Are there negative CNS impacts of aluminum adjuvants used in vaccines and immunotherapy?

Papers of special note have been highlighted as: •• of considerable interest

References

• 1 Baylor NW, Egan W, Richman P. Aluminum salts in vaccines – US perspective. Vaccine 20(Suppl. 3), S18–S23 (2002).
  Medline CASGoogle Scholar
• 2 Glenny AT, Pope CG, Waddington H, Wallace U. XXIII – the antigenic value of toxoid precipitated by potassium alum. J. Pathol Bacteriol. 29, 38–39 (1926).
  Google Scholar
• 3 Exley C. Aluminium adjuvants and adverse events in sub-cutaneous allergy immunotherapy. Allergy Asthma Clin. Immunol. 10(1), 4 (2014).
  MedlineGoogle Scholar
• 4 Shaw CA, Petrik MS. Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration. J. Inorg. Biochem. 103(11), 1555–1562 (2009).
  Medline CASGoogle Scholar
• 5 Li X, Zheng H, Zhang Z et al. Glia activation induced by peripheral administration of aluminum oxide nanoparticles in rat brains. Nanomedicine 5(4), 473–479 (2009).
  Medline CASGoogle Scholar
• 6 Passeri E, Villa C, Couette M et al. Long-term follow-up of cognitive dysfunction in patients with aluminum hydroxide-induced macrophagic myofasciitis (MMF). J. Inorg. Biochem. 105(11), 1457–1463 (2011).•• Demonstration of a unique cognitive dysfunction syndrome in patients with post-vaccinal macrophagic myofasciitis, which provides further evidence of the multisystemic nature of macrophagic myofasciitis (MMF).
  Medline CASGoogle Scholar
• 7 Couette M, Boisse MF, Maison P et al. Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction. J. Inorg. Biochem. 103(11), 1571–1578 (2009).
  Medline CASGoogle Scholar
• 8 Gherardi R, Authier F. Macrophagic myofasciitis: characterization and pathophysiology. Lupus 21(2), 184–189 (2012).
  Medline CASGoogle Scholar
• 9 Zafrir Y, Agmon-Levin N, Paz Z, Shilton T, Shoenfeld Y. Autoimmunity following Hepatitis B vaccine as part of the spectrum of ‘Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants’ (ASIA): analysis of 93 cases. Lupus 21(2), 146–152 (2012).
  Medline CASGoogle Scholar
• 10 Shaw AC, Li Y, Tomljenovic L. Administration of aluminium in vaccine-relevant amounts in neonatal mice is associated with long-term adverse neurological outcomes. J. Inorg. Biochem. 128, 237–244 (2013).
  Medline CASGoogle Scholar
• 11 Khan Z, Combadiere C, Authier FJ et al. Slow CCL2-dependent translocation of biopersistent particles from muscle to brain. BMC Med. 11, 99 (2013).•• Demonstration of neurodelivery and long-term accumulation of peripherally injected vaccine-derived aluminum compounds in mice.
  Medline CASGoogle Scholar
• 12 Offit PA, Jew RK. Addressing parents’ concerns: do vaccines contain harmful preservatives, adjuvants, additives, or residuals? Pediatrics 112(6 Pt 1), 1394–1397 (2003).
  MedlineGoogle Scholar
• 13 Eldred BE, Dean AJ, McGuire TM, Nash AL. Vaccine components and constituents: responding to consumer concerns. Med. J. Aust. 184(4), 170–175 (2006).
  MedlineGoogle Scholar
• 14 Priest ND. Satellite symposium on Alzheimer's disease and dietary aluminium. Proc. Nutr. Soc. 52, 231–240 (1993).
  Medline CASGoogle Scholar
• 15 Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for aluminum. US Department of Health and Human services, Atlanta, GA, USA (2008). www.atsdr.cdc.gov/toxprofiles/tp22.pdf
  Google Scholar
• 16 Exley C. Human exposure to aluminium. Environ. Sci. Process Impacts 15(10), 1807–1816 (2013).
  Medline CASGoogle Scholar
• 17 Tomljenovic L. Aluminum and Alzheimer's disease: after a century of controversy, is there a plausible link? J. Alzheimers Dis. 23(4), 567–598 (2011).
  Medline CASGoogle Scholar
• 18 Walton JR. Evidence that Ingested Aluminum additives contained in processed foods and alum-treated drinking water are a major risk factor for Alzheimer's Disease. Curr. Inorg. Chem. 2(1), 19–39 (2012).
  CASGoogle Scholar
• 19 Exley C, House E. Aluminium in the human brain. Monatsh. Chem. 142, 357–363 (2011).
  CASGoogle Scholar
• 20 Fewtrell MS, Edmonds CJ, Isaacs E, Bishop NJ, Lucas A. Aluminium exposure from parenteral nutrition in preterm infants and later health outcomes during childhood and adolescence. Proc. Nutr. Soc. 70(3), 299–304 (2011).
  Medline CASGoogle Scholar
• 21 Power G, Loh JSC, Vernon C. Organic compounds in the processing of lateritic bauxites to alumina Part 2: effects of organics in the Bayer process. Hydrometallurgy 127–128, 125–149 (2012).
  CASGoogle Scholar
• 22 Dapson RW. The history, chemistry and modes of action of carmine and related dyes. Biotech. Histochem. 82(4), 173–187 (2007).
  Medline CASGoogle Scholar
• 23 Nicholson S, Exley C. Aluminum: a potential pro-oxidant in sunscreens/sunblocks? Free Radic. Biol. Med. 43(8), 1216–1217 (2007).
  Medline CASGoogle Scholar
• 24 Ai-Ashmawy MA. Prevalence and public health significance of aluminum residues in milk and some dairy products. J. Food Sci. 76(3), T73–T76 (2011).
  MedlineGoogle Scholar
• 25 Bishop NJ, Morley R, Day JP, Lucas A. Aluminum neurotoxicity in preterm infants receiving intravenous-feeding solutions. N. Engl. J. Med. 336(22), 1557–1561 (1997).
  Medline CASGoogle Scholar
• 26 Fewtrell MS, Bishop NJ, Edmonds CJ, Isaacs EB, Lucas A. Aluminum exposure from parenteral nutrition in preterm infants: bone health at 15-year follow-up. Pediatrics 124(5), 1372–1379 (2009).
  MedlineGoogle Scholar
• 27 Gies WJ. Some objections to the use of alum baking-powder. JAMA 57(10), 816–821 (1911).
  Google Scholar
• 28 Exley C. Aluminium and medicine. In: Molecular and Supramolecular Bioinorganic Chemistry: Applications in Medical Sciences. Merce ALR, Felcman J, Recio MAL (Eds). Nova Biomedical Books, NY, USA, 45–68 (2009).
  Google Scholar
• 29 Tomljenovic L, Shaw CA. Aluminum vaccine adjuvants: are they safe? Curr. Med. Chem. 18(17), 2630–2637 (2011).
  Medline CASGoogle Scholar
• 30 Yokel RA, Hicks CL, Florence RL. Aluminum bioavailability from basic sodium aluminum phosphate, an approved food additive emulsifying agent, incorporated in cheese. Food Chem. Toxicol. 46(6), 2261–2266 (2008).
  Medline CASGoogle Scholar
• 31 Yokel RA, McNamara PJ. Aluminium toxicokinetics: an updated minireview. Pharmacol. Toxicol. 88(4), 159–167 (2001).
  Medline CASGoogle Scholar
• 32 Walton JR. Brain lesions comprised of aluminum-rich cells that lack microtubules may be associated with the cognitive deficit of Alzheimer's disease. Neurotoxicology 30(6), 1059–1069 (2009).
  Medline CASGoogle Scholar
• 33 Walton JR. Aluminum in hippocampal neurons from humans with Alzheimer's disease. Neurotoxicology 27(3), 385–394 (2006).
  Medline CASGoogle Scholar
• 34 Kowall NW, Pendlebury WW, Kessler JB, Perl DP, Beal MF. Aluminum-induced neurofibrillary degeneration affects a subset of neurons in rabbit cerebral cortex, basal forebrain and upper brainstem. Neuroscience 29(2), 329–337 (1989).
  Medline CASGoogle Scholar
• 35 Polizzi S, Pira E, Ferrara M et al. Neurotoxic effects of aluminium among foundry workers and Alzheimer's disease. Neurotoxicology 23(6), 761–774 (2002).
  Medline CASGoogle Scholar
• 36 Sinczuk-Walczak H, Szymczak M, Razniewska G, Matczak W, Szymczak W. Effects of occupational exposure to aluminum on nervous system: clinical and electroencephalographic findings. Int. J. Occup. Med. Environ. Health 16(4), 301–310 (2003).
  MedlineGoogle Scholar
• 37 Saiyed SM, Yokel RA. Aluminium content of some foods and food products in the USA, with aluminium food additives. Food Addit. Contam. 22(3), 234–244 (2005).
  Medline CASGoogle Scholar
• 38 Greger JL. Aluminum metabolism. Annu Rev. Nutr. 13, 43–63 (1993).
  Medline CASGoogle Scholar
• 39 Pennington JA, Schoen SA. Estimates of dietary exposure to aluminium. Food Addit. Contam. 12(1), 119–128 (1995).
  Medline CASGoogle Scholar
• 40 Food and Agriculture Organization (FAO)/WHO. Summary and conclusions of the sixty-seventh meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 67th meeting in Rome, Italy, 20–29 June 2006. ftp://ftp.fao.org/ag/agn/jecfa/jecfa67_final.pdf
  Google Scholar
• 41 Flendrig JA, Kruis H, Das HA. Aluminium intoxication: the cause of dialysis dementia? Proc. Eur. Dial. Transpl. Assoc. 13, 355–368 (1976).
  Google Scholar
• 42 Rozas VV, Port FK, Easterling RE. An outbreak of dialysis dementia due to aluminum in the dialysate. J. Dial. 2(5–6), 459–470 (1978).
  Medline CASGoogle Scholar
• 43 Melendez L, Santos D, Luna Polido L et al. Aluminium and other metals may pose a risk to children with autism spectrum disorder: biochemical and behavioural impairments. Clin. Exp. Pharmacol. 3, 1 (2013).
  Google Scholar
• 44 Yasuda H, Tsutsui T. Assessment of infantile mineral imbalances in autism spectrum disorders (ASDs). Int. J. Environ. Res. Public Health 10(11), 6027–6043 (2013).
  Medline CASGoogle Scholar
• 45 Seneff S, Davidson RM, Liu J. Empirical data confirm autism symptoms related to aluminum and acetaminophen exposure. Entropy 14, 2227–2253 (2012).
  CASGoogle Scholar
• 46 Tomljenovic L, Shaw CA. Do aluminum vaccine adjuvants contribute to the rising prevalence of autism? J. Inorg. Biochem. 105(11), 1489–1499 (2011).
  Medline CASGoogle Scholar
• 47 Perl DP, Moalem S. Aluminum, Alzheimer's disease and the geospatial occurrence of similar disorders. Rev. Mineral Geochem. 64, 115–134 (2006).
  CASGoogle Scholar
• 48 Exley C. Aluminum and Alzheimer's disease. J. Alzheimers Dis. 3(6), 551–552 (2001).
  MedlineGoogle Scholar
• 49 McLachlan DRC, Krishnan SS, Dalton AJ. Brain aluminum distribution in Alzheimer's disease and experimental neurofibrillary degeneration. Science 180(85), 511–513 (1973).
  MedlineGoogle Scholar
• 50 McLachlan DRC, Dalton AJ. Alterations in short-term retention, conditioned avoidance response acquisition and motivation following aluminum induced neurofibrillary degeneration. Physiol. Behav. 10(5), 925–933 (1973).
  MedlineGoogle Scholar
• 51 Lukiw WJ. Aluminum and gene transcription in the mammalian central nervous system – implications for Alzheimer's disease. In: Aluminium and Alzheimer's Disease: The science that Describes the Link (1st Edition). Exley C (Ed.), Elsevier Science, Amsterdam, The Netherlands, 147–169 (2001).
  Google Scholar
• 52 Lukiw WJ. Evidence supporting a biological role for aluminum in chromatin compaction and epigenetics. J. Inorg. Biochem. 104(9), 1010–1012 (2010).
  Medline CASGoogle Scholar
• 53 Lukiw WJ, Kruck TP, McLachlan DR. Linker histone–DNA complexes: enhanced stability in the presence of aluminum lactate and implications for Alzheimer's disease. FEBS Lett. 253(1–2), 59–62 (1989).
  Medline CASGoogle Scholar
• 54 Wu J, Du F, Zhang P, Khan IA, Chen J, Liang Y. Thermodynamics of the interaction of aluminum ions with DNA: implications for the biological function of aluminum. J. Inorg. Biochem. 99(5), 1145–1154 (2005).
  Medline CASGoogle Scholar
• 55 Lukiw WJ, LeBlanc HJ, Carver LA, McLachlan DR, Bazan NG. Run-on gene transcription in human neocortical nuclei. Inhibition by nanomolar aluminum and implications for neurodegenerative disease. J. Mol. Neurosci. 11(1), 67–78 (1998).
  Medline CASGoogle Scholar
• 56 McLachlan DRC, Lukiw WJ, Kruck TPA. Aluminum, altered transcription, and the pathogenesis of Alzheimer's disease. Environ. Geochem. Health 12(1–2), 103–114 (1990).
  Medline CASGoogle Scholar
• 57 Alexandrov PN, Zhao Y, Pogue AI et al. Synergistic effects of iron and aluminum on stress-related gene expression in primary human neural cells. J. Alzheimers Dis. 8(2), 117–127; discussion 209–115 (2005).
  Medline CASGoogle Scholar
• 58 Lukiw WJ, Percy ME, Kruck TP. Nanomolar aluminum induces pro-inflammatory and pro-apoptotic gene expression in human brain cells in primary culture. J. Inorg. Biochem. 99(9), 1895–1898 (2005).
  Medline CASGoogle Scholar
• 59 Lukiw WJ, Bazan NG. Neuroinflammatory signaling upregulation in Alzheimer's disease. Neurochem. Res. 25(9–10), 1173–1184 (2000).
  Medline CASGoogle Scholar
• 60 Herbert MR, Russo JP, Yang S et al. Autism and environmental genomics. Neurotoxicology 27(5), 671–684 (2006).
  Medline CASGoogle Scholar
• 61 Ruiperez F, Mujika JI, Ugalde JM, Exley C, Lopez X. Pro-oxidant activity of aluminum: promoting the Fenton reaction by reducing Fe(III) to Fe(II). J. Inorg. Biochem. 117, 118–123 (2012).
  Medline CASGoogle Scholar
• 62 Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl Acad. Sci. USA 94(18), 9866–9868 (1997).
  Medline CASGoogle Scholar
• 63 Carson BL. Aluminum compounds. Review of toxicological literature, abridged final report: p 84. Integrated Laboratory Systems, Research Triangle Park, NC, USA (2000). http://ntp.niehs.nih.gov/ntp/htdocs/chem_background/exsumpdf/aluminum_508.pdf
  Google Scholar
• 64 Shafer TJ, Mundy WR. Effects of aluminum on neuronal signal transduction: mechanisms underlying disruption of phosphoinositide hydrolysis. Gen. Pharmacol. 26(5), 889–895 (1995).
  Medline CASGoogle Scholar
• 65 Mundy WR, Kodavanti PR, Dulchinos VF, Tilson HA. Aluminum alters calcium transport in plasma membrane and endoplasmic reticulum from rat brain. J. Biochem. Toxicol. 9(1), 17–23 (1994).
  Medline CASGoogle Scholar
• 66 Macdonald TL, Humphreys WG, Martin RB. Promotion of tubulin assembly by aluminum ion in vitro. Science 236(4798), 183–186 (1987).
  Medline CASGoogle Scholar
• 67 McLachlan DRC, Farnell BJ. Cellular mechanisms of aluminium toxicity. Ann. Ist. Super Sanita 22(2), 697–702 (1986).
  MedlineGoogle Scholar
• 68 Siegel N, Haug A. Aluminum interaction with calmodulin. Evidence for altered structure and function from optical and enzymatic studies. Biochim. Biophys. Acta 744(1), 36–45 (1983).
  Medline CASGoogle Scholar
• 69 Joshi JG. Neurochemical hypothesis: participation by aluminum in producing critical mass of colocalized errors in brain leads to neurological disease. Comp. Biochem. Physiol. C. 100(1–2), 103–105 (1991).
  Medline CASGoogle Scholar
• 70 Joshi JG, Dhar M, Clauberg M, Chauthaiwale V. Iron and aluminum homeostasis in neural disorders. Environ. Health Perspect. 102(Suppl. 3), 207–213 (1994).
  Medline CASGoogle Scholar
• 71 Roskams AJ, Connor JR. Aluminum access to the brain: a role for transferrin and its receptor. Proc. Natl Acad. Sci. USA 87(22), 9024–9027 (1990).
  Medline CASGoogle Scholar
• 72 Exley C. A molecular mechanism of aluminium-induced Alzheimer's disease? J. Inorg. Biochem. 76(2), 133–140 (1999).
  Medline CASGoogle Scholar
• 73 Silva VS, Duarte AI, Rego AC, Oliveira CR, Goncalves PP. Effect of chronic exposure to aluminium on isoform expression and activity of rat (Na⁺/K⁺)ATPase. Toxicol. Sci. 88(2), 485–494 (2005).
  Medline CASGoogle Scholar
• 74 Exley C, Price NC, Birchall JD. Aluminum inhibition of hexokinase activity in vitro: a study in biological availability. J. Inorg. Biochem. 54(4), 297–304 (1994).
  Medline CASGoogle Scholar
• 75 McLachlan DRC, Dam TV, Farnell BJ, Lewis PN. Aluminum inhibition of ADP-ribosylation in vivo and in vitro. Neurobehav. Toxicol. Teratol. 5(6), 645–647 (1983).
  Medline CASGoogle Scholar
• 76 Cherroret G, Desor D, Hutin MF, Burnel D, Capolaghi B, Lehr PR. Effects of aluminum chloride on normal and uremic adult male rats. Tissue distribution, brain choline acetyltransferase activity, and some biological variables. Biol. Trace Elem. Res. 54(1), 43–53 (1996).
  Medline CASGoogle Scholar
• 77 King RG. Do raised brain aluminium levels in Alzheimer's dementia contribute to cholinergic neuronal deficits? Med. Hypotheses 14(3), 301–306 (1984).
  Medline CASGoogle Scholar
• 78 King RG, Sharp JA, Boura AL. Aluminium, choline transportation and Alzheimer's disease. Med. J. Aust. 2(12), 606–607 (1983).
  Medline CASGoogle Scholar
• 79 Huber CT, Frieden E. The inhibition of ferroxidase by trivalent and other metal ions. J. Biol. Chem. 245(15), 3979–3984 (1970).
  Medline CASGoogle Scholar
• 80 Abdel-Ghany M, el-Sebae AK, Shalloway D. Aluminum-induced nonenzymatic phospho-incorporation into human tau and other proteins. J. Biol. Chem. 268(16), 11976–11981 (1993).
  Medline CASGoogle Scholar
• 81 Banks WA, Kastin AJ. Aluminum-induced neurotoxicity: alterations in membrane function at the blood–brain barrier. Neurosci. Biobehav. Rev. 13(1), 47–53 (1989).
  Medline CASGoogle Scholar
• 82 Walton JR. Functional impairment in aged rats chronically exposed to human range dietary aluminum equivalents. Neurotoxicology 30(2), 182–193 (2009).
  Medline CASGoogle Scholar
• 83 Walton JR, Wang MX. APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer's disease. J. Inorg. Biochem. 103(11), 1548–1554 (2009).
  Medline CASGoogle Scholar
• 84 Nehru B, Anand P. Oxidative damage following chronic aluminium exposure in adult and pup rat brains. J. Trace Elem. Med. Biol. 19(2–3), 203–208 (2005).
  Medline CASGoogle Scholar
• 85 Jing Y, Wang Z, Song Y. Quantitative study of aluminum-induced changes in synaptic ultrastructure in rats. Synapse 52(4), 292–298 (2004).
  Medline CASGoogle Scholar
• 86 Deloncle R, Fauconneau B, Piriou A, Huguet F, Guillard O. Aluminum L-glutamate complex in rat brain cortex: in vivo prevention of aluminum deposit by magnesium D-aspartate. Brain Res. 946(2), 247–252 (2002).
  Medline CASGoogle Scholar
• 87 Matyja E. Aluminum enhances glutamate-mediated neurotoxicity in organotypic cultures of rat hippocampus. Folia Neuropathol. 38(2), 47–53 (2000).
  Medline CASGoogle Scholar
• 88 Walton JR. Amyloid, aluminium and the aetiology of Alzheimer's disease. Med. J. Aust. 164(6), 382–383 (1996).
  Medline CASGoogle Scholar
• 89 Bondy SC, Ali SF, Guo-Ross S. Aluminum but not iron treatment induces pro-oxidant events in the rat brain. Mol. Chem. Neuropathol. 34(2–3), 219–232 (1998).
  Medline CASGoogle Scholar
• 90 Jope RS, Johnson GV. Neurotoxic effects of dietary aluminium. Ciba Found Symp. 169, 254–262; discussion 262–257 (1992).
  Medline CASGoogle Scholar
• 91 Johnson GV, Watson AL Jr, Lartius R, Uemura E, Jope RS. Dietary aluminum selectively decreases MAP-2 in brains of developing and adult rats. Neurotoxicology 13(2), 463–474 (1992).
  Medline CASGoogle Scholar
• 92 Bowdler NC, Beasley DS, Fritze EC et al. Behavioral effects of aluminum ingestion on animal and human subjects. Pharmacol. Biochem. Behav. 10(4), 505–512 (1979).
  Medline CASGoogle Scholar
• 93 Thorne BM, Donohoe T, Lin KN, Lyon S, Medeiros DM, Weaver ML. Aluminum ingestion and behavior in the Long-Evans rat. Physiol. Behav. 36(1), 63–67 (1986).
  Medline CASGoogle Scholar
• 94 Yokel RA, Allen DD, Meyer JJ. Studies of aluminum neurobehavioral toxicity in the intact mammal. Cell Mol. Neurobiol. 14(6), 791–808 (1994).
  Medline CASGoogle Scholar
• 95 Campbell A, Becaria A, Lahiri DK, Sharman K, Bondy SC. Chronic exposure to aluminum in drinking water increases inflammatory parameters selectively in the brain. J. Neurosci. Res. 75(4), 565–572 (2004).
  Medline CASGoogle Scholar
• 96 Pivnick EK, Kerr NC, Kaufman RA, Jones DP, Chesney RW. Rickets secondary to phosphate depletion. A sequela of antacid use in infancy. Clin. Pediatr. 34(2), 73–78 (1995).
  Medline CASGoogle Scholar
• 97 McDermott JR, Smith AI, Iqbal K, Wisniewski HM. Brain aluminum in aging and Alzheimer disease. Neurology 29(6), 809–814 (1979).
  Medline CASGoogle Scholar
• 98 Crapper DR, Quittkat S, Krishnan SS, Dalton AJ, De Boni U. Intranuclear aluminum content in Alzheimer's disease, dialysis encephalopathy, and experimental aluminum encephalopathy. Acta Neuropathol. 50(1), 19–24 (1980).
  Medline CASGoogle Scholar
• 99 Perl DP, Brody AR. Alzheimer's disease: x-ray spectrometric evidence of aluminum accumulation in neurofibrillary tangle-bearing neurons. Science 208(4441), 297–299 (1980).
  Medline CASGoogle Scholar
• 100 Candy JM, Oakley AE, Mountfort SA et al. The imaging and quantification of aluminium in the human brain using dynamic secondary ion mass spectrometry (SIMS). Biol. Cell 74(1), 109–118 (1992).
  Medline CASGoogle Scholar
• 101 Edwardson JA, Candy JM, Ince PG et al. Aluminium accumulation, beta-amyloid deposition and neurofibrillary changes in the central nervous system. Ciba Found Symp. 169, 165–179; discussion 179–185 (1992).
  Medline CASGoogle Scholar
• 102 Lukiw WJ, Krishnan B, Wong L, Kruck TP, Bergeron C, Crapper McLachlan DR. Nuclear compartmentalization of aluminum in Alzheimer's disease (AD). Neurobiol. Aging. 13(1), 115–121 (1992).
  Medline CASGoogle Scholar
• 103 Perl DP, Moalem S. Aluminum and Alzheimer's disease, a personal perspective after 25 years. J. Alzheimers Dis. 9(3 Suppl.), 291–300 (2006).
  Medline CASGoogle Scholar
• 104 International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 431(7011), 931–945 (2004).
  MedlineGoogle Scholar
• 105 Bohrer D, do Nascimento PC, Mendonca JK, Polli VG, de Carvalho LM. Interaction of aluminium ions with some amino acids present in human blood. Amino Acids 27(1), 75–83 (2004).
  Medline CASGoogle Scholar
• 106 Brothers PJ, Ruggerio CE. Coordination and solution chemistry of the metals: biological, medical, and environmental relevance. In: The Group 13 Metals Aluminium, Gallium, Indium and Thallium, Chemical Patterns and Peculiarities. Aldridge S, Downs AJ (Eds.), John Wiley and Sons, Chichester, UK, 519–611 (2011).
  Google Scholar
• 107 Tomljenovic L, Shaw CA. Mechanisms of aluminum adjuvant toxicity in pediatric populations. Lupus 21(2), 223–230 (2012).
  Medline CASGoogle Scholar
• 108 Caulfield MJ, Shi L, Wang S et al. Effect of alternative aluminum adjuvants on the absorption and immunogenicity of HPV16 L1 VLPs in mice. Hum. Vaccin. 3(4), 139–145 (2007).
  MedlineGoogle Scholar
• 109 Mitkus RJ, King DB, Hess MA, Forshee RA, Walderhaug MO. Updated aluminum pharmacokinetics following infant exposures through diet and vaccination. Vaccine 29(51), 9538–9543 (2011).
  Medline CASGoogle Scholar
• 110 Priest ND. The biological behaviour and bioavailability of aluminium in man, with special reference to studies employing aluminium-26 as a tracer: review and study update. J. Environ. Monit. 6(5), 375–403 (2004).
  Medline CASGoogle Scholar
• 111 Flarend RE, Hem SL, White JL et al. In vivo absorption of aluminium-containing vaccine adjuvants using 26Al. Vaccine 15(12–13), 1314–1318 (1997).
  Medline CASGoogle Scholar
• 112 Hem SL. Elimination of aluminum adjuvants. Vaccine 20(Suppl.), S40–S43 (2002).
  Medline CASGoogle Scholar
• 113 Lee SH. Melting profiles may affect detection of residual HPV L1 gene DNA fragments in Gardasil. Curr. Med. Chem. 21(7), 932–940 (2014).
  Medline CASGoogle Scholar
• 114 Lee SH. Topological conformational changes of human papillomavirus (HPV) DNA bound to an insoluble aluminum salt-A study by low temperature PCR Adv. Biol. Chem. 3, 76–85 (2013).
  CASGoogle Scholar
• 115 Lee SH. Detection of human papillomavirus L1 gene DNA fragments in postmortem blood and spleen after Gardasil^® vaccination – a case report Adv. Biosc. Biotech. 3, 1214–1224 (2012).
  Google Scholar
• 116 Walton JR. A longitudinal study of rats chronically exposed to aluminum at human dietary levels. Neurosci. Lett. 412(1), 29–33 (2007).
  Medline CASGoogle Scholar
• 117 Gherardi RK, Coquet M, Cherin P et al. Macrophagic myofasciitis: an emerging entity. Groupe d’Etudes et Recherche sur les Maladies Musculaires Acquises et Dysimmunitaires (GERMMAD) de l’Association Francaise contre les Myopathies (AFM). Lancet 352(9125), 347–352 (1998).
  Medline CASGoogle Scholar
• 118 Gherardi RK, Coquet M, Cherin P et al. Macrophagic myofasciitis lesions assess long-term persistence of vaccine-derived aluminium hydroxide in muscle. Brain 124(Pt 9), 1821–1831 (2001). •• Control study showing that MMF constitutes a systemic pathology rather than simply a presence of a benign localized aluminum-rich muscle lesion as frequently falsely contended.
  Medline CASGoogle Scholar
• 119 Authier FJ, Sauvat S, Champey J, Drogou I, Coquet M, Gherardi RK. Chronic fatigue syndrome in patients with macrophagic myofasciitis. Arthritis Rheum. 48(2), 569–570 (2003).
  MedlineGoogle Scholar
• 120 Gherardi RK, Authier FJ. Aluminum inclusion macrophagic myofasciitis: a recently identified condition. Immunol. Allergy Clin. North Am. 23(4), 699–712 (2003).
  MedlineGoogle Scholar
• 121 Hassan IS, Bannister BA, Akbar A, Weir W, Bofill M. A study of the immunology of the chronic fatigue syndrome: correlation of immunologic parameters to health dysfunction. Clin. Immunol. Immunopathol. 87(1), 60–67 (1998).
  Medline CASGoogle Scholar
• 122 Landay AL, Jessop C, Lennette ET, Levy JA. Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet 338(8769), 707–712 (1991).
  Medline CASGoogle Scholar
• 123 Konstantinov K, von Mikecz A, Buchwald D, Jones J, Gerace L, Tan EM. Autoantibodies to nuclear envelope antigens in chronic fatigue syndrome. J. Clin. Invest. 98(8), 1888–1896 (1996).
  Medline CASGoogle Scholar
• 124 Nishikai M, Tomomatsu S, Hankins RW et al. Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders. Rheumatology 40(7), 806–810 (2001).
  Medline CASGoogle Scholar
• 125 Gherardi RK, Plonquet A, André C, Intrator L, Poron F, Coquet M. Macrophagic myofasciitis: evidence for chronic local and systemic immune activation associated with persistence of aluminum hydroxide-loaded macrophages in muscle [abstract]. Neurology 56(Suppl. 3), A62 (2001).
  MedlineGoogle Scholar
• 126 Brewer JM. (How) do aluminium adjuvants work? Immunol. Lett. 102(1), 10–15 (2006).
  Medline CASGoogle Scholar
• 127 Gherardi RK. [Lessons from macrophagic myofasciitis: towards definition of a vaccine adjuvant-related syndrome]. Rev. Neurol. 159(2), 162–164 (2003).
  Medline CASGoogle Scholar
• 128 Bonnefont-Rousselot D, Chantalat-Auger C, Teixeira A, Jaudon MC, Pelletier S, Cherin P. Blood oxidative stress status in patients with macrophagic myofasciitis. Biomed. Pharmacother. 58(9), 516–519 (2004).
  Medline CASGoogle Scholar
• 129 Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch. Neurol. 56(3), 303–308 (1999).
  Medline CASGoogle Scholar
• 130 Petersen RC. Mild cognitive impairment as a diagnostic entity. J. Intern. Med. 256(3), 183–194 (2004).
  Medline CASGoogle Scholar
• 131 Dickerson BC, Wolk DA. Dysexecutive versus amnesic phenotypes of very mild Alzheimer's disease are associated with distinct clinical, genetic and cortical thinning characteristics. J. Neurol. Neurosurg. Psychiatry 82(1), 45–51 (2011).
  MedlineGoogle Scholar
• 132 Cadusseau J, Ragunathan-Thangarajah N, Surenaud M, Hue S, Authier FJ, Gherardi RK. Selective elevation of circulating CCL2/MCP1 levels in patients with longstanding post-vaccinal macrophagic myofasciitis and ASIA. Curr. Med. Chem. 21(4), 511–517 (2014).
  Medline CASGoogle Scholar
• 133 Ganrot PO. Metabolism and possible health effects of aluminum. Environ. Health Perspect. 65, 363–441 (1986).
  Medline CASGoogle Scholar
• 134 Shin RW, Lee VM, Trojanowski JQ. Aluminum modifies the properties of Alzheimer's disease PHF tau proteins in vivo and in vitro. J. Neurosci. 14(11 Pt 2), 7221–7233 (1994).
  Medline CASGoogle Scholar
• 135 Redhead K, Quinlan GJ, Das RG, Gutteridge JM. Aluminium-adjuvanted vaccines transiently increase aluminium levels in murine brain tissue. Pharmacol. Toxicol. 70(4), 278–280 (1992).
  Medline CASGoogle Scholar
• 136 Petrik MS, Wong MC, Tabata RC, Garry RF, Shaw CA. Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice. Neuromol. Med. 9(1), 83–100 (2007).
  Medline CASGoogle Scholar
• 137 Lujan L, Perez M, Salazar E et al. Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep. Immunol. Res. 56(2–3), 317–324 (2013). •• Experimental reproduction of an immune-mediated inflammatory syndrome induced by adjuvants in commercial sheep, linked to the repetitive inoculation of aluminum-containing adjuvants through vaccination.
  Medline CASGoogle Scholar
• 138 Corrigan FM, Reynolds GP, Ward NI. Hippocampal tin, aluminum and zinc in Alzheimer's disease. Biometals 6(3), 149–154 (1993).
  Medline CASGoogle Scholar
• 139 Dietert RR, Dietert JM. Potential for early-life immune insult including developmental immunotoxicity in autism and autism spectrum disorders: focus on critical windows of immune vulnerability. J. Toxicol. Environ. Health B Crit. Rev. 11(8), 660–680 (2008).
  Medline CASGoogle Scholar
• 140 Poole RL, Hintz SR, Mackenzie NI, Kerner JA Jr. Aluminum exposure from pediatric parenteral nutrition: meeting the new FDA regulation. JPEN J. Parenter. Enteral. Nutr. 32(3), 242–246 (2008).
  Medline CASGoogle Scholar
• 141 Shoenfeld Y, Agmon-Levin N. ‘ASIA’ – autoimmune/inflammatory syndrome induced by adjuvants. J. Autoimmun. 36(1), 4–8 (2011).
  Medline CASGoogle Scholar
• 142 Agmon-Levin N, Hughes G, Shoenfeld Y. The spectrum of ASIA: ‘Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants’. Lupus 21(2), 118–120 (2012).
  Medline CASGoogle Scholar
• 143 Rosenblum H, Shoenfeld Y, Amital H. The common immunogenic etiology of chronic fatigue syndrome: from infections to vaccines via adjuvants to the ASIA syndrome. Infect. Dis. Clin. N. Am. 25, 851–863 (2011).
  MedlineGoogle Scholar
• 144 Meroni PL. Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): old truths and a new syndrome? J. Autoimmun. 36(1), 1–3 (2010).
  MedlineGoogle Scholar
• 145 Quiroz-Rothe E, Ginel PJ, Pérez J, Lucena R, Rivero JLL. Vaccine-associated acute polyneuropathy resembling Guillain-Barré syndrome in a dog. Eur. J. Companion Animal Practice 15(2), 155 (2005).
  Google Scholar
• 146 Hogenesch H, Azcona-Olivera J, Scott-Moncrieff C, Snyder PW, Glickman LT. Vaccine-induced autoimmunity in the dog. Adv. Vet. Med. 41, 733–747 (1999).
  Medline CASGoogle Scholar
• 147 Shoenfeld Y, Aron-Maor A. Vaccination and autoimmunity-’vaccinosis’: a dangerous liaison? J. Autoimmun. 14(1), 1–10 (2000).
  Medline CASGoogle Scholar
• 148 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. 453(7198), 1122–1126 (2008).
  Medline CASGoogle Scholar
• 149 Li H, Nookala S, Re F. Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1beta and IL-18 release. J. Immunol. 178(8), 5271–5276 (2007).
  Medline CASGoogle Scholar
• 150 Exley C, Siesjo P, Eriksson H. The immunobiology of aluminium adjuvants: how do they really work? Trends Immunol. 31(3), 103–109 (2010).
  Medline CASGoogle Scholar
• 151 Jha S, Srivastava SY, Brickey WJ et al. The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J. Neurosci. 30(47), 15811–15820 (2010).
  Medline CASGoogle Scholar
• 152 Chakraborty S, Kaushik DK, Gupta M, Basu A. Inflammasome signaling at the heart of central nervous system pathology. J. Neurosci. Res. 88(8), 1615–1631 (2010).
  Medline CASGoogle Scholar
• 153 Rajamaki K, Lappalainen J, Oorni K et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS ONE 5(7), e11765 (2010).
  MedlineGoogle Scholar
• 154 Wen H, Gris D, Lei Y et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12(5), 408–415 (2011).
  Medline CASGoogle Scholar
• 155 Bauer C, Duewell P, Mayer C et al. Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut 59(9), 1192–1199 (2010).
  Medline CASGoogle Scholar
• 156 Exley C, Mamutse G, Korchazhkina O et al. Elevated urinary excretion of aluminium and iron in multiple sclerosis. Mult. Scler. 12(5), 533–540 (2006).
  Medline CASGoogle Scholar
• 157 Nohynek H, Jokinen J, Partinen M et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS ONE 7(3), e33536 (2012).
  Medline CASGoogle Scholar
• 158 Partinen M, Saarenpaa-Heikkila O, Ilveskoski I et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS ONE 7(3), e33723 (2012).
  Medline CASGoogle Scholar
• 159 Dauvilliers Y, Arnulf I, Lecendreux M et al. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain 136(Pt 8), 2486–2496 (2013).
  MedlineGoogle Scholar
• 160 Szakacs A, Darin N, Hallbook T. Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination. Neurology 80(14), 1315–1321 (2013).
  MedlineGoogle Scholar
• 161 Miller E, Andrews N, Stellitano L et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 346, f794 (2013).
  MedlineGoogle Scholar
• 162 Chen L, Zhang B, Toborek M. Autophagy is involved in nanoalumina-induced cerebrovascular toxicity. Nanomedicine 9(2), 212–221 (2013).
  Medline CASGoogle Scholar
• 163 Walton JR. An aluminum-based rat model for Alzheimer's disease exhibits oxidative damage, inhibition of PP2A activity, hyperphosphorylated tau, and granulovacuolar degeneration. J. Inorg. Biochem. 101(9), 1275–1284 (2007).
  Medline CASGoogle Scholar
• 164 Joshi JG. Aluminum, a neurotoxin which affects diverse metabolic reactions. Biofactors 2(3), 163–169 (1990).
  Medline CASGoogle Scholar
• 165 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 72(2), 135–139 (2009).
  Medline CASGoogle Scholar
• 166 Hindsen M. Contact allergy to aluminium in patients hyposensitized with aluminium-containing hyposensitizing extracts. Contact Dermatitis 53(5), 301–302 (2005).
  MedlineGoogle Scholar
• 167 Bergfors E, Trollfors B, Inerot A. Unexpectedly high incidence of persistent itching nodules and delayed hypersensitivity to aluminium in children after the use of adsorbed vaccines from a single manufacturer. Vaccine 22(1), 64–69 (2003).
  MedlineGoogle Scholar
• 168 Exley C, Birchall JD. The cellular toxicity of aluminium. J. Theor. Biol. 159(1), 83–98 (1992).
  Medline CASGoogle Scholar
• 169 Berin MC, Mayer L. Immunophysiology of experimental food allergy. Mucosal Immunol. 2(1), 24–32 (2009).
  Medline CASGoogle Scholar
• 170 Brandt EB, Strait RT, Hershko D et al. Mast cells are required for experimental oral allergen-induced diarrhea. J. Clin. Invest. 112(11), 1666–1677 (2003).
  Medline CASGoogle Scholar
• 171 Theoharides TC, Kempuraj D, Redwood L. Autism: an emerging ‘neuroimmune disorder’ in search of therapy. Expert Opin. Pharmacother. 10(13), 2127–2143 (2009).
  Medline CASGoogle Scholar