The Neuroimmunology of Gluten Intolerance

Hadjivassiliou, Marios; Sanders, David S.; Aeschlimann, Daniel

doi:10.1007/978-3-319-28609-9_15

Cited by 5 publications

(5 citation statements)

References 128 publications

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“…How the development of adaptive immunity leads to extraintestinal manifestations remains a matter of debate, although some evidence that the autoantibodies themselves play a role in this has been put forth [ 9 ]. Perivascular antibody deposition, as observed in GRD patients can drive organ-specific inflammatory processes that result in tissue damage.…”

Section: Discussionmentioning

confidence: 99%

“…The discovery of another transglutaminase primarily expressed in neural tissue (TG6), that shared enzymatic properties with both TG2 and TG3, offered further insights into the pathophysiology of neurological manifestations of GRD [ 7 ]. Patient-derived autoantibodies to these different isozymes are not crossreactive [ 7 , 8 ], and their development appears to be linked to the shared enzymatic properties of these enzymes rather than their structural similarity and potential shared epitopes (for review see [ 9 ]). This, therefore, suggests that any of these transglutaminases could be the primary immunological target of the gluten-driven immune response, although relative abundance in the gut and sensitivity to regulation by proinflammatory mediators explains the unique association of TG2 with GRD development.…”

Section: Introductionmentioning

confidence: 99%

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TG6 Auto-Antibodies in Dermatitis Herpetiformis

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TG6 Auto-Antibodies in Dermatitis Herpetiformis

et al. 2020

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“…Patients with GA have evidence of IgA deposits against tissue transglutaminase on vessels within cerebellum and brainstem. Transglutaminase leads to vascular based inflammation that may results in breakdown of blood brain barrier thus allowing the entry of gluten-sensitive antibodies in brain (Hadjivassiliou et al, 2006 ), the same antibodies can cross-react with Purkinje cells in the cerebellum causing their irreversible depletion (Hadjivassiliou et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, it has been reported that gluten-mediated neurological pathogenesis may occur due to deposition of immune-complex, cross-reaction of antibodies, and direct neurotoxicity, leading to an inflammatory response in the nervous system (Zelnik et al, 2004 ; Bushara, 2005 ; Abenavoli, 2010 ; Parisi et al, 2015 ). It has been reported that the antibodies generated against gliadin make the gut leaky and also cross-react with Purkinje cells in the cerebellum causing their irreversible depletion (Hadjivassiliou et al, 2016 ). Lymphocytic infiltration of the dorsal columns and even peripheral nerves has also been documented (Fitzsimmons et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

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

Rawat

Tyagi

Singh

et al. 2022

Front. Hum. Neurosci.

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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.

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“…TG6 is primarily expressed in the central nervous system but shares common characteristics with TG2 (the autoantigen in CD) and TG3 (the autoantigen in dermatitis herpetiformis). All three transglutaminases share 65% homology, are capable of deamidating gliadin, and are eliminated from the serum by strict adherence to gluten-free diet (GFD) (Hadjivassiliou et al 2016b). As such TG6 antibodies may prove to be an important specific biomarker of GA.…”

Section: Nomentioning

confidence: 99%