r
Review For reprint orders, please contact: [email protected]
Brain autoantibodies in autism spectrum disorder
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in reciprocal social interactions as well as restricted, repetitive and stereotyped patterns of behavior. The etiology of ASD is not well understood, although many factors have been associated with its pathogenesis, such genetic, neurological, environmental and immunological factors. Several studies have reported the production of numerous autoantibodies that react with specific brain proteins and brain tissues in autistic children and alter the function of the attacked brains tissue. In addition, the potential role of maternal autoantibodies to the fatal brain in the etiology of some cases of autism has also been reported. Identification and understanding of the role of brain autoantibodies as biological biomarkers may allow earlier detection of ASD, lead to a better understanding of the pathogenesis of ASD and have important therapeutic implications.
Nadra E Elamin1 & Laila Y AL-Ayadhi*,1,2 Autism Research & Treatment Center, Shaik AL-Amodi Autism Research Chair, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia 2 Department of Physiology, Faculty of Medicine, King Saud University, PO Box 2925, Riyadh 11461, Saudi Arabia *Author for correspondence: Tel.: +966 11 467 1614 Fax: +966 11 462 07207 ayadh2@ gmail.com 1
Keywords: animal models • autism • autoimmunity • brain autoantibodies • BTBR mice • maternal antibodies • neurodevelopmental disorders
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in reciprocal social interactions, such as verbal and nonverbal communication, and restricted, repetitive and stereotyped pat terns of behavior. Recently, the prevalence of ASD has increased dramatically; the current prevalence of ASDs is estimated at 1 in 88 chil dren, with a male to female ratio of approxi mately 5:1 [1] . Patients are typically diagnosed before the age of 36 months [2] . The etiology and the clinical expression of the disorder is heterogeneous and complex [3,4] ; multiple fac tors have been suggested to be involved in its pathogenesis such as genetic, environmental, neurological and immunological factors [5–7] . There is strong evidence that genetic fac tors such as HLADRB1*04 and complement component C4B can contribute to the patho genesis of autism, as well as environmental fac tors such as a viral infection that may cause autoimmunity to the brain and thereby may lead to pathological changes in the brain of autistic children [8].
10.2217/BMM.14.1 © 2014 Future Medicine Ltd
The potential role of the immune system in ASD has been addressed in several studies, especially autoimmunity to CNS. It has been proposed that autoimmunity may play a key role in the pathogenesis of neurologic disorders, including ASD [2,9–12] . These are shown by several autoimmune factors: presence of brainspecific autoantibodies; impaired lymphocyte functions; abnormal cytokine regulation; viral associations; and indirect association of certain immunogenetic factors [13] , as well as neuroglial activation and neuroinflammation in the CNS in autistic children [14] . In addition, a number of immune system-related genes have been linked to this disorder. These include the null allele of the C4B gene, a complement component, as well as the extended HLA [15–17] . The poten tial role for maternal antibodies as a pathogenic factor has also been proposed [18–20] . Moreover, children with ASD were found to have a family history of autoimmune dis orders, including asthma, multiple sclerosis (MS), rheumatoid arthritis, Type 2 diabetes mellitus and celiac disease [2,12,21] . Recently,
Biomarkers Med. (2014) 8(3), 345–352
part of
ISSN 1752-0363
345
Review Elamin & AL-Ayadhi Mostafa and AL-Ayadhi have postulated that immune responses associated with allergy may contribute to the pathogenesis of ASD, as allergy may induce the pro duction of brain-specific autoantibodies secondary to exposure to allergens [22] . In this article we will focus on brain autoantibodies that have been previously reported in subjects with ASD and their prospective contribution in the pathogenesis of ASD. The presence of antibodies to ‘self’ tissue, or auto antibodies, which are immune proteins that mistakenly attack the body’s own cells, to various proteins has been observed in a subset of patients with ASD, and they are associated with neurological or neuropsychiatric symp toms [2] . Under normal conditions, large molecules such as IgG and other immune components are excluded from the CNS by the blood–brain barrier (BBB). How ever, infectious and environmental factors can increase permeability of the BBB. Thus, these antibodies may cross the BBB, enter the CNS and combine with brain tissue antigens forming immune complexes that cause damage to the neurological tissue, and thus may lead to behavioral changes and congenital impairments [23] . Autoantibodies are classified into three groups: anti bodies that are linked with symptom development; anti bodies that are produced as a secondary response during brain disease as a result of brain injury; and antibodies that are not associated with the disease. Three main mecha nisms of antibody function have been proposed. Some antibodies act as receptor agonists or antagonists, some antibodies might cause antigenic modulation, thereby altering the density of the target antigen on the cell sur face, whereas as some other antibodies require interac tion with diverse components of the immune system to mediate their effects, such as complement activation [23] . Brain autoantibodies to specific brain proteins Several studies have reported the production of numerous autoantibodies that react with some brain proteins and brain tissue in autistic children [22,24–28] . Brain-reactive antibodies have also been observed in individuals with other disorders including attention-deficit/hyperactivity disorder (ADHD), Down’s syndrome, Behcet’s disease, Alzheimer’s disease, schizophrenia and cerebral folate deficiency (CDF) [29–32] . Although brain autoantibody production in autistic children is not fully understood, it is speculated that an autoimmune reaction to neurons might be induced by some environmental antigens, such as food allergies, infectious agents, heavy metals and natural rubber latex proteins, resulting in the release of neuronal antigens that in turn may induce autoim mune reactions through the activation of the inflam matory cells in genetically susceptible individuals [26] . Moreover, it may be due to a Th1:Th2 imbalance that
346
Biomarkers Med. (2014) 8(3)
leads to antibody production and allergic response in a subgroup of autistic children [10] . Circulating brain autoantibodies can alter the func tion of the attacked brains tissues, and react with several proteins such as MBP, frontal cortex, cerebral endothe lial cells and neurofilament protein in autistic children. Several myelin-type proteins were proposed to be associ ated with myelin destruction, such as MBP and MAG, which are responsible for nerve myelination in the CNS. Thus, the circulating anti-MBP and anti-MAG antibod ies lead to the production of abnormal myelin sheaths during brain development [33] , and therefore impairment of brain functions, such as speech, language, commu nication and social interaction, as well as other neuro logic symptoms manifested in autistic subjects [12] . An increased serum level of anti-MBPs in ASD was reported in several studies [24,25,34] . Moreover, Mostafa and ALAyadhi described the association of anti-MBP and antiMAG with allergic manifestation in autistic children; the serum level of these autoantibodies was highly sig nificant in the study group due to the induction of auto immune reactions to the CNS by allergic substances [22] . Furthermore, MBP and MAG were described as play ing a role in other demyelinating diseases, particularly MS, due to the formation of large demyelinated plaques that lack MAG. Several studies revealed the contribu tion of anti-MBP in the pathogenesis of MS, as well as in autoimmune chronic demyelinating neuropathy [33,35,36] . Elevated levels of neurotrophins and neuropeptides have been suggested to be a predictive indicator for intel lectual and social development abnormalities [37] . One pf these factors is BDNF, which is a small protein found throughout the CNS and peripheral blood. BDNF is involved in the survival and differentiation of dopami nergic neurons in the developing brain, and may con tribute to the pathophysiology of ASD and other psy chiatric diseases. Recently, it has been reported that IgG and IgM BDNF autoantibodies were elevated in chil dren with autism [6,38] , in contrast to a study carried out by Hashimoto et al., who reported a significantly lower level of serum BDNF in autistic children compared with age-matched healthy controls [39] . An explanation for this discrepancy may be the difference in the age range of the subjects between the different studies, or method ological differences (e.g., time of sample collection and preparation of serum) [39] . In addition, the presence of anti-ganglioside M1 anti bodies has been observed in some autistic children; gan gliosides could be a target molecule in the complex auto immune response due to their location in the nervous system [27,40] . Previous studies reported elevated levels of anti-phospholipid antibodies in a subset of neuropsy chiatric patients with cognitive impairment, psychosis, depression and seizures. Moreover, anti-phospholipid
future science group
Brain autoantibodies in autism spectrum disorder
antibodies were detected for the first time in high levels in young children with ASD compared with controls, and were found to be associated with behavior impair ments, mainly cognition, anxiety and hyperactivity. When anti-phospholipid antibodies were administered in mice models it induced a number of psychological symptoms, including anxiety and decreased cognition, learning and memory [41] . Folate receptor autoantibodies (FRAs) are the main cause of CFD, where they affect folate transport across the BBB and lead to the development of neurological abnormalities. In ASD children, the presence of FRAs leads to increased oxidative stress in some children with ASD, and impairment in communication, social interac tion, attention and stereotypical behavior [32] . Moreover, autoantibodies to neuronal and glial filament proteins [28,42] and antinuclear antibodies [26] have been identified in some autistic children. Serum levels of those autoanti bodies were found to be significantly elevated in autistic children compared with the control group, and have a positive correlation with the severity of the disease. Interestingly, these autoantibodies are not specific to ASD as they have been detected in patients with other neurological disorders, as well as in normal individuals, and are not present in all subjects with ASD. For exam ple, MBP autoantibodies are found in patients with MS [35,36] , and neurofilament protein autoantibodies are also found in household contacts of autistic children, anti-brain IgG autoantibodies were present in sera from healthy individuals and clinically depressed patients, and IgG autoantibodies to endothelial cells are common in sera from children with Landau–Kleffner syndrome (LKS) and ASD [43] . This may lead to speculation that the production of these antibodies may be secondary to innate CNS pathology [44]. Brain autoantibodies to brain tissue The occurrence of autoreactivities to brain tissue in autistic children may represent the immune system’s neuroprotective response to a previous brain injury that may have occurred during neurodevelopment [45] . Antibodies against Purkinje cells [46] and IgM antibrain endothelial cell antibodies [43,47] were found in autistic children, idiopathic mental retardation and epi lepsy. The contribution of neuron or glial cell dysfunc tion to the pathogenesis of ASD was also reported, as autoantibodies were detected in autistic children [48] . Singer et al. investigated the reactivity of serum auto antibodies to various areas of human brain in sera of children with ASD, siblings of children with ASD and healthy controls. Children with ASD showed greater immunoreactivity to basal ganglia and frontal lobe, as well as to cingulate gyrus and cerebellum (Cb) deep nuclei, compared with controls [11] .
future science group
Review
In a study carried out by Singh and Rivas, brainspecific antibodies to five different brain regions were studied; caudate nucleus (Cn), cerebral cortex (Cx), Cb, brainstem (Bs) and hippocampus (Hpc). Brain antibod ies to neural proteins of the Cn (49%), Cx (18%) and Cb (9%) were detected in the serum of autistic children; no antibodies to Bs or Hpc were detected [25] . This find ing suggests that the neurons in the Cn might be a tar get of autoimmune pathology in ASD, and hence it may cause neurological impairments in autistic children and manifestation of neurological and behavioral symptoms. Furthermore, Vargas et al. postulated that neuro glial reactions are associated with neural dysfunction in autism and that the Cb is the focus of an active and chronic neuroinflammatory process in autistic children [49] . More recently, Mazur-Kolecka et al. have demon estrated the presence of different autoantibodies to the stimulated neuronal progenitor cell (NPC) proteins in the serum of autistic children in a higher frequency than in the control group, suggesting alteration of adap tive immunity in children and an effect on postnatal neuronal plasticity [50] . Furthermore, in a study combining analysis of moth ers’ and children’s autoantibody reactivity to brain tis sue, extracted fetal brain protein mixtures from rhesus macaque brain tissue were used. Anti-brain IgG reactiv ity to Golgi cells of the Cb and a subset of interneurons, nuclei or beaded axons was detected in the plasma from children with ASD and their mothers, but not in controls. Specific combinations of protein reactivity were found to be highly specific to mothers of ASD children (fetal pro teins at 37 and 73 kDa, and at 39 and 73 kDa, which are specific for autism) [29] . Previous studies confirmed the same finding; autoimmune reactivity to these combina tions of proteins was not detected in maternal samples from mothers of children with developmental delay with out autism [6,18] , and were found to be associated with increased behavioral and emotional impairments [29,51] . All these reports strengthen the hypothesis that the crossreactivity of brain autoantibodies with specific brain parts may cause a dysfunction of the affected area. Potential role of maternal autoantibodies in autistic children In addition to the presence of autoantibodies in children with autism, few studies suggest the presence of auto antibodies to brain proteins in the blood of mothers of children with autism, and other neuropsycaric disorders. The effect of the maternal immune response, especially maternal autoantibodies, on the developing immune and CNSs in autistic children has been studied extensively. These studies have suggested a role for maternal autoan tibodies to the fetal brain in the etiology of some cases of ASD [18,49,52–54] , as they were shown to be associated
www.futuremedicine.com
347
Review Elamin & AL-Ayadhi with behavioral alteration in offspring (Figure 1). There are several potential mechanisms by which the maternal immune system could generate antibodies to fetal brain tissue. They proposed that the maternal reactivity to fetal proteins may result from maternal environmental expo sures [56] , and those maternal autoantibodies can cross the placenta and enter the fetal brain, and subsequently alter brain development, and cause behavioral changes as well [6,20,53,57] . However, autoantibodies that react to fetal ‘self’-proteins can also cross the placenta and potentially impact fetal development [6] . This could be explained by the fact that the BBB is not fully formed, making the developing brain vulnerable to autoantibodies that in turn affect its development. On the other hand, the pres ence of specific anti-fetal brain antibodies in the circula tion of mothers during pregnancy may induce a down stream effect on neurodevelopment leading to ASD. However, the same antibody might have different effects on fetal and adult neurons, either because of differences in antigen expression and accessibility, or because of dif ferences in antibody-induced signaling cascades. Another possibility is the specificity of antibodies to either adult neurons or fetal neurons [23,58] . In addition, recent studies identified the presence of specific maternal IgG autoantibodies to fetal brain proteins that affect brain development, leading to abnormal enlargement [19,20] . A recent study reported autoreactivity to human fetal brain proteins; they detected the significantly higher presence of maternal autoantibodies in the plasma of mothers of autistic children than in mothers of children with other developmental delays or typical development [18] . A large cohort study of mothers of autistic children by Brimberg et al. showed that anti-brain antibodies were highly significant in a subset of mothers with autis tic children compared with controls, and it may be asso ciated with autoimmune diseases, especially rheumatoid arthritis and systemic lupus erythematosus [59] . Increased risk of ASD in the children was detected when mothers had an autoimmune disease [60] . They also reported that anti-nuclear antibodies, which are associated with many autoimmune diseases, and autoimmune diseases were increased in mothers with anti-brain antibodies with an ASD child compared with controls. The association between familial history of autoimmune diseases and ASD could be linked to many factors, including fetal environmental changes or antibody exposure during pregnancy, as well as common genetic factors [59] . Animal models & maternal autoantibodies A considerable number of studies used animal models, mice or monkeys, to study the role of maternal auto antibodies to fetal brain in the pathogenesis of ASD. In spite of the difficulties in developing animal models with autistic characteristics, many models were devel
348
Biomarkers Med. (2014) 8(3)
oped and they show the major three characteristics of ASD, namely repetitive behaviors, communication impairment and social abnormalities [61] . Among the well-characterized animal models is the BTBR T+tf/J (BTBR) mouse model; it is an inbred mouse strain that shows several autism-like behaviors compared with con trol mice. [62,63] . BTBR is widely used in ASD research to explore the genetic background and immunological characteristics involved in the etiology of ASD. Heo et al. studied the relationship between the immuno reactivity and the abnormal behaviors in BTBR mice. They demonstrated elevated levels of anti-brain anti bodies and proinflammatory cytokines, in BTBR mice compared with control mice, and their association with abnormal behaviors, which is comparable with the findings reported in autistic children. These findings suggest that the BTBR mice could be a useful model for further study of the influences of immunity, espe cially brain autoantibodies, on abnormal behaviors in ASD [62] . Moreover, a recent study has identified new brain pro teins that react with maternal autoantibodies; LDH-A, LDH-B, cypin, STIP1, CRMP1, CRMP2 and Y-boxbinding protein; collectively known as maternal auto antibody-related autism (MAR). Using a proteomic approach, the research group extracted and purified those newly discovered maternal autoantibodies from fetal rhesus macaque brain, produced recombinant pro teins and subsequently incubated them with maternal plasma samples to study the maternal antibody reactiv ity for candidate antigens. Maternal IgG reactivity, to individual or recombinant proteins, was highly signifi cant in mothers of autistic children compared with con trols, and it is also associated with the outcome of ASD. In addition, there were several combinations of autoan tibodies that were highly specific to ASD and were not detected in the plasma of controls. Increased impair ments in the stereotypical behavior were found in chil dren of mothers having antibodies reactive to LDH and CRMP1, as well as combined reactivity to LDH and STIP1 or LDH/STIP1/CRMP1 compared with chil dren with ASD from mothers lacking autoantibodies against these antigens [64] . This may support the notion that maternal antibodies are responsible for neurode velopmental changes in ASD. Those newly discovered proteins could be promising biomarkers of ASD risk and may be beneficial for therapeutic interventions. Shi and colleagues used a mouse model to demonstrate that a maternal inflammatory response during gestation was sufficient for the generation of behavioral altera tions in the offspring [65] . In another study, researchers gave serum with anti-brain antibodies from mothers of children with autism to pregnant mice. The offspring showed deficits in social behavior and motor skills, as
future science group
Brain autoantibodies in autism spectrum disorder
Maternal immune system
Potential triggers or Potential cofactors (innate immune cells or adaptive immunity) and mediators
Fetal nervous system
Maternal cytokines, antibodies and T cells Family history pass placenta (e.g., autoimmune Macrophage and immature disease) Cytokines fetal BBB Immunogentics/ HLA associations
T cell
Epigenics
B cell
External and internal environmental factors (e.g., self-antigens and microorganisms)
Review
Impairment of fetal brain development
Cytokines, antigens, antibodies, T cells (antigen–antibody complex?) induce chronic brain inflammation
Autistic behavior
Antibodies NK cell Monocyte
Microglia: Microglia: normal swelling in ASD Swelling of microglia by chronic inflammation
Figure 1. Possible association of altered immune responses and outcome of autism spectrum disorder. ASD: Autism spectrum disorder; BBB: Blood–brain barrier; NK: Natural killer. Reproduced with permission from [55] .
well as cerebellar abnormalities, in addition to antibody deposition on Purkinje cells and other neurons [52] . Further studies have shown that injecting pregnant mice or monkeys with blood or purified antibodies from mothers of children with autism lead to brain and behavioral changes in their offspring [2,6,53,66] . In the serum from a mother with an autistic child, IgG antibody was found to bind to Purkinje cells and other neurons. When injected into gestating mice, these auto antibodies induced behavioral changes including altered exploration and motor coordination, and changes in the Cb in the offspring. By contrast, mice injected with sera from mothers with typically developing children showed no behavioral changes [52] . In a subsequent study, when pregnant mice were given autoantibodies isolated from the blood of mothers of children with autism, their offspring were found to be more anxious during adolescence, were more sensi tive to noise than controls and had alterations in social behaviors [67] . Conclusion The etiology of ASD is not well understood, although many factors have been associated with its pathogen esis, such as genetic, immunologic and environmental factors [68] . Previous studies have linked autism to auto immune reactions, especially to the presence of brain autoantibodies in the serum of autistic children. None
future science group
theless, autoantibodies have been found also in patients with other neurological disorders, as well as in normal individuals. This leads to the hypothesis that the pro duction of these antibodies may be secondary to innate CNS pathology and may simply be a marker of an event in the CNS that allows for the presentation of self-anti gens [43,69] . Furthermore, antibodies present in the serum of mothers of autistic children have been suggested to affect brain development and alter social behavior. Therefore, a better understanding of the involvement of the immune response in brain development may have important therapeutic implications. Identification of brain autoantibodies, which could be used as an early marker for ASD, will lead to a bet ter understanding of the pathogenesis of ASD and may allow earlier detection of ASD. Their presence before clinical diagnosis may permit earlier recognition and possibly earlier treatment intervention. Moreover, detec tion of serum autoantibodies will be valuable in clinical practice as a diagnostic tool. Understanding the role of these autoantibodies may lead to a better understanding of the relationship between the immune system and this group of disorders in order to provide insights into disease mechanisms [38] . In addition, the identification of the protein targets of these autoantibodies will allow us to better understand potential pathogenic mechanisms, as well as to create specific screening assays [18] .
www.futuremedicine.com
349
Review Elamin & AL-Ayadhi Future perspective It is becoming apparent that genetics and environment are the main contributing factors in the pathogenesis of ASD. Autoimmunity and brain autoantibodies may have a role in the pathogenesis of ASD; understanding the role of these autoantibodies may lead to a better understand ing of the relationship between the immune system and this group of disorders in order to provide insights into disease mechanisms [37] . In addition, the identification of the protein targets of these autoantibodies will allow us to better understand potential pathogenic mecha nisms, as well as to create specific screening assays [17] . However, large cohort studies with well-defined autistic children and well-matched controls are needed to con firm the potential role of autoantibodies in the pathology of all or subsets of autistic children. On the other hand, further investigations in larger cohort studies of mothers of autistic children are required to resolve the potential
role of maternal antibodies in autism and other neuro developmental disorders. Moreover, the development of animal models will be crucial to determine the role of autoantibodies in the neuropathology of autism. Fur ther investigations at immunological, cellular, molecu lar and genetic levels will allow researchers to unravel the immunopathological mechanisms associated with autistic processes in the developing brain. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Executive summary Brain autoantibodies to specific brain proteins • Autoimmunity has been proposed to play a key role in the pathogenesis of neurologic disorders. • Brain-specific autoimmunity could be responsible for neuropathology in autism spectrum disorder (ASD). • Autoantibodies may cross the blood–brain barrier and combine with brain tissue antigens to form immune complexes that cause damage of the neurological tissue. • Some autoantibodies could be considered as biological markers for autism, and they may play a role in the pathophysiology of this disorder.
Brain autoantibodies to brain tissue • Autoantibodies might be pathogenic for the fetal brain in ASD. • The cross reactivity of brain autoantibodies with some brain parts may cause a dysfunction of the affected area.
Potential role of maternal autoantibodies in autistic children • Maternal antibodies may contribute to prenatal brain development by interfering with cell signaling in the developing brain, as well as disturbing the patterns of CNS organization. • Maternal antibodies may influence neurodevelopmental processes in a subset of autism cases.
Animal models & maternal autoantibodies • Animal model development is important to determine the role of autoantibodies in the neuropathology of autism. • The BTRB mice model (Black and Tan, Brachyury inbred strain, which have reduced corpus callosum and hippocampal commisures) is considered to be an ideal model to the study the outcome of ASD, due to its development of most of autistic-like behaviors.
References
5
Papers of special note have been highlighted as: • of interest •• of considerable interest
Ashwood P, Wills S, Van de Water J. The immune response in autism: a new frontier for autism research. J. Leuk. Biol. 80(1), 1–15 (2006).
•
Review covering a variety of immunological aspects in autism spectrum disorder (ASD).
6
Croen LA, Braunschweig D, Haapanen L et al. Maternal mid-pregnancy autoantibodies to fetal brain protein: the Early Markers for Autism study. Biol. Psychiatry 64(7), 583–588 (2008).
7
Ratajczak HV. Theoretical aspects of autism: causes – a review. J. Immunotoxicol. 8(1), 68–79 (2011).
8
Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav. Immun. 26(4), 607–616 (2012).
1
2
Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D, Van de Water J. Autoantibodies in autism spectrum disorders (ASD). Ann. NY Acad. Sci. 1107(1), 79–91 (2007).
3
American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders (4th Edition). American Psychiatric Association, DC, USA (2000).
4
350
CDC. Prevalence of autism spectrum disorders – autism and developmental disabilities monitoring network, 14 sites, United States, 2008. MMWR Surveill. Summ. 61(3), 1–19 (2012).
Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J. Clin. Psychiatry 66(10), 3–8 (2005).
Biomarkers Med. (2014) 8(3)
future science group
Brain autoantibodies in autism spectrum disorder
9
Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ. Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics 112(5), e420–e424 (2003).
26
Mostafa GA, Kitchener N. Serum anti-nuclear antibodies as a marker of autoimmunity in Egyptian autistic children. Pediatr. Neurol. 40(2), 107–112 (2009).
10
Cohly HH, Panja A. Immunological findings in autism. Int. Rev. Neurobiol. 71, 317–341 (2005).
27
Mostafa GA, AL-Ayadhi LY. Increased serum levels of antiganglioside M1 autoantibodies in autistic children: relation to the disease severity. J. Neuroinflammation 8, 39 (2011).
11
Singer HS, Morris CM, Williams PN, Yoon DY, Hong JJ, Zimmerman AW. Antibrain antibodies in children with autism and their unaffected siblings. J. Neuroimmunol. 178(1), 149–155 (2006).
28
Mostafa GA, AL-Ayadhi LY. The relationship between the increased frequency of serum antineuronal antibodies and the severity of autism in children. Eur. J. Paediatr. Neurol. 16(5), 464–468 (2012).
12
Singh VK. Phenotypic expression of autoimmune autistic disorder (AAD): a major subset of autism. Ann. Clin. Psychiatry 21(3), 148–161 (2009).
29
13
Singh VK, Jensen RL. Elevated levels of measles antibodies in children with autism. Pediatr. Neurol. 28(4), 292–294 (2003).
Rossi CC, Joaquin Fuentes J, Van de Water J, Amaral DG. Brief report: antibodies reacting to brain tissue in Basque Spanish children with autism spectrum disorder and their mothers. J. Autism Dev. Disord. doi:10.1007/ s10803-013-1859-y (2013) (Epub ahead of print).
30
14
Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int. Rev. Psychiat. 17(6), 485–495 (2005).
Vural B, Ugurel E, Tuzun E et al. Anti-neuronal and stress induced-phosphoprotein 1 antibodies in neuro-Behcet’s disease. J. Neuroimmunol. 239, 91–97 (2011).
31
15
Odell D, Maciulis A, Cutler A et al. Confirmation of the association of the C4B null allelle in autism. Hum. Immunol. 66(2), 140–145 (2005).
Hensley K, Venkova K, Christov A, Gunning W, Park J. Collapsin response mediator protein-2: an emerging pathologic feature and therapeutic target for neurodisease indications. Mol. Neurobiol. 43, 180–191 (2011).
16
Watts TJ. The pathogenesis of autism. Clin. Med. Pathol. 1, 99–103 (2008).
32
17
Mostafa GA, Shehab AA, AL-Ayadhi LY. The link between some alleles on human leukocyte antigen system and autism in children. J. Neuroimmunol. 255(1–2), 70–74 (2013).
Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol. Psychiatry 18, 369–381 (2013).
33
18
Braunschweig D, Ashwood P, Krakowiak P et al. Autism: maternally derived antibodies specific for fetal brain proteins. NeuroToxicology 29( 2), 226–231 (2008).
Aboul-Enein F, Rauschka H, Kornek B et al. Preferential loss of myelin-associated glycoprotein reflects hypoxia like white matter damage in stroke and inflammatory brain diseases. J. Neuropathol. Exp. Neurol. 62(1), 25–33 (2003).
•
Highlights the possible role of maternal autoantibodies in the pathogenesis of ASD.
34
19
Nordahl CW, Braunschweig D, Iosif AM et al. Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder. Brain Behav. Immun. 30, 61–65 (2013).
Mostafa GA, AL-Ayadhi LY. A lack of association between hyperserotonemia and the increased frequency of serum antimyelin basic protein auto-antibodies in autistic children. J. Neuroinflammation 8, 71 (2011).
35
Angelucci F, Mirabella M, Frisullo G, Caggiula M, Tonali PA, Batocchi AP. Serum levels of anti-myelin antibodies in relapsing-remitting multiple sclerosis patients during different phases of disease activity and immunomodulatory therapy. Dis. Markers 21, 49–55 (2005).
36
Hedegaard CJ, Chen N, Sellebjerg F et al. Autoantibodies to myelin basic protein (MBP) in healthy individuals and in patients with multiple sclerosis: a role in regulating cytokine responses to MBP. Immunology 128, e451–e461 (2009).
37
Nelson KB, Grether JK, Croen LA et al. Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann. Neurol. 49, 597–606 (2001).
38
Connolly AM, Chez M, Streif EM et al. Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau– Kleffner syndrome, and epilepsy. Biol. Psychiatry 59 (4), 354–363 (2006).
39
Hashimoto K, Iwata Y, Nakamura K et al. Reduced serum levels of brain-derived neurotrophic factor in adult male patients with autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 1529–1531 (2006).
40
Moeller S, Lau NM, Green PH et al. Lack of association between autism and anti-GM1 ganglioside antibody. Neurology 81(18), 1640–1641 (2013).
20
21
22
Bauman MD, Iosif AM, Ashwood P et al. Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl. Psychiatry 3, e278 (2013). Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN. Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J. Child Neurol. 14(6), 388–394 (1999). Mostafa GA, AL-Ayadhi LY. The possible relationship between allergic manifestations and elevated serum levels of brain specific auto-antibodies in autistic children. J. Neuroimmunol. 261(1–2), 77–81 (2013).
23
Diamond B, Huerta PT, Mina-Osorio P, Kowal C, Volpe BT. Losing your nerves? Maybe it’s the antibodies. Nat. Rev. Immunol. 9(6), 445–456 (2009).
24
Singh VK, Warren RP, Odell JD, Warren WL, Cole P. Antibodies to myelin basic protein in children with autistic behavior. Brain Behav. Immun. 7(1), 97–103 (1993).
25
Singh VK, Rivas WH. Prevalence of serum antibodies to caudate nucleus in autistic children. Neurosci. Lett. 355(1–2), 53–56 (2004).
future science group
www.futuremedicine.com
Review
351
Review Elamin & AL-Ayadhi 41
Careaga M, Hansen RL, Hertz-Piccotto I, Van de Water J, Ashwood P. Increased anti-phospholipid antibodies in autism spectrum disorders. Mediators Inflamm. 2013, 935608 (2013).
42
Singh VK, Warren R, Averett R, Ghaziuddin M. Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr. Neurol. 17(1), 88–90 (1997).
43
44
Goines P, Haapanen L, Boyce R et al. Autoantibodies to cerebellum in children with autism associate with behavior. Brain. Behav. Immun. 25(3), 514–523 (2011).
45
Silva SC, Correia C, Fesel C et al. Autoantibody repertoires to brain tissue in autism nuclear families. J. Neuroimmunol. 152(1–2), 176–182 (2004).
46
Vojdani A, O’Bryan T, Green JA et al. Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr. Neurosci. 7(3), 151–161 (2004).
47
Chez MG, Connolly AM, Nowinski C, Buchanan C. The presence of autoantibodies in idiopathic/acquired versus genetic variants of pediatric epilepsy. Epilepsia 41S, 183 (2000).
48
Aschner M, Allen JW, Kimelberg HK, LoPachin RM, Streit WJ. Glial cells in neurotoxicity development. Annu. Rev. Pharmacol. Toxicol. 39, 151–173 (1999).
49
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 57(1), 67–81 (2005).
50
Mazur-Kolecka B, Cohen IL, Gonzalez M et al. Autoantibodies against neuronal progenitors in sera from children with autism. Brain Dev. doi:10.1016/j.braindev.04.015 (2013) (Epub ahead of print).
51
Rossi CC, Van de Water J, Rogers SJ, Amaral DG. Detection of plasma autoantibodies to brain tissue in young children with and without autism spectrum disorders. Brain Behav. Immun. 25, 1123–1135 (2011).
52
•
Dalton P, Deacon R, Blamire A et al. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53(4), 533–537 (2003). First study to administer maternal plasma containing autoantibodies to gestating mice to study their role on behavioral deficits in ASD children.
53
Singer HS, Moriss CM, Gause CD, Gillin PK, Crawford S, Zimmerman AW. Antibodies against fetal brain in sera of mothers with autistic children. J. Neuroimmunol. 194(1–2), 165–172 (2008).
54
Schwartzer JJ, Careaga M, Onore CE, Rushakoff JA, Berman RF, Ashwood P. Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice. Transl. Psychiatry 12, e240 (2013).
55
352
Connolly AM, Chez MG, Pestronk A, Arnold ST, Mehta S, Deuel RK. Serum autoantibodies to brain in Landau–Kleffner variant, autism, and other neurologic disorders. J. Pediatr. 134(5), 607–613 (1999).
Gesundheit B, Rosenzweig JP, Naor D et al. Immunological and autoimmune considerations of autism spectrum disorders. J. Autoimmun. 44, 1–7 (2013).
Biomarkers Med. (2014) 8(3)
56
Zimmerman AW, Connors SL, Matteson KJ et al. Maternal antibrain antibodies in autism. Brain Behav. Immun. 21, 351–357 (2007).
57
Fox E, Amaral D, Van de Water J. Maternal and fetal anti-brain antibodies in development and disease. Develop. Neurobiol. 72(10), 1327–1334 (2012).
58
Braunschweig D, Golub MS, Koenig CM et al. Maternal autism-associated IgG antibodies delay development and produce anxiety in a mouse gestational transfer model. J. Neuroimmunol. 252(1–2), 56–65 (2012).
59
Brimberg L, Sadiq A, Gregersen PK, Diamond B. Brainreactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder. Mol. Psychiatry 18, 1171–1177 (2013).
•
Study on a large cohort of mothers of ASD children to assess the association of brain autoantibody reactivity with autoimmunity.
60
Atladottir HO, Pedersen MG, Thorsen P et al. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 124, 687–694 (2009).
61
Patterson PH. Modeling autistic features in animals. Pediatr. Res. 69(3), 34R–40R (2011).
62
Heo Y, Zhang Y, Gao D, Miller VM, Lawrence DA. Aberrant immune responses in a mouse with behavioral disorders. PLoS ONE 6(7), e20912 (2011).
•
Describes the role of immune responses in behavioral deficit in BTBR mice.
63
Onore CE, Careaga M, Babineau BA, Schwartzer JJ, Berman RF, Ashwood A. Inflammatory macrophage phenotype in BTBR T+tf/J mice. Front. Neurosci. 7, 158 (2013).
64
Braunschweig D, Krakowiak P, Duncanson P et al. Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Transl. Psychiatry 3, e277 (2013).
••
Describes six new biomarkers that are specific for ASD.
65
Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J. Neurosci. 23(1), 297–302 (2003).
66
Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral DG. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain Behav. Immun. 22(6), 806–816 (2008).
67
Singer HS, Morris C, Gause C, Pollard M, Zimmerman AW, Pletnikov M. Prenatal exposure to antibodies from mothers of children with autism produces neurobehavioral alterations: a pregnant dam mouse model. J. Neuroimmunol. 211(1–2), 39–48 (2009).
68
Volkmar FR, Lord C, Bailey A, Schultz RT, Klin A. Autism and pervasive developmental disorders. J. Child Psychol. Psychiatry 45(1), 135–170 (2004).
69
Russo AJ, Krigsman A, Jepson B, Wakefield A. Generalized autoimmunity of ANCA and ASCA related to severity of disease in autistic children with GI disease. Immunol. Immunogenet. Insights 1, 37–47 (2009).
future science group
Review For reprint orders, please contact: [email protected]
Brain autoantibodies in autism spectrum disorder
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in reciprocal social interactions as well as restricted, repetitive and stereotyped patterns of behavior. The etiology of ASD is not well understood, although many factors have been associated with its pathogenesis, such genetic, neurological, environmental and immunological factors. Several studies have reported the production of numerous autoantibodies that react with specific brain proteins and brain tissues in autistic children and alter the function of the attacked brains tissue. In addition, the potential role of maternal autoantibodies to the fatal brain in the etiology of some cases of autism has also been reported. Identification and understanding of the role of brain autoantibodies as biological biomarkers may allow earlier detection of ASD, lead to a better understanding of the pathogenesis of ASD and have important therapeutic implications.
Nadra E Elamin1 & Laila Y AL-Ayadhi*,1,2 Autism Research & Treatment Center, Shaik AL-Amodi Autism Research Chair, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia 2 Department of Physiology, Faculty of Medicine, King Saud University, PO Box 2925, Riyadh 11461, Saudi Arabia *Author for correspondence: Tel.: +966 11 467 1614 Fax: +966 11 462 07207 ayadh2@ gmail.com 1
Keywords: animal models • autism • autoimmunity • brain autoantibodies • BTBR mice • maternal antibodies • neurodevelopmental disorders
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in reciprocal social interactions, such as verbal and nonverbal communication, and restricted, repetitive and stereotyped pat terns of behavior. Recently, the prevalence of ASD has increased dramatically; the current prevalence of ASDs is estimated at 1 in 88 chil dren, with a male to female ratio of approxi mately 5:1 [1] . Patients are typically diagnosed before the age of 36 months [2] . The etiology and the clinical expression of the disorder is heterogeneous and complex [3,4] ; multiple fac tors have been suggested to be involved in its pathogenesis such as genetic, environmental, neurological and immunological factors [5–7] . There is strong evidence that genetic fac tors such as HLADRB1*04 and complement component C4B can contribute to the patho genesis of autism, as well as environmental fac tors such as a viral infection that may cause autoimmunity to the brain and thereby may lead to pathological changes in the brain of autistic children [8].
10.2217/BMM.14.1 © 2014 Future Medicine Ltd
The potential role of the immune system in ASD has been addressed in several studies, especially autoimmunity to CNS. It has been proposed that autoimmunity may play a key role in the pathogenesis of neurologic disorders, including ASD [2,9–12] . These are shown by several autoimmune factors: presence of brainspecific autoantibodies; impaired lymphocyte functions; abnormal cytokine regulation; viral associations; and indirect association of certain immunogenetic factors [13] , as well as neuroglial activation and neuroinflammation in the CNS in autistic children [14] . In addition, a number of immune system-related genes have been linked to this disorder. These include the null allele of the C4B gene, a complement component, as well as the extended HLA [15–17] . The poten tial role for maternal antibodies as a pathogenic factor has also been proposed [18–20] . Moreover, children with ASD were found to have a family history of autoimmune dis orders, including asthma, multiple sclerosis (MS), rheumatoid arthritis, Type 2 diabetes mellitus and celiac disease [2,12,21] . Recently,
Biomarkers Med. (2014) 8(3), 345–352
part of
ISSN 1752-0363
345
Review Elamin & AL-Ayadhi Mostafa and AL-Ayadhi have postulated that immune responses associated with allergy may contribute to the pathogenesis of ASD, as allergy may induce the pro duction of brain-specific autoantibodies secondary to exposure to allergens [22] . In this article we will focus on brain autoantibodies that have been previously reported in subjects with ASD and their prospective contribution in the pathogenesis of ASD. The presence of antibodies to ‘self’ tissue, or auto antibodies, which are immune proteins that mistakenly attack the body’s own cells, to various proteins has been observed in a subset of patients with ASD, and they are associated with neurological or neuropsychiatric symp toms [2] . Under normal conditions, large molecules such as IgG and other immune components are excluded from the CNS by the blood–brain barrier (BBB). How ever, infectious and environmental factors can increase permeability of the BBB. Thus, these antibodies may cross the BBB, enter the CNS and combine with brain tissue antigens forming immune complexes that cause damage to the neurological tissue, and thus may lead to behavioral changes and congenital impairments [23] . Autoantibodies are classified into three groups: anti bodies that are linked with symptom development; anti bodies that are produced as a secondary response during brain disease as a result of brain injury; and antibodies that are not associated with the disease. Three main mecha nisms of antibody function have been proposed. Some antibodies act as receptor agonists or antagonists, some antibodies might cause antigenic modulation, thereby altering the density of the target antigen on the cell sur face, whereas as some other antibodies require interac tion with diverse components of the immune system to mediate their effects, such as complement activation [23] . Brain autoantibodies to specific brain proteins Several studies have reported the production of numerous autoantibodies that react with some brain proteins and brain tissue in autistic children [22,24–28] . Brain-reactive antibodies have also been observed in individuals with other disorders including attention-deficit/hyperactivity disorder (ADHD), Down’s syndrome, Behcet’s disease, Alzheimer’s disease, schizophrenia and cerebral folate deficiency (CDF) [29–32] . Although brain autoantibody production in autistic children is not fully understood, it is speculated that an autoimmune reaction to neurons might be induced by some environmental antigens, such as food allergies, infectious agents, heavy metals and natural rubber latex proteins, resulting in the release of neuronal antigens that in turn may induce autoim mune reactions through the activation of the inflam matory cells in genetically susceptible individuals [26] . Moreover, it may be due to a Th1:Th2 imbalance that
346
Biomarkers Med. (2014) 8(3)
leads to antibody production and allergic response in a subgroup of autistic children [10] . Circulating brain autoantibodies can alter the func tion of the attacked brains tissues, and react with several proteins such as MBP, frontal cortex, cerebral endothe lial cells and neurofilament protein in autistic children. Several myelin-type proteins were proposed to be associ ated with myelin destruction, such as MBP and MAG, which are responsible for nerve myelination in the CNS. Thus, the circulating anti-MBP and anti-MAG antibod ies lead to the production of abnormal myelin sheaths during brain development [33] , and therefore impairment of brain functions, such as speech, language, commu nication and social interaction, as well as other neuro logic symptoms manifested in autistic subjects [12] . An increased serum level of anti-MBPs in ASD was reported in several studies [24,25,34] . Moreover, Mostafa and ALAyadhi described the association of anti-MBP and antiMAG with allergic manifestation in autistic children; the serum level of these autoantibodies was highly sig nificant in the study group due to the induction of auto immune reactions to the CNS by allergic substances [22] . Furthermore, MBP and MAG were described as play ing a role in other demyelinating diseases, particularly MS, due to the formation of large demyelinated plaques that lack MAG. Several studies revealed the contribu tion of anti-MBP in the pathogenesis of MS, as well as in autoimmune chronic demyelinating neuropathy [33,35,36] . Elevated levels of neurotrophins and neuropeptides have been suggested to be a predictive indicator for intel lectual and social development abnormalities [37] . One pf these factors is BDNF, which is a small protein found throughout the CNS and peripheral blood. BDNF is involved in the survival and differentiation of dopami nergic neurons in the developing brain, and may con tribute to the pathophysiology of ASD and other psy chiatric diseases. Recently, it has been reported that IgG and IgM BDNF autoantibodies were elevated in chil dren with autism [6,38] , in contrast to a study carried out by Hashimoto et al., who reported a significantly lower level of serum BDNF in autistic children compared with age-matched healthy controls [39] . An explanation for this discrepancy may be the difference in the age range of the subjects between the different studies, or method ological differences (e.g., time of sample collection and preparation of serum) [39] . In addition, the presence of anti-ganglioside M1 anti bodies has been observed in some autistic children; gan gliosides could be a target molecule in the complex auto immune response due to their location in the nervous system [27,40] . Previous studies reported elevated levels of anti-phospholipid antibodies in a subset of neuropsy chiatric patients with cognitive impairment, psychosis, depression and seizures. Moreover, anti-phospholipid
future science group
Brain autoantibodies in autism spectrum disorder
antibodies were detected for the first time in high levels in young children with ASD compared with controls, and were found to be associated with behavior impair ments, mainly cognition, anxiety and hyperactivity. When anti-phospholipid antibodies were administered in mice models it induced a number of psychological symptoms, including anxiety and decreased cognition, learning and memory [41] . Folate receptor autoantibodies (FRAs) are the main cause of CFD, where they affect folate transport across the BBB and lead to the development of neurological abnormalities. In ASD children, the presence of FRAs leads to increased oxidative stress in some children with ASD, and impairment in communication, social interac tion, attention and stereotypical behavior [32] . Moreover, autoantibodies to neuronal and glial filament proteins [28,42] and antinuclear antibodies [26] have been identified in some autistic children. Serum levels of those autoanti bodies were found to be significantly elevated in autistic children compared with the control group, and have a positive correlation with the severity of the disease. Interestingly, these autoantibodies are not specific to ASD as they have been detected in patients with other neurological disorders, as well as in normal individuals, and are not present in all subjects with ASD. For exam ple, MBP autoantibodies are found in patients with MS [35,36] , and neurofilament protein autoantibodies are also found in household contacts of autistic children, anti-brain IgG autoantibodies were present in sera from healthy individuals and clinically depressed patients, and IgG autoantibodies to endothelial cells are common in sera from children with Landau–Kleffner syndrome (LKS) and ASD [43] . This may lead to speculation that the production of these antibodies may be secondary to innate CNS pathology [44]. Brain autoantibodies to brain tissue The occurrence of autoreactivities to brain tissue in autistic children may represent the immune system’s neuroprotective response to a previous brain injury that may have occurred during neurodevelopment [45] . Antibodies against Purkinje cells [46] and IgM antibrain endothelial cell antibodies [43,47] were found in autistic children, idiopathic mental retardation and epi lepsy. The contribution of neuron or glial cell dysfunc tion to the pathogenesis of ASD was also reported, as autoantibodies were detected in autistic children [48] . Singer et al. investigated the reactivity of serum auto antibodies to various areas of human brain in sera of children with ASD, siblings of children with ASD and healthy controls. Children with ASD showed greater immunoreactivity to basal ganglia and frontal lobe, as well as to cingulate gyrus and cerebellum (Cb) deep nuclei, compared with controls [11] .
future science group
Review
In a study carried out by Singh and Rivas, brainspecific antibodies to five different brain regions were studied; caudate nucleus (Cn), cerebral cortex (Cx), Cb, brainstem (Bs) and hippocampus (Hpc). Brain antibod ies to neural proteins of the Cn (49%), Cx (18%) and Cb (9%) were detected in the serum of autistic children; no antibodies to Bs or Hpc were detected [25] . This find ing suggests that the neurons in the Cn might be a tar get of autoimmune pathology in ASD, and hence it may cause neurological impairments in autistic children and manifestation of neurological and behavioral symptoms. Furthermore, Vargas et al. postulated that neuro glial reactions are associated with neural dysfunction in autism and that the Cb is the focus of an active and chronic neuroinflammatory process in autistic children [49] . More recently, Mazur-Kolecka et al. have demon estrated the presence of different autoantibodies to the stimulated neuronal progenitor cell (NPC) proteins in the serum of autistic children in a higher frequency than in the control group, suggesting alteration of adap tive immunity in children and an effect on postnatal neuronal plasticity [50] . Furthermore, in a study combining analysis of moth ers’ and children’s autoantibody reactivity to brain tis sue, extracted fetal brain protein mixtures from rhesus macaque brain tissue were used. Anti-brain IgG reactiv ity to Golgi cells of the Cb and a subset of interneurons, nuclei or beaded axons was detected in the plasma from children with ASD and their mothers, but not in controls. Specific combinations of protein reactivity were found to be highly specific to mothers of ASD children (fetal pro teins at 37 and 73 kDa, and at 39 and 73 kDa, which are specific for autism) [29] . Previous studies confirmed the same finding; autoimmune reactivity to these combina tions of proteins was not detected in maternal samples from mothers of children with developmental delay with out autism [6,18] , and were found to be associated with increased behavioral and emotional impairments [29,51] . All these reports strengthen the hypothesis that the crossreactivity of brain autoantibodies with specific brain parts may cause a dysfunction of the affected area. Potential role of maternal autoantibodies in autistic children In addition to the presence of autoantibodies in children with autism, few studies suggest the presence of auto antibodies to brain proteins in the blood of mothers of children with autism, and other neuropsycaric disorders. The effect of the maternal immune response, especially maternal autoantibodies, on the developing immune and CNSs in autistic children has been studied extensively. These studies have suggested a role for maternal autoan tibodies to the fetal brain in the etiology of some cases of ASD [18,49,52–54] , as they were shown to be associated
www.futuremedicine.com
347
Review Elamin & AL-Ayadhi with behavioral alteration in offspring (Figure 1). There are several potential mechanisms by which the maternal immune system could generate antibodies to fetal brain tissue. They proposed that the maternal reactivity to fetal proteins may result from maternal environmental expo sures [56] , and those maternal autoantibodies can cross the placenta and enter the fetal brain, and subsequently alter brain development, and cause behavioral changes as well [6,20,53,57] . However, autoantibodies that react to fetal ‘self’-proteins can also cross the placenta and potentially impact fetal development [6] . This could be explained by the fact that the BBB is not fully formed, making the developing brain vulnerable to autoantibodies that in turn affect its development. On the other hand, the pres ence of specific anti-fetal brain antibodies in the circula tion of mothers during pregnancy may induce a down stream effect on neurodevelopment leading to ASD. However, the same antibody might have different effects on fetal and adult neurons, either because of differences in antigen expression and accessibility, or because of dif ferences in antibody-induced signaling cascades. Another possibility is the specificity of antibodies to either adult neurons or fetal neurons [23,58] . In addition, recent studies identified the presence of specific maternal IgG autoantibodies to fetal brain proteins that affect brain development, leading to abnormal enlargement [19,20] . A recent study reported autoreactivity to human fetal brain proteins; they detected the significantly higher presence of maternal autoantibodies in the plasma of mothers of autistic children than in mothers of children with other developmental delays or typical development [18] . A large cohort study of mothers of autistic children by Brimberg et al. showed that anti-brain antibodies were highly significant in a subset of mothers with autis tic children compared with controls, and it may be asso ciated with autoimmune diseases, especially rheumatoid arthritis and systemic lupus erythematosus [59] . Increased risk of ASD in the children was detected when mothers had an autoimmune disease [60] . They also reported that anti-nuclear antibodies, which are associated with many autoimmune diseases, and autoimmune diseases were increased in mothers with anti-brain antibodies with an ASD child compared with controls. The association between familial history of autoimmune diseases and ASD could be linked to many factors, including fetal environmental changes or antibody exposure during pregnancy, as well as common genetic factors [59] . Animal models & maternal autoantibodies A considerable number of studies used animal models, mice or monkeys, to study the role of maternal auto antibodies to fetal brain in the pathogenesis of ASD. In spite of the difficulties in developing animal models with autistic characteristics, many models were devel
348
Biomarkers Med. (2014) 8(3)
oped and they show the major three characteristics of ASD, namely repetitive behaviors, communication impairment and social abnormalities [61] . Among the well-characterized animal models is the BTBR T+tf/J (BTBR) mouse model; it is an inbred mouse strain that shows several autism-like behaviors compared with con trol mice. [62,63] . BTBR is widely used in ASD research to explore the genetic background and immunological characteristics involved in the etiology of ASD. Heo et al. studied the relationship between the immuno reactivity and the abnormal behaviors in BTBR mice. They demonstrated elevated levels of anti-brain anti bodies and proinflammatory cytokines, in BTBR mice compared with control mice, and their association with abnormal behaviors, which is comparable with the findings reported in autistic children. These findings suggest that the BTBR mice could be a useful model for further study of the influences of immunity, espe cially brain autoantibodies, on abnormal behaviors in ASD [62] . Moreover, a recent study has identified new brain pro teins that react with maternal autoantibodies; LDH-A, LDH-B, cypin, STIP1, CRMP1, CRMP2 and Y-boxbinding protein; collectively known as maternal auto antibody-related autism (MAR). Using a proteomic approach, the research group extracted and purified those newly discovered maternal autoantibodies from fetal rhesus macaque brain, produced recombinant pro teins and subsequently incubated them with maternal plasma samples to study the maternal antibody reactiv ity for candidate antigens. Maternal IgG reactivity, to individual or recombinant proteins, was highly signifi cant in mothers of autistic children compared with con trols, and it is also associated with the outcome of ASD. In addition, there were several combinations of autoan tibodies that were highly specific to ASD and were not detected in the plasma of controls. Increased impair ments in the stereotypical behavior were found in chil dren of mothers having antibodies reactive to LDH and CRMP1, as well as combined reactivity to LDH and STIP1 or LDH/STIP1/CRMP1 compared with chil dren with ASD from mothers lacking autoantibodies against these antigens [64] . This may support the notion that maternal antibodies are responsible for neurode velopmental changes in ASD. Those newly discovered proteins could be promising biomarkers of ASD risk and may be beneficial for therapeutic interventions. Shi and colleagues used a mouse model to demonstrate that a maternal inflammatory response during gestation was sufficient for the generation of behavioral altera tions in the offspring [65] . In another study, researchers gave serum with anti-brain antibodies from mothers of children with autism to pregnant mice. The offspring showed deficits in social behavior and motor skills, as
future science group
Brain autoantibodies in autism spectrum disorder
Maternal immune system
Potential triggers or Potential cofactors (innate immune cells or adaptive immunity) and mediators
Fetal nervous system
Maternal cytokines, antibodies and T cells Family history pass placenta (e.g., autoimmune Macrophage and immature disease) Cytokines fetal BBB Immunogentics/ HLA associations
T cell
Epigenics
B cell
External and internal environmental factors (e.g., self-antigens and microorganisms)
Review
Impairment of fetal brain development
Cytokines, antigens, antibodies, T cells (antigen–antibody complex?) induce chronic brain inflammation
Autistic behavior
Antibodies NK cell Monocyte
Microglia: Microglia: normal swelling in ASD Swelling of microglia by chronic inflammation
Figure 1. Possible association of altered immune responses and outcome of autism spectrum disorder. ASD: Autism spectrum disorder; BBB: Blood–brain barrier; NK: Natural killer. Reproduced with permission from [55] .
well as cerebellar abnormalities, in addition to antibody deposition on Purkinje cells and other neurons [52] . Further studies have shown that injecting pregnant mice or monkeys with blood or purified antibodies from mothers of children with autism lead to brain and behavioral changes in their offspring [2,6,53,66] . In the serum from a mother with an autistic child, IgG antibody was found to bind to Purkinje cells and other neurons. When injected into gestating mice, these auto antibodies induced behavioral changes including altered exploration and motor coordination, and changes in the Cb in the offspring. By contrast, mice injected with sera from mothers with typically developing children showed no behavioral changes [52] . In a subsequent study, when pregnant mice were given autoantibodies isolated from the blood of mothers of children with autism, their offspring were found to be more anxious during adolescence, were more sensi tive to noise than controls and had alterations in social behaviors [67] . Conclusion The etiology of ASD is not well understood, although many factors have been associated with its pathogen esis, such as genetic, immunologic and environmental factors [68] . Previous studies have linked autism to auto immune reactions, especially to the presence of brain autoantibodies in the serum of autistic children. None
future science group
theless, autoantibodies have been found also in patients with other neurological disorders, as well as in normal individuals. This leads to the hypothesis that the pro duction of these antibodies may be secondary to innate CNS pathology and may simply be a marker of an event in the CNS that allows for the presentation of self-anti gens [43,69] . Furthermore, antibodies present in the serum of mothers of autistic children have been suggested to affect brain development and alter social behavior. Therefore, a better understanding of the involvement of the immune response in brain development may have important therapeutic implications. Identification of brain autoantibodies, which could be used as an early marker for ASD, will lead to a bet ter understanding of the pathogenesis of ASD and may allow earlier detection of ASD. Their presence before clinical diagnosis may permit earlier recognition and possibly earlier treatment intervention. Moreover, detec tion of serum autoantibodies will be valuable in clinical practice as a diagnostic tool. Understanding the role of these autoantibodies may lead to a better understanding of the relationship between the immune system and this group of disorders in order to provide insights into disease mechanisms [38] . In addition, the identification of the protein targets of these autoantibodies will allow us to better understand potential pathogenic mechanisms, as well as to create specific screening assays [18] .
www.futuremedicine.com
349
Review Elamin & AL-Ayadhi Future perspective It is becoming apparent that genetics and environment are the main contributing factors in the pathogenesis of ASD. Autoimmunity and brain autoantibodies may have a role in the pathogenesis of ASD; understanding the role of these autoantibodies may lead to a better understand ing of the relationship between the immune system and this group of disorders in order to provide insights into disease mechanisms [37] . In addition, the identification of the protein targets of these autoantibodies will allow us to better understand potential pathogenic mecha nisms, as well as to create specific screening assays [17] . However, large cohort studies with well-defined autistic children and well-matched controls are needed to con firm the potential role of autoantibodies in the pathology of all or subsets of autistic children. On the other hand, further investigations in larger cohort studies of mothers of autistic children are required to resolve the potential
role of maternal antibodies in autism and other neuro developmental disorders. Moreover, the development of animal models will be crucial to determine the role of autoantibodies in the neuropathology of autism. Fur ther investigations at immunological, cellular, molecu lar and genetic levels will allow researchers to unravel the immunopathological mechanisms associated with autistic processes in the developing brain. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Executive summary Brain autoantibodies to specific brain proteins • Autoimmunity has been proposed to play a key role in the pathogenesis of neurologic disorders. • Brain-specific autoimmunity could be responsible for neuropathology in autism spectrum disorder (ASD). • Autoantibodies may cross the blood–brain barrier and combine with brain tissue antigens to form immune complexes that cause damage of the neurological tissue. • Some autoantibodies could be considered as biological markers for autism, and they may play a role in the pathophysiology of this disorder.
Brain autoantibodies to brain tissue • Autoantibodies might be pathogenic for the fetal brain in ASD. • The cross reactivity of brain autoantibodies with some brain parts may cause a dysfunction of the affected area.
Potential role of maternal autoantibodies in autistic children • Maternal antibodies may contribute to prenatal brain development by interfering with cell signaling in the developing brain, as well as disturbing the patterns of CNS organization. • Maternal antibodies may influence neurodevelopmental processes in a subset of autism cases.
Animal models & maternal autoantibodies • Animal model development is important to determine the role of autoantibodies in the neuropathology of autism. • The BTRB mice model (Black and Tan, Brachyury inbred strain, which have reduced corpus callosum and hippocampal commisures) is considered to be an ideal model to the study the outcome of ASD, due to its development of most of autistic-like behaviors.
References
5
Papers of special note have been highlighted as: • of interest •• of considerable interest
Ashwood P, Wills S, Van de Water J. The immune response in autism: a new frontier for autism research. J. Leuk. Biol. 80(1), 1–15 (2006).
•
Review covering a variety of immunological aspects in autism spectrum disorder (ASD).
6
Croen LA, Braunschweig D, Haapanen L et al. Maternal mid-pregnancy autoantibodies to fetal brain protein: the Early Markers for Autism study. Biol. Psychiatry 64(7), 583–588 (2008).
7
Ratajczak HV. Theoretical aspects of autism: causes – a review. J. Immunotoxicol. 8(1), 68–79 (2011).
8
Malkova NV, Yu CZ, Hsiao EY, Moore MJ, Patterson PH. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav. Immun. 26(4), 607–616 (2012).
1
2
Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D, Van de Water J. Autoantibodies in autism spectrum disorders (ASD). Ann. NY Acad. Sci. 1107(1), 79–91 (2007).
3
American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders (4th Edition). American Psychiatric Association, DC, USA (2000).
4
350
CDC. Prevalence of autism spectrum disorders – autism and developmental disabilities monitoring network, 14 sites, United States, 2008. MMWR Surveill. Summ. 61(3), 1–19 (2012).
Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J. Clin. Psychiatry 66(10), 3–8 (2005).
Biomarkers Med. (2014) 8(3)
future science group
Brain autoantibodies in autism spectrum disorder
9
Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ. Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics 112(5), e420–e424 (2003).
26
Mostafa GA, Kitchener N. Serum anti-nuclear antibodies as a marker of autoimmunity in Egyptian autistic children. Pediatr. Neurol. 40(2), 107–112 (2009).
10
Cohly HH, Panja A. Immunological findings in autism. Int. Rev. Neurobiol. 71, 317–341 (2005).
27
Mostafa GA, AL-Ayadhi LY. Increased serum levels of antiganglioside M1 autoantibodies in autistic children: relation to the disease severity. J. Neuroinflammation 8, 39 (2011).
11
Singer HS, Morris CM, Williams PN, Yoon DY, Hong JJ, Zimmerman AW. Antibrain antibodies in children with autism and their unaffected siblings. J. Neuroimmunol. 178(1), 149–155 (2006).
28
Mostafa GA, AL-Ayadhi LY. The relationship between the increased frequency of serum antineuronal antibodies and the severity of autism in children. Eur. J. Paediatr. Neurol. 16(5), 464–468 (2012).
12
Singh VK. Phenotypic expression of autoimmune autistic disorder (AAD): a major subset of autism. Ann. Clin. Psychiatry 21(3), 148–161 (2009).
29
13
Singh VK, Jensen RL. Elevated levels of measles antibodies in children with autism. Pediatr. Neurol. 28(4), 292–294 (2003).
Rossi CC, Joaquin Fuentes J, Van de Water J, Amaral DG. Brief report: antibodies reacting to brain tissue in Basque Spanish children with autism spectrum disorder and their mothers. J. Autism Dev. Disord. doi:10.1007/ s10803-013-1859-y (2013) (Epub ahead of print).
30
14
Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int. Rev. Psychiat. 17(6), 485–495 (2005).
Vural B, Ugurel E, Tuzun E et al. Anti-neuronal and stress induced-phosphoprotein 1 antibodies in neuro-Behcet’s disease. J. Neuroimmunol. 239, 91–97 (2011).
31
15
Odell D, Maciulis A, Cutler A et al. Confirmation of the association of the C4B null allelle in autism. Hum. Immunol. 66(2), 140–145 (2005).
Hensley K, Venkova K, Christov A, Gunning W, Park J. Collapsin response mediator protein-2: an emerging pathologic feature and therapeutic target for neurodisease indications. Mol. Neurobiol. 43, 180–191 (2011).
16
Watts TJ. The pathogenesis of autism. Clin. Med. Pathol. 1, 99–103 (2008).
32
17
Mostafa GA, Shehab AA, AL-Ayadhi LY. The link between some alleles on human leukocyte antigen system and autism in children. J. Neuroimmunol. 255(1–2), 70–74 (2013).
Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA. Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol. Psychiatry 18, 369–381 (2013).
33
18
Braunschweig D, Ashwood P, Krakowiak P et al. Autism: maternally derived antibodies specific for fetal brain proteins. NeuroToxicology 29( 2), 226–231 (2008).
Aboul-Enein F, Rauschka H, Kornek B et al. Preferential loss of myelin-associated glycoprotein reflects hypoxia like white matter damage in stroke and inflammatory brain diseases. J. Neuropathol. Exp. Neurol. 62(1), 25–33 (2003).
•
Highlights the possible role of maternal autoantibodies in the pathogenesis of ASD.
34
19
Nordahl CW, Braunschweig D, Iosif AM et al. Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder. Brain Behav. Immun. 30, 61–65 (2013).
Mostafa GA, AL-Ayadhi LY. A lack of association between hyperserotonemia and the increased frequency of serum antimyelin basic protein auto-antibodies in autistic children. J. Neuroinflammation 8, 71 (2011).
35
Angelucci F, Mirabella M, Frisullo G, Caggiula M, Tonali PA, Batocchi AP. Serum levels of anti-myelin antibodies in relapsing-remitting multiple sclerosis patients during different phases of disease activity and immunomodulatory therapy. Dis. Markers 21, 49–55 (2005).
36
Hedegaard CJ, Chen N, Sellebjerg F et al. Autoantibodies to myelin basic protein (MBP) in healthy individuals and in patients with multiple sclerosis: a role in regulating cytokine responses to MBP. Immunology 128, e451–e461 (2009).
37
Nelson KB, Grether JK, Croen LA et al. Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann. Neurol. 49, 597–606 (2001).
38
Connolly AM, Chez M, Streif EM et al. Brain-derived neurotrophic factor and autoantibodies to neural antigens in sera of children with autistic spectrum disorders, Landau– Kleffner syndrome, and epilepsy. Biol. Psychiatry 59 (4), 354–363 (2006).
39
Hashimoto K, Iwata Y, Nakamura K et al. Reduced serum levels of brain-derived neurotrophic factor in adult male patients with autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 1529–1531 (2006).
40
Moeller S, Lau NM, Green PH et al. Lack of association between autism and anti-GM1 ganglioside antibody. Neurology 81(18), 1640–1641 (2013).
20
21
22
Bauman MD, Iosif AM, Ashwood P et al. Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl. Psychiatry 3, e278 (2013). Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN. Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J. Child Neurol. 14(6), 388–394 (1999). Mostafa GA, AL-Ayadhi LY. The possible relationship between allergic manifestations and elevated serum levels of brain specific auto-antibodies in autistic children. J. Neuroimmunol. 261(1–2), 77–81 (2013).
23
Diamond B, Huerta PT, Mina-Osorio P, Kowal C, Volpe BT. Losing your nerves? Maybe it’s the antibodies. Nat. Rev. Immunol. 9(6), 445–456 (2009).
24
Singh VK, Warren RP, Odell JD, Warren WL, Cole P. Antibodies to myelin basic protein in children with autistic behavior. Brain Behav. Immun. 7(1), 97–103 (1993).
25
Singh VK, Rivas WH. Prevalence of serum antibodies to caudate nucleus in autistic children. Neurosci. Lett. 355(1–2), 53–56 (2004).
future science group
www.futuremedicine.com
Review
351
Review Elamin & AL-Ayadhi 41
Careaga M, Hansen RL, Hertz-Piccotto I, Van de Water J, Ashwood P. Increased anti-phospholipid antibodies in autism spectrum disorders. Mediators Inflamm. 2013, 935608 (2013).
42
Singh VK, Warren R, Averett R, Ghaziuddin M. Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr. Neurol. 17(1), 88–90 (1997).
43
44
Goines P, Haapanen L, Boyce R et al. Autoantibodies to cerebellum in children with autism associate with behavior. Brain. Behav. Immun. 25(3), 514–523 (2011).
45
Silva SC, Correia C, Fesel C et al. Autoantibody repertoires to brain tissue in autism nuclear families. J. Neuroimmunol. 152(1–2), 176–182 (2004).
46
Vojdani A, O’Bryan T, Green JA et al. Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr. Neurosci. 7(3), 151–161 (2004).
47
Chez MG, Connolly AM, Nowinski C, Buchanan C. The presence of autoantibodies in idiopathic/acquired versus genetic variants of pediatric epilepsy. Epilepsia 41S, 183 (2000).
48
Aschner M, Allen JW, Kimelberg HK, LoPachin RM, Streit WJ. Glial cells in neurotoxicity development. Annu. Rev. Pharmacol. Toxicol. 39, 151–173 (1999).
49
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 57(1), 67–81 (2005).
50
Mazur-Kolecka B, Cohen IL, Gonzalez M et al. Autoantibodies against neuronal progenitors in sera from children with autism. Brain Dev. doi:10.1016/j.braindev.04.015 (2013) (Epub ahead of print).
51
Rossi CC, Van de Water J, Rogers SJ, Amaral DG. Detection of plasma autoantibodies to brain tissue in young children with and without autism spectrum disorders. Brain Behav. Immun. 25, 1123–1135 (2011).
52
•
Dalton P, Deacon R, Blamire A et al. Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53(4), 533–537 (2003). First study to administer maternal plasma containing autoantibodies to gestating mice to study their role on behavioral deficits in ASD children.
53
Singer HS, Moriss CM, Gause CD, Gillin PK, Crawford S, Zimmerman AW. Antibodies against fetal brain in sera of mothers with autistic children. J. Neuroimmunol. 194(1–2), 165–172 (2008).
54
Schwartzer JJ, Careaga M, Onore CE, Rushakoff JA, Berman RF, Ashwood P. Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice. Transl. Psychiatry 12, e240 (2013).
55
352
Connolly AM, Chez MG, Pestronk A, Arnold ST, Mehta S, Deuel RK. Serum autoantibodies to brain in Landau–Kleffner variant, autism, and other neurologic disorders. J. Pediatr. 134(5), 607–613 (1999).
Gesundheit B, Rosenzweig JP, Naor D et al. Immunological and autoimmune considerations of autism spectrum disorders. J. Autoimmun. 44, 1–7 (2013).
Biomarkers Med. (2014) 8(3)
56
Zimmerman AW, Connors SL, Matteson KJ et al. Maternal antibrain antibodies in autism. Brain Behav. Immun. 21, 351–357 (2007).
57
Fox E, Amaral D, Van de Water J. Maternal and fetal anti-brain antibodies in development and disease. Develop. Neurobiol. 72(10), 1327–1334 (2012).
58
Braunschweig D, Golub MS, Koenig CM et al. Maternal autism-associated IgG antibodies delay development and produce anxiety in a mouse gestational transfer model. J. Neuroimmunol. 252(1–2), 56–65 (2012).
59
Brimberg L, Sadiq A, Gregersen PK, Diamond B. Brainreactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder. Mol. Psychiatry 18, 1171–1177 (2013).
•
Study on a large cohort of mothers of ASD children to assess the association of brain autoantibody reactivity with autoimmunity.
60
Atladottir HO, Pedersen MG, Thorsen P et al. Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 124, 687–694 (2009).
61
Patterson PH. Modeling autistic features in animals. Pediatr. Res. 69(3), 34R–40R (2011).
62
Heo Y, Zhang Y, Gao D, Miller VM, Lawrence DA. Aberrant immune responses in a mouse with behavioral disorders. PLoS ONE 6(7), e20912 (2011).
•
Describes the role of immune responses in behavioral deficit in BTBR mice.
63
Onore CE, Careaga M, Babineau BA, Schwartzer JJ, Berman RF, Ashwood A. Inflammatory macrophage phenotype in BTBR T+tf/J mice. Front. Neurosci. 7, 158 (2013).
64
Braunschweig D, Krakowiak P, Duncanson P et al. Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Transl. Psychiatry 3, e277 (2013).
••
Describes six new biomarkers that are specific for ASD.
65
Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J. Neurosci. 23(1), 297–302 (2003).
66
Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral DG. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain Behav. Immun. 22(6), 806–816 (2008).
67
Singer HS, Morris C, Gause C, Pollard M, Zimmerman AW, Pletnikov M. Prenatal exposure to antibodies from mothers of children with autism produces neurobehavioral alterations: a pregnant dam mouse model. J. Neuroimmunol. 211(1–2), 39–48 (2009).
68
Volkmar FR, Lord C, Bailey A, Schultz RT, Klin A. Autism and pervasive developmental disorders. J. Child Psychol. Psychiatry 45(1), 135–170 (2004).
69
Russo AJ, Krigsman A, Jepson B, Wakefield A. Generalized autoimmunity of ANCA and ASCA related to severity of disease in autistic children with GI disease. Immunol. Immunogenet. Insights 1, 37–47 (2009).
future science group
