Gluten sensitivity
Encyclopedia
Gluten sensitivity belongs to a spectrum of disorders in which gluten
has an adverse effect on the body. It can be defined as a non-allergic and non-autoimmune condition in which the consumption of gluten can lead to symptoms similar to those observed in coeliac disease
or wheat allergy
(other conditions which fall under the gluten-related disorders spectrum).
Gluten sensitivity is thought to affect approximately 6% of the general population . Symptoms of gluten sensitivity include bloating, abdominal discomfort, pain or diarrhoea; or it may present with a variety of extraintestinal symptoms including headaches and migraines, lethargy and tiredness, attention-deficit disorder and hyperactivity, autism and schizophrenia, muscular disturbances as well as bone and joint pain
Until recently, the terms gluten sensitivity and coeliac disease were used interchangeably in literature. However, emerging research is beginning to identify the differences that exist between coeliac disease and gluten sensitivity. If the medical history of a patient, along with clinical tests, rule out coeliac disease and wheat allergy, a diagnosis of gluten sensitivity can be considered. However, certain criteria need to be met before a diagnosis of gluten sensitivity can be confirmed (see diagnosis section). Treatment for all three conditions is a gluten-free diet; the difference being that with wheat allergy the interruption is temporary and drugs may be administered; in the case of coeliac disease the diet is lifelong and even ingesting very small amounts of gluten-containing food could damage their health and, in the case of gluten sensitivity the withdrawal of gluten from the diet may only be temporary.
Gluten is a protein
composite found in foods processed from wheat and related species, including barley and rye. It gives elasticity to dough helping it to rise and to keep its shape. It is found in many staple foods in the Western diet. Gluten is composed of a gliadin fraction (alcohol soluble) and a glutenin fraction (only soluble in dilute acids or alkali).
and wheat allergy
, a diagnosis of gluten sensitivity can be considered. However, before a diagnosis of gluten sensitivity can be confirmed the following criteria need to be met:
If the above criteria are met then the person can be classed as ‘gluten sensitive’ and it can be treated with a gluten-free diet for a period of time. This should lead to symptom resolution.
A diagnostic algorithm for gluten sensitivity has been proposed:
In comparison, in a recent clinical paper, gluten sensitivity was defined as ‘one or more of a variety of immunological, morphological or symptomatic manifestations that may also be shared by coeliac disease and irritable bowel syndrome (IBS) . In cases where there is reactivity to gluten, yet coeliac disease and wheat allergy are eliminated as possibilities, gluten sensitivity may be considered. Whilst the general clinical picture for gluten sensitivity is similar to coeliac disease in particular, it is usually less severe and neither anti-tissue transglutaminase antibodies nor autoimmune comorbidities are found.
It is believed that approximately 40-50% of gluten sensitivity patients may have IgG or IgA anti-gliadin antibodies (AGA) There is also a study identifying approximately 50% of gluten sensitivity patients, few more than the general population, carry either HLA DQ 2 or 8
On closer inspection, it has also been found that gluten-sensitive subjects do not develop full histological lesions; their lesions, if any, are limited to types 0-1 of the Marsh classification. In addition, it has been found that they have normal intestinal permeability and an increased expression of Toll Like receptors 2 (TLR2) but no change in the cytokines involved in adaptive immune responses Th1 and Th17 such as IL-6, IL-17 A, IL 21, which are increased only in patients with coeliac disease. The knowledge of the response in gluten sensitivity to date suggests that only the innate immune system is involved, whereas coeliac disease is an adaptive immune response (autoimmunity).
Gluten sensitivity should have a defined cause, although not apparent always with first examination, affected individuals should eventually fall into GSE or wheat allergy. Only rarely should gluten sensitivity be idiopathic. Idiopathic gluten sensitivity (IGS) arises spontaneously or from an obscure or unknown cause and may involve neuropathy, myopathy, dermal, or intestinal abnormalities. Anti-gliadin antibodies are the primary link between gluten and idiopathic sensitivity in instances "in which enteropathy or allergy are not clearly involved". This form of gluten sensitivity is controversial at the moment but there is a growing body of research to support the concept of gluten sensitivity that is different from coeliac disease and wheat allergy.
Gluten-sensitive enteropathy develops as a consequence of genetic and environmental factors. Other than the involvement of certain HLA-DQ isoforms (antigen presenting proteins in humans) and certain wheat proteins, there is no clarity in the involvement of other genes or other environmental factors (see risk modifiers). Strong genetic factors such as seen in GSE have not been seen in gluten allergy, and with idiopathic gluten-sensitivity the HLA-DQ associations are weak.
Researchers reported extreme fatigue and pain in patients without celiac disease, with gliadin antibodies. They called this a “non-celiac gluten intolerance” for which there is no explanation as to the mechanisms involved.
The rise of gluten sensitivity (particularly in adults) may reflect the convergence of many phenomena. An aging population, genetic risks associated with westernization, excesses in the diet, sensitizing chemicals (e.g.NSAIDs), and allergy-enhancing chemical treatment of foods (e.g. enzymatic deamidation of gluten) may act together with natural defensive agents in foods to cross the threshold between normality and pathology.
s. These junctions prevent leakage around the cells that line the small intestine, resulting in the leaking of food proteins into the body. These toxicities of gluten that are not part of the adaptive immune response may be the link between wheat and gluten sensitivity, and possibly type 1 diabetes.
are important factors in several inflammatory diseases. The immunochemistry can be subdivided into innate responses (direct stimulation of immune system), class II
mediated presentation (HLA DQ), class I
mediated stimulation of killer cells, and antibody
recognition. The responses to gluten
protein
s and polypeptide regions differs according to the type of gluten sensitivity. The response is also dependent on the genetic makeup of the human leukocyte antigen
genes. In enteropathy, there are at least 3 types of recognition, innate immunity (a form of cellular immunity priming), HLA-DQ
and antibody
recognition of gliadin and transglutaminase. The three dominant sequences responsible for the antibody reaction have been identified. With idiopathic disease only antibody recognition to gliadin has been resolved. In wheat allergy
, there appears to be an innate components and the response pathways are mediated through IgE against gliadin and other wheat proteins.
, gluten sensitivity and wheat allergy
. Since individuals with coeliac disease can also have wheat allergy, a finding of wheat allergy does not eliminate the possibility of enteropathy. Individuals highly suspect of coeliac disease may be tested for anti-transglutaminase antibodies
followed by duodenal biopsy, this will confirm or refute active coeliac disease. The study that recommends this, however, has a number of ATA
positive/biopsy-negative individuals, this could result from patchy villous atrophy or subclinical pathology. One current study recommended at biopsy samples running distally from the duodenum to avoid the risk of false negatives. Eliminating the possibility of coeliac disease can generally be done by adding HLA-DQ
typing, in which DQ2
and DQ8
are found in enteropathy 98% of the time in caucasians, DQ7.5 the remaining 1.6% and 0.4% not found with either of these 3. Without ATA or HLA-DQ2/8 positivity, coeliac disease is not likely the cause of the sensitivity.
In either case, other avenues of diagnostics, such as allergy testing are available. Rarely gluten sensitivity may be idiopathic, a potential that wheat proteins play a role in other disease, in these instances DQ1
may be associated with sensitivity. There is research showing that in certain patients with gluten ataxia early diagnosis and treatment with a GFD can improve ataxia and prevent its progression. Recently, a classification of gluten-related disorders has been proposed:
Coeliac disease as the classically defined gluten-sensitivity and dermatitis herpetiformis was appended to a broadening definition of gluten sensitivity. The diagnostic "gold standard" of coeliac disease is the villus atrophy detected in duodenal
biopsies. However, it is now recognized that inflammation of the epithelial tissue of the small intestine precedes atrophy. Early in the disease, gluten elicits T-lymphocyte recognition of gluten hydrolysates (polypeptides of gluten) and gluten peptides bind to mammalian tissue transglutaminase
(tTG). This second interaction results in the production of "self" antibodies to tTG
. This increases lymphocytes within the epithelia of the small intestine (Marsh grade 1 and 2) and antibody-tTG complexes seen as deposits. This usually progresses to coeliac disease (Marsh grade 3 and 4). The dietary cause of GSE is not limited to wheat gluten; 'glutens'
from all known edible cultivar
s of Triticeae can induce GSE in susceptible individuals (see: Gluten immunochemistry
).
There are a large number of medical conditions that result from GSE that can occur prior to the development of coeliac disease and might be gluten responsive. While the level of villus atrophy in some cases of GSE may not reach clinical coeliac disease recognition, the elevation of cellular immunity is capable of producing disorders more frequently found in coeliac disease. Conditions secondary to GSE are important diagnostic criteria for gluten sensitivity when there may be no obvious intestinal abnormality. Presentation of GSE is often the result of initial recognition of the secondary condition which in followup testing (ATA
test, AGA
test, HLA-DQ
typing, and/or biopsy) recognizes the primary condition. The secondary conditions associated with GSE tend to make late onset coeliac disease a systemic phenomena.
IgA or IgG. Common symptoms are peripheral neuropathies and cerebral ataxia. Within the GSE set these may be explained by calcification of brain channels and avitaminosis. Within the remaining 'DQ2 and DQ8'less cohort. Given that this cohort of GS is idiopathic, the role of allergies, other sensitivities (e.g. aspirin), or other factors in IGS is also unresolved.
Silent Disease. Depending on testing somewhere between 3 and 15% of the normal population have anti-gliadin antibodies (AGA). Studies using anti-gliadin antibodies (AGA) reveal that in undiagnosed or untreated individuals with AGA, with increasing risk for lymphoid cancers and decreased risk for other associated with affluence. Though it is unknown in these studies the percentage that are early stage GSE.
have been significantly increased in non-coeliacs individuals with oral ulceration. Anti-α-gliadin antibodies are frequently found in coeliac disease
(CD), to a lesser degree subclinical CD, but are also found in a subset who do not have the disease. The 1991 reference comes from a period when testing for subclinical CD was undeveloped. Of people with pseudo-exfoliation syndrome, 25% showed increased levels of anti-gliadin IgA. One forth of people with Sjögren's syndrome had responses to gluten, of 5 that had positive response to gluten, only one could be confirmed as CD and another was potentially GSE, the remaining 3 appear to be gluten-sensitive. All were HLA-DQ2 and/or DQ8-positive. Treatment to produce remission of Crohns disease(CrD) symptoms on elimination diet indicated the most important foods provoking symptoms were wheat and dairy. A later paper showed little IgE mediated response except to the dairy, while another paper showed no significant anti-food IgE association. Crohn's disease (CrD) may have a link to wheat that is independent of gluten. CrD appears to be associated with high anti-yeast antibodies (ASCA - yeast antigens that are found in bread and other cereal derived products) and affected individuals lack lectin binding proteins such that the mannins in yeast, the antibodies that bind them and aggravate inflammatory colitis. One concern of the above studies is the high prevalence of markers for gluten-sensitive enteropathy, one has to question how idiopathic these conditions are if close examination for GSE has not been undertaken.
apparent that allergies to certain substances do not behave in predictable ways. One clear example of this is exercise induced anaphylaxis and asthma, WDEIA (Wheat Dependent Exercise Induced Anaphylaxis
) is now believed to be induced by ingested gluten that finds a way into the blood stream. This pathway is now believed responsible for some forms of eczema. Recent studies on two wheat allergens show that they possess the capability of bypassing the gut/blood barrier. The most active of these is ω-5 gliadin, a gluten component that is a strong allergen and causes WDEIA. Allergy tests may not reveal allergies to gluten because the unfractionated allergens are 'hidden' from these tests, and most currently available tests cannot detect these new allergens. Finally, allergies typically involve IgE, but some studies indicate there are several classes of responses, for example IgG1,IgG2, IgG4 that are associated with IgE. Gluten allergy may be a cause of some idiopathic gluten sensitivity and gluten allergy can be a secondary consequence of gluten-sensitive enteropathy.
covers all immunoglobulin isotypes and all gliadin isoforms. T-cell, Killer cell, and other gluten recognitions are covered in Gluten immunochemistry
.
From the perspective of gluten sensitivity there is no single definition of gluten that concisely defines all potentially pathogenic glutens. With wheat allergies, there can be a wide spectrum of species that may trigger allergies with similar proteins, the omega-gliadin proteins have similar proteins found in oats at high frequency, but omega-gliadin allergy is not a predictor of oat allergy or intolerance. A person can have an allergy to wheat, but not rye.
Glutelins have not been characterized over broad taxa. With idiopathic gluten sensitivity, the antibodies that correlate with disease are anti-gliadin antibodies
. Whether these antibodies are pathogenic or are simply indicators of circulating gliadin is unknown. For gluten-sensitive enteropathy, gliadin and homologous proteins from rye and barley cause disease. T-cell epitopes implicated in disease have been found in glutinous protein genes in all species sequenced within the tribe Triticeae. Also, since barley is distantly related to wheat, but carries pathogenic epitopes it can be assumed that all members of Triticeae should carry T-cell sites capable of sustaining disease (see also Genetics of Triticeae). While often not explicitly stated in some standards, pathogenic glutens found in wheat are also found in Spelt
and Kamut(both types of wheat), Triticale
(a trans-species Triticeae hybrid).
s are a species within the grass tribe Aveneae, which is in the Pooideae
subfamily along with Triticeae
(contains wheat, rye, barley and many other genera). Oats are the most closely related cereal species to Triticeae cereals. Some, but not all, cultivars of oat contain the pathogenic proteins that provoke a response in gluten sensitive individuals and those with celiac disease. Alternatively, oat seeds appear similar to seeds of wheat, barley and rye; cross-contamination between these grains is difficult to resolve.
, wheat was suspected as the cause of coeliac disease, and the gluten from wheat was identified as a cause soon after. At the time, duodenal biopsy—the current "gold standard
" of diagnosis—had not yet been developed; indirect measures of disease were used. In two studies, three children were fed 75 to 150 grams of oats per day and developed symptoms. In three concurrent studies, 10 children and two adults were allowed to eat 28 to 60 grams of oats and developed no symptoms. Since wheat, barley and sometimes rye are common contaminants in oats, until this was investigated, oats were considered to be toxic to coeliacs.
A barley-sensitive ELISA
called the R5 sandwich assay does not detect gluten in any of 25 pure oat varieties, but it does detect barley, wheat and rye. Disease-sensitive farming practices, antibody testing and species specific genetic testing are capable of producing pure oats. In the United States, 3 domestic GF-brands are available and one brand imported from Ireland 'reckons' to be 99.95% pure oats. Two brands in the United States use the R5 antibody test and claim to be below 20 PPM in defined gluten. However, the R5 antibody test has not been proven to be as sensitive as the G12 test.
Gluten
Gluten is a protein composite found in foods processed from wheat and related grain species, including barley and rye...
has an adverse effect on the body. It can be defined as a non-allergic and non-autoimmune condition in which the consumption of gluten can lead to symptoms similar to those observed in coeliac disease
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
or wheat allergy
Wheat allergy
Wheat allergy is a food allergy, but can also be a contact allergy resulting from occupational exposure. Like all allergies wheat allergy involves IgE and mast cell response. Typically the allergy is limited to the seed storage proteins of wheat, some reactions are restricted to wheat proteins,...
(other conditions which fall under the gluten-related disorders spectrum).
Gluten sensitivity is thought to affect approximately 6% of the general population . Symptoms of gluten sensitivity include bloating, abdominal discomfort, pain or diarrhoea; or it may present with a variety of extraintestinal symptoms including headaches and migraines, lethargy and tiredness, attention-deficit disorder and hyperactivity, autism and schizophrenia, muscular disturbances as well as bone and joint pain
Until recently, the terms gluten sensitivity and coeliac disease were used interchangeably in literature. However, emerging research is beginning to identify the differences that exist between coeliac disease and gluten sensitivity. If the medical history of a patient, along with clinical tests, rule out coeliac disease and wheat allergy, a diagnosis of gluten sensitivity can be considered. However, certain criteria need to be met before a diagnosis of gluten sensitivity can be confirmed (see diagnosis section). Treatment for all three conditions is a gluten-free diet; the difference being that with wheat allergy the interruption is temporary and drugs may be administered; in the case of coeliac disease the diet is lifelong and even ingesting very small amounts of gluten-containing food could damage their health and, in the case of gluten sensitivity the withdrawal of gluten from the diet may only be temporary.
Gluten is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
composite found in foods processed from wheat and related species, including barley and rye. It gives elasticity to dough helping it to rise and to keep its shape. It is found in many staple foods in the Western diet. Gluten is composed of a gliadin fraction (alcohol soluble) and a glutenin fraction (only soluble in dilute acids or alkali).
Symptoms
Symptoms of gluten sensitivity may include bloating, abdominal discomfort, pain or diarrhea; or it may present with a variety of extraintestinal symptoms including headaches and migraines, lethargy and tiredness, attention-deficit disorder and hyperactivity, autism and schizophrenia, muscular disturbances as well as bone and joint painDiagnosis of Gluten Sensitivity
If the medical history of a patient, along with clinical tests, rule out coeliac diseaseCoeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
and wheat allergy
Wheat allergy
Wheat allergy is a food allergy, but can also be a contact allergy resulting from occupational exposure. Like all allergies wheat allergy involves IgE and mast cell response. Typically the allergy is limited to the seed storage proteins of wheat, some reactions are restricted to wheat proteins,...
, a diagnosis of gluten sensitivity can be considered. However, before a diagnosis of gluten sensitivity can be confirmed the following criteria need to be met:
- Wheat allergy excluded (anti IgE antibody negative)
- Coeliac disease excluded (negative serological results of tTG/EMA/dAGA and IgA deficiency)
- Not HLA restricted- the absence of HLA DQ2/8 heterodimers makes it possible to practically rule out coeliac disease, however, it is also important to note that the presence of HLA DQ 2 or DQ8 does not always mean coeliac disease
- Intestinal biopsy shows no villous atrophy (Marsh III classification) but there may be minimal changes to the lining of the gut (Marsh 0-I classification)
- Possible presence of serum anti-gliadin antibodies (AGA) IgA and/or IgG investigated
- If the patient reports alleviation of symptoms on a gluten-free diet
If the above criteria are met then the person can be classed as ‘gluten sensitive’ and it can be treated with a gluten-free diet for a period of time. This should lead to symptom resolution.
A diagnostic algorithm for gluten sensitivity has been proposed:
Difference between gluten sensitivity and coeliac disease
Whilst the research surrounding gluten sensitivity is still very much emerging, coeliac disease is a well-defined condition. It is a lifelong autoimmune condition characterised by the chronic inflammation of the intestine. In genetically-predisposed children and adults the intake of foods containing gluten leads to an immune response in the small intestine. This results in the flattening of the intestinal villi and in reduced absorption of nutrients from food which can lead to nutritional deficiencies and associated long-term complications such as osteoporosis. It is believed coeliac disease affects 1% of the general population in the Western world.In comparison, in a recent clinical paper, gluten sensitivity was defined as ‘one or more of a variety of immunological, morphological or symptomatic manifestations that may also be shared by coeliac disease and irritable bowel syndrome (IBS) . In cases where there is reactivity to gluten, yet coeliac disease and wheat allergy are eliminated as possibilities, gluten sensitivity may be considered. Whilst the general clinical picture for gluten sensitivity is similar to coeliac disease in particular, it is usually less severe and neither anti-tissue transglutaminase antibodies nor autoimmune comorbidities are found.
It is believed that approximately 40-50% of gluten sensitivity patients may have IgG or IgA anti-gliadin antibodies (AGA) There is also a study identifying approximately 50% of gluten sensitivity patients, few more than the general population, carry either HLA DQ 2 or 8
On closer inspection, it has also been found that gluten-sensitive subjects do not develop full histological lesions; their lesions, if any, are limited to types 0-1 of the Marsh classification. In addition, it has been found that they have normal intestinal permeability and an increased expression of Toll Like receptors 2 (TLR2) but no change in the cytokines involved in adaptive immune responses Th1 and Th17 such as IL-6, IL-17 A, IL 21, which are increased only in patients with coeliac disease. The knowledge of the response in gluten sensitivity to date suggests that only the innate immune system is involved, whereas coeliac disease is an adaptive immune response (autoimmunity).
Gluten sensitivity should have a defined cause, although not apparent always with first examination, affected individuals should eventually fall into GSE or wheat allergy. Only rarely should gluten sensitivity be idiopathic. Idiopathic gluten sensitivity (IGS) arises spontaneously or from an obscure or unknown cause and may involve neuropathy, myopathy, dermal, or intestinal abnormalities. Anti-gliadin antibodies are the primary link between gluten and idiopathic sensitivity in instances "in which enteropathy or allergy are not clearly involved". This form of gluten sensitivity is controversial at the moment but there is a growing body of research to support the concept of gluten sensitivity that is different from coeliac disease and wheat allergy.
Etiology
Gluten sensitivity can develop at any point in life, and symptomatic disease may appear years after disease develops. When enteropathy develops in early childhood symptomatic disease is more rapidly evident. A survey of geriatrics with coeliac disease in Finland revealed that the incidence of disease was much higher than the general population. Allergic disease may rise or fall with age; however, certain evidence points to the increased or daily use of non-steroidal anti-inflammatory factors (aspirin, ibuprofen) as an increased risk factor for urticaria or anaphylaxis, and the sensitizing dose may include low-dose aspirin therapy used in the treatment of heart disease. Idiopathic disease appears largely late onset.Gluten-sensitive enteropathy develops as a consequence of genetic and environmental factors. Other than the involvement of certain HLA-DQ isoforms (antigen presenting proteins in humans) and certain wheat proteins, there is no clarity in the involvement of other genes or other environmental factors (see risk modifiers). Strong genetic factors such as seen in GSE have not been seen in gluten allergy, and with idiopathic gluten-sensitivity the HLA-DQ associations are weak.
Researchers reported extreme fatigue and pain in patients without celiac disease, with gliadin antibodies. They called this a “non-celiac gluten intolerance” for which there is no explanation as to the mechanisms involved.
Causes of gluten sensitivity
EWLINE
|
Triticeae and the potential role of selective evolution in gluten sensitivities
The fruiting bodies of plants contain genes as well as reserves of nutrients that allow seedlings to grow. The enrichment of nutrients is an attractant to herbivores and omnivores. For annual grasses that release seeds during a brief period each year there is a need to protect seeds during maturation from insects or animals, which might stock seeds for year round usage. For wheat, alpha-gliadins are seed-storage proteins, but also act as inhibitors of alpha-amylase activity in some animals, particularly in insects. It is also known that wheat gliadins create intestinal disease when fed to very young rodents. One recent publication even raises the question 'is wheat safe for anyone to eat?'. Critically, pathology in insects or artificially fed rodents does not reflect what causes disease in humans, but it is interesting that toxicological effects of wheat are being uncovered that do have the potential to cause pathology in humans. One interesting consequence of these studies is that there may be a general gluten sensitivity that underlies various pathological manifestations, such as coeliac disease, urticaria and idiopathic sensitivity.The rise of gluten sensitivity (particularly in adults) may reflect the convergence of many phenomena. An aging population, genetic risks associated with westernization, excesses in the diet, sensitizing chemicals (e.g.NSAIDs), and allergy-enhancing chemical treatment of foods (e.g. enzymatic deamidation of gluten) may act together with natural defensive agents in foods to cross the threshold between normality and pathology.
Gluten toxicity
An increasing number of studies on gliadin indicate gluten has a direct and modifying effect on the cells of the small intestine. Two different lines of research show that different gliadins can increase permeability of the epithelial cells (outermost cells of the villus) allowing food proteins to enter. One study examined the effect of ω-5 gliadin, the primary cause of exercise/aspirin induced anaphylaxis, and found increased permeability of intestinal cells caused by this gliadin and another wheat albumin. Another line of research shows gliadin binds a chemoattractant receptor and causes increases of a factor that destroys tight junctionTight junction
Tight junctions, or zonula occludens, are the closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid. It is a type of junctional complex present only in vertebrates...
s. These junctions prevent leakage around the cells that line the small intestine, resulting in the leaking of food proteins into the body. These toxicities of gluten that are not part of the adaptive immune response may be the link between wheat and gluten sensitivity, and possibly type 1 diabetes.
Immunochemistry of glutens
Triticeae glutensTriticeae glutens
Triticeae glutens are seed storage proteins found in mature seeds of grass tribe Triticeae. Seed glutens of non-Triticeae plants have varieties of similar properties, but none singly can perform on a par with those of the Triticeae taxa, particularly the triticum species...
are important factors in several inflammatory diseases. The immunochemistry can be subdivided into innate responses (direct stimulation of immune system), class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
mediated presentation (HLA DQ), class I
MHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...
mediated stimulation of killer cells, and antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
recognition. The responses to gluten
Gluten
Gluten is a protein composite found in foods processed from wheat and related grain species, including barley and rye...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s and polypeptide regions differs according to the type of gluten sensitivity. The response is also dependent on the genetic makeup of the human leukocyte antigen
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
genes. In enteropathy, there are at least 3 types of recognition, innate immunity (a form of cellular immunity priming), HLA-DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
and antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
recognition of gliadin and transglutaminase. The three dominant sequences responsible for the antibody reaction have been identified. With idiopathic disease only antibody recognition to gliadin has been resolved. In wheat allergy
Wheat allergy
Wheat allergy is a food allergy, but can also be a contact allergy resulting from occupational exposure. Like all allergies wheat allergy involves IgE and mast cell response. Typically the allergy is limited to the seed storage proteins of wheat, some reactions are restricted to wheat proteins,...
, there appears to be an innate components and the response pathways are mediated through IgE against gliadin and other wheat proteins.
Separating forms of gluten sensitivity
Only rarely should gluten sensitivity be without cause. Generally the sensitivity can be split between coeliac diseaseCoeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
, gluten sensitivity and wheat allergy
Wheat allergy
Wheat allergy is a food allergy, but can also be a contact allergy resulting from occupational exposure. Like all allergies wheat allergy involves IgE and mast cell response. Typically the allergy is limited to the seed storage proteins of wheat, some reactions are restricted to wheat proteins,...
. Since individuals with coeliac disease can also have wheat allergy, a finding of wheat allergy does not eliminate the possibility of enteropathy. Individuals highly suspect of coeliac disease may be tested for anti-transglutaminase antibodies
Anti-transglutaminase antibodies
Anti-transglutaminase antibodies are autoantibodies against the transglutaminase protein. Antibodies serve an important role in the immune system by detecting cells and substances that the rest of the immune system then eliminates. These cells and substance can be foreign and also can be producd...
followed by duodenal biopsy, this will confirm or refute active coeliac disease. The study that recommends this, however, has a number of ATA
Anti-transglutaminase antibodies
Anti-transglutaminase antibodies are autoantibodies against the transglutaminase protein. Antibodies serve an important role in the immune system by detecting cells and substances that the rest of the immune system then eliminates. These cells and substance can be foreign and also can be producd...
positive/biopsy-negative individuals, this could result from patchy villous atrophy or subclinical pathology. One current study recommended at biopsy samples running distally from the duodenum to avoid the risk of false negatives. Eliminating the possibility of coeliac disease can generally be done by adding HLA-DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
typing, in which DQ2
HLA-DQ2
HLA-DQ2 is a serotype group within HLA-DQ serotyping system. The serotype is determined by the antibody recognition of β2 subset of DQ β-chains. The β-chain of DQ is encoded by HLA-DQB1 locus and DQ2 are encoded by the HLA-DQB1*02 allele group. This group currently contains two common alleles,...
and DQ8
HLA-DQ8
HLA-DQ8 is a human leukocyte antigen serotype within the HLA-DQ serotype group. DQ8 is a split antigen of the DQ3 broad antigen. DQ8 is determined by the antibody recognition of β8 and this generally detects the gene product of DQB1*0302....
are found in enteropathy 98% of the time in caucasians, DQ7.5 the remaining 1.6% and 0.4% not found with either of these 3. Without ATA or HLA-DQ2/8 positivity, coeliac disease is not likely the cause of the sensitivity.
In either case, other avenues of diagnostics, such as allergy testing are available. Rarely gluten sensitivity may be idiopathic, a potential that wheat proteins play a role in other disease, in these instances DQ1
HLA-DQ1
HLA-DQ1 is a serotype that covers a broad range of HLA-DQ haplotypes. Historically it was identified as a DR-like alpha chain called DC1, later, it was among 3 types DQw1 , DQw2 and DQw3. Of these three serotyping specificities only DQw1 recognized DQ alpha chain. The serotype is positive in...
may be associated with sensitivity. There is research showing that in certain patients with gluten ataxia early diagnosis and treatment with a GFD can improve ataxia and prevent its progression. Recently, a classification of gluten-related disorders has been proposed:
Gluten-sensitive enteropathy
Coeliac disease as the classically defined gluten-sensitivity and dermatitis herpetiformis was appended to a broadening definition of gluten sensitivity. The diagnostic "gold standard" of coeliac disease is the villus atrophy detected in duodenal
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
biopsies. However, it is now recognized that inflammation of the epithelial tissue of the small intestine precedes atrophy. Early in the disease, gluten elicits T-lymphocyte recognition of gluten hydrolysates (polypeptides of gluten) and gluten peptides bind to mammalian tissue transglutaminase
Transglutaminase
Transglutaminases are a family of enzymes that catalyze the formation of a covalent bond between a free amine group and the gamma-carboxamid group of protein- or peptide-bound glutamine. Bonds formed by transglutaminase exhibit high resistance to proteolytic degradation.Transglutaminases were...
(tTG). This second interaction results in the production of "self" antibodies to tTG
Anti-transglutaminase antibodies
Anti-transglutaminase antibodies are autoantibodies against the transglutaminase protein. Antibodies serve an important role in the immune system by detecting cells and substances that the rest of the immune system then eliminates. These cells and substance can be foreign and also can be producd...
. This increases lymphocytes within the epithelia of the small intestine (Marsh grade 1 and 2) and antibody-tTG complexes seen as deposits. This usually progresses to coeliac disease (Marsh grade 3 and 4). The dietary cause of GSE is not limited to wheat gluten; 'glutens'
Triticeae glutens
Triticeae glutens are seed storage proteins found in mature seeds of grass tribe Triticeae. Seed glutens of non-Triticeae plants have varieties of similar properties, but none singly can perform on a par with those of the Triticeae taxa, particularly the triticum species...
from all known edible cultivar
Cultivar
A cultivar'Cultivar has two meanings as explained under Formal definition. When used in reference to a taxon, the word does not apply to an individual plant but to all those plants sharing the unique characteristics that define the cultivar. is a plant or group of plants selected for desirable...
s of Triticeae can induce GSE in susceptible individuals (see: Gluten immunochemistry
Gluten immunochemistry
The immunochemistry of Triticeae glutens is important in several inflammatory diseases. It can be subdivided into innate responses , class II mediated presentation , class I meditiated stimulation of killer cells, and antibody recognition. The responses to gluten proteins and polypeptide regions...
).
| DQ haplotypes -Celiac Disease | |||||
| DQ hap | 2.5 | 2.2 | 7.5 | 8.0 | Other |
| 2.5 | 34 | 22 | 4.0 | 2.0 | 22 |
| 2.2 | 1.1 | 4.0 | 1.1 | 2.9 | |
| 7.5 | 0.3 | 0.0 | 1.3 | ||
| 8.1 | 2.9 | 2.0 | |||
| other | 0.4 | ||||
| DQ haplotypes -Normal Population | |||||
| DQ hap | 2.5 | 2.2 | 7.5 | 8.1 | Other |
| 2.5 | 1.7 | 2.9 | 2.9 | 1.8 | 15.1 |
| 2.2 | 1.2 | 2.4 | 1.6 | 12.8 | |
| 7.5 | 1.2 | 1.5 | 1.3 | ||
| 8.1 | 0.5 | 8.0 | |||
| other | 33.4 | ||||
| Odds ratios | |||||
| DQ hap | 2.5 | 2.2 | 7.5 | 8.1 | Other |
| 2.5 | 20:11 | 8:12 | 1.4:16 | 1.1:1 | 1.5:15 |
| 2.2 | 1:1.1 | 1.6:14 | 1:1.3 | 1:5 | |
| 7.5 | 1:4 | 0 | 1:10 | ||
| 8.1 | 6:13 | 1:4 | |||
| other | 1:100 | ||||
| DQ Types by allele numbers (e.g. 0501) can be found here | |||||
There are a large number of medical conditions that result from GSE that can occur prior to the development of coeliac disease and might be gluten responsive. While the level of villus atrophy in some cases of GSE may not reach clinical coeliac disease recognition, the elevation of cellular immunity is capable of producing disorders more frequently found in coeliac disease. Conditions secondary to GSE are important diagnostic criteria for gluten sensitivity when there may be no obvious intestinal abnormality. Presentation of GSE is often the result of initial recognition of the secondary condition which in followup testing (ATA
Anti-transglutaminase antibodies
Anti-transglutaminase antibodies are autoantibodies against the transglutaminase protein. Antibodies serve an important role in the immune system by detecting cells and substances that the rest of the immune system then eliminates. These cells and substance can be foreign and also can be producd...
test, AGA
Anti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies...
test, HLA-DQ
HLA-DQ
HLA-DQ is a cell surface receptor type protein found on antigen presenting cells. DQ is an αβ heterodimer of the MHC Class II type. The α and β chains are encoded by HLA-DQA1 and HLA-DQB1, respectively. These two loci are adjacent to each other on chromosome 6p21.3. Both the α-chain and β-chain...
typing, and/or biopsy) recognizes the primary condition. The secondary conditions associated with GSE tend to make late onset coeliac disease a systemic phenomena.
Idiopathic gluten sensitivity
Idiopathic diseases are proposed as an expansion of the gluten-sensitivity. By the definition of idiopathic disease, the cause is not well defined. One hundred years ago, before gluten was discovered as the cause of coeliac disease, coeliac disease in adults was called adult idiopathic steatorrhoea, non-tropical sprue, sprue nostras, and many other names. The debate over this subset stems from the fact that identification of all grades of GSE and allergies is not uniformly approached. Most cases of early GSE go undetected, particularly before 2005. There appears to be a small fraction of non-GSE gluten-sensitive individuals that show neither gluten-allergies but do have elevated anti-gliadinAnti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies...
IgA or IgG. Common symptoms are peripheral neuropathies and cerebral ataxia. Within the GSE set these may be explained by calcification of brain channels and avitaminosis. Within the remaining 'DQ2 and DQ8'less cohort. Given that this cohort of GS is idiopathic, the role of allergies, other sensitivities (e.g. aspirin), or other factors in IGS is also unresolved.
Silent Disease. Depending on testing somewhere between 3 and 15% of the normal population have anti-gliadin antibodies (AGA). Studies using anti-gliadin antibodies (AGA) reveal that in undiagnosed or untreated individuals with AGA, with increasing risk for lymphoid cancers and decreased risk for other associated with affluence. Though it is unknown in these studies the percentage that are early stage GSE.
Other conditions
Antibodies to α-gliadinAnti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies...
have been significantly increased in non-coeliacs individuals with oral ulceration. Anti-α-gliadin antibodies are frequently found in coeliac disease
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
(CD), to a lesser degree subclinical CD, but are also found in a subset who do not have the disease. The 1991 reference comes from a period when testing for subclinical CD was undeveloped. Of people with pseudo-exfoliation syndrome, 25% showed increased levels of anti-gliadin IgA. One forth of people with Sjögren's syndrome had responses to gluten, of 5 that had positive response to gluten, only one could be confirmed as CD and another was potentially GSE, the remaining 3 appear to be gluten-sensitive. All were HLA-DQ2 and/or DQ8-positive. Treatment to produce remission of Crohns disease(CrD) symptoms on elimination diet indicated the most important foods provoking symptoms were wheat and dairy. A later paper showed little IgE mediated response except to the dairy, while another paper showed no significant anti-food IgE association. Crohn's disease (CrD) may have a link to wheat that is independent of gluten. CrD appears to be associated with high anti-yeast antibodies (ASCA - yeast antigens that are found in bread and other cereal derived products) and affected individuals lack lectin binding proteins such that the mannins in yeast, the antibodies that bind them and aggravate inflammatory colitis. One concern of the above studies is the high prevalence of markers for gluten-sensitive enteropathy, one has to question how idiopathic these conditions are if close examination for GSE has not been undertaken.
Gluten-allergy related sensitivities
Why treat gluten allergies as sensitivities? Over the last 10 years it has becomeapparent that allergies to certain substances do not behave in predictable ways. One clear example of this is exercise induced anaphylaxis and asthma, WDEIA (Wheat Dependent Exercise Induced Anaphylaxis
Exercise-induced anaphylaxis
Exercise-induced anaphylaxis is a syndrome in which the symptoms of anaphylaxis occur related to exercise.In some incidents, individuals experienced anaphylaxis only after combination exposure to a triggering agent and increased physical activity shortly after the ingestion of the triggering agent...
) is now believed to be induced by ingested gluten that finds a way into the blood stream. This pathway is now believed responsible for some forms of eczema. Recent studies on two wheat allergens show that they possess the capability of bypassing the gut/blood barrier. The most active of these is ω-5 gliadin, a gluten component that is a strong allergen and causes WDEIA. Allergy tests may not reveal allergies to gluten because the unfractionated allergens are 'hidden' from these tests, and most currently available tests cannot detect these new allergens. Finally, allergies typically involve IgE, but some studies indicate there are several classes of responses, for example IgG1,IgG2, IgG4 that are associated with IgE. Gluten allergy may be a cause of some idiopathic gluten sensitivity and gluten allergy can be a secondary consequence of gluten-sensitive enteropathy.
Comparative pathophysiology
Notes on table. Features of idiopathic neuropathy assume that all GSE cohort has been removed, assuming there is a gluten-sensitive, but not GSE contingent. Anti-gliadin antibodiesAnti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies...
covers all immunoglobulin isotypes and all gliadin isoforms. T-cell, Killer cell, and other gluten recognitions are covered in Gluten immunochemistry
Gluten immunochemistry
The immunochemistry of Triticeae glutens is important in several inflammatory diseases. It can be subdivided into innate responses , class II mediated presentation , class I meditiated stimulation of killer cells, and antibody recognition. The responses to gluten proteins and polypeptide regions...
.
Gluten sources
EWLINE
|
From the perspective of gluten sensitivity there is no single definition of gluten that concisely defines all potentially pathogenic glutens. With wheat allergies, there can be a wide spectrum of species that may trigger allergies with similar proteins, the omega-gliadin proteins have similar proteins found in oats at high frequency, but omega-gliadin allergy is not a predictor of oat allergy or intolerance. A person can have an allergy to wheat, but not rye.
Glutelins have not been characterized over broad taxa. With idiopathic gluten sensitivity, the antibodies that correlate with disease are anti-gliadin antibodies
Anti-gliadin antibodies
Antigliadin antibodies are produced in response to gliadin, a prolamin found in wheat. In bread wheat it is encoded by three different alleles, AA, BB, and DD. These alleles can produce slightly different gliadins, which can cause the body to produce different antibodies...
. Whether these antibodies are pathogenic or are simply indicators of circulating gliadin is unknown. For gluten-sensitive enteropathy, gliadin and homologous proteins from rye and barley cause disease. T-cell epitopes implicated in disease have been found in glutinous protein genes in all species sequenced within the tribe Triticeae. Also, since barley is distantly related to wheat, but carries pathogenic epitopes it can be assumed that all members of Triticeae should carry T-cell sites capable of sustaining disease (see also Genetics of Triticeae). While often not explicitly stated in some standards, pathogenic glutens found in wheat are also found in Spelt
Spelt
Spelt is a hexaploid species of wheat. Spelt was an important staple in parts of Europe from the Bronze Age to medieval times; it now survives as a relict crop in Central Europe and northern Spain and has found a new market as a health food. Spelt is sometimes considered a subspecies of the...
and Kamut(both types of wheat), Triticale
Triticale
Triticale is a hybrid of wheat and rye first bred in laboratories during the late 19th century. The grain was originally bred in Scotland and Sweden. Commercially available triticale is almost always a second generation hybrid, i.e., a cross between two kinds of primary triticales...
(a trans-species Triticeae hybrid).
The oat controversy
OatOat
The common oat is a species of cereal grain grown for its seed, which is known by the same name . While oats are suitable for human consumption as oatmeal and rolled oats, one of the most common uses is as livestock feed...
s are a species within the grass tribe Aveneae, which is in the Pooideae
Pooideae
The Pooideae is a subfamily of the true grass family Poaceae. It includes some major cereals such as wheat, barley, oat, rye and many lawn and pasture grasses.- List :...
subfamily along with Triticeae
Triticeae
Triticeae is a tribe within the Pooideae subfamily of grasses that includes genera with many domesticated species. Major crop genera are found in this tribe including wheat , barley, and rye; crops in other genera include some for human consumption and others used for animal feed or rangeland...
(contains wheat, rye, barley and many other genera). Oats are the most closely related cereal species to Triticeae cereals. Some, but not all, cultivars of oat contain the pathogenic proteins that provoke a response in gluten sensitive individuals and those with celiac disease. Alternatively, oat seeds appear similar to seeds of wheat, barley and rye; cross-contamination between these grains is difficult to resolve.
Origin of controversy
After World War IIWorld War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...
, wheat was suspected as the cause of coeliac disease, and the gluten from wheat was identified as a cause soon after. At the time, duodenal biopsy—the current "gold standard
Gold standard (test)
In medicine and statistics, gold standard test refers to a diagnostic test or benchmark that is the best available under reasonable conditions. It does not have to be necessarily the best possible test for the condition in absolute terms...
" of diagnosis—had not yet been developed; indirect measures of disease were used. In two studies, three children were fed 75 to 150 grams of oats per day and developed symptoms. In three concurrent studies, 10 children and two adults were allowed to eat 28 to 60 grams of oats and developed no symptoms. Since wheat, barley and sometimes rye are common contaminants in oats, until this was investigated, oats were considered to be toxic to coeliacs.
Current findings
While the problem of contamination has been known for several years, scientists' understanding of how oats and gluten are related continues to evolve. A study published in February 2011 uncovered differing levels of toxicity amongst different varieties of oat, indicating that cross-contamination is not the only reason why some oats provoke reactions in some people with a gluten intolerance. A study published in June 2008 found that of 109 sources of oats screened, 85 had unacceptable levels of gluten from wheat, barley or rye. Triticeae contaminated oats in the study came from many countries indicating that most sources of oats are unacceptable for GS based on contamination.Tolerable levels of gluten
In summary of recent developments, oats can be tolerated in a gluten-free diet, but oat products should be limited in contamination from Triticeae derived gluten to 20 PPM (20 mg per kg). US states are free to deny the GF-label standard for oat products, if warranted (see Politics of Gluten-Free and oats).Gluten-free testing
As of February 2011, G12, the newest monoclonal antibody (moAb) available, is the only one proven to detect both cross-contamination in oats and also the inherent gluten / avenin that is only found in some varieties of oat. Alternative methods of detection, while currently accepted by many gluten-free certification organizations, are not in fact able to detect this second form of gluten in oats. This may partially explain why some celiacs react to oats and others do not.A barley-sensitive ELISA
ELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...
called the R5 sandwich assay does not detect gluten in any of 25 pure oat varieties, but it does detect barley, wheat and rye. Disease-sensitive farming practices, antibody testing and species specific genetic testing are capable of producing pure oats. In the United States, 3 domestic GF-brands are available and one brand imported from Ireland 'reckons' to be 99.95% pure oats. Two brands in the United States use the R5 antibody test and claim to be below 20 PPM in defined gluten. However, the R5 antibody test has not been proven to be as sensitive as the G12 test.