differentiate between gluten hypersensitivity with enteropathy (celiac disease) and gluten hypersensitivity without enteropathy.

Antibodies as Predictors of Complex Autoimmune Diseases

“…Both IgG and IgA antibodies against these antigens have been used in patients with classic celiac disease with sensitivity, specificity and predictive values of 70-100% (20). Since 1966, in both patients with celiac disease and gluten intolerance, antibodies against a variety of tissue antigens, including thyroid, joints, bone, heart, pancreas, brain and even synapses have been reported (21)(22). From these reports and our findings summarized in Table II and Fig.…”

“…In these individuals, gliadin peptide found in gluten extracted from wheat, rye and barley by binding to tTG incites the immune system to attack the lining of the small intestine, resulting in autoimmunity or enteropathy (20). However, since 1966, scientific evidence has been accumulated demonstrating that gluten sensitivity or intolerance and antibody production against gliadin can exist in the absence of tTG antibody and enteropathy (21)(22). For this reason we measured IgG and IgA antibodies in patients with classic celiac disease with enteropathy and in patients with gluten intolerance.…”

“…Celiac disease is another autoimmune disease associated with tissue antibodies against endomysial and reticulin, and antibodies against gliadin (20)(21)(22). Both IgG and IgA antibodies against these antigens have been used in patients with classic celiac disease with sensitivity, specificity and predictive values of 70-100% (20).…”

Differentiation between Celiac Disease, Nonceliac Gluten Sensitivity, and Their Overlapping with Crohn’s Disease: A Case Series

“…They believed that measurements of toll-like receptors and IFN- γ , IL-21, and IL-17A would enable them to differentiate between CD and NCGS [ 5 , 6 ] with a method that is highly invasive and would require a biopsy. Immediate type 1 hypersensitivity to gluten is IgE mediated, while delayed type hypersensitivity to gluten is an antibody- (IgG, IgA) and T-cell-mediated reaction, which is called celiac disease or nonceliac gluten sensitivity with enteropathy [ 8 ]. In the absence of IgG and IgA against tTg, elevated IgG and IgA against various wheat antigens and peptides indicate the loss of mucosal immune tolerance against wheat peptides and the development of nonceliac gluten sensitivity [ 8 ].…”

“…Immediate type 1 hypersensitivity to gluten is IgE mediated, while delayed type hypersensitivity to gluten is an antibody- (IgG, IgA) and T-cell-mediated reaction, which is called celiac disease or nonceliac gluten sensitivity with enteropathy [ 8 ]. In the absence of IgG and IgA against tTg, elevated IgG and IgA against various wheat antigens and peptides indicate the loss of mucosal immune tolerance against wheat peptides and the development of nonceliac gluten sensitivity [ 8 ]. Due to antigenic similarities between wheat antigens and human tissue, both CD and NCGS can result in many autoimmune conditions, including type 1 diabetes, arthritis, thyroiditis, and even neuroautoimmune conditions such as gluten ataxia and multiple sclerosis [ 9 – 11 ].…”