American Asperger's Association Support Group

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» More research (genetics)
Tue Jul 21, 2009 11:43 am by csweepigirl

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John Hopkins Autism Research

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1 John Hopkins Autism Research on Sat Jan 24, 2009 6:43 am


Autism is a neurodevelopmental disorder characterized by significant impairments in social, behavioral and communicative functions. Current evidence suggests that neurobiological abnormalities in autism are associated with changes in cytoarchitectural and neuronal organization that may be determined by genetic, environmental, immunological and toxic factors. Neuropathological studies have shown that cytoarchitectural organizational abnormalities of the cerebral cortex, cerebellum and other subcortical structures as well as a reduction in the number of cortical minicolumns appear to be the most prominent morphological changes in autism.

The main goal of our research on autism is to determine the role of neuroglia (astrocytes and microglia) and immune mediated responses in pathogenic mechanisms responsible for autism.

Neuroglia such as astrocytes and microglia, along with perivascular macrophages and endothelial cells, play important roles in neuronal function and homeostasis. Neuroglial cells also have a number of crucial roles in the regulation of the CNS immune responses. Astrocytes, for example, are important in the detoxification of excess excitatory amino acids, integrity of the blood brain barrier, production of neurotrophic factors and play a fundamental role in the metabolism of glutamate. In normal homeostatic stages, astrocytes facilitate neuronal survival by production of growth factors, and uptake/removal of excitotoxic neurotransmitters, such as glutamate, from the synaptic microenvironment. However, during stages of astroglial activation secondary to injury or in response to neuronal dysfunction, astrocytes can produce several factors that may modulate inflammatory responses. Astrocytes can secrete pro-inflammatory cytokines, chemokines and metalloproteinases that may contribute to the magnification of immune reactions within the CNS. Similarly, microglial activation is an important factor in the neuroglial responses to injury or dysfunction. Microglia participate in processes of synaptic stripping, cortical plasticity and immune surveillance. In several neurological disorders such as Alzheimer's disease, HIV dementia, epilepsy and multiple sclerosis, astroglial and microglial responses are prominent and appear to mediate important mechanisms that lead to neuronal dysfunction. In HIV dementia for example, microglial activation and infiltration by macrophages participate in the mechanisms of neuronal damage responsible for the dementia. In other disorders such as epilepsy and particularly in Rasmussen's syndrome, a rare pediatric epileptic disorder, both astroglial and microglial reactions occur in parallel with T cell infiltration. Changes in astroglia and microglia can therefore produce marked neuronal dysfunction that is likely to be associated with mechanisms of seizure activity.

Why study neuroglial and immune reactions in autism?
Current evidence suggests that neurobiological abnormalities in autism are associated with changes in cytoarchitectural and neuronal organization that may be determined by genetic, environmental, immunological and toxic factors. Since neuroglia have central roles during brain development, cortical organization, neuronal function and immune responses, we hypothesize that neuroglia may contribute to the pathogenesis of autism in several ways:
Neuroglia may be dysfunctional during the process of neuronal organization and plasticity of cortical and subcortical structures, a change that may contribute to the neuropathological abnormalities observed in autism.
Neuroglia may react to extrinsic factors, such as systemic immune responses, toxins or infections, and produce disturbances in the CNS microenvironment that facilitate the development of immune mediated reactions.
Abnormal neuroglial activation may be present in autistic patients due to genetic susceptibility to inflammation, a change that can lead to abnormalities in neuronal-neuroglial interactions.
Neuroglial activation can trigger the development of cellular or humoral immune responses that lead to neuronal/neuroglial dysfunction.
Systemic immune responses may trigger abnormal pathogenic reactions in neuroglia.
Our experimental approaches include study of brain tissues obtained from patients with autism, determination of the profile of cytokines and chemokines and characterization of immune mediated reactions in cortical and subcortical regions of autistic brains. Further understanding of the role of neuroglia and immune reactions in the neurobiology of autism may contribute to the design of therapeutic interventions that minimize the neurological and behavioral abnormalities that occur in this disease.

2 Research Findings from John Hopkins on Sat Jan 24, 2009 6:44 am


Our Findings on Autism

Increased microglial and astroglial activation is present in the
brain of patients with autism
Our analysis of the neuropathological changes in brain tissues of autistic patients revealed extensive neuroglial responses characterized by microglial and astroglial activation. As compared to normal controls, GFAP immunostaining in three brain regions of the autistic brains (frontal cortex, cingulate gyrus and cerebellum) revealed increased astroglial reactions characterized by an increase in the volume of perikarya and glial processes. In the brains of autistic patients, GFAP immunostaining of the cerebellum showed a marked reactivity of the Bergmann's astroglia in areas of Purkinje cell loss within the PCL, as well as a marked astroglial reaction in the GCL and cerebellar white matter (Astroglia in cerebellum of autistic brain). Microglial activation in autistic brains was further characterized by immunocytochemical staining for MHC class II markers (HLA-DR). Marked microglial activation was observed in the cerebellum, cortical regions and white matter of autistic patients (Microglia in autism). The most prominent microglial reaction was observed in the cerebellum, where the immunoreactivity for HLA-DR showed a significantly higher fractional area of immunoreactivity in both the GCL and cerebellar white matter of autistic subjects than in controls.
Cerebellum is one of the most affected regions in the brain regions in autism
In our studies of brains of autistic patients, the most prominent histologic changes were observed in the cerebellum, characterized by a patchy loss of neurons in the Purkinje cell layer (PCL) and granular cell layer (GCL) (Cerebellum in autism)
There is a lack of evidence of adaptive immune responses in the brain of autistic patients
An examination of immunopathological reactions associated with adaptive immunity in the brain of autistic patients was carried out by immunocytochemical studies to identify T- and B-lymphocyte infiltration and deposition of immunoglobulin and complement, as indicators of cellular and humoral immune responses. We observed a few isolated perivascular CD3+ and CD20+ cells in both autistic and control brains but saw no evidence of leptomeningeal, parenchymal, or perivascular inflammatory infiltration in autistic brains in any of the regions studied. There was no evidence of IgG, IgA, or IgM deposition in neuronal or neuroglial cell populations.
There is an increased level of pro-inflammatory cytokines and chemokines in different cortical and subcortical regions
We assessed the profiles of expression of proteins involved in inflammatory pathways by cytokine protein array methodology in brain tissue homogenates from autistic (n=7) and control (n=7) patients. A statistical analysis of the relative expression of cytokines in autistic and control tissues showed a consistent and significantly higher level of subsets of cytokines in the brains of autistic patients: the anti-inflammatory cytokine tumor growth factor ß1 (TGF-ß1) was increased in the frontal cortex (P=0.026), cingulate cortex (P=0.011) and cerebellum (P=0.035), and the pro-inflammatory chemokines, macrophage chemoattractant protein-1 (MCP-1) and thymus and activation-regulated chemokine (TARC), were increased in the cingulate cortex (P=0.026 and 0.035, respectively) and cerebellum (P=0.026 and 0.035, respectively). Only insulin-like growth factor binding protein-1 (IGFBP-1), a growth and differentiation factor involved in immune and cellular growth pathways, was consistently increased in the cortical regions (frontal, P= 0.038; cingulate, P=0.011), but the difference did not reach statistical significance in the cerebellum (P= 0.11). Interestingly, a larger spectrum of increased pro-inflammatory and modulatory cytokines was seen in the cingulated cortex, where there was a significant increase in interleukin-6 (IL-6), interleukin-10 (IL-10), macrophage chemoattractant protein-3 (MCP-3), eotaxin, eotaxin 2, macrophage-derived chemokine (MDC), chemokine-ß8 (Ckß8.1), neutrophil activating peptide-2 (NAP-2), monokine induced by interferon-γ (MIG), B-lymphocyte chemoattractant (BLC), leptin and osteoprotegerin.
Reactive neuroglial cells are the main source of cytokines and chemokines in the brain of autistic patients To determine the cellular sources of the most significantly increased cytokines in the brains of autistic patients, we carried out immunocytochemical staining for TGF-ß1, MCP-1, IGFBP-1, and IL-6 in the MFG, ACG and CBL. The staining patterns observed indicated that astrocytes were the main source of both MCP-1 and IL-6. Both cytokines were prominently expressed in reactive astrocytes in the cerebellum and cortical and subcortical white matter regions. It is noteworthy that TGF-ß1 and IGFBP-1 expression was seen not only in reactive astrocytes but also in the Purkinje cell population and in subsets of GCL cells in the CBL. Some microglial cells were also labeled with the antibodies recognizing TGF-ß1 and IGFBP-1. Purkinje cells with degenerative changes appeared strongly immunoreactive for TGF-ß1.
The cerebrospinal fluid from patients with autism shows the fingerprints of inflammatory reactions Since brain tissues from patients with autism showed a prominent pro-inflammatory profile, we also studied CSF from autistic patients to determine its cytokine inflammatory profile. Cytokine protein arrays were used to compare the cytokine profiles of CSF from 6 autistic patients to that of CSF from a pool of donors without CNS pathology or inflammatory disorders (e.g., pseudotumor cerebri or headaches). As we had observed in brain tissue, CSF from autistic patients showed a significant increase in MCP-1 (12 fold increase) when compared to controls. There were no differences in expression of TARC or TGF-ß1 in the CSF. However, other pro-inflammatory and modulatory cytokines such as IL-6, IFN-γ, IL-8, macrophage inflammatory protein-1ß (MIP1ß), NAP-2, interferon-γ inducing protein-10 (IP-10) and angiogenin, as well as growth factors such as mesoderm inducing factor (MIF), vascular endothelial growth factor (VEGF), leukemia inhibitory factor (LIF), osteoprotegerin, hepatic growth factor (HGF), PARC, FGF-4, FGF-9, IGFBP3 and IGFBP4, were all significantly increased when compared to control CSF.

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