Cytokines - Pieces of the Autism Puzzle

Figure 1
Figure 1. Theory presented at the 2001 Jonty Foundation Conference, Integrating Autism Research, courtesy of: Xue Ming, M.D. Ph.D., Assistant Professor of Neuroscience and Pediatrics, Director of Autism Clinical Center, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07103. Jonty Foundation, PO Box 50683, Mendota, MN 55150 (

Autism is a neurodegenerative disorder characterized by impairment of normal brain development in the areas of social interaction and communication skills. Genetic alterations, prenatal exposure to viruses and/or toxins, maternal and fetal immune interactions, and other, as yet undetermined, causes may contribute independently or synergistically to the development of autism (see Figure 1). The common pathways shared by these potential causes may result in abnormal neurotransmission and/or abnormal brain development leading to the symptoms associated with this disease. Cytokines and the immune system are active in many of these pathways and are thus believed to play vital roles in the manifestation of autism spectrum disorders (ASD).

A number of potential causes for autism have been proposed. Increasing evidence points to a role for genetic alterations in autism. WNT2 and HOXA1, for example, have both been implicated as autism susceptibility genes.1,2 Genetic alterations associated with autism may impact immune function. A prevalence of autoimmune diseases (e.g. type 1 diabetes and adult rheumatoid arthritis) have been noted in families of autistic individuals suggesting a genetic susceptibility link between these two diseases.3 Success with metabolic approaches in the treatment of autism point to a role for metabolic gene defects in the development of autism.4 The gastrointestinal symptoms experienced by ASD children show a common intolerance to dietary protein antigens such as gluten and casein. Low casein and/or gluten diets, believed to lessen the production of toxic peptides, reduce autism symptoms in subjects that excrete abnormal levels of some peptides.5,6 Neonatal viral infection might also lead to autism.7 Neonatal rat exposure to Borna Disease virus results in behavioral symptomology that parallels autism.8 A subacute, chronic tetanus infection in the intestinal tract can promote the symptoms of autism as well.9 Tetanus toxins may be transported to the brain through the vagus nerve disrupting the release of neurotransmitters. In addition, maternal/fetal immune interactions may result in autism. Some mothers of autistic children express antibodies that are reactive to both lymphocytes from their autistic children as well as lymphocytes from their husbands.10 A large percentage of these mothers also exhibit a history of pregnancy disorder suggesting the possibility that their antibodies may be reacting with embryonic tissue antigens, possibly damaging developing neural tissue and promoting infantile autism. Apoptosis may be yet another mechanism contributing to ASD. Levels of Bcl-2, an anti-apoptotic protein, are reduced in the cerebellum of autistic patients.11 An imbalance of apoptosis regulating proteins may lead to atrophy of the cerebellum and contribute to autistic symptomology.

In light of the many potential causes, immune system abnormalities and cytokines are repeatedly implicated in ASD (see reference 12 for a review). Detection of elevated IL-2 serum levels in autistic subjects suggests that activation of a T cell subpopulation may be important in autism.13 Disruption of the normal balance of Th1/Th2 cytokines may be linked to the pathogenesis of autism. Autistic patients can demonstrate elevated levels of plasma IL-12 and IFN-gamma, while levels of IL-6, TNF-alpha, and IFN-alpha remain unaffected.14 A study comparing the intracellular levels of Th1-like (IL-2, IFN-gamma) vs. Th2-like (IL-4, IL-6, and IL-10) cytokines noted a lower proportion of IFN-gamma and IL-2 producing CD4+ and CD8+ cells in autistic patients compared to controls.15 Abnormalities in cytokine production from B cells, natural killer cells, and macrophages have also been reported (see reference 16 for specific references). Elevated levels of TNF-alpha have been produced from LPS-stimulated PBMCs obtained from autistic individuals, suggesting atypical innate immune responses.17 Alterations in circulating levels of other cytokines may impact brain development as well. Prolonged exposure of the central nervous system to elevated cytokine levels could result in neurotoxicity18 and autism symptomology. Brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4), for example, have been implicated in the development of inhibitor synapses and abnormal levels may compromise brain development and transmission. Archived samples of neonatal blood demonstrate increased levels of BDNF and NT-4/5 in autistic children compared to control children.19

It is clear that the complexities of ASD defy a simplistic explanation. The impact of genetic alterations (including autoimmunity), viral infection, maternal/fetal immune interactions, as well as various forms of mechanical injuries and ischemia on the levels of circulating cytokines may prove to be extremely important in understanding autism. Identification of cytokines that serve as key pieces may help define the direction and lead to the assembly of the “autism puzzle”


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