Recent advances in diagnosis of immune-mediated cerebellar ataxias: novel concepts and fundamental questions on autoimmune mechanisms.

Immune-mediated cerebellar ataxias (IMCAs) represent a group of disorders in which the immune system targets mainly the cerebellum and related structures. We address fundamental questions on the diagnosis and immunological pathogenesis of IMCAs, as illuminated by recent advances in the field. Various types of IMCAs have been identified, including post-infectious cerebellitis, Miller Fisher syndrome, gluten ataxia, paraneoplastic cerebellar degeneration (PCD), opsoclonus and myoclonus syndrome, and anti-GAD ataxia. In some cases, identification of several well-characterized autoantibodies points to a specific etiology in IMCAs and leads to a firm diagnosis. In other cases, various autoantibodies have been reported, but their interpretation requires a careful consideration. Indeed, some autoantibodies have only been documented in a limited number of cases and the causal relationship is not established. In order to facilitate an early treatment and prevent irreversible lesions, new entities have been defined in recent years, such as primary autoimmune cerebellar ataxia (PACA) and latent autoimmune cerebellar ataxia (LACA). PACA is characterized by autoimmune features which do not align with traditional etiologies, while LACA corresponds to a prodromal stage. LACA does not imply the initiation of an immunotherapy but requires a close follow-up. Concurrently, accumulation of clinical data has led to intriguing hypotheses regarding the mechanisms of autoimmunity, such as a pathogenesis of autoimmunity against synapses (synaptopathies), and the vulnerability of the entire nervous system when the immunity targets ion channels and astrocytes. The development of PCD in patients treated with immune-checkpoint inhibitors suggests that molecular mimicry specifically determines the direction of autoimmunity, and that the strength of this response is modulated by co-signaling molecules that either enhance or dampen signals from the antigen-specific T cell receptor.

Autoantibodies related to ataxia and other central nervous system manifestations of gluten enteropathy.

Gluten ataxia and other central nervous system disorders could be linked to gluten enteropathy and related autoantibodies. In this narrative review, we focus on the various neuro-logical manifestations in patients with gluten sensitivity/celiac disease, immunological and autoimmune mechanisms of ataxia in connection to gluten sensitivity and the autoantibodies that could be used as a biomarker for diagnosing and following. We focused on the anti-gliadin antibodies, antibodies to different isoforms of tissue transglutaminase (TG) (anti-TG2, 3, and 6 antibodies), anti-glycine receptor antibodies, anti-glutamine acid decarboxylase antibodies, anti-deamidated gliadin peptides antibodies, etc. Most studies found a higher prevalence of these antibodies in patients with gluten sensitivity and neurological dysfunction, presented as different neurological disorders. We also discuss the role of a gluten-free diet on the clinical improvement of patients and also on imaging of these disorders.

Cerebellar degeneration in gluten ataxia is linked to microglial activation.

Gluten sensitivity has long been recognized exclusively for its gastrointestinal involvement; however, more recent research provides evidence for the existence of neurological manifestations that can appear in combination with or independent of the small bowel manifestations. Amongst all neurological manifestations of gluten sensitivity, gluten ataxia is the most commonly occurring one, accounting for up to 40% of cases of idiopathic sporadic ataxia. However, despite its prevalence, its neuropathological basis is still poorly defined. Here, we provide a neuropathological characterization of gluten ataxia and compare the presence of neuroinflammatory markers glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, major histocompatibility complex II and cluster of differentiation 68 in the central nervous system of four gluten ataxia cases to five ataxia controls and seven neurologically healthy controls. Our results demonstrate that severe cerebellar atrophy, cluster of differentiation 20+ and cluster of differentiation 8+ lymphocytic infiltration in the cerebellar grey and white matter and a significant upregulation of microglial immune activation in the cerebellar granular layer, molecular layer and cerebellar white matter are features of gluten ataxia, providing evidence for the involvement of both cellular and humoral immune-mediated processes in gluten ataxia pathogenesis.

Pyracanthas.

The poem came to me after a particularly bruising appointment with a doctor at the practice I was then a patient at. It was after this encounter that I transferred to another practice. The practice was rated then as requiring improvement, and as a School Improvement Officer retired through ill health I understood what the implications were. I think this painful recall of my previous role had an influence on the arrival of the poem. I certainly was not expecting to write it. Since developing ataxia, I set myself the task of making my writing move from 'Mawkish to Hawkish', a metaphor I used when l asked to contribute to the 'Storying Sheffield' project under Professor Brendan Stone (http://www.storyingsheffield.com/project/). The metaphor of "trams" used in this project was chosen to represent tram stops in the city and I have used it subsequently in presentations to illustrate something about what rehabilitation can entail. The "Burden-gift" of living with rare diseases is something I have found clinicians have found hard to encounter and acknowledge that these are "new" to them, and patients being ambassadors a challenge; I have seen doctors Googling their queries as they turn away to go down the corridor, to return moments later to continue the appointment....Nature is generally perceived as being healing, and yet here was someone indifferent, impatient and unwilling to hear what my expert team at a Centre for Excellence were saying - so different in nature to what I had hoped for in that appointment.This variety of Pyracanthas might be named 'Schadenfreude'.

Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation.

Celiac disease (CD) is a complex multi-organ disease with a high prevalence of extra-intestinal involvement, including neurological and psychiatric manifestations, such as cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive impairment, and depression. However, the mechanisms behind the neurological involvement in CD remain controversial. Recent evidence shows these can be related to gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and in severe cases, vitamins or nutrients deficiency. Here, we have summarized new evidence related to gut microbiota and the so-called "gut-liver-brain axis" involved in CD-related neurological manifestations. Additionally, there has yet to be an agreement on whether serological or neurophysiological findings can effectively early diagnose and properly monitor CD-associated neurological involvement; notably, most of them can revert to normal with a rigorous gluten-free diet. Moving from a molecular level to a symptom-based approach, clinical, serological, and neurophysiology data might help to disentangle the many-faceted interactions between the gut and brain in CD. Eventually, the identification of multimodal biomarkers might help diagnose, monitor, and improve the quality of life of patients with "neuroCD".

Cerebellar Abnormalities on Proton MR Spectroscopy and Imaging in Patients With Gluten Ataxia: A Pilot Study.

Gluten ataxia is a rare immune-mediated neurological disorder caused by the ingestion of gluten. The diagnosis is not straightforward as antibodies are present in only up to 38% of patients, but often at lower titers. The symptoms of ataxia may be mild at the onset but lead to permanent damage if remain untreated. It is characterized by damage to the cerebellum however, the pathophysiology of the disease is not clearly understood. The present study investigated the neurochemical profile of vermis and right cerebellum and structural changes in various brain regions of patients with gluten ataxia (n = 6, age range 40-65 years) and compared it with healthy controls (n = 10, 40-55 years). Volumetric 3-D T1 and T1-weighted magnetic resonance imaging (MRI) in the three planes (axial, coronal, and sagittal) of the whole brain and single-voxel 1H- magnetic resonance spectroscopy (MRS) of the vermis and right cerebellum were acquired on 3 T human MR scanner. The metabolite concentrations were estimated using LC Model (6.1-4A) while brain volumes were estimated using the online tool volBrain pipeline and CERES and corrected for partial volumes. The levels of neuro-metabolites (N-acetyl aspartate + N-acetyl aspartate glutamate, glycerophosphocholine + phosphocholine, and total creatine) were found to be significantly lower in vermis, while N-acetyl aspartate + N-acetyl aspartate glutamate and glycerophosphocholine + phosphocholine was lower in cerebellum regions in the patients with gluten ataxia compared to healthy controls. A significant reduction in the white matter of (total brain, cerebellum, and cerebrum); reduction in the volumes of cerebellum lobe (X) and thalamus while lateral ventricles were increased in the patients with gluten ataxia compared to healthy controls. The reduced neuronal metabolites along with structural changes in the brain suggested neuronal degeneration in the patients with gluten ataxia. Our preliminary findings may be useful in understanding the gluten-induced cerebral damage and indicated that MRI and MRS may serve as a non-invasive useful tool in the early diagnosis, thereby enabling better management of these patients.

Recognition and management of rapid-onset gluten ataxias: case series.

BACKGROUND: Most immune-mediated cerebellar ataxias, including those associated with gluten sensitivity (Gluten Ataxia), tend to present subacutely and usually progress gradually. Acute presentations with rapid progression outside the context of paraneoplastic cerebellar degeneration require prompt diagnosis and early access to disease-modifying immunotherapy in order to avert severe and permanent neurological disability. CASE PRESENTATIONS: We describe three cases of rapid-onset Gluten Ataxia, an immune-mediated cerebellar ataxia due to gluten sensitivity. We detail their presentation, clinical and neuroimaging findings, and our treatment strategy with immunotherapy. CONCLUSIONS: Our cases highlight the potential for immune-mediated cerebellar ataxias to present acutely, with rapid-onset symptoms and devastating neurological consequences. We caution against the diagnosis of 'post-infective cerebellitis' in adults, and advocate early consideration of an immune-mediated cerebellar ataxia and initiation of immunotherapy to prevent irreversible cerebellar damage.

Neurological manifestation of coeliac disease with particular emphasis on gluten ataxia and immunological injury: a review article.

Coeliac disease (CD) is a gluten-induced enteropathy affecting 1% of the population and has extra intestinal manifestations. One such expression involves nervous system, and CD may present as gluten ataxia (GA), peripheral neuropathy and epileptiform disorder among others. Considerable controversy exists on the exact pathophysiological mechanism of gluten leading to ataxia. It is, however, clear that in intestinal axis tissue transglutaminase 2 (tTG2) is the primary target but in the nervous system, tTG6 may be the causative antigen although its exact role is not clear. Furthermore, it has also been postulated that anti-gangliodise antibodies may play a role in the emergence of central pathology if not the key contender. Moreover, the association of neurological injury with non-coeliac gluten sensitivity (NCGS), a related but pathologically different condition implies an independent mechanism of neuronal injury by gluten in the absence of CD. This review will touch on the salient features of CD and the nervous system and will highlight current controversies in relation to gluten and GA.

Immune-Mediated Cerebellar Ataxias: Clinical Diagnosis and Treatment Based on Immunological and Physiological Mechanisms.

Since the first description of immune-mediated cerebellar ataxias (IMCAs) by Charcot in 1868, several milestones have been reached in our understanding of this group of neurological disorders. IMCAs have diverse etiologies, such as gluten ataxia, postinfectious cerebellitis, paraneoplastic cerebellar degeneration, opsoclonus myoclonus syndrome, anti-GAD ataxia, and primary autoimmune cerebellar ataxia. The cerebellum, a vulnerable autoimmune target of the nervous system, has remarkable capacities (collectively known as the cerebellar reserve, closely linked to plasticity) to compensate and restore function following various pathological insults. Therefore, good prognosis is expected when immune-mediated therapeutic interventions are delivered during early stages when the cerebellar reserve can be preserved. However, some types of IMCAs show poor responses to immunotherapies, even if such therapies are introduced at an early stage. Thus, further research is needed to enhance our understanding of the autoimmune mechanisms underlying IMCAs, as such research could potentially lead to the development of more effective immunotherapies. We underscore the need to pursue the identification of robust biomarkers.

Celiac Disease, Beyond the Bowel: A Review of Its Neurological Manifestations.

Celiac disease (CD) is a multi-systemic autoimmune condition that causes a hyperinflammatory response when gluten is ingested. There has been a shift in the clinical presentation of CD from a mere malabsorption disorder to an autoimmune condition that affects multiple organ systems, which could increase the rate of hospitalizations and a decreased quality of life. This article has compiled various studies that have explored the neurological manifestations of celiac disease, their epidemiology, possible pathogenic mechanisms, diagnosis, and treatment. The most common neurological conditions include gluten ataxia (GA), gluten neuropathy, gluten encephalopathy, and epilepsy which usually present as sporadic diseases which are difficult to diagnose in the absence of gastrointestinal (GI) symptoms. The treatment for most of these conditions is a gluten-free diet (GFD) regardless of GI involvement.

Clinical Characteristics and Management of 50 Patients with Anti-GAD Ataxia: Gluten-Free Diet Has a Major Impact.

The objective of this study is to report the clinical characteristics and treatment of patients with progressive cerebellar ataxia associated with anti-GAD antibodies. We performed a retrospective review of all patients with anti-GAD ataxia managed at the Sheffield Ataxia Centre over the last 25 years. We identified 50 patients (62% females) with anti-GAD ataxia. The prevalence was 2.5% amongst 2000 patients with progressive ataxia of various causes. Mean age at onset was 55 and mean duration 8 years. Gaze-evoked nystagmus was present in 26%, cerebellar dysarthria in 26%, limb ataxia in 44% and gait ataxia in 100%. Nine patients (18%) had severe, 12 (24%) moderate and 29 (58%) mild ataxia. Ninety percent of patients had a history of additional autoimmune diseases. Family history of autoimmune diseases was seen in 52%. Baseline MR spectroscopy of the vermis was abnormal at presentation in 72%. Thirty-five patients (70%) had serological evidence of gluten sensitivity. All 35 went on gluten-free diet (GFD). Eighteen (51%) improved, 13 (37%) stabilised, 3 have started the GFD too recently to draw conclusions and one deteriorated. Mycophenolate was used in 16 patients, 7 (44%) improved, 2 stabilised, 6 have started the medication too recently to draw conclusions and one did not tolerate the drug. There is considerable overlap between anti-GAD ataxia and gluten ataxia. For those patients with both, strict GFD alone can be an effective treatment. Patients with anti-GAD ataxia and no gluten sensitivity respond well to immunosuppression.

TG6 Auto-Antibodies in Dermatitis Herpetiformis.

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of gluten sensitivity, in which an autoimmune response is directed against transglutaminase 3 (TG3), an epidermal transglutaminase. TG2 is the autoantigen in celiac disease (CD), defined by the presence of enteropathy, and TG6 is the autoantigen in neurological manifestations of gluten sensitivity. The interplay between B cell responses to these 3 transglutaminases in developing the clinical spectrum of disease manifestations is not completely understood. Also, the individual or combined diagnostic and predictive value of the respective autoantibodies is not fully explored. We examined the prevalence of TG6 antibodies in a cohort of patients with DH. TG6 positivity was found in 13/33 (39%), with IgA detected in 11 patients, IgG in 3, and both in 1. This was significantly higher compared to what is seen in the classic CD cases (14%) in a Finnish population. TG6 positive baseline samples constituted 60% of DH patients with no enteropathy (n = 10), as opposed to 17% positivity in those with overt enteropathy (n = 12; Marsh IIIB). Repeat testing after adherence to a gluten-free diet for 1 year showed reduced titers for TG6 antibodies in 11/13 (85%), whereby 7 patients were now TG6 antibody-negative. Four patients seroconverted and tested positive for TG6 antibodies at one year, due to the ongoing exposure to gluten. We report another patient who presented with neurological manifestations (encephalopathy) leading to the diagnosis of CD, who was intermittently adhering to a gluten-free diet. Serological testing at baseline showed him to be positive for antibodies to all 3 transglutaminases. Eleven years later, he developed DH. He also subsequently developed ataxia and peripheral neuropathy. Although TG3 and TG6 autoantibodies are linked to certain disease manifestations, TG2, TG3, and TG6 autoantibodies can be present across the spectrum of GRD patients and might develop years before onset of symptoms of extraintestinal manifestations. This is consistent with gluten-dependent adaptive immunity being a necessary but not sufficient pretext to organ-specific damage. TG6 antibodies appear to develop more frequently in patients where tolerance to gluten was broken but, either there was no development of the molecular state driving the tissue destruction at the level of the gut, or perhaps more likely, there was more resistance to developing this phenotype.

European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders.

This guideline presents recommendations for the management of coeliac disease (CD) and other gluten-related disorders both in adults and children. There has been a substantial increase in the prevalence of CD over the last 50 years and many patients remain undiagnosed. Diagnostic testing, including serology and biopsy, should be performed on a gluten-containing diet. The diagnosis of CD is based on a combination of clinical, serological and histopathological data. In a group of children the diagnosis may be made without biopsy if strict criteria are available. The treatment for CD is primarily a gluten-free diet (GFD), which requires significant patient education, motivation and follow-up. Slow-responsiveness occurs frequently, particularly in those diagnosed in adulthood. Persistent or recurring symptoms necessitate a review of the original diagnosis, exclude alternative diagnoses, confirm dietary adherence (dietary review and serology) and follow-up biopsy. In addition, evaluation to exclude complications of CD, such as refractory CD or lymphoma, should be performed. The guideline also deals with other gluten-related disorders, such as dermatitis herpetiformis, which is a cutaneous manifestation of CD characterized by granular IgA deposits in the dermal papillae. The skin lesions clear with gluten withdrawal. Also, less well-defined conditions such as non-coeliac gluten sensitivity (NCGS) and gluten-sensitive neurological manifestations, such as ataxia, have been addressed. Newer therapeutic modalities for CD are being studied in clinical trials but are not yet approved for use in practice.

Neurological Manifestations of Neuropathy and Ataxia in Celiac Disease: A Systematic Review.

Celiac disease (CD) is an immune-mediated gastrointestinal disorder driven by innate and adaptive immune responses to gluten. Patients with CD are at an increased risk of several neurological manifestations, frequently peripheral neuropathy and gluten ataxia. A systematic literature review of the most commonly reported neurological manifestations (neuropathy and ataxia) associated with CD was performed. MEDLINE, Embase, the Cochrane Library, and conference proceedings were systematically searched from January 2007 through September 2018. Included studies evaluated patients with CD with at least one neurological manifestation of interest and reported prevalence, and/or incidence, and/or clinical outcomes. Sixteen studies were included describing the risk of gluten neuropathy and/or gluten ataxia in patients with CD. Gluten neuropathy was a neurological manifestation in CD (up to 39%) in 13 studies. Nine studies reported a lower risk and/or prevalence of gluten ataxia with a range of 0%⁻6%. Adherence to a gluten-free diet appeared to improve symptoms of both neuropathy and ataxia. The prevalence of gluten neuropathy and gluten ataxia in patients with CD varied in reported studies, but the increased risk supports the need for physicians to consider CD in patients with ataxia and neurological manifestations of unknown etiology.

Advances in Therapies of Cerebellar Disorders: Immune-mediated Ataxias.

The identification of an increasing number of immune mediated ataxias suggests that the cerebellum is often a target organ for autoimmune insults. The diagnosis of immune mediated ataxias is challenging as there is significant clinical overlap between immune mediated and other forms of ataxia. Furthermore the classification of immune mediated ataxias requires further clarification particularly for those ataxias where no specific antigenic trigger and associated antibodies have been identified. Recognition of immune mediated ataxias remains imperative as therapeutic interventions can be effective, although given the relative rarity of this entity, large-scale treatment trials may not be feasible. This review will discuss advances in therapies for immune mediated ataxias based on what is currently available in the literature.

Immune-mediated Cerebellar Ataxias: Practical Guidelines and Therapeutic Challenges.

Immune-mediated cerebellar ataxias (IMCAs), a clinical entity reported for the first time in the 1980s, include gluten ataxia (GA), paraneoplastic cerebellar degenerations (PCDs), antiglutamate decarboxylase 65 (GAD) antibody-associated cerebellar ataxia, post-infectious cerebellitis, and opsoclonus myoclonus syndrome (OMS). These IMCAs share common features with regard to therapeutic approaches. When certain factors trigger immune processes, elimination of the antigen( s) becomes a priority: e.g., gluten-free diet in GA and surgical excision of the primary tumor in PCDs. Furthermore, various immunotherapeutic modalities (e.g., steroids, immunoglobulins, plasmapheresis, immunosuppressants, rituximab) should be considered alone or in combination to prevent the progression of the IMCAs. There is no evidence of significant differences in terms of response and prognosis among the various types of immunotherapies. Treatment introduced at an early stage, when CAs or cerebellar atrophy is mild, is associated with better prognosis. Preservation of the "cerebellar reserve" is necessary for the improvement of CAs and resilience of the cerebellar networks. In this regard, we emphasize the therapeutic principle of "Time is Cerebellum" in IMCAs.

The Significance of Low Titre Antigliadin Antibodies in the Diagnosis of Gluten Ataxia.

BACKGROUND: Patients with gluten ataxia (GA) without enteropathy have lower levels of antigliadin antibodies (AGA) compared to patients with coeliac disease (CD). Magnetic Resonance Spectroscopy (NAA/Cr area ratio) of the cerebellum improves in patients with GA following a strict gluten-free diet (GFD). This is associated with clinical improvement. We present our experience of the effect of a GFD in patients with ataxia and low levels of AGA antibodies measured by a commercial assay. METHODS: Consecutive patients with ataxia and serum AGA levels below the positive cut-off for CD but above a re-defined cut-off in the context of GA underwent MR spectroscopy at baseline and after a GFD. RESULTS: Twenty-one consecutive patients with GA were included. Ten were on a strict GFD with elimination of AGA, 5 were on a GFD but continued to have AGA, and 6 patients did not go on a GFD. The NAA/Cr area ratio from the cerebellar vermis increased in all patients on a strict GFD, increased in only 1 out of 5 (20%) patients on a GFD with persisting circulating AGA, and decreased in all patients not on a GFD. CONCLUSION: Patients with ataxia and low titres of AGA benefit from a strict GFD. The results suggest an urgent need to redefine the serological cut-off for circulating AGA in diagnosing GA.

Extra-intestinal manifestations of non-celiac gluten sensitivity: An expanding paradigm.

Non celiac gluten sensitivity (NCGS) is a syndrome characterized by a cohort of symptoms related to the ingestion of gluten-containing food in subjects who are not affected by celiac disease (CD) or wheat allergy. The possibility of systemic manifestations in this condition has been suggested by some reports. In most cases they are characterized by vague symptoms such as 'foggy mind', headache, fatigue, joint and muscle pain, leg or arm numbness even if more specific complaints have been described. NCGS has an immune-related background. Indeed there is a strong evidence that a selective activation of innate immunity may be the trigger for NCGS inflammatory response. The most commonly autoimmune disorders associated to NCGS are Hashimoto thyroiditis, dermatitis herpetiformis, psoriasis and rheumatologic diseases. The predominance of Hashimoto thyroiditis represents an interesting finding, since it has been indirectly confirmed by an Italian study, showing that autoimmune thyroid disease is a risk factor for the evolution towards NCGS in a group of patients with minimal duodenal inflammation. On these bases, an autoimmune stigma in NCGS is strongly supported; it could be a characteristic feature that could help the diagnosis and be simultaneously managed. A possible neurological involvement has been underlined by NCGS association with gluten ataxia, gluten neuropathy and gluten encephalopathy. NCGS patients may show even psychiatric diseases such as depression, anxiety and psychosis. Finally, a link with functional disorders (irritable bowel syndrome and fibromyalgia) is a topic under discussion. In conclusion, the novelty of this matter has generated an expansion of literature data with the unavoidable consequence that some reports are often based on low levels of evidence. Therefore, only studies performed on large samples with the inclusion of control groups will be able to clearly establish whether the large information from the literature regarding extra-intestinal NCGS manifestations could be supported by evidence-based agreements.

Immune-mediated cerebellar ataxias: from bench to bedside.

The cerebellum is a vulnerable target of autoimmunity in the CNS. The category of immune-mediated cerebellar ataxias (IMCAs) was recently established, and includes in particular paraneoplastic cerebellar degenerations (PCDs), gluten ataxia (GA) and anti-GAD65 antibody (Ab) associated-CA, all characterized by the presence of autoantibodies. The significance of onconeuronal autoantibodies remains uncertain in some cases. The pathogenic role of anti-GAD65Ab has been established both in vitro and in vivo, but a consensus has not been reached yet. Recent studies of anti-GAD65 Ab-associated CA have clarified that (1) autoantibodies are generally polyclonal and elicit pathogenic effects related to epitope specificity, and (2) the clinical course can be divided into two phases: a phase of functional disorder followed by cell death. These features provide the rationale for prompt diagnosis and therapeutic strategies. The concept "Time is brain" has been completely underestimated in the field of immune ataxias. We now put forward the concept "Time is cerebellum" to underline the importance of very early therapeutic strategies in order to prevent or stop the loss of neurons and synapses. The diagnosis of IMCAs should depend not only on Ab testing, but rather on a rapid and comprehensive assessment of the clinical/immune profile. Treatment should be applied during the period of preserved cerebellar reserve, and should encompass early removal of the conditions (such as remote primary tumors) or diseases that trigger the autoimmunity, followed by the combinations of various immunotherapies.

Extraintestinal manifestations of celiac disease: 33-mer gliadin binding to glutamate receptor GRINA as a new explanation.

We propose a biochemical mechanism for celiac disease and non-celiac gluten sensitivity that may rationalize many of the extradigestive disorders not explained by the current immunogenetic model. Our hypothesis is based on the homology between the 33-mer gliadin peptide and a component of the NMDA glutamate receptor ion channel - the human GRINA protein - using BLASTP software. Based on this homology the 33-mer may act as a natural antagonist interfering with the normal interactions of GRINA and its partners. The theory is supported by numerous independent data from the literature, and provides a mechanistic link with otherwise unrelated disorders, such as cleft lip and palate, thyroid dysfunction, restless legs syndrome, depression, ataxia, hearing loss, fibromyalgia, dermatitis herpetiformis, schizophrenia, toxoplasmosis, anemia, osteopenia, Fabry disease, Barret's adenocarcinoma, neuroblastoma, urinary incontinence, recurrent miscarriage, cardiac anomalies, reduced risk of breast cancer, stiff person syndrome, etc. The hypothesis also anticipates better animal models, and has the potential to open new avenues of research.