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Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep


We describe a form of the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep, linked to the repetitive inoculation of aluminum-containing adjuvants through vaccination. The syndrome shows an acute phase that affects less than 0.5 % of animals in a given herd, it appears 2–6 days after an adjuvant-containing inoculation and it is characterized by an acute neurological episode with low response to external stimuli and acute meningoencephalitis, most animals apparently recovering afterward. The chronic phase is seen in a higher proportion of flocks, it can follow the acute phase, and it is triggered by external stimuli, mostly low temperatures. The chronic phase begins with an excitatory phase, followed by weakness, extreme cachexia, tetraplegia and death. Gross lesions are related to a cachectic process with muscular atrophy, and microscopic lesions are mostly linked to a neurodegenerative process in both dorsal and ventral column of the gray matter of the spinal cord. Experimental reproduction of ovine ASIA in a small group of repeatedly vaccinated animals was successful. Detection of Al(III) in tissues indicated the presence of aluminum in the nervous tissue of experimental animals. The present report is the first description of a new sheep syndrome (ovine ASIA syndrome) linked to multiple, repetitive vaccination and that can have devastating consequences as it happened after the compulsory vaccination against bluetongue in 2008. The ovine ASIA syndrome can be used as a model of other similar diseases affecting both human and animals. A major research effort is needed in order to understand its complex pathogenesis.

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  1. Zandman-Goddard G, Blank M, Ehrenfeld M, Gilburd B, Peter J, Shoenfeld Y. A comparison of autoantibody production in asymptomatic and symptomatic women with silicone breast implants. J Rheumatol. 1999;26:73–7.

    PubMed  CAS  Google Scholar 

  2. Gherardi RK, Coquet M, Cherin P, Belec L, Moretto P, Dreyfus PA, Pellissier JF, Chariot P, Authier FJ. Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle. Brain. 2001;124:1821–31.

    PubMed  Article  CAS  Google Scholar 

  3. Shoenfeld Y, Agmon-Levin N. ‘ASIA’—autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011;36:4–8.

    PubMed  Article  CAS  Google Scholar 

  4. Israeli E. Gulf War syndrome as a part of the autoimmune (autoinflammatory) syndrome induced by adjuvant (ASIA). Lupus. 2012;21:190–4.

    PubMed  Article  CAS  Google Scholar 

  5. Baylor NW, Egan W, Richman P. Aluminum salts in vaccines-US perspective. Vaccine. 2002;20(Suppl 3):S18–23.

    PubMed  Article  CAS  Google Scholar 

  6. Kumar V, Gill KD. Aluminium neurotoxicity: neurobehavioural and oxidative aspects. Arch Toxicol. 2009;83:965–78.

    PubMed  Article  CAS  Google Scholar 

  7. Exley C, Swarbrick L, Gherardi RK, Authier FJ. A role for the body burden of aluminium in vaccine-associated macrophagic myofasciitis and chronic fatigue syndrome. Med Hypotheses. 2009;72:135–9.

    PubMed  Article  CAS  Google Scholar 

  8. Tomljenovic L, Shaw CA. Aluminum vaccine adjuvants: are they safe? Curr Med Chem. 2011;18:2630–7.

    PubMed  Article  CAS  Google Scholar 

  9. Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 2008;453:1122–6.

    PubMed  Article  CAS  Google Scholar 

  10. Marrack P, McKee AS, Munks MW. Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol. 2009;9:287–93.

    PubMed  Article  CAS  Google Scholar 

  11. Exley C, Siesjö P, Erikssson H. The immunobiology of aluminium adjuvants: how do they really work? Trends Immunol. 2010;31:103–9.

    PubMed  Article  CAS  Google Scholar 

  12. González JM, Figueras L, Ortega ME, Lozano M, Ruíz de Arcaute M, Royo R, Cebrián LM, Ferrer LM, Fariñas F, de Jalón JA, de las Heras M. Possible adverse reactions in sheep after vaccination with inactivated BTV vaccines. Vet Rec. 2010;166:757–8.

    PubMed  Article  Google Scholar 

  13. Tourbah A, Gout O, Liblau R, Lyon-Caen O, Bougniot C, Iba-Zizen MT, Cabanis EA. Encephalitis after hepatitis B vaccination: recurrent disseminated encephalitis or MS? Neurology. 1999;53:396–401.

    PubMed  Article  CAS  Google Scholar 

  14. Huynh W, Cordato DJ, Kehdi E, Masters LT, Dedousis C. Post-vaccination encephalomyelitis: literature review and illustrative case. J Clin Neurosci. 2008;15:1315–22.

    PubMed  Article  Google Scholar 

  15. Gherardi RK, Authier FJ. Macrophagic myofasciitis: characterization and pathophysiology. Lupus. 2012;21:184–9.

    PubMed  Article  CAS  Google Scholar 

  16. Yang YQ, Li JC. Progress of research in cell-in-cell phenomena. Anat Rec. 2012;295:372–7.

    Article  Google Scholar 

  17. Guis S, Pellissier JF, Nicoli F, Reviron D, Mattei JP, Gherardi RK, Pelletier J, Kaplanski G, Figarella-Branger D, Roudier J. HLA-DRB1*01 and macrophagic myofasciitis. Arthritis Rheum. 2002;46:2535–7.

    PubMed  Article  CAS  Google Scholar 

  18. Divers TJ, Mohammed HO, Cummings JF. Equine motor neuron disease. Vet Clin North Am Equine Pract. 1997;13:97–105.

    PubMed  CAS  Google Scholar 

  19. Couette M, Boisse MF, Maison P, Brugieres P, Cesaro P, Chevalier X, Gherardi RK, Bachoud-Levi AC, Authier FJ. Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction. J Inorg Biochem. 2009;103:1571–8.

    PubMed  Article  CAS  Google Scholar 

  20. Shaw CA, Petrik MS. Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration. J Inorg Biochem. 2009;103:1555–62.

    PubMed  Article  CAS  Google Scholar 

  21. Trendelenburg G. Acute neurodegeneration and the inflammasome: central processor for danger signals and the inflammatory response? J Cereb Blood Flow Metab. 2008;28:867–81.

    PubMed  Article  CAS  Google Scholar 

  22. Shi F, Yang L, Kouadir M, Yang Y, Wang J, Zhou X, Yin X, Zhao D. The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation. J Neuroinflammation. 2012;9:73.

    PubMed  Article  CAS  Google Scholar 

  23. Kubota T, Koike R. Cryopyrin-associated periodic syndromes: background and therapeutics. Mod Rheumatol. 2010;20:213–21.

    PubMed  Article  Google Scholar 

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This work has been possible thanks to the interest and effort of many veterinarians and farmers that are all deeply acknowledged. We are indebted to many colleagues that helped with many analyses of ovine samples. We are also very thankful to Rosario Puyó and Santiago Becerra for technical help.

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Correspondence to Lluís Luján.

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José Luis Gracia Chapullé: Deceased.

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Luján, L., Pérez, M., Salazar, E. et al. Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep. Immunol Res 56, 317–324 (2013).

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  • Sheep
  • Aluminum
  • Vaccines
  • Adjuvant
  • Autoimmunity
  • Cachexia
  • Intoxication