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HLA-DR3-DQ2 Mice Do Not Develop Ataxia in the Presence of High Titre Anti-gliadin Antibodies

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Abstract

Recently, it has been suggested that anti-gliadin antibodies (αGAb) may produce “gluten ataxia”, even in the absence of celiac disease enteropathy. αGAb are reportedly present in 12–50 % of patients with sporadic ataxia, but also in 12 % of the general population, such that the importance of αGAb as a cause of sporadic ataxia is not conclusively settled. We aimed to determine whether mice transgenic for HLA-DR3-DQ2 and immunised with gliadin to achieve high titres of αGAb would develop ataxia and/or cerebellar damage. From 6 weeks of age, HLA-DR3-DQ2 transgenic mice were immunised fortnightly with gliadin (n = 10) or a saline control (n = 6) in adjuvant. Serum titres were measured by αGAb enzyme-linked immunosorbent assay. At 24 weeks of age, mice were tested for locomotor function using the accelerating rotarod, ledged beam, ink-paw gait, and several neurological severity score subtests. Brains were then collected and processed for immunohistochemistry. Sections were analysed for lymphocytic infiltration, changes in morphology and Purkinje cell (PC) dendritic volume and the number of PCs counted via unbiased stereology. Gliadin-immunised mice developed high αGAb titres while controls did not. There was no statistically significant difference between the gliadin and sham-immunised HLA-DR3-DQ2 mice on any of the tests of motor coordination, in lymphocytic infiltration, PC number or in dendritic volume. High levels of αGAb are not sufficient to produce ataxia or cerebellar damage in HLA-DR3-DQ2 transgenic mice.

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References

  1. Sollid LM, Thorsby E. HLA susceptibility genes in celiac disease: genetic mapping and role in pathogenesis. Gastroenterology. 1993;105:910–22.

    PubMed  CAS  Google Scholar 

  2. Catassi C, Rätsch IM, Fabiani E, Rossini M, Bordicchia F, Candela F, et al. Coeliac disease in the year 2000: exploring the iceberg. Lancet. 1994;343:200–3.

    Article  PubMed  CAS  Google Scholar 

  3. Cooke WT, Smith WT. Neurological disorders associated with adult coeliac disease. Brain. 1966;89:683–722.

    Article  PubMed  CAS  Google Scholar 

  4. Vaknin A, Eliakim R, Ackerman Z, Steiner I. Neurological abnormalities associated with celiac disease. J Neurol. 2004;251:1393–7.

    Article  PubMed  Google Scholar 

  5. Finelli PF, McEntee WJ, Ambler M, Kestenbaum D. Adult celiac disease presenting as cerebellar syndrome. Neurology. 1980;30:245–9.

    Article  PubMed  CAS  Google Scholar 

  6. Hadjivassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet. 1996;347:369–71.

    Article  PubMed  CAS  Google Scholar 

  7. Hadjivassiliou M, Grünewald RA, Chattopadhyay AK, Davies-Jones GA, Gibson A, Jarratt JA, et al. Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet. 1998;352:1582–5.

    Article  PubMed  CAS  Google Scholar 

  8. Pellecchia MT, Scala R, Filla A, De Michele G, Ciacci C, Barone P. Idiopathic cerebellar ataxia associated with celiac disease: lack of distinctive neurological features. JNNP. 1999;66:32–5.

    CAS  Google Scholar 

  9. Bürk K, Bösch S, Müller CA, Melms A, Zühlke C, Stern M, et al. Sporadic cerebellar ataxia associated with gluten sensitivity. Brain. 2001;124:1013–9.

    Article  PubMed  Google Scholar 

  10. Unsworth DJ, Brown DL. Serological screening suggests that adult coeliac disease is underdiagnosed in the UK and increases the incidence by up to 12 %. Gut. 1994;35:61–4.

    Article  PubMed  CAS  Google Scholar 

  11. Bushara K, Hallett M. Prevalence of antigliadin antibodies in ataxia patients. Neurology. 2004;62:1237–8.

    Article  PubMed  Google Scholar 

  12. Combarros O, Infante J, López-Hoyos M, Bartolomé MJ, Berciano J, Corral J, et al. Celiac disease and idiopathic cerebellar ataxia. Neurology. 2000;54:2346.

    Article  PubMed  CAS  Google Scholar 

  13. Wills AJ, Turner B, Lock RJ, Johnston SL, Unsworth DJ, Fry L. Dermatitis herpetiformis and neurological dysfunction. J Neurol Neurosurg Psychiatr. 2002;72:259–61.

    Article  PubMed  CAS  Google Scholar 

  14. Ruuskanen A, Kaukinen K, Collin P, Huhtala H, Valve R, Mäki M, et al. Positive serum antigliadin antibodies without celiac disease in the elderly population: does it matter? Scand J Gastroenterol. 2010;45:1197–202.

    Article  PubMed  Google Scholar 

  15. de Kauwe AL, Chen Z, Anderson RP, Keech CL, Price JD, Wijburg O, et al. Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells. J Immunol. 2009;182:7440–50.

    Article  PubMed  Google Scholar 

  16. Chen Y, Constantini S, Trembovler V, Weinstock M, Shohami E. An experimental model of closed head injury in mice: pathophysiology, histopathology, and cognitive deficits. J Neurotrauma. 1996;13:557–68.

    Article  PubMed  CAS  Google Scholar 

  17. Klapdor K, Dulfer BG, Hammann A, Van der Staay FJ. A low-cost method to analyse footprint patterns. J Neurosci Meth. 1997;75:49–54.

    Article  CAS  Google Scholar 

  18. Bye N, Habgood MD, Callaway JK, Malakooti N, Potter A, Kossmann T, et al. Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Exp Neurol. 2007;204:220–33.

    Article  PubMed  CAS  Google Scholar 

  19. Jones BJ, Roberts DJ. The quantitative measurement of motor inco–ordination in naive mice using an accelerating rotarod. J Pharma Pharmacol. 1968;20:302–4.

    Article  CAS  Google Scholar 

  20. Woodruff-Pak DS. Stereological estimation of Purkinje neuron number in C57BL/6 mice and its relation to associative learning. Neuroscience. 2006;141:233–43.

    Article  PubMed  CAS  Google Scholar 

  21. Grossman G. Neurological complications of coeliac disease: what is the evidence? Pract Neurol. 2008;8:77–89.

    Article  PubMed  CAS  Google Scholar 

  22. Hadjivassiliou M, Sanders D, Woodroofe N, Williamson C, Grünewald R. Gluten ataxia. Cerebellum. 2008;7:494–8.

    Article  PubMed  CAS  Google Scholar 

  23. Kamens HM, Crabbe JC. The parallel rod floor test: a measure of ataxia in mice. Nat Protoc. 2007;2:277–81.

    Article  PubMed  Google Scholar 

  24. Rustay NR, Wahlsten D, Crabbe JC. Assessment of genetic susceptibility to ethanol intoxication in mice. PNAS. 2003;100:2917–22.

    Article  PubMed  CAS  Google Scholar 

  25. Mittelbronn M, Schittenhelm J, Bakos G, de Vos RA, Wehrmann M, Meyermann R, et al. CD8(+)/perforin/granzyme B(+) effector cells infiltrating cerebellum and inferior olives in gluten ataxia. Neuropathology. 2010;30:92–6.

    Article  PubMed  Google Scholar 

  26. Boscolo S, Sarich A, Lorenzon A, Passoni M, Rui V, Stebel M, et al. Gluten ataxia: passive transfer in a mouse model. Ann NY Acad Sci. 2007;1107:319–28.

    Article  PubMed  CAS  Google Scholar 

  27. Boscolo S, Lorenzon A, Sblattero D, Florian F, Stebel M, Marzari R, et al. Anti transglutaminase antibodies cause ataxia in mice. PLoS One. 2010;5:e9698.

    Article  PubMed  Google Scholar 

  28. Alaedini A, Okamoto H, Briani C, Wollenberg K, Shill HA, Bushara KO, et al. Immune cross-reactivity in celiac disease: anti-gliadin antibodies bind to neuronal synapsin I. J Immunol. 2007;178:6590–5.

    PubMed  CAS  Google Scholar 

  29. Thomas H, Beck K, Adamczyk M, Aeschlimann P, Langley M, Oita RC et al (2011) Transglutaminase 6: a protein associated with central nervous system development and motor function. Amino Acids. Available from: http://www.springerlink.com/content/j032glrt53077845/

  30. Wang JL, Yang X, Xia K, Hu ZM, Weng L, Jin X, et al. TGM6 identified as a novel causative gene of spinocerebellar ataxias using exome sequencing. Brain. 2010;133:3510–8.

    Article  PubMed  Google Scholar 

  31. Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodrofe N, Aeschlimann D. Autoantibodies in gluten ataxia recognise a novel neuronal transglutaminase. Ann Neurol. 2008;64:332–43.

    Article  PubMed  CAS  Google Scholar 

  32. Versino M, Franciotta D, Colnaghi S, Biagi F, Zardini E, Bianchi PI, et al. Cerebellar signs in celiac disease. Neurology. 2009;72:2046–8.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grant (436791) from the National Health and Research Council (NH & MRC). We thank Dr J. McCluskey and Dr Kate Keech (Department of Immunology, Melbourne University, Australia) for kindly providing the HLA-DR3-DQ2 transgenic mice.

Conflict of Interest

The authors declare no conflict of interest for this submission.

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Authors and Affiliations

  1. Department of Medicine and Van Cleef Roet Centre for Nervous Disease, Monash University (Alfred Hospital Campus), Commercial Road, Melbourne, VIC, 3004, Australia

    Volga Tarlac, Louise Kelly, Nupur Nag, Judy Allen-Graham & Elsdon Storey

  2. Division of Immunology, Walter & Eliza Hall Institute of Medical Research, Royal Parade, Parkville, VIC, 3052, Australia

    Robert P. Anderson

  3. Department of Neuroscience, The Alfred Hospital, Commercial Road, Melbourne, VIC, 3004, Australia

    Elsdon Storey

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  1. Volga Tarlac
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  2. Louise Kelly
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Correspondence to Elsdon Storey.

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Tarlac, V., Kelly, L., Nag, N. et al. HLA-DR3-DQ2 Mice Do Not Develop Ataxia in the Presence of High Titre Anti-gliadin Antibodies. Cerebellum 12, 370–376 (2013). https://doi.org/10.1007/s12311-012-0425-z

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  • DOI: https://doi.org/10.1007/s12311-012-0425-z

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