Autoantibody repertoires to brain tissue in autism nuclear families

Silva, Susana C; Correia, Catarina; Fesel, Constantin; Barreto, Marta; Coutinho, Ana; Marques, Célio Gonçalo; Miguel, Teresa S.; Ataíde, Assunção; Bento, Celeste; Borges, Luís; Oliveira, Guiomar; Vicente, Astrid M.

doi:10.1016/j.jneuroim.2004.03.015

Cited by 71 publications

(45 citation statements)

References 26 publications

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“…This possibility further leads to a notion that some highly toxic autoantibodies (as proposed in a few CSF samples from MRL-lpr mice) may have long-lasting consequences on behavior. The increased prevalence of autism spectrum disorders is a novel medical conundrum which involves autoreactivity to brain antigens (Todd et al, 1988;Singh et al, 1998Singh et al, , 2002Silva et al, 2004) and other autoimmune phenomena (Singh and Rivas, 2004;Sweeten et al, 2003;Croonenberghs et al, 2002). Together with immunological changes in schizophrenia spectrum disorders (Jones and Cannon, 1998) and epilepsies (Rogers et al, 1996), the above correlations beg for a deeper understanding of the relationship between autoimmunity and the developing brain.…”

Section: Discussionmentioning

confidence: 99%

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease

Šakić

Kirkham

Ballok

et al. 2005

Journal of Neuroimmunology

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Brain atrophy, neurologic and psychiatric (NP) manifestations are common complications in the systemic autoimmune disease, lupus erythematosus (SLE). Here we show that the cerebrospinal fluid (CSF) from autoimmune MRL-lpr mice and a deceased NP-SLE patient reduce the viability of brain cells which proliferate in vitro. This detrimental effect was accompanied by periventricular neurodegeneration in the brains of autoimmune mice and profound in vivo neurotoxicity when their CSF was administered to the CNS of a rat. Multiple ionic responses with microfluorometry and protein peaks on electropherograms suggest more than one mechanism of cellular demise. Similar to the CSF from diseased MRL-lpr mice, the CSF from a deceased SLE patient with a history of psychosis, memory impairment, and seizures, reduced viability of the C17.2 neural stem cell line. Proposed mechanisms of cytotoxicity involve binding of intrathecally synthesized IgG autoantibodies to target(s) common to different mammalian species and neuronal populations. More importantly, these results indicate that the viability of proliferative neural cells can be compromised in systemic autoimmune disease. Antibody-mediated lesions of germinal layers may impair the regenerative capacity of the brain in NP-SLE and possibly, brain development and function in some forms of CNS disorders in which autoimmune phenomena have been documented. AbbreviationsACA, anti-cardiolipin antibodiesx; Abbreviations, anti-nuclear antibodies; CSF, cerebrospinal fluid; FJB, Fluoro Jade B stain; NP-SLE, neuropsychiatric systemic lupus erythematosus; PBS, phosphate buffered saline

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Section: Discussionmentioning

confidence: 99%

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease

Šakić

Kirkham

Ballok

et al. 2005

Journal of Neuroimmunology

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“…The maternal transfer of autoantibodies from the mother to child during pregnancy is well documented, and is associated with a number of factors that can affect both pregnancy and neonatal outcome. 11 The presence of autoantibodies directed against critical neuronal components of fetal brain extracts in a subset of mothers of ASD children provides supporting evidence that one potential mechanism linking maternal immune components with ASD involves the transfer of autoantibodies from mother to the developing fetus during pregnancy 15,16,17,20 (Table 2).…”

Section: Maternal Antibodiesmentioning

confidence: 91%

“…PTEN is a major upstream regulator in the mTOR pathway, and mutations in this protein are associated with higher rates of ASD. 46 In an animal model with PTEN-deficient cells, Foxp3, a putative controller for the generation of regulatory T-cells, was found to be downregulated, 88 leading to decreased number of cells that suppress immune responses and thus favoring immune dysfunction, activa- 63 (1993) Myelin basic protein (MBP) Positive Singh et al 64 (1997) Neuron-axon acidic protein (NAFP); glial fibrillary acidic protein (GFAP) Positive Singh et al 65 (1998) Myelin basic protein (MBP); neuron-axon filament Positive Evers et al 66 (2002) Heat shock protein 90 (HSP90) Positive Vodjani et al 67 (2004) Gliadin; cerebellar peptides; heat shock protein 60 (HSP60) Positive Singh et al 68 (2004) Caudate nucleus; cerebral cortex; cerebellum Positive Singh et al 69 (2004) Nucleus and laminin Negative Silva et al 20 (2004) Unknown ϳ20 kDa protein Positive* Connolly et al 70 69 found a positive finding for a ϳ20 kDa protein, but determined it not to be MBP. (1998) tion, or both.…”

Section: Deficits In Immune and Neurological Signaling Pathwaysmentioning

confidence: 99%

Immune Dysfunction in Autism: A Pathway to Treatment

2010

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Summary: Autism is a complex and clinically heterogeneous disorder with a spectrum of symptoms. Clinicians, schools, and service agencies worldwide have reported a dramatic increase in the number of children identified with autism. Despite expanding research, the etiology and underlying biological processes of autism remain poorly understood, and the relative contribution from genetic, epigenetic, and environmental factors remains unclear. Although autism affects primarily brain function (especially affect, social functioning, and cognition), it is unknown to what extent other organs and systems are disrupted. Published findings have identified widespread changes in the immune systems of children with autism, at both systemic and cellular levels. Brain specimens from autism subjects exhibit signs of active, ongoing inflammation, as well as alterations in gene pathways associated with immune signaling and immune function. Moreover, many genetic studies have indicated a link between autism and genes that are relevant to both the nervous system and the immune system. Alterations in these pathways can affect function in both systems. Together, these reports suggest that autism may in fact be a systemic disorder with connections to abnormal immune responses. Such immune system dysfunction may represent novel targets for treatment. A better understanding of the involvement of the immune response in autism, and of how early brain development is altered, may have important therapeutic implications.

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“…[28][29][30][31][32][33][34] Other immune system alterations reported in subjects who have autism include the presence of autoantibodies in the blood directed to central nervous system (CNS) or brain antigens, and the presence of inflammation within the brain. [35][36][37][38] Finally, an increased frequency of autoimmune disorders has been described in the families of individuals with autism. Comi et al 39 found a positive correlation between the risk of autism and the number of family members affected with an autoimmune disease, with the highest risk associated with maternal autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

A proteomic study of serum from children with autism showing differential expression of apolipoproteins and complement proteins

Corbett

Kantor²,

Schulman³

et al. 2006

Mol Psychiatry

167

113

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Modern methods that use systematic, quantitative and unbiased approaches are making it possible to discover proteins altered by a disease. To identify proteins that might be differentially expressed in autism, serum proteins from blood were subjected to trypsin digestion followed by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) on time-of-flight (TOF) instruments to identify differentially expressed peptides. Children with autism 4-6 years of age (n = 69) were compared to typically developing children (n = 35) with similar age and gender distributions. A total of 6348 peptide components were quantified. Of these, five peptide components corresponding to four known proteins had an effect size > 0.99 with a P < 0.05 and a Mascot identification score of 30 or greater for autism compared to controls. The four proteins were: Apolipoprotein (apo) B-100, Complement Factor H Related Protein (FHR1), Complement C1q and Fibronectin 1 (FN1). In addition, apo B-100 and apo A-IV were higher in children with high compared to low functioning autism. Apos are involved in the transport of lipids, cholesterol and vitamin E. The complement system is involved in the lysis and removal of infectious organisms in blood, and may be involved in cellular apoptosis in brain. Despite limitations of the study, including the low fold changes and variable detection rates for the peptide components, the data support possible differences of circulating proteins in autism, and should help stimulate the continued search for causes and treatments of autism by examining peripheral blood.

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Autoantibody repertoires to brain tissue in autism nuclear families

Cited by 71 publications

References 26 publications

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease

Immune Dysfunction in Autism: A Pathway to Treatment

A proteomic study of serum from children with autism showing differential expression of apolipoproteins and complement proteins

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