Autism, asthma, inflammation, and the hygiene hypothesis
Introduction
Autism is an enigmatic childhood disorder of unknown origin. It is characterized by developmental, language, and social deficits, ranging in severity from patients with profound deficits to individuals that are high functioning. Although the underlying etiological basis of autism has eluded researchers, the genetic heritability of autism is quite strong [1]. Specifically what genes are involved and how they contribute to the disease phenotype is unclear.
Many theories regarding the biological basis of autism have been suggested, including neurodevelopmental, exposure to environmental toxins, particularly to mercury [2], and immune [3] hypotheses. More recently, theories of hyper-systemizing and assortative mating [4], [5] and hyper-dopamine [6] have been proposed. At this time there is little definitive evidence to support any single theory of the fundamental biological nature of autism.
Numerous reports have described imbalances in immune and inflammatory processes in autistic patients, including aberrations in antibody levels, cytokines, and cellular subsets [7], [8], [9], [10], [11], [12]. Additionally, recent reports have described an increased frequency of HLA-A2 [13] and HLA-DR4 [14] antigens in autism. Interestingly, epidemiological studies have provided evidence for the association of asthma and allergies [15] or autoimmune disorders in families with autistic children [16], [17], [18], [19]. The exact significance of immune abnormalities and the relationship of infections, immunizations, allergies, inflammation, or other aspects of immune response to disease etiology are unclear and controversial. Alterations of immune and inflammatory processes in autism have recently been reviewed [3], [20], [21], [22], [23], [24].
One of the challenges in the early study of the molecular basis of classical autoimmune disorders was the attempt to establish the relevance of highly variable and fluctuating immune serum proteins and cell populations to disease etiology. That is, are fluctuations in any set of cytokines, immune mediators, or T cell populations, causative or are they epiphenomena due to peripheral effects of target tissue destruction, transient common infections, or more importantly, are they echoes of long ago infections. There is an ever present “which came first, the chicken or the egg” nature in the study of highly variable immune mediators. Are oligoclonal antibody bands found in the CSF of multiple sclerosis patients [25] related to the etiology of the disease or are they end stage phenomena? Do alterations in cytokines from a patient with systemic lupus erythematosus have a role in disease etiology or are they late stage responses to tissue destruction brought on by other mechanisms? Similarly, are immune aberrations in autism disease causing or are they epiphenomena?
Section snippets
Other comparisons of autism to asthma and autoimmune/inflammatory disorders
In addition to imbalances in immune molecular mediators, there are other seemingly unrelated parallels in the study of immune and inflammatory disorders as compared to autism that, when viewed collectively, may provide additional support for shared aspects of disease etiology between immune and inflammatory disorders and autism. These include; sex bias, birth order, age-of-onset, neonatal head circumference, increasing prevalence in the population, rural versus urban disease comparisons, and
Summary of disease comparisons
The epidemiological, morphometric, molecular, and genetic comparisons between autism and inflammatory disorders stated above highlight multiple lines of evidence in addition to humoral and cellular immune abnormalities with the goal to strengthen an etiological relationship between autism and autoimmune and inflammatory disorders. It is not suggested that these comparisons support any direct link between these disorders. However, these shared observations between autism and inflammatory
The hygiene hypothesis
The hygiene hypothesis is a widely held theory of the etiology of asthma and atopic disorders which builds on observations of rural versus urban distribution of disease. It suggests that cleaner environmental conditions in westernized countries, as compared to developing countries, play a role in the increase of the prevalence of these disorders in western countries [106]. Moreover, low levels of asthma and allergies are found with early exposure to cats [107], [108], being raised in a farm
Autism and the hygiene hypothesis
As compared above, similarities between autism, asthma, and inflammatory disorders raise the possibilities of shared mechanisms between these disease types. These include altered immune function in both types of disorders, a similar sex bias at diagnosis, similar birth order relationships, unexplained increased neonatal head circumference, a similar increase in prevalence rates during the last quarter century, a possible rural–urban distribution of the diagnosis with disease being more
Acknowledgements
The author thank M. Pazin, A. Wurster, F. Indig, and B. Schauer for critical reading of the manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging.
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