Immunological Findings in Autism
Introduction
The initial identification of autism dates back to 1943, when Dr. Kanner first observed a syndrome of abnormal neurological development and impaired social interactions, restricted stereotyped interests, and abnormalities in verbal and nonverbal behavior among several children. Kanner called this stereotypic behavioral disorder autism. Since then, the incidence rate in autism has increased and this disorder is currently one of the major pediatric health concerns in the United States. In 1997, the Centers for Disease Control and Prevention (1999) estimated that a broad definition of autism or autistic spectrum disorders (ASD) may be present in as many as one out of every 500 children. Studies in neuroimaging (Minshew et al., 1993), anatomy, and cytotechnology (Bauman 1994, Bailey 1998a), and epidemiologic (Gillberg, 1990) findings suggest that ASD results from a variety of quantitative and qualitative abnormalities in brain structure. Some molecular, genetic, and cellular characteristics have been identified in cell types including the neurons, glial cells, endothelial cells, microglial cells, and astrocytes of the central nervous system.
Symptomatic manifestations of autism occur within the first 5 years of life and persist into adulthood. The neuropathological abnormalities in this disease have been largely confined to the cerebellum and medial temporal structures. Thus, their possible involvement in autistic development has been the subject of much interest. Several investigators reported cerebellar abnormality in autistic samples (Bauman 1994, Courchesne 1988, Courchesne 1994, Ritvo 1986). However, some of these studies are debatable and need further confirmation (Bailey 1996, Bailey 1998b). Furthermore, evidence for a decrease in cerebellar cell size with no differences in Purkinje cell densities between the normal and autistic children has been reported in literature (Fatemi et al., 2002). Studies of Carper 2000, Bailey 1998b have demonstrated that the degree of frontal lobe abnormality correlated with the degree of cerebellar abnormality. The frontal lobe appears to have an excess of neural tissue while the cerebellum has too little neuronal cells in autistic patients.
Even though the causes of autism remain debatable, some scientific findings provide further clues. Large/small brain size and volume, asymmetry in the right hemisphere, attention to details, overlooking the whole along with clumsy behavior, and chronic inflammation in the central nervous system (CNS) are hallmarks of autism. Studies by Courchesne and his colleagues have shown that newborns who later develop autism have a smaller head size at birth but their head size grows rapidly between 1–2 months and 6–24 (Courchesne et al., 2003). In addition, studies by Herbert and colleagues (2003) demonstrated that there is asymmetrical development of the brain's white matter in autistic children. The brain of children with autism seems to grow normally until age 9 months followed by a rapid period of white matter growth between the period 9–24 months (Courchesne et al., 2003). Thus, in autism, there is asymmetrical‐brain maldevelopment and potential abnormality/ies either how the brain is processing information or in the ability of the corpus callosum to network the two sides together where the right hemisphere is especially affected. In addition, studies from Just and his colleagues (2004) illustrated an alteration in brain circuitry causes the inability of autistic patients to utilize the right hemisphere of their brain that normally processes structures to recall the alphabet. However, autistic patients have good ability to appreciate details but little or no ability at conceiving the whole picture. This suggests an overconnectivity of local brain networks while long‐range brain wiring are under‐connected. Moreover, Teitelbaum and his colleagues (2004) showed that due to skewed brain wiring autistic subjects are clumsy and therefore use unusual strategies for locomotion. In conjunction with these reports is the finding of Goldberg (2000), who demonstrated that the parts of the cerebellum that govern the ability to restore balance operate normally in autistic children. Finally, Vargas et al. (2005) reported that the brain tissue of people with autism shows signs of chronic inflammation in the same areas that show excessive growth. The inflammation appears to last a lifetime with a characteristic increase in the number of astroglial cells. The brain areas that show hyperproliferation in white matter also show inflammation. There is also evidence for activated microglia in the spinal fluid (Vargas et al., 2005). Thus, in autistic inflammation there is involvement of astroglial and microglial cells in the absence of lymphocyte infiltration or immunoglobulin deposition in the CNS. There is also increased production of pro‐inflammatory and anti‐inflammatory cytokines such as MCP‐1 and TGFß‐1 by neuroglia (Vargas et al., 2005). All of these findings support a potential role for dysregulated immunoregulatory process and neuroinflammation in the CNS of patients with autism.
Section snippets
Immune Dysfunction in Autism
Substantial evidence suggests that the immune system plays an important role in the pathogenesis of autism (Bock 2002, Gupta 2000, Wakefield 1998). While the exact mechanism of immune dysfunction in autistic patients remains undefined, two general possibilities have been outlined. First, there might be a defect in immune regulation that causes hyper‐ or hypo‐activation of the cellular components of the nervous system. This causes a homeostatic imbalance among the immunoregulatory factors in the
Role of Viral Infections in Autistic Development
Given the immunopathogenic features of autism, the development process of this disease is likely to include infection. In fact, it has been shown in neonatal rat infection with Borna disease virus, a neurotropic noncytolytic RNA virus, is associated with marked alterations in the cerebellum, along with reductions in granule and Purkinje cell numbers. In this infectious model, neurons are lost predominantly by apoptosis, by an increase in mRNA levels for pro‐apoptotic products (Fas, caspase‐1),
Role of Environmental Factors in Autistic Development
Occupational and/or environmental exposure to mercury is believed to harm human health possibly through modulation of immune homeostasis (Lawrence and McCabe, 2002). Several studies have demonstrated that imbalances in immune regulation by metals can lead to inadequate or excessive production of inflammatory cytokines (Gilmore, 2003; Croonenberghs 2002, Safieh‐Garabedian 2004). Alternatively, metals can lead to inappropriate activation of lymphoid subsets involved in acquired immunity to
Inflammatory Mediators in Autism
Inflammation has an important repairing function, but, in CNS, frequently is the cause of damage. Usually neuroinflammation has the tendency to succumb to damage, which would explain the CNS pathology associated with autism (Chavarria and Alcocer‐Varela, 2004).
The various components involved in the inflammatory response in the CNS include the participation of different cellular types of the immune system (macrophages, mast cells, T and B lymphocytes, dendritic cells), resident cells of the CNS
Involvement of Toll‐Like Receptors (TLRs) in Autism
The inflammatory signaling cascades leading to c‐fos activation in glial cells have shown that activation by LPS in glial cells occurs via the serum response element (SRE) or cyclic AMP/calcium response element (CRE) in an independent manner, and involves the Elk1 or CREB/ATF‐1 transcription factors. Elk1‐mediated transactivation was dependent on p38 mitogen‐activated protein kinase (MAPK), suggesting a crucial role of these factors in mediating inflammatory responses in the CNS (Simi et al.,
Autoimmunity in Autism
Inflammation has been linked with autoimmune insult. Aberrant innate immune response against endotoxin and immune reactivity to dietary proteins may be associated with apparent dietary product associated gastrointestinal inflammation in autistic children (Jyonouchi 2002, Jyonouchi 2005). Another piece of information is the virus‐induced autoimmune response to developing brain myelin that may impair anatomical development of neural pathways in autistic children (Singh et al., 1993). The
Summary
The immunopathogenesis of autism is presented schematically in Fig. 1. Two main immune dysfunctions in autism are immune regulation involving pro‐inflammatory cytokines and autoimmunity. Mercury and an infectious agent like the measles virus are currently two main candidate environmental triggers for immune dysfunction in autism. Genetically immune dysfunction in autism involves the MHC region, as this is an immunologic gene cluster whose gene products are Class I, II, and III molecules. Class
References (124)
- et al.
Neuronal plasticity and cellular immunity: Shared molecular mechanisms
Curr. Opin. Neurobiol.
(2001) - et al.
Is damage in central nervous system due to inflammation?
Autoimmun Rev.
(2004) - et al.
Serum autoantibodies to brain in Landau‐Kleffner variant, autism, and other neurological disorders
J. Pediatrics
(1999) - et al.
Immunotoxicology of cadmium and mercury on B‐lymphocytes–I. Effects on lymphocyte function
Int. J. Immunopharmacol.
(1993) - et al.
The human CD46 molecule is a receptor for measles virus (Edmonston strain)
Cell
(1993) - et al.
Psychiatric manifestations of mercury poisoning
J. Am. Acad. Child Adolesc. Psychiatry
(1992) - et al.
Metallothionein‐1+2 deficiency increases brain pathology in transgenic mice with astrocyte‐targeted expression of interleukin 6
Neurobiology Dis.
(2002) - et al.
Viruses evade the immune system through type I interferon‐mediated STAT2‐dependent, but STAT1‐independent, signaling
Immunity
(2005) - et al.
Major histocompatibility complex class II antigens are required for both cytokine production and proliferation induced by mercuric chloride in vitro
J. Autoimmun.
(1997) - et al.
Transforming growth factor‐beta 1 differentially regulates proliferation and MHC class‐II antigen expression in forebrain and brainstem astrocyte primary cultures
Brain Res.
(1992)