01. May 2015

Transglutaminase antibodies in ataxia

by Daniel Aeschlimann (Cardiff University, UK) and Marios Hadjivassiliou (Sheffield Teaching Hospitals NHS Trust, UK)

Sensitivity to gluten can present with neurological problems, whereby cerebellar ataxia is the most frequent manifestation and is referred to as gluten ataxia. Gluten ataxia has indeed been suggested to be a common cause of sporadic idiopathic ataxia. Up to 60% of patients with gluten ataxia have no evidence of enteropathy (celiac disease) on small bowel biopsy, yet such patients respond to a gluten free diet. Originally, a diagnosis of gluten ataxia was considered in patients serologically positive for antibodies to gliadins, proteins derived from wheat gluten. In patients with sensitivity to gluten, systemic levels of antigliadin IgA/IgG appear to mirror the immune reaction triggered by gluten, including their reduction in response to clinical improvement. However, the large variation between different commercial antigliadin antibody assays and the fact that up to 12% of the healthy population are positive for these antibodies, makes their use for diagnostic purposes rather problematic, particularly for physicians and neurologists that are not familiar with such shortcomings.

Sensitivity to gluten results in a systemic immune-mediated disease that can present with diverse manifestations. Besides the strong gluten-specific T cell response, another hallmark of gluten-related diseases (GRD) is a robust autoantibody response to one or more transglutaminase (TG) isozymes. Formation of TG-gluten peptide complexes allows B cells carrying TG-specific IgD to take up and subsequently present gluten-peptides complexed to MHC, and thereby allowing for B cell activation and differentiation in the absence of TG-specific T cells. It is thought that stable thioester complexes of gluten peptides with the active site Cys residue formed during catalysis play a role in this process and such complexes are indeed formed by all TGs to which autoantibodies are developed in GRD (Stamnaes et al., 2010).

MR brain imaging of a patient with gluten encephalopathy showing excessive white matter signal change. Such patients usually present with intractable headaches. Gluten free diet results in elimination of the headaches and stops the progression of the white matter changes. If untreated such patients may end up with vascular dementia.

Courtesy of Marios Hadjivassiliou.

In GRD patients with neurological deficits, there is a bias of the immune response towards TG6 (Hadjivassiliou et al., 2008). Most of the available evidence pertains to idiopathic cerebellar ataxia but it is likely that a spectrum of neurological conditions including ataxia with myoclonus, peripheral neuropathy, myopathy, myelopathy, cerebral calcifications, headache with white matter abnormalities (sometimes associated with vascular dementia), chorea or Stiff-person syndrome may be caused by pathogenic antibodies (Hadjivassiliou et al., 2010). Evidence for a link between neurological deficits and GRD is two-fold. Firstly, the production of anti-TG6 antibodies is gluten dependent which substantiates the link to the gluten-specific T cell population (Hadjivassiliou et al., 2013). Secondly, similar to anti-TG3 autoantibodies and dermatitis herpetiformis, passive transfer of the disease through antibodies in an animal model directly implicates these in pathogenesis (Boscolo et al., 2010). TG6 expression is indeed associated with neurogenesis in the central nervous system, and a role of the enzyme in neurons controlling motor function is strongly suggested by an association of mutations in the TGM6 gene with spinocerebellar ataxia 35. Molecular modeling and biochemical assays, have shown that TG6 is allosterically regulated by Ca2+ and GTP similar to TG2, and that disease associated mutations compromise regulation of enzymatic function (Thomas et al., 2013). However, how this impacts on neuronal survival remains to be shown.  

While it is at present not clear whether all GRD patients can develop antibodies to different TG isozymes, detection of autoantibodies to TG6 may not only facilitate diagnosis of GRD in a neurology setting but screening of patients with established celiac disease for circulatory antibodies to TG6 may provide an opportunity to identify patients at risk of developing neurological problems.

This research overview reflects the professional opinion of the authors and although invited, was not sponsored or incentivised by the company.

Boscolo et al., PLOS ONE 2010, 5:e9698 (1-9); Hadjivassiliou et al., Ann. Neurol. 2008. 64, 332-43; Hadjivassiliou et al., Lancet Neurol. 2010, 9:318-30; Hadjivassiliou et al., Neurology 2013, 80:1-6; Stamnaes et al., Amino Acids 2010, 39:1183-91; Thomas et al., Amino Acids 2013, 44:167-77.

The authors:
Daniel Aeschlimann, PhD is a professor of biological sciences at College of Biomedical and Life Sciences, Cardiff University, UK.
His research focuses on understanding and manipulating the interface between extracellular matrix and the diversity of cells in the craniofacial complex with the long-term goal of counteracting pathological processes leading to tissue destruction or create functional tissue through application of life science principles.
Professor Marios Hadjivassiliou is a Consultant Neurologist at the Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Trust, UK.
He has conducted and published extensive research into Gluten Ataxia, having first described the condition in the 1990’s. He runs a dedicated weekly clinic for patients with neurological manifestations of sensitivity to gluten.


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