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      Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity

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      Immunologic Research
      Springer Science and Business Media LLC

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          Abstract

          We have examined the neurotoxicity of aluminum in humans and animals under various conditions, following different routes of administration, and provide an overview of the various associated disease states. The literature demonstrates clearly negative impacts of aluminum on the nervous system across the age span. In adults, aluminum exposure can lead to apparently age-related neurological deficits resembling Alzheimer's and has been linked to this disease and to the Guamanian variant, ALS-PDC. Similar outcomes have been found in animal models. In addition, injection of aluminum adjuvants in an attempt to model Gulf War syndrome and associated neurological deficits leads to an ALS phenotype in young male mice. In young children, a highly significant correlation exists between the number of pediatric aluminum-adjuvanted vaccines administered and the rate of autism spectrum disorders. Many of the features of aluminum-induced neurotoxicity may arise, in part, from autoimmune reactions, as part of the ASIA syndrome.

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          The epidemiology of autism spectrum disorders.

          Autism spectrum disorders (ASDs) are complex, lifelong, neurodevelopmental conditions of largely unknown cause. They are much more common than previously believed, second in frequency only to mental retardation among the serious developmental disorders. Although a heritable component has been demonstrated in ASD etiology, putative risk genes have yet to be identified. Environmental risk factors may also play a role, perhaps via complex gene-environment interactions, but no specific exposures with significant population effects are known. A number of endogenous biomarkers associated with autism risk have been investigated, and these may help identify significant biologic pathways that, in turn, will aid in the discovery of specific genes and exposures. Future epidemiologic research should focus on expanding population-based descriptive data on ASDs, exploring candidate risk factors in large well-designed studies incorporating both genetic and environmental exposure data and addressing possible etiologic heterogeneity in studies that can stratify case groups and consider alternate endophenotypes.
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            The adjuvants aluminum hydroxide and MF59 induce monocyte and granulocyte chemoattractants and enhance monocyte differentiation toward dendritic cells.

            Aluminum hydroxide (alum) and the oil-in-water emulsion MF59 are widely used, safe and effective adjuvants, yet their mechanism of action is poorly understood. We assessed the effects of alum and MF59 on human immune cells and found that both induce secretion of chemokines, such as CCL2 (MCP-1), CCL3 (MIP-1alpha), CCL4 (MIP-1beta), and CXCL8 (IL-8), all involved in cell recruitment from blood into peripheral tissue. Alum appears to act mainly on macrophages and monocytes, whereas MF59 additionally targets granulocytes. Accordingly, monocytes and granulocytes migrate toward MF59-conditioned culture supernatants. In monocytes, both adjuvants lead to increased endocytosis, enhanced surface expression of MHC class II and CD86, and down-regulation of the monocyte marker CD14, which are all phenotypic changes consistent with a differentiation toward dendritic cells (DCs). When monocyte differentiation into DCs is induced by addition of cytokines, these adjuvants enhanced the acquisition of a mature DC phenotype and lead to an earlier and higher expression of MHC class II and CD86. In addition, MF59 induces further up-regulation of the maturation marker CD83 and the lymph node-homing receptor CCR7 on differentiating monocytes. Alum induces a similar but not identical pattern that clearly differs from the response to LPS. This model suggests a common adjuvant mechanism that is distinct from that mediated by danger signals. We conclude that during vaccination, adjuvants such as MF59 may increase recruitment of immune cells into the injection site, accelerate and enhance monocyte differentiation into DCs, augment Ag uptake, and facilitate migration of DCs into tissue-draining lymph nodes to prime adaptive immune responses.
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              Aluminium as a risk factor in Alzheimer's disease, with emphasis on drinking water.

              Aluminium (Al) is clearly a powerful neurotoxicant. Considerable evidence exists that Al may play a role in the aetiology or pathogenesis of Alzheimer's disease (AD), but whether the link is causal is still open to debate. This paper reviews the epidemiological evidence linking Al and AD. Nine out of 13 published epidemiological studies of Al in drinking water and AD have shown statistically significant positive relations. Given the difficulty in producing high-quality data for the occurrence of AD and also for Al exposure, with the resulting unavoidable misclassification errors biasing any true association towards the null value, these studies are remarkably consistent. A major problem in their interpretation is that drinking water, even at high Al concentrations, only contributes a fraction of the total dietary intake of Al. In particular, regular consumers of antacids ingest gram amounts of Al daily, thousands of times the amounts taken in through drinking water, and epidemiological studies of antacid exposure and AD have been largely negative. However, Al is very poorly absorbed in the gastrointestinal tract, and the possibility that some Al fractions present in drinking water may be particularly bioavailable cannot be dismissed at present. The combined evidence linking Al and AD warrants substantial research efforts. Such efforts should focus on clarification of the cellular and molecular mechanisms in Al toxicity and of the basic metabolism and kinetics of Al in the human body, and on further epidemiological studies including diverse routes of Al exposure and also variables that are known or suspected to influence the individuals' susceptibility to AD, such as apolipoprotein E allele status and family history of AD.
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                Author and article information

                Journal
                Immunologic Research
                Immunol Res
                Springer Science and Business Media LLC
                0257-277X
                1559-0755
                July 2013
                April 23 2013
                July 2013
                : 56
                : 2-3
                : 304-316
                Article
                10.1007/s12026-013-8403-1
                23609067
                f8ad812b-7c5f-4566-ad5f-30fe2c93d851
                © 2013

                http://www.springer.com/tdm

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