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Contents lists available at Brain, Behavior, and Immunity Invited Minireview The role of immune dysfunction in the pathophysiology of autism Charity Onore, Milo Careaga, Paul Ashwood Department of Medical Microbiology and Immunology, University of California, Davis, CA, USAThe Medical Investigation of Neurodevelopmental Disorders (M.I.N.D) Institute, UC Davis Health System, Sacramento, CA, USA Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders encompassing Received 1 June 2011 impairments in communication, social interactions and restricted stereotypical behaviors. Although a Received in revised form 19 August 2011 link between altered immune responses and ASD was ﬁrst recognized nearly 40 years ago, only recently Accepted 22 August 2011 has new evidence started to shed light on the complex multifaceted relationship between immune dys- Available online 28 August 2011 function and behavior in ASD. Neurobiological research in ASD has highlighted pathways involved inneural development, synapse plasticity, structural brain abnormalities, cognition and behavior. At the same time, several lines of evidence point to altered immune dysfunction in ASD that directly impacts some or all these neurological processes. Extensive alterations in immune function have now been described in both children and adults with ASD, including ongoing inﬂammation in brain specimens, elevated pro-inﬂammatory cytokine proﬁles in the CSF and blood, increased presence of brain-speciﬁc Social interactions auto-antibodies and altered immune cell function. Furthermore, these dysfunctional immune responses Maternal immune activation are associated with increased impairments in behaviors characteristic of core features of ASD, in partic-ular, deﬁcits in social interactions and communication. This accumulating evidence suggests thatimmune processes play a key role in the pathophysiology of ASD. This review will discuss the currentstate of our knowledge of immune dysfunction in ASD, how these ﬁndings may impact on underlyingneuro-immune mechanisms and implicate potential areas where the manipulation of the immuneresponse could have an impact on behavior and immunity in ASD.
Ó 2011 Elsevier Inc. All rights reserved.
increased risk of developing ASD. In addition to the heritabilityobserved in twin-pairs, the risk of developing ASD in non-twin sib- Autism spectrum disorders (ASD) are a series of pervasive devel- lings is increased 25-fold in comparison to the general population opment disorders which include autistic disorder, Rett's disorder, (). While the heritability of ASD suggests a genetic childhood disintegrative disorder, Asperger's syndrome or pervasive component in the disorders etiology, the genes involved vary greatly developmental disorder not otherwise speciﬁed (PDD-NOS). Autism among individuals and family clusters.
spectrum disorders are characterized by severe and pervasive Whole-genome linkage studies, gene association studies, copy impairment in several areas of development: reciprocal social inter- number variation screening and SNP analyses have uncovered a action skills, communication skills, or the presence of stereotyped large number of ASD candidate genes ( behavior, interests and activities (). According to the most Associations with ASD have been demonstrated for genes recent estimates calculated by the US Center of Disease Control, ASD involved in a diverse range of functions including RELN ( affects 1 in 110 children under the age of eight ), SHANK3 (), NLGN3, NLGN4X Although current research suggests there may be no single genetic cause for ASD, there are several lines of evidence to suggest that (), OXTR ), and SLC6A4 ( the disorder is highly heritable. There is a concordance rate for Furthermore, in several syndromic disorders with sin- ASD of 0–37% reported for dizygotic twins, while concordance rates gle gene mutations, including Rett's syndrome (MeCP2) ( of 44–91% are reported for monozygotic twins ), Fragile X (FMR1) ( tuberous sclerosis (either TSC1 or TSC2) (), Timo- ), suggesting that genetic composition may contribute to thy syndrome (CACNA1C), Cowden's syndrome (PTEN), and Angel-man's syndrome (UBE3A) the occurrence of ASD is higher than thegeneral population. Among these potential candidate genes several ⇑ Corresponding author. Address: Department of Microbiology and Immunology, play important roles in immune function. Proteins within the The Medical Investigation of Neurodevelopmental Disorders (M.I.N.D) Institute, phosphoinositide-3-kinase (PI3K) pathway, including those coded 2805, 50th Street, Sacramento, CA 95817, USA. Fax: +1 916 703 0367.
by MET, PTEN, TSC1 and TSC2, have a major role in regulating E-mail address: (P. Ashwood).
0889-1591/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi: C. Onore et al. / Brain, Behavior, and Immunity 26 (2012) 383–392 interleukin (IL)-12 production from myeloid cells and are involved to some autistic features, including decreased prepulse inhibition in shifting macrophage phenotypes from inﬂammatory (M1) to and latent inhibition, as well as impaired sociability (reviewed in alternative activated (M2) subsets Additional These models are becoming more established candidate genes including the major histocompatibility complex and can be induced by congenital exposure to bacteria, the bac- type 2 (MHC-II) haplotypes (), terial compound LPS, inﬂuenza virus or, the viral mimic and toll- as well as complement 4B (C4B) (), and macro- phage inhibitory factor (MIF) (are impor- [poly(I:C)]. In all four versions of the model, IL-6 appears to play tant in directing and controlling immune responses. Even with an essential role and exposure to IL-6 alone during gestation is the recent advancements in identifying candidate genes involved sufﬁcient to elicit behavioral changes in the offspring in ASD, all identiﬁed genetic risk factors combined account for only The similarities between 10–20% of the total ASD population ( the behaviors seen in models of MIA and the symptoms of ASD ). A number of these genetic risk factors can also be present have spurred further investigation into the physiological features in individuals without ASD, suggesting that many of these muta- of the offspring. For example, an increase in IL-6 is present up to tions may increase the risk of developing ASD, but additional risk 24 weeks postnatally in brains of offspring of dams exposed to factors are also necessary.
poly(I:C) (While elevated numbers of The absence of a known genetic cause in the majority of splenic TH17 cells have been observed in offspring after maternal cases, and the incomplete penetrance of known genetic risk fac- poly(I:C) exposure ). This evidence suggests tors, suggests that environmental factors are linked with the that in the MIA model, there are prolonged inﬂammatory re- causation of ASD. Growing research has highlighted maternal sponses that persist in adult offspring and are likely maintained immune activation (MIA), especially during the ﬁrst or second by alterations in the immune system of the affected offspring.
trimesters of pregnancy, as one potential environmental factor These data bear more than passing resemblance to features of that increases the risk for ASD In 1964 a ru- dysfunctional immune activity frequently observed in children bella epidemic in the US which affected many pregnant mothers and adults with ASD.
resulted in a large increase in the number of children who devel-oped ASD (). More- 2. Immune activity in ASD over, using medical information obtained in a large Danishdatabase, increased risk for ASD is associated with mothers that 2.1. Neuroinﬂammation required hospitalization for a viral infection in the ﬁrst trimesterof pregnancy, or mothers hospitalized for a bacterial infection in A key ﬁnding in ASD research has been the observations of the second trimester of pregnancy (), sug- marked ongoing neuroinﬂammation in postmortem brain speci- gesting that bacterial and viral infections may confer different mens from individuals with ASD over a wide range of ages (4– risks depending on gestational age. Further data suggest that 45 years of age) season of birth is important, with increased rates of ASD associ- These ﬁndings include prominent microglia activation ated with experiencing the ﬁrst trimester of pregnancy during and, increased inﬂammatory cytokine and chemokine production, the winter months, timing which coincided with the inﬂuenza including interferon (IFN)-c, IL-1b, IL-6, IL-12p40, tumor necrosis season ). Increased psoriasis, asthma and aller- factor (TNF)-a and chemokine C–C motif ligand (CCL)-2 in the gies during pregnancy have also been suggested as risk factors brain tissue and cerebral spinal ﬂuid for the development of ASD The potential role of a heightened or activated maternal im- Microglia are the resident mononuclear phagocytic cells of the mune response in the risk for ASD is further strengthened by CNS, and participate in immune surveillance of the CNS as well epidemiological data from large population based studies that as synaptic pruning in normal neurodevelopment show increased rates of autoimmune disorders in the families Microglia are also activated in the postmortem brain speci- of individuals with ASD ( mens of individuals with other neurological diseases of unknown ). Separately or coincidentally, the presence of speciﬁc genetic etiology such as Multiple Sclerosis, Alzheimer's and Parkin- anti-fetal brain antibodies in approximately 12% of mothers of son's Expression proﬁling of postmortem children with ASD, which are absent in mothers of children brain tissue from ASD individuals revealed increased messenger who are typically developing or mothers of children with devel- RNA transcript levels of several immune system associated genes, opmental delays, suggests a potential inﬂammatory process that further implicating neuroinﬂammatory processes in this disorder leads to the production of antibodies directed to the developing ). Moreover, a recent study looking at tran- scriptome organization patterns showed that gene co-expression ). Such fetal brain-speciﬁc antibodies could alter networks reﬂect abnormalities in cortical patterning in the brain neurodevelopment as is seen in systemic lupus erythematosis of ASD individuals (These ﬁndings were (SLE) (). In experiments associated with changes in microglia and immune activation; sug- using IgG collected from mothers of children with ASD, admin- gesting a causative role for immune dysregulation in ongoing neu- istration of these antibodies to pregnant rhesus macaques, in- rological dysfunction and synapse plasticity in the brains of duced stereotypic behavior and hyperactivity in the offspring, individuals with ASD.
symptoms that share homology to ASD ).
Similarly, anti-brain protein reactive antibodies from motherswho have children with ASD mediate behavioral changes and 2.2. Systemic immune activation neuro-pathology in the offspring of pregnant dams that are in-jected with these antibodies ). These data As well as signs of neuroinﬂammation in ASD, there are mul- suggest a potential pathogenic/pathological effect of anti-fetal tiple lines of evidence indicating that immune responses in the brain antibodies in some mothers who have children that devel- periphery are also dysfunctional and are associated with in- creased severity of core and related symptoms of ASD In rodent models of MIA, several abnormal behavioral fea- Immune abnormalities were ﬁrst described in individuals with tures are exhibited in the offspring that may have face validity ASD in 1977 Since this report Table 1Immune dysfunction and behaviors in ASD.
Studies in chronological Ratio of CD4 to CD8 positive T Administration of naltrexone led to reduction of ‘‘autistic'' symptomology and increased ratio of CD4 to CD8 cells No formal testing immunoglobulin levels IVIG resulted in improvements in eye contact, calmer behavior, improvement in speech and echolalia No formal testing IVIG treatment resulted in transient improvements in attention span and hyperactivity; improvement declined Improvements in communication and asocial behaviors after vancomycin treatment, but were lost after conclusionof treatment No formal testing Treatment with prednisone resulted in marked improvement in social and communication skills Fewer aberrant behaviors were recorded for subjects with fever (>100.4°F) compared with controls. Improvements were transient.
ADI-R, ADOS, SCQ, Plasma levels of active TGFb1 Lower TGFb1 levels were associated with lower adaptive behaviors and worse behavioral symptoms Plasma levels of P-Selectin Lower levels of P-Selectin associated with poor social development IgG levels in plasma Decreased IgG associated with increased aberrant behaviors Genotyping of the MIF gene, Plasma MIF levels were positively correlated with worse scores on ADOS for social impairment and imaginative and plasma levels of MIF Induced cytokine response to Negative correlation between PHA induced IL-23 production and sociability scores of the ADOS ADI-R, ADOS, SCQ, Monocyte TLR ligand More impaired social behaviors and non-verbal communication are associated with increased production of IL-1b and IL-6 after TLR4 stimulation ADI-R, ADOS, SCQ, Induced cytokine response to Pro-inﬂammatory or TH1 cytokines were associated with greater impairments in core features of ASD as well as aberrant behaviors; GM-CSF and TH2 cytokines were associated with better cognitive and adaptive function ADI-R, ADOS, SCQ, Antibodies directed against a Children with antibodies directed against a 45 kDa cerebellum protein had increased, lethargy and stereotypy; 45 or 62 kDa cerebellum children with antibodies against a 62 kDa cerebellum protein showed increased aberrant behaviors on the VABS composite standard score Serum levels of PDGF Increased serum levels of PDGF-BB homodimers positively associated with increased restricted, repetitive andstereotyped patterns of behavior and interests ADI-R, ADOS, SCQ, Plasma chemokines CCL2, CCL5 Plasma chemokine levels associated with higher aberrant behavior scores and more impaired developmental and adaptive function ADI-R, ADOS, SCQ, Plasma levels of cytokines IL- Elevated cytokine levels in plasma were associated with more impaired communication and aberrant behaviors 1b, IL-6, IL-8 and IL-12p40 BSE = behavior summarized evaluation; ABC = aberrant behavior checklist; CARS = childhood autism rating scale; ADI-R = autism diagnostic interview, revised; ADOS = autism diagnostic observation schedule; SCQ = socialcommunication questionnaire; VABS = vineland adaptive behavior scale; GI = gastrointestinal; MIF = macrophage migration inhibitory factor; PDGF = platelet derived growth factor; n.s. = not signiﬁcant.
C. Onore et al. / Brain, Behavior, and Immunity 26 (2012) 383–392 several research groups, from around the world, have identiﬁed interaction and communication, as well as associated features a variety of immune functions that are atypical in ASD; yet, such as aberrant behaviors ( not surprisingly, these ﬁndings are often as heterogeneous as The occurrence of a differential antibody repertoire has been the behavioral phenotypes which make up ASD.
studied extensively in ASD. For example, decreased total levels of Proteomic analysis indicates that the levels of many immune IgM and IgG classes of immunoglobulin have been reported, with proteins in plasma/sera, such as cytokines, chemokines, comple- lower levels found to correlate with more aberrant behaviors ment proteins, adhesion molecules and growth factors are However, within this proﬁle, atypical antibody iso- altered in ASD. Notably, increased plasma levels of pro-inﬂam- type levels are frequently reported in the plasma of individuals matory cytokines such as IL-1b, IL-6, IL-8 and IL-12p40 as well with ASD including increases in levels of the neutralizing IgG4 as MIF and platelet derived growth factor (PDGF), have been re- ported in ASD (; Antibodies reportedly reactive to human and non-human primate Moreover, elevated levels of these cyto- brain and CNS proteins have also been described in children and kines in the plasma were found to be associated with poor com- adults with ASD. Using Western blotting and ELISA techniques an munication and impaired social interaction behaviors ().
increased presence of antibodies can be detected in ASD that exhi- Plasma levels of chemokines CCL2 and CCL5 are also higher in bit reactivity against a diverse set of targets or speciﬁcities. These ASD and again are associated with worsening behavioral scores targets vary between studies, many of which have not be repli- (). In parallel, decreased circulating levels cated but have at one time included; antibodies against serotonin of the anti-inﬂammatory cytokine, transforming growth factor receptors ), myelin basic protein (TGF)-b, has been documented in ASD, with lower levels associ- ), heat shock proteins ated with worsening behavioral scores ( ), glial ﬁlament proteins ), as Collectively, these data reveal a trend to- well as various brain tissue proteins that have yet to be identiﬁed wards pro-inﬂammatory immune activity and away from regula- tory measures in ASD. As many of the cytokines have profound ). It is tempting to speculate that the increased diversity effects on neuronal development, migration, differentiation and and lack of a single speciﬁc target is due to antibody generation as synapse formation (see below), a disrupted balance in the cyto- a result of cellular damage and the emergence/revealing of seques- kine milieu may directly inﬂuence neurodevelopment, early tered or new epitopes. A similar ﬁnding is seen in many autoim- brain development and alter behavior. To this end it is of note mune diseases where diverse clonal antibody generation occurs that the shift in cytokine balance in ASD is linked with greater throughout the course of the disease, such as in SLE and multiple impairments in key autism behavioral domains including social sclerosis (MS). Whether a single antibody or cell response is Central Nervous System Synaptic Pruning Fig. 1. Immune dysfunction in ASD involves a network of interactions between several cell types, from the innate and adaptive arms of the immune system. The CNS isselective but several immune factors mediate profound effects of CNS function. Increased cytokine production, such TNF-a and IL-1b inhibit neurogenesis and promoteneuron death, while IL-6 may promote the growth and proliferation of neurons and oligodendrocytes. Increased levels of complement proteins can participate in synapticscaling, opsonizing synapses and targeting them for removal by phagocytic microglia. Activated microglia may additionally mediate synaptic pruning via MHCI interactions.
Collectively this immune dysfunction in ASD can exert several negative effects on behavior, including impaired cognitive function, and social withdrawal as well as aberrantbehavior observed in ASD.
C. Onore et al. / Brain, Behavior, and Immunity 26 (2012) 383–392 responsible for initiating this cascade or whether all the antibodies atypical adaptive T cell responses are repeatedly observed in indi- reactive to brain tissue hitherto observed in ASD are as a result of viduals with ASD (A predominance of IL-4+ cell/tissue damage, requires further research. Indeed, in contrast to IFN-c T cells was observed in the circulating CD4+ T cell popula- that observed for the maternal antibodies (discussed above) tion in individuals with ASD ). This bias towards ), what role auto-antibodies a TH2 phenotype and reduced TH1 responses has been observed in a play in children with ASD is unknown and it has yet to be demon- number of other studies. In corroboration with this ﬁnding, we strated whether any of these antibodies block receptor function, observed increased mononuclear cell production of IL-13 and activate neuronal/glial cells, induce cellular damage or have any GM-CSF in response to PHA stimulus, while IFN-c was decreased.
Production of the pro-inﬂammatory cytokine TNF-a was also in- In SLE, N-methyl-D-aspartate receptor (NMDAR) reactive anti- creased in response to in vitro stimulation, and is consistent with bodies are capable of mediating negative effects on cognitive func- an activated TH2 immune response in humans. Moreover increased tion (). Although antibody passage through TNF-a production was associated with increased stereotypical the BBB is restricted, these antibodies can be found in the CNS behaviors a hallmark symptom of ASD ().
). These brain protein reactive antibod- Analysis of intracellular cytokine production showed an increase ies are implicitly involved in cognitive impairments in individuals in frequency of TNF-a+ T cells but reduced frequency of IL-10+ T who carry them, and are also suspected to exert pathological ef- cells in both peripheral and intestinal mucosal tissue in children fects on fetal neurodevelopment during gestation ( ). It is possible that the brain protein-reactive antibodies These studies show, once again, a shift towards a pro-inﬂammatory found in the plasma of children with ASD may mediate pathology cytokine milieu and mirror the plasma cytokine data.
in a similarly direct fashion. Some experimental evidence has The activation proﬁle of circulating T cell phenotypes was also shown, that irrespective of the target epitope, antibodies from different in ASD and CD3+ T cells display higher levels of HLA-DR, ASD subjects bind speciﬁcally to cerebellar interneurons and golgi a marker of late cellular activation (In addi- type II cells in tissue obtained from rhesus macaque monkeys tion, CD26 (dipeptidyl peptidase IV), a marker associated with an ). The binding of these antibodies to speciﬁc effector cell phenotype in human CNS disorders such as multiple cellular targets could lead to decreased or increased cellular activ- sclerosis, was increased on CD8+ T cells ().
ity. Moreover, the presence of these antibodies in children with Following in vitro stimulation an altered pattern of co-stimulatory ASD correlated strongly with antibody reactivity observed to a and activation markers was observed, with increased expression of 45 kD cerebellar protein of unknown identity and was positively CD137 (4-1BB) but decreased CD134 (OX40) and CD25 (IL-2 a associated with worsening of aberrant behavior ( receptor) on T lymphocytes of children with ASD ( ). Elucidating the exact target of these cells and their function Increased T cell activation may also be linked with de- on neuronal cell cultures in vitro would help to establish their role creased apoptosis leading to the survival of activated cells that in the pathogenesis of ASD.
would otherwise be eliminated (a feature Cell damage/death can be induced following the binding of that has been described in chronic inﬂammatory conditions such complement proteins to antibodies and may be another mecha- as Crohn's disease (Collectively, evidence nism in which auto-reactive antibodies contribute to ASD pathol- of atypical cytokine production, altered T cell activation and poten- ogy. Moreover, the complement proteins C1q and C3, which tial impaired apoptotic activity suggest there is a predisposition to classically make up a portion of the immune complement cas- chronic inﬂammation which could negatively affect healthy cogni- cade, are also involved in synaptic scaling. Complement mediates tive development in ASD. Exciting ﬁndings from animal models synaptic pruning by opsonizing synapses, effectively targeting suggest that neurogenesis is modulated by the interaction between them for removal by phagocytic microglia T cells and CNS cells (). Al- ). An increase in complement proteins, including the lytic tered T cell activation in ASD may therefore directly affect the component C1q, has been shown in sera from children with course of neurodevelopment. However, whether the T cells that ASD compared to age, ethnicity and gender matched typically are active in the periphery in ASD also interact with CNS tissue is developing children Co-localization of IgG and C1q has also been reported in the mucosa of children with Adhesion molecules known to control the passage of T cells ASD (). Whether the antibodies spe- across endothelial barriers play an important role in mediating ciﬁc for CNS proteins are the same as those in the mucosa and T cell passage and T cell/CNS interactions. Circulating levels of whether they are capable of ﬁxing complement and eliciting cel- soluble adhesion molecules P-Selectin, L-Selectin and PECAM-1 lular damage in ASD is not known. In particular, the potential accurately represent levels on endothelial cells. In high function- interaction between auto-antibodies speciﬁc for GABAergic inter- ing individuals with ASD levels of sPECAM-1, sP-Selectin and sL- neurons and complement in children with ASD requires further selectin were decreased compared with controls investigation. Increased complement production in ASD may Furthermore, lower levels of P- therefore modulate neuronal function in several ways either by Selectin were associated with more impaired social skills synapse pruning or through an interaction with speciﬁc auto- ). These data suggest that modulating immune cell reactive antibodies leading to cell death.
access to the brain in ASD may inﬂuence abnormal social inter-actions. In line with these ﬁndings, during fever episodes, some 2.3. Adaptive cellular response children with ASD show a transient improvement in behaviorsthat diminishes back to baseline after the child's fever improves The examination of immune cell function in ASD has been hin- (During fever, upregulation of adhesion mol- dered by problems arising from study design including the use of ecules and changes in endothelial barriers occurs as a result of small sample sizes, variable diagnostic criteria, non-matching of pyrogenic cytokine release. In ASD it is possible that fever may cases and controls for gender or age and, the use of unevaluated evoke a transient increase in T cell–brain interactions and hence siblings as controls. Such issues have plagued the ﬁeld and led to an improvement in behavior. These data are provocative and confusion in the interpretation of the various study ﬁndings. De- suggest that immune activation, including activation of T-lym- spite these drawbacks many studies have observed reproducible phocyte subsets, could be important in improving behaviors in ﬁndings of altered cellular function in ASD. Among these ﬁndings some individuals with ASD.
C. Onore et al. / Brain, Behavior, and Immunity 26 (2012) 383–392 2.4. Innate cellular response a proﬁle representative of myeloid cell activation, i.e. the produc-tion of IL-12p40, TNFa, IL-1b and IL-6 As well as changes in adaptive immune responses the activity of a number of other cell subsets has been described, including atyp-ical natural killer (NK) cell activity. Reduced ability of NK cells to 3. Potential impact of immune dysfunction in ASD on CNS kill K562 target cells in ASD was ﬁrst described by activity and behavior and has now been conﬁrmed in more contemporary reports(In addition to reduced Although a singular pathology of ASD remains elusive, a wealth lytic activity, changes in several factors that contribute to NK cell of evidence suggests that ASD symptoms may be related to im- activity such as perforin, granzyme B and IFN-c have been identi- mune dysfunction ( ﬁed. NK cells appear to produce higher levels of perforin, granzyme ). Further detailed investigations are needed B, and IFN-c while under resting conditions in children with ASD to concretely identify whether the immunological ﬁndings in ASD (These data suggest that in vivo, there is in- converge to a single immunopathology. However, in the following creased NK cell activation; however, following a strong in vitro sig- section we will try and identify potential mechanisms of action in nal, such as with target cells, NK cells from children with ASD are which the observed immune dysfunction in ASD could impact neu- unable to produce more of their effector molecules thus leading to ronal function and behavior in ASD.
the reduced capability to lyse the targets ).
Activity of the immune system can elicit profound effects on As early responders of the innate immune system, NK cells help behavior (). Several immune proteins function within the shape the initial immune response during an inﬂammatory event nervous system as mediators of normal neurodevelopment ( and aberrant activity of these cells are likely an important contrib- ). Cytokines, such as TNF-a, IL-1b, the utor to the atypical immune activity observed in individuals with TGF-b family of molecules, and the gp130 ligand family mediate di- rect effects on neuronal activity. For example, TNF-a is produced Monocytes are among the ﬁrst responders during inﬂammation, by wide variety of cells during an inﬂammatory event ( and are robust cytokine producers, creating a cytokine milieu that and, in addition to its role in inﬂammation, can mod- profoundly inﬂuences the activity of neighboring immune cells.
ulate neuronal cell proliferation or cell death, and play an impor- Monocytes also serve as precursors for a number of tissue speciﬁc tant role in synaptic pruning myeloid lineage cells including macrophages, dendritic cells, and Other neuropoeitic cytokines, microglia (). An increased such as IL-1b and IL-6, also exert varied affects on neuronal sur- number of circulating monocytes has been reported in ASD ( vival, proliferation, synapse formation, migration, and differentia- ). Furthermore, upregulation of activation markers on tion. IL-6 is member of the gp130 ligand family that includes circulating CD14+ monocytes suggest that these cells are activated IL-11, ciliary neurotrophic factor (CNTF), oncostatin M, and leuko- in vivo In research conducted in our labo- cyte inhibitory factor (LIF), that play important roles in promoting ratory, an atypical pattern of cytokine responses were observed and maintaining oligodendrocyte (ODC) survival in the CNS following TLR agonist stimulation of isolated CD14+ monocytes ). Generation of IL-6 knock-out mouse from young children with ASD (Speciﬁcally, models results in viable offspring; however, they display impaired increased inﬂammatory cytokine production, IL-1b, TNF-a and IL- recognition memory, suggesting an essential role for IL-6 in learn- 6, was observed in response to the TLR2 ligand, lipoteichoic acid ing Both IL-6 and IL-1b (LTA) and to a lesser extent the TLR4 ligand, LPS. Conversely, re- are involved in mediating ‘‘sickness behavior,'' an adaptive change duced cytokine production was observed in response to a TLR9 in behaviors accompanying inﬂammation that are characterized by agonist, an unmethylated CpG repeat synthetic oligonucleotide, lethargy, depression, loss of appetite, anxiety, impaired ability to resembling bacterial DNA. Furthermore, increased monocyte IL-6 focus and social withdrawal (Notably, the so- and IL-1b production in response to LPS stimulation was associated cial withdrawal of sickness behavior can be alleviated when ani- with more impaired social behavior in individuals with ASD mals are given minocycline, a broad spectrum antibiotic with These atypical monocyte responses are intriguing, and indi- anti-inﬂammatory qualities ( cate abnormal myeloid involvement in ASD. Hyperactivation of In addition, the cytokines IL-2 and IL-4 have been shown to myeloid cells in ASD is implicated in both the periphery and CNS, inﬂuence repetitive and cognitive behaviors. Treatment of mice as increased inﬁltration of monocytes and perivascular macro- with IL-2 results in increased ‘‘climbing behavior'' that are thought phages are observed in brain specimens from individuals with to denote repetitive behaviors, a pattern of behaviors that are ASD (). Moreover, there is a striking similarity characteristic of ASD (IL-4 knock-out mice show in cytokine levels in the plasma of children with ASD that exhibit impaired cognition, possibly as a result of loss of T cell function Table 2Inﬂuence of cytokines on behaviors with relevance to ASD.
CNS effects relevant to the symptoms of ASD Sustained expression of IL-1b in hippocampus impairs spatial memory ( IL-1b promotes the adaptive stress responses ) Blockage of IL-1b results in a reversible impairment of long-term potentiation and can alter synaptic plasticity IL-1 alters sleep patterns Sickness behavior – social withdrawal ) IL-2 treatment results in increased climbing (repetitive) behaviors, which are mediated by dopaminergic processes () IL-4 KO mice show cognitive impairments ( IL-6 KO mice display impaired recognition memory ) Increased plasma levels of IL-6 in subjects with depression (Musselman et al., 2001) TNF-a induces cell death on neurons, and is thought to play an important role in synaptic pruning () Sickness behavior - Social withdrawal ) C. Onore et al. / Brain, Behavior, and Immunity 26 (2012) 383–392 in the CNS (). There is some evidence in individ- Peripheral and or neuronal production of cytokines uals with ASD that cognition is impaired; however, largely due to could also lead to an activated proﬁle in these cells. For example, the deﬁcits in verbal and non-verbal communication as well as increased GM-CSF production has been detected in ASD and will poor social interaction, the speciﬁc nature of these cognitive issues drive the release of myeloid progenitor cells that can become tissue has been hard to deﬁne and remain somewhat controversial.
macrophages (). In Collectively these ﬁndings suggest that cytokines are both nec- turn the production of cytokines from microglia and macrophages essary for normal neurodevelopment and behavior and that any will inﬂuence neuronal survival, proliferation, function and synap- perturbation in the cytokine network can impact neurodevelop- tic plasticity .
ment . Observed increases in TNF-a, IL-1b and IL-6 in the Furthermore, perhaps due to their activities as immunological blood, CSF and brain tissues from children with ASD represents sentinels of the CNS, or their role in synaptic pruning, genetic the ﬁrst piece of the puzzle of a disrupted neuro-immune network.
abnormalities in microglia can result in profound effects on behav- Associations with greater impairment in core autistic behaviors ior. Recently, a landmark paper described the source of repetitive and increased cytokine levels highlight a potential new avenue of grooming behavior in Hoxb8 / mice ().
research in which cytokine patterns could be manipulated to ben- The Hoxb8 protein is expressed exclusively in bone marrow-de- eﬁt behavioral outcome in ASD. For example, minocycline has been rived microglia in the CNS, and deﬁciency in this protein results shown to successfully alleviate aberrant behavior symptoms in in reduced numbers of bone marrow-derived microglia cells within children with Fragile X, a neurodevelopmental disorder with high the CNS. Transplantation of bone marrow containing functional rates of ASD ).
Hoxb8 was sufﬁcient to restore normal grooming behavior in these In ASD, linkage with speciﬁc MHC molecules has been fre- mice, providing solid evidence of the role of microglia cells in the quently reported ( atypical grooming behavior of Hoxb8 / mice ).
). In addition, two large GWAS studies in schizophrenia high- These data also suggests that atypical microglia function plays a light changes within the MHC region on chromosome 6 ( role in repetitive behaviors, a characteristic of several disorders These data suggest that abnormali- including ASD. In addition, DAP12 and the triggering receptor ex- ties in the expression of MHC genes and their effects on brain pressed on myeloid cells 2 (TREM2) protein form a complex in development and synaptic function may be involved in the patho- myeloid cells which is reportedly exclusively expressed in microg- genesis of complex neurodevelopmental disorders such as ASD and lia cells within the CNS (This complex is essen- schizophrenia. Until relatively recently neurons were considered to tial for the phagocytosis of apoptotic cells, and for limiting be negative for the MHC I molecules; however, emerging data sup- inﬂammatory cytokine production in the CNS port the role of these molecules in CNS development A loss of function mutation of genes encoding either TREM2 MHCI is expressed on virtually every cell or DAP12 results in Nasu–Hakola disease, also known as polycystic type within the body, and can display cytosolic proteins to CD8+ T lipomembranous osteodysplasia with sclerosing leukoencephalop- cells, alerting them to the presence of non-self proteins, for exam- athy (PLOSL). PLOSL results in cysts within the bone, and early on- ple, during a viral infection. In the CNS, MHCI plays a dual role in set dementia (). The disorder is characterized regulating synaptic scaling, likely by engaging with a CD3f or PIRB by severe microglia activation in brain tissue. The example of molecules MHCI is expressed in the CNS under non- PLOSL suggests that unchecked microglia driven inﬂammation inﬂammatory conditions, and correlates with times and regions of can contribute to cognitive degeneration, and bears some resem- synaptic plasticity ). Double knock-out of the blance to the microglia activation observed in individuals with b-2-microglobulin (b2m) subunit of the MHCI molecule, and the ASD. A number of genetic risk factors for ASD such as MET and transporter with antigen processing (TAP) protein, virtually elimi- MIF, are known to directly impact the function of myeloid cells nates all allotypes of MHCI from the cell surface and their activation status and if these cells are skewed towards The elimination of functional MHCI results in a tolerance or pro-inﬂammatory inducing phenotype. Further atypical synaptic plasticity in animal models, further illustrating investigation of genes that control microglia function in ASD could the essential role for MHCI in synapse remodeling ( provide clues to the pathogenesis and potential treatment of this Thus, the role of MHC in ASD may be twofold, ﬁrstly, by their ability to modulate synapse formation during develop- Inﬂammatory activity of microglia may be inﬂuence by polari- ment and, secondly, in their role in shaping the T cell repertoire zation towards an inﬂammatory (M1) or alternatively activated and the speciﬁcity, diversity and conformation of antigens that (M2) phenotype. Recently, in a model of T cell deﬁciency and cog- are presented to T cells.
nitive impairment, administration of M2 microglia was beneﬁcial Microglial cells are uniquely positioned to robustly respond to to cognitive performance (The recent ﬁnding immune signals, and inﬂuence the CNS environment, through the of altered transciptome proﬁles in microglia in brain specimens production of inﬂammatory cytokines and the generation of reac- from individuals with ASD also suggests tive oxygen species (ROS) within the CNS ( that environmental factors may play a role in the activation of The presence of activated these cells. TH2 cells generate IL-4, and IL-10, skewing the microen- perivascular macrophages and microglia have been described in vironment and potentially polarize neighboring microglia into an brain specimens in ASD alternative M2 phenotype (). In ); however, what the cause of this hyperactive ASD the data suggest that a TH2 cytokine proﬁle may predominate state is still unknown. The phagocytosis of dead or dying neurons (and may thereby skew by microglia is believed to be a normal and relatively non-inﬂam- the microglia/macrophage response. This data highlights the matory function ). However, upon phagocytosis importance of all arms of the immune system in immune regula- of antibody-bound targets, microglia produce increased inﬂamma- tion within the CNS, and the bi-directional regulation between tory cytokines and ROS The potentially pro- the adaptive and innate immune system required to maintain a inﬂammatory activity of microglia in ASD could be associated with healthy neuro-immune environment, that may be dysfunctional the presence of brain-reactive antibodies in the CNS. Similarly, dys- regulated complement production in ASD may have a similar effect as complement opsoniza- (especially affect, social functioning and cognition) evidence of tion can mediate the phagocytosis of neurons by microglia ( extensive immune dysfunction suggest other systems are also C. Onore et al. / Brain, Behavior, and Immunity 26 (2012) 383–392 disrupted. The ﬁndings so far point towards a disruption of many evidence of immune dysfunction and are associated with impaired behavioral facets of the immune responses including polymorphisms in im- outcome. Brain Behav. Immun. 25, 40–45.
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