Anti Transglutaminase Antibodies Cause Ataxia in Mice

Abstract

BackgroundCeliac disease (CD) is an autoimmune gastrointestinal disorder characterized by the presence of anti-transglutaminase 2 (TG2) and anti-gliadin antibodies. Amongst the neurological dysfunctions associated with CD, ataxia represents the most common one.MethodsWe analyzed by immunohistochemistry, the anti-neural reactivity of the serum from 20 CD patients. To determine the role of anti-TG2 antibodies in ataxia, two anti-TG2 single chain variable fragments (scFv), isolated from a phage-display IgA antibody library, were characterized by immunohistochemistry and ELISA, and injected in mice to study their effects on motor coordination. We found that 75% of the CD patient population without evidence of neurological involvement, has circulating anti-neural IgA and/or IgG antibodies. Two anti-TG2 scFvs, cloned from one CD patient, stained blood vessels but only one reacted with neurons. This anti-TG2 antibody showed cross reactivity with the transglutaminase isozymes TG3 and TG6. Intraventricular injection of the anti-TG2 or the anti-TG2/3/6 cross-reactive scFv provoked transient, equally intensive ataxia in mice.ConclusionThe serum from CD patients contains anti-TG2, TG3 and TG6 antibodies that may potentially cause ataxia.

Distribution of Transglutaminase 6 in the Central Nervous System of Adult Mice

“…Mutations of the TGM6 gene may lead to functional impairment and finally neuronal loss in these brain regions as SCA development progresses. An in vivo study has shown that intraventricular injection of anti-TG2/3/6 cross-reactive antibody provoked ataxia in mice (Boscolo et al, 2010). Taken together, the high distribution density of TG6-positive neurons in the extrapyramidal system supports the hypothesis that TGM6 is the causative gene in the development of SCA 35 (Wang et al, 2010).…”

Transglutaminase 6 antibodies in gluten neuropathy

“…All three TG isozymes (TG2, TG3, TG6) for which autoantibodies have been described, can form thioester-linked complexes with gluten peptides which are thought to be responsible for the B cell response to TG isozymes [14,18]. Pathogenicity of such circulating anti-TG antibodies in terms of leading to extraintestinal disease has been demonstrated in animal models [19,20].…”

The Neuroimmunology of Gluten Intolerance

“…When using sera from patients with GA there is evidence of additional antibodies targeting Purkinje cell epitopes since elimination of AGA alone is not sufficient to eliminate such reactivity. There is evidence that the additional antibodies that may be causing such reactivity, are antibodies against one or more transglutaminase isoenzymes (TG2, TG3, TG6) (Boscolo et al, 2010). TG2 belongs to a family of enzymes that covalently crosslink or modify proteins through transamidation, deamidation or esterification of a peptidebound glutamine residue (Aeschlimann and Thomazy, 2000).…”

“…A common problem in such studies is to be able to demonstrate whether it is these specific antibodies or other autoantibodies in the IgG-fraction of patient sera that cause neuronal damage. Using a mouse model we have recently shown that serum from GA patients as well as clonal monovalent anti-TG immunoglobulins derived using phage display, cause ataxia when injected intraventricularly in mice (Boscolo et al, 2010). The fact that not only Ig fractions but also monospecific scFv's mediate functional deficits shows that there is no requirement for complement activation or for the engagement of Fc receptors on Fc-receptor bearing cells in the brain.…”