absent in healthy individuals.() Whether these antibodies are a result of epitope spreading or whether they truly are directed towards the specific transglutaminase is unclear. TG2, TG3 and TG6 are encoded on the same chromosome in humans (20q11-12) and all three can specifically deamidate gluten T cell epitopes, albeit with subtle functional differences.(; ) Given the overall homology between transglutaminases, autoantibody cross-reactivity and epitope spreading is worth consideration.() However, current evidence is conflicting in this regard. A recent report using ELISA and immunohistochemistry showed cross-reactivity between anti-TG2 antibodies and the isozymes TG3 and TG6.() This contrasted earlier studies reporting an absence of cross-reactivity between different transglutaminase isoforms, although these observations were based on competitive inhibition ELISAs, which can prevent the detection of very low affinity transglutaminase Also, cross-reactivity does not explain why some patients have antibodies exclusive to one transglutaminase isozyme.() It is apparent that current literature has addressed some of the criteria (albeit at differing levels of evidence) that suggest antibodies against gluten-related peptides mediate a neurological disease. (Box 1) Very recently, Hadjivassiliou and colleagues conducted a prospective cohort study to investigate the role of TG6 antibodies in diagnosing GA.() Patients were recruited from the ataxia, gluten/neurology, CD, and movement disorders clinic at Royal Hallamshire Hospital, Sheffield, UK, and also from the Tampere University Hospital (Finland). Patients were divided into two groups: (1) those with idiopathic sporadic ataxia negative for antigliadin antibodies (AGA), TG2 antibodies, and endomysial antibodies (EMA) and (2) patients with GA based on the original definition of an idiopathic cerebellar ataxia with positive antigliadin IgA and/or IgG antibodies irrespective of positivity for TG2 and EMA. Neurologic control groups included patients with genetically confirmed neurologic and
absent in healthy individuals.() Whether these antibodies are a result of epitope spreading or whether they truly are directed towards the specific transglutaminase is unclear. TG2, TG3 and TG6 are encoded on the same chromosome in humans (20q11-12) and all three can specifically deamidate gluten T cell epitopes, albeit with subtle functional differences.(; ) Given the overall homology between transglutaminases, autoantibody cross-reactivity and epitope spreading is worth consideration.() However, current evidence is conflicting in this regard. A recent report using ELISA and immunohistochemistry showed cross-reactivity between anti-TG2 antibodies and the isozymes TG3 and TG6.() This contrasted earlier studies reporting an absence of cross-reactivity between different transglutaminase isoforms, although these observations were based on competitive inhibition ELISAs, which can prevent the detection of very low affinity transglutaminase Also, cross-reactivity does not explain why some patients have antibodies exclusive to one transglutaminase isozyme.() It is apparent that current literature has addressed some of the criteria (albeit at differing levels of evidence) that suggest antibodies against gluten-related peptides mediate a neurological disease. (Box 1) Very recently, Hadjivassiliou and colleagues conducted a prospective cohort study to investigate the role of TG6 antibodies in diagnosing GA.() Patients were recruited from the ataxia, gluten/neurology, CD, and movement disorders clinic at Royal Hallamshire Hospital, Sheffield, UK, and also from the Tampere University Hospital (Finland). Patients were divided into two groups: (1) those with idiopathic sporadic ataxia negative for antigliadin antibodies (AGA), TG2 antibodies, and endomysial antibodies (EMA) and (2) patients with GA based on the original definition of an idiopathic cerebellar ataxia with positive antigliadin IgA and/or IgG antibodies irrespective of positivity for TG2 and EMA. Neurologic control groups included patients with genetically confirmed neurologic and
Post%20Viva%20Revised_SCurrie_PhD%20thesis_BW_Neurological%20extent%20GRD.docx