Gluten sensitivity

Gluten sensitivity (GS) describes the collection of medical conditions in which the patient responds favorably, either directly or indirectly, to the removal of gluten from the diet. Direct improvement can be seen for patients with enteropathy. The improvements are observed clinically by the restoration of villus architecture or lower lymphocyte densities in the intestine. Indirect improvements may be seen in the neurological state, blood chemistry , treatability of certain autoimmune diseases, and/or an untreated improvement in autoimmune conditions.

Glutens are the seed storage proteins of grasses. Gluten-sensitive enteropathy (GSE), coeliac disease describes the physical changes within the gut, ultimately destructive, that occur as a result of cellular immunity to 2 types of Triticeae glutens, prolamins and glutelins. This involves both an innate immune response and T-helper cell response. Gluten allergy is a subset of allergic (Mast cell and IgE) responses that are directed toward any of all 4 gluten types. These are not especially different from other allergies, but sensitivity to gluten may be diagnosed in advance of the diagnosis of allergy as some gluten proteins are not detected as allergens using certain procedures, and some of the modes which the reaction occurs are not obviously allergic. Idiopathic gluten sensitivity (IGS) arises "spontaneously or from an obscure or unknown cause". IGS is identified as a neuropathy, myopathy, etc. without a defined GSE or allergic cause, and typically shows elevated anti-gliadin antibodies.

There relationship between gluten and these various sensitivities is complex. For gluten enteropathy, T-cell reactivity almost entirely restricted to prolamin-glutelin/species within the grass tribe Triticeae. For some 2% of GSE, it may also include some pure oat cultivars. Gluten allergies may extend over wide taxa or may be specific to certain wheat proteins.

Causes of gluten sensitivity
Triticeae and the potential role of selective evolution in gluten sensitivities. Some of the recently discovered biochemical and immunochemical properties of these proteins suggest they evolved for protection against dedicated or continuous consumption by mammalian seed eaters. One recent publication even raises the question 'is wheat safe for anyone to eat?'. The cause of wheat gluten sensitive enteropathy points prominently to 2 regions of alpha gliadin, regions that contain two motifs, an innate and a cellular-immunity (T-cell) recognition site, these sites are poorly digested in the gut. The target of both GSE and IGS appear to be regions of this protein(s). Gluten allergies have no specific cause, other than GSE itself in many cases, as allergies react to a wide variety of proteins in wheat. The rise of gluten sensitivity (particularly in adults) appears to reflect overconsumption of wheat, feeding habits of small children, overuse of intestine damaging chemicals (MSG, aspirin, NSAIDS), and allergy-enhancing chemical treatment of wheat (enzymatic deamidation).

Gluten-sensitive enteropathy
Brief overiew. Gluten sensitive enteropathy (GSE) is a condition in which gluten elicits T-lymphocyte recognition and gluten bound to mammalian tissue transglutaminase (tTG). This second interaction results in the production of antibodies to tTG. Since tTG is a 'self' protein GSE is an autoimmune disease. The disease, GSE, begins with the increase in lymphocyte number within the epithelia of the small intestine (Marsh grade 1 and 2) and with an increase of (anti-tTG)-tTG complexes seen as deposits. This usually progresses to coeliac disease (Marsh grade 3 and 4).

Involvement of Triticeae proteins
Triticeae glutens are the principal cause of GSE. Glutens from cultivars of Triticeae can induce GSE in susceptible individuals. While commonly considered an allergy, the effects of wheat gliadin (α/β or γ), barley hordein and rye secalin (In some individuals glutenin or glutenin like proteins can play a role) acts as a poison which cause a destructive innate immunity and cellular immunity that flattens the intestinal epithelium of affected individuals. This causes malabsorption, GI distress, and a large list of secondary problems. The primary autoimmune target for GSE is tissue transglutaminase (tTG), a protein involved in deamidation and transamidation of gliadin's glutamine amide motif. These proteins bind DQα5β2 which then stimulated gliadin reactive T-cells.

Conditions Secondary to GSE
Conditions secondary to GSE are important diagnostic criteria for gluten sensitivity because initial clinical presentation of GSE is often the result of initial recognition of the secondary condition which in followup recognizes the primary condition. The secondary conditions associated with GSE make late onset celiac disease a systemic phenomena. While the level of villous atropy in some cases of GSE may not reach clinical celiac disease recognition, the elevation of cellular immunity is capable of producing, to a lessor degree, secondary conditions found in coeliac disease.

Idiopathic gluten sensitivity
Idiopathic gluten sensitivities are not as well defined as GSEA and gluten-allergy associated sensitivities. 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-gliadin IgA or IgG. Common symptoms are peripheral neuropathies and cerebral ataxia. Within the GSEA set these may be explained by calcification of brain channels and avitaminosis. Within the 'true' IGS close examination has not been done. It is unclear how much of the phenomena can be explained by allergies, by contribution of innate immunity, or some altered T-cell mediated immunity.

At present about the only thing that can be defined is an improvement in patient condition on gluten-free (GF) Diet. Some of the categories listed below may be moved to GSE or Gluten allergy with more research or in the case of Crohn's Disease, should be removed as being gluten sensitive.

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 GSE.

IGS Non-neurological conditions
Multiple sclerosis. Significantly increased levels of IgA and IgG antibodies against gliadin and gluten were found in multiple sclerosis compared with controls. IgA antibodies against casein were significantly increased. Anti-endomycium and anti-transglutaminase antibodies were negative.

Oral Ulcerations. Antibodies to α-gliadin have been significantly increased non-CD individuals with oral ulceration. Anti-α-gliadin antibodies are freqeuntly found in patients with coeliac disease, to a lessor 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.

Ocular exfoliations. Of people with pseudo-exfoliation syndrome, 25% showed increased levels of anti-gliadin IgA.

Sjögren's syndrome, primary(pSS). 1/4th of patients with Sjögren's syndrome had responses to gluten, of 5 that has positive response to gluten, only one could be confirmed as CD and another was potentially GSE, the remaining 3 appear to be idiopathic gluten sensitivities. All were HLA-DQ2 and/or DQ8-positive.

Crohn's disease. Treatment to produce remission of symptoms on elimination diet indicated the most important foods provoking symptoms were wheat and dairy. . A later paper showed little IgE mediated response to the except to dairy, and still 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) and may lack lectin binding proteins such that the Mannans in yeast and the antibodies that bind them aggravate colitis.

Gluten-allergy related sensitivities
Why treat gluten allergies as sensitivities?. Over the last 10 years is has become apparent that allergies to certain substances do not behave in predictable ways. One clear example of this is exercise induced anaphylaxis and asthma, WDEIA is now believed to be induced by injested gluten that finds a way into the blood stream. This pathway is now believed responsible for some forms of eczema. 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 these. Gluten allergy may be a cause of some idiopathic gluten sensitivity.

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 antibodies covers all immunoglobulin isotypes and all gliadin isoforms. T-cell, Killer cell, and other gluten recognitions are covered in.

Immunochemistry of glutens
The immunochemistry of Triticeae glutens is important in several autoimmune diseases. It can be subdivided into innate responses (direct stimulation of immune system), Class II mediated presentation (HLA DQ), Class I meditiated stimulation of killer cells, and Antibody recognition. The DQ restricted class II mediated presentation of gliadin to T-helper lymphocytes appears to be the primary process involved in Coeliac Disease. Numbers in parenthese (###-###) refer to amino acid sequences in the proteins that are immunogenic by the stated categories (Innate, Antibody epitopes, HLA Class II epitopes, HLA Class I epitopes.

Differential involvement
GSE IGS Gluten Allergy
 * Innate immunity - Priming of cellular immunity
 * HLA class I - Destructive immunity, Apoptosis mediator stage 3 and 4 coeliac disease
 * Antibody recognition - Transfer immunity to tTG (IgG & IgA), secondary autoimmune triggers (IgG), allergy triggers (IgE, IgG, IgA).
 * Antibody recognition - Anti-gliadin IgG, IgA?
 * Antibody recognition - IgE against array of glutens.

Innate immunity

 * α-/β-gliadins
 * α-2 gliadin (31-43)
 * α-9 gliadin (31-43)

HLA class I restrictions
Restrictions of CD8+ T-lymphocytes (Apoptosis mediators)
 * A2 (A*0201 in DQ8+)
 * α-/β-gliadins (carboxyl end)
 * A-gliadin (123-131), (144-152), (172-180)

HLA class II''' restrictions
Restrictions of CD4+ T-lymphocytes (anti-gluten response mediators)

DQ2
DQ2 (α5) - DQα5β2 isoforms
 * DQ2.5 - DQ(A1*0501:B1*0201)
 * DQα5β201 isoform
 * DQ2.2/DQ7.5 - DQ (A1*0201:B1*0202 / A1*0505:B1*0301)
 * DQα5β202 isoform
 * DQ2.2 - DQ(A1*0201:B1*0202)
 * DQα2β202 isoform (less stimulatory)

Gliadins
 * α-/β-gliadins (amino, central and carboxyl ends)
 * α-2 gliadin (57-68), (62-75), (56-88, the 33mer)
 * α-4 gliadin (57-68), (62-75), (69-79)
 * α-9 gliadin (57-68), (62-75), (69-79), (76-83)
 * α-_ gliadin ' 'α-20' ' motif many sites, see details
 * -α-2 secalin (8-19), (13-23)
 * γ-gliadins
 * γ-5 gliadin (60-79), (66-78), (102-113), (115-123), (228-236)
 * γ-M369999 gliadin (16-24), (65-76), (70-79), (79-90), (94-102), (115-126), (128-136), (233-241)
 * γ-_ gliadin ' 'γ-30' ' motif see details
 * -γ- secalin (80-93), (117-125)
 * --- hordein (56-69)
 * ω-gliadins
 * ω-ABI20696 gliadin (T. timopheevii) (96-106)
 * ω-5-gliadin
 * LMW glutenin
 * K1-like (46-60)
 * pGH3-like (41-59), GF1(33-51)
 * HMW glutenin - (not yet characterized to the epitope level)

DQ8
DQ8 (DQA1*0301:DQB1*0302)
 * α-/β-gliadins (carboxyl end)
 * α-AJ133612 gliadin (~230-240), (>241-<255)
 * γ-gliadins
 * γ-M369999 gliadin (~16-24), (>41-<60), (~79-90), (~94-102), (>101-<120)
 * HMW glutenin (higher than DQ2.5) - (not yet characterized to the epitope level),

Other DQ
Gluten sensitive enteropathy and idiopathic gluten sensitivity has been associated with other DQ isoforms by certain diagnostic laboratories and research groups. DQ2.5 and DQ8 cover the 99+% of all GSE instances within the western eurasian derived population (Europe, Central Asia, North America). There is the small potential that other haplotypes can mediate this disease in Africa or Asia. Gluten sensitive neuropathy has been loosely associated with DQ1, others have associated gluten sensitivities with DQ3. DQ1, DQ2, DQ3 cover all DQ types in the modern population except the rather rare DQ4 haplotypes. Such broad associations lack statistical significance.

Antibody recognition

 * IgA/IgG
 * A-2 gliadin Â(57-73)-
 * glb-1 (a globulin) - implicated in crossreactive autoantigenic antibodies that destroy islet cells in the pancrease of Type 1 diabetes.
 * Synapsin I (mammalian, autoantigenic, gliadin crossreactive)
 * Tissue Transglutaminase (tTG) - Covelant linkage of tTG to gliadin facilitates the gliadin restricted T-cell activation of tTG reactive B-cells, causing primary autoimmunity in celiac disease.
 * IgE (true allergic responses)
 * ω-gliadin - antigen responsible for gluten sensitive exercise induced anaphylaxis and Baker's allergy
 * HMW Glutenin subunit - antigen responsible for gluten sensitive exercise induced anaphylaxis
 * alpha-amylase/trypsin inhibitor subunits -
 * LTP (albumin/globulin) -
 * thioredoxin-hB (wheat allergen #25) - antigen involved in Baker's Allergy, cross reactive with homologous corn thioredoxin.
 * Wheat flour peroxidase
 * "Q-Q-Q-P-P" motif in undefined gliadin

Taming Triticeae Immunochemistry
New immunogenic motifs appear in the literature almost monthly and new gliadin and Triticeae protein sequences appear that contain these motifs. The HLA DQ2.5 restricted peptide "I I Q P Q Q P A Q" produced approximately 50 hits of identical sequences in NCBI-Blast search is one of a several dozen known motifs whereas only a small fraction of Triticeae gluten variants have been examined. For this reason the immunochemisty is best discussed at the level of Triticeae, because it is clear that the special immunological properties of the proteins appear to have basal affinities to this taxa, appearing concentrated in wheat as a result of its three various genomes. Some current studies claim that removing the toxicity of gliadins from wheat as plausbile, but, as the above illustrates, the problem is monumental. There are many gluten proteins, 3 genomes with many genes each for alpha, gamma, and omega gliadins. For each motif many genome-loci are present, and there are many motifs, some still not known. Different strains of triticeae exist for different industrial applications; durum for pasta and food pastes, 2 types of barley for beer, bread wheats used in different areas with different growing conditions. Replacing these motifs is not a plausible task since a contamination of 0.02% wheat in a GF diet is considered to be pathogenic and would require replacing motifs in all known regional varieties, potentially 1000s of genetic modifications. Class I and Antibody responses are downstream of Class II recognition and are of little remedial value in change. The innate response peptide could be a silver bullet, assuming there is only one of these per protein and only a few genome loci with the protein. The bigger question is why late onset gluten sensitivity rapidly rising, is this truly a wheat problem or is it something that being done to wheat, or to those who are eating wheat (for example communicable diseases as trigger)? Some individuals are susceptible by genetics (early onset), but many late onset cases could have variable triggers because there is nothing genetically that separates the 30 to 40% of caucasians that could have Triticeae senstivity from the ~1% that, in their lifetime, will have some level of this disease. Another strategy in making wheat less immunogenic is to insert proteolytic sites in the longer motifs (25-mer and 33-mer) facilitating more complete digestion.

Meta-medical phenomena
Fads. Gluten-free dieting needs to be separated from gluten-sensitivity. The gluten free diet has become increasingly popular, and wheat-free aspects have become popular parts of other diets, such as the A-B-O diet. Excepting gluten allergies, most people who require a gluten-free diet are genetically predisposed by the HLA-DQ genetics, and this has nothing to do with the A-B-O genetics.

Since bleached wheat flour is a major source of fast carbs in western societies many improvements may be seen with wheat product reduction, but starch (polysaccharide) is not a gluten (protein) and does not cause a protein mediated immune response. Gluten sensitivity differs from diseases of affluence that are largely mediated by excess simple sugars, starches and saturated fats in the diet in that the primary targets of GSE are proteins,(prolamins and glutelins of the grass tribe Triticeae, and in some allergic sensitivities albumins and globulins). Wheat is more so dangerous because it has an enriched level of glutens derived from three ancestral species of wheat or goat grasses.