Reversal of autism through immune modulation: evidence of link btw mmune irregularities and Autism

July 18, 2012

Autism, immune irregularities linked in new researchPosted on July 17, 2012 by Stone Hearth News Scientists at the California Institute of Technology (Caltech) pioneered the study of the link between irregularities in the immune system and neurodevelopmental disorders such as autism a decade ago. Since then, studies of postmortem brains and of individuals with autism, as well as epidemiological studies, have supported the correlation between alterations in the immune system and autism spectrum disorder.What has remained unanswered, however, is whether the immune changes play a causative role in the development of the disease or are merely a side effect. Now a new Caltech study suggests that specific changes in an overactive immune system can indeed contribute to autism-like behaviors in mice, and that in some cases, this activation can be related to what a developing fetus experiences in the womb.The results appear in a paper this week in the Proceedings of the National Academy of Sciences (PNAS).“We have long suspected that the immune system plays a role in the development of autism spectrum disorder,” says , the Anne P. and F. Biaggini Professor of Biological Sciences at Caltech, who led the work. “In our studies of a mouse model based on an environmental risk factor for autism, we find that the immune system of the mother is a key factor in the eventual abnormal behaviors in the offspring.”The first step in the work was establishing a mouse model that tied the autism-related behaviors together with immune changes. Several large epidemiological studies—including one that involved tracking the medical history of every person born in Denmark between 1980 and 2005—have found a correlation between viral infection during the first trimester of a mother’s pregnancy and a higher risk for autism spectrum disorder in her child. To model this in mice, the researchers injected pregnant mothers with a viral mimic that triggered the same type of immune response a viral infection would.“In mice, this single insult to the mother translates into autism-related behavioral abnormalities and neuropathologies in the offspring,” says Elaine Hsiao, a graduate student in ’s lab and lead author of the PNAS paper.The team found that the offspring exhibit the core behavioral symptoms associated with autism spectrum disorder—repetitive or stereotyped behaviors, decreased social interactions, and impaired communication. In mice, this translates to such behaviors as compulsively burying marbles placed in their cage, excessively self grooming, choosing to spend time alone or with a toy rather than interacting with a new mouse, or vocalizing ultrasonically less often or in an altered way compared to typical mice.Next, the researchers characterized the immune system of the offspring of mothers that had been infected and found that the offspring display a number of immune changes. Some of those changes parallel those seen in people with autism, including decreased levels of regulatory T cells, which play a key role in suppressing the immune response. Taken together, the observed immune alterations add up to an immune system in overdrive—one that promotes inflammation.“Remarkably, we saw these immune abnormalities in both young and adult offspring of immune-activated mothers,” Hsiao says. “This tells us that a prenatal challenge can result in long-term consequences for health and development.”With the mouse model established, the group was then able to test whether the offspring’s immune problems contribute to their autism-related behaviors. In a revealing test of this hypothesis, the researchers were able to correct many of the autism-like behaviors in the offspring of immune-activated mothers by giving the offspring a bone-marrow transplant from typical mice. The normal stem cells in the transplanted bone marrow not only replenished the immune system of the host animals but altered their autism-like behavioral impairments.The researchers emphasize that because the work was conducted in mice, the results cannot be readily extrapolated to humans, and they certainly do not suggest that bone-marrow transplants should be considered as a treatment for autism. They also have yet to establish whether it was the infusion of stem cells or the bone-marrow transplant procedure itself—complete with irradiation—that corrected the behaviors.However, says, the results do suggest that immune irregularities in children could be an important target for innovative immune manipulations in addressing the behaviors associated with autism spectrum disorder. By correcting these immune problems, he says, it might be possible to ameliorate some of the classic developmental delays seen in autism.In future studies, the researchers plan to examine the effects of highly targeted anti-inflammatory treatments on mice that display autism-related behaviors and immune changes. They are also interested in considering the gastrointestinal (GI) bacteria, or microbiota, of such mice. Coauthor Sarkis Mazmanian, a professor of biology at Caltech, has shown that gut bacteria are intimately tied to the function of the immune system. He and are investigating whether changes to the microbiota of these mice might also influence their autism-related behaviors.###Along with , Hsiao, and Mazmanian, additional Caltech coauthors on the PNAS paper, “Modeling an autism risk factor in mice leads to permanent immune dysregulation,” are Mazmanian lab manager Sara McBride and former graduate student Janet Chow. The work was supported by an Autism Speaks Weatherstone Fellowship, National Institutes of Health Graduate Training Grants, a Weston Havens Foundation grant, a O. and W. Caltech Innovation Fellowship, a Caltech Innovation grant, and a Congressionally Directed Medical Research Program Idea Development Award.Source PNAS Proceedings of the National Academy of Sciences of the United States of America Skip to main page content

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Modeling an autism risk factor in mice leads to permanent immune dysregulation

Elaine Y. Hsiao1,

Sara W. McBride,

Janet Chow,

Sarkis K. Mazmanian, and

H. + Author Affiliations

Biology Division, California Institute of Technology, Pasadena, CA 91125

Edited by Carla J. Shatz, Stanford University, Stanford, CA, and approved June 19, 2012 (received for review February 15, 2012) AbstractIncreasing evidence highlights a role for the immune system in the pathogenesis of autism spectrum disorder (ASD), as immune dysregulation is observed in the brain, periphery, and gastrointestinal tract of ASD individuals. Furthermore, maternal infection (maternal immune activation, MIA) is a risk factor for ASD. Modeling this risk factor in mice yields offspring with the cardinal behavioral and neuropathological symptoms of human ASD. In this study, we find that offspring of immune-activated mothers display altered immune profiles and function, characterized by a systemic deficit in CD4+ TCR£]+ Foxp3+ CD25+ T regulatory cells, increased IL-6 and IL-17 production by CD4+ T cells, and elevated levels of peripheral Gr-1+ cells. In addition, hematopoietic stem cells from MIA offspring exhibit altered myeloid lineage potential and differentiation. Interestingly, repopulating irradiated control mice with bone marrow derived from MIA offspring does not confer MIA-related immunological deficits, implicating the peripheral environmental context in long-term programming of immune dysfunction. Furthermore, behaviorally abnormal MIA offspring that have been irradiated and transplanted with immunologically normal bone marrow from either MIA or control offspring no longer exhibit deficits in stereotyped/repetitive and anxiety-like behaviors, suggesting that immune abnormalities in MIA offspring can contribute to ASD-related behaviors. These studies support a link between cellular immune dysregulation and ASD-related behavioral deficits in a mouse model of an autism risk factor.

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July 18, 2012

Hi,

Surely there can't have been that big an increase in the number of mothers

getting a viral infection in the first three months of pregnancy to account for

the vast increase in the incidence of autism?

I suspect the answer lies right at the end of the piece - the effect of gut bugs

on the immune system.

Patience

>

> Autism, immune irregularities linked in new research

>

> Posted on July 17, 2012

> <http://www.stonehearthnewsletters.com/autism-immune-irregularities-linked-i

> n-new-research/autism/> by Stone Hearth News

> <http://www.stonehearthnewsletters.com/author/admin/>

> Scientists at the California Institute of Technology (Caltech) pioneered the

> study of the link between irregularities in the immune system and

> neurodevelopmental disorders such as autism a decade ago. Since then,

> studies of postmortem brains and of individuals with autism, as well as

> epidemiological studies, have supported the correlation between alterations

> in the immune system and autism spectrum disorder.

>

> What has remained unanswered, however, is whether the immune changes play a

> causative role in the development of the disease or are merely a side

> effect. Now a new Caltech study suggests that specific changes in an

> overactive immune system can indeed contribute to autism-like behaviors in

> mice, and that in some cases, this activation can be related to what a

> developing fetus experiences in the womb.

>

> The results appear in a paper this week in the Proceedings of the National

> Academy of Sciences (PNAS).

>

> ¡§We have long suspected that the immune system plays a role in the

> development of autism spectrum disorder,¡¨ says , the Anne P.

> and F. Biaggini Professor of Biological Sciences at Caltech, who

> led the work. ¡§In our studies of a mouse model based on an environmental

> risk factor for autism, we find that the immune system of the mother is a

> key factor in the eventual abnormal behaviors in the offspring.¡¨

>

> The first step in the work was establishing a mouse model that tied the

> autism-related behaviors together with immune changes. Several large

> epidemiological studies¡Xincluding one that involved tracking the medical

> history of every person born in Denmark between 1980 and 2005¡Xhave found a

> correlation between viral infection during the first trimester of a mother¡¦s

> pregnancy and a higher risk for autism spectrum disorder in her child. To

> model this in mice, the researchers injected pregnant mothers with a viral

> mimic that triggered the same type of immune response a viral infection

> would.

>

> ¡§In mice, this single insult to the mother translates into autism-related

> behavioral abnormalities and neuropathologies in the offspring,¡¨ says Elaine

> Hsiao, a graduate student in ¡¦s lab and lead author of the PNAS

> paper.

>

> The team found that the offspring exhibit the core behavioral symptoms

> associated with autism spectrum disorder¡Xrepetitive or stereotyped

> behaviors, decreased social interactions, and impaired communication. In

> mice, this translates to such behaviors as compulsively burying marbles

> placed in their cage, excessively self grooming, choosing to spend time

> alone or with a toy rather than interacting with a new mouse, or vocalizing

> ultrasonically less often or in an altered way compared to typical mice.

>

> Next, the researchers characterized the immune system of the offspring of

> mothers that had been infected and found that the offspring display a number

> of immune changes. Some of those changes parallel those seen in people with

> autism, including decreased levels of regulatory T cells, which play a key

> role in suppressing the immune response. Taken together, the observed immune

> alterations add up to an immune system in overdrive¡Xone that promotes

> inflammation.

>

> ¡§Remarkably, we saw these immune abnormalities in both young and adult

> offspring of immune-activated mothers,¡¨ Hsiao says. ¡§This tells us that a

> prenatal challenge can result in long-term consequences for health and

> development.¡¨

>

> With the mouse model established, the group was then able to test whether

> the offspring¡¦s immune problems contribute to their autism-related

> behaviors. In a revealing test of this hypothesis, the researchers were able

> to correct many of the autism-like behaviors in the offspring of

> immune-activated mothers by giving the offspring a bone-marrow transplant

> from typical mice. The normal stem cells in the transplanted bone marrow not

> only replenished the immune system of the host animals but altered their

> autism-like behavioral impairments.

>

> The researchers emphasize that because the work was conducted in mice, the

> results cannot be readily extrapolated to humans, and they certainly do not

> suggest that bone-marrow transplants should be considered as a treatment for

> autism. They also have yet to establish whether it was the infusion of stem

> cells or the bone-marrow transplant procedure itself¡Xcomplete with

> irradiation¡Xthat corrected the behaviors.

>

> However, says, the results do suggest that immune irregularities

> in children could be an important target for innovative immune manipulations

> in addressing the behaviors associated with autism spectrum disorder. By

> correcting these immune problems, he says, it might be possible to

> ameliorate some of the classic developmental delays seen in autism.

>

> In future studies, the researchers plan to examine the effects of highly

> targeted anti-inflammatory treatments on mice that display autism-related

> behaviors and immune changes. They are also interested in considering the

> gastrointestinal (GI) bacteria, or microbiota, of such mice. Coauthor Sarkis

> Mazmanian, a professor of biology at Caltech, has shown that gut bacteria

> are intimately tied to the function of the immune system. He and

> are investigating whether changes to the microbiota of these mice might also

> influence their autism-related behaviors.

>

> ###

> Along with , Hsiao, and Mazmanian, additional Caltech coauthors on

> the PNAS paper, ¡§Modeling an autism risk factor in mice leads to permanent

> immune dysregulation,¡¨ are Mazmanian lab manager Sara McBride and former

> graduate student Janet Chow. The work was supported by an Autism Speaks

> Weatherstone Fellowship, National Institutes of Health Graduate Training

> Grants, a Weston Havens Foundation grant, a O. and W.

> Caltech Innovation Fellowship, a Caltech Innovation grant, and a

> Congressionally Directed Medical Research Program Idea Development Award.

>

> Source <http://www.eurekalert.org/pub_releases/2012-07/ciot-crf071712.php>

>

> PNAS <http://www.pnas.org/>

> Proceedings of the National Academy of Sciences of the United States of

> America <http://www.pnas.org/>

>

> Skip to main page content

> <http://www.pnas.org/content/early/2012/07/10/1202556109.abstract#content-bl

> ock>

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> * <http://www.pnas.org/content/early/2012/07/10/1202556109.abstract#>

> Modeling an autism risk factor in mice leads to permanent immune

> dysregulation

> 1. Elaine Y. Hsiao

> <http://www.pnas.org/search?author1=Elaine+Y.+Hsiao & sortspec=date & submit=Sub

> mit> 1

> <http://www.pnas.org/content/early/2012/07/10/1202556109.abstract#corresp-1>

> ,

> 2. Sara W. McBride

> <http://www.pnas.org/search?author1=Sara+W.+McBride & sortspec=date & submit=Sub

> mit> ,

> 3. Janet Chow

> <http://www.pnas.org/search?author1=Janet+Chow & sortspec=date & submit=Submit>

> ,

> 4. Sarkis K. Mazmanian

> <http://www.pnas.org/search?author1=Sarkis+K.+Mazmanian & sortspec=date & submit

> =Submit> , and

> 5. H.

> <http://www.pnas.org/search?author1=+H.+ & sortspec=date & submit=S

> ubmit>

> + <http://www.pnas.org/content/early/2012/07/10/1202556109.abstract#>

> Author Affiliations

> 1. Biology Division, California Institute of Technology, Pasadena, CA

> 91125

> 2.

> 3.

> 4. Edited by Carla J. Shatz, Stanford University, Stanford, CA, and

> approved June 19, 2012 (received for review February 15, 2012)

>

> Abstract

> Increasing evidence highlights a role for the immune system in the

> pathogenesis of autism spectrum disorder (ASD), as immune dysregulation is

> observed in the brain, periphery, and gastrointestinal tract of ASD

> individuals. Furthermore, maternal infection (maternal immune activation,

> MIA) is a risk factor for ASD. Modeling this risk factor in mice yields

> offspring with the cardinal behavioral and neuropathological symptoms of

> human ASD. In this study, we find that offspring of immune-activated mothers

> display altered immune profiles and function, characterized by a systemic

> deficit in CD4+ TCR£]+ Foxp3+ CD25+ T regulatory cells, increased IL-6 and

> IL-17 production by CD4+ T cells, and elevated levels of peripheral Gr-1+

> cells. In addition, hematopoietic stem cells from MIA offspring exhibit

> altered myeloid lineage potential and differentiation. Interestingly,

> repopulating irradiated control mice with bone marrow derived from MIA

> offspring does not confer MIA-related immunological deficits, implicating

> the peripheral environmental context in long-term programming of immune

> dysfunction. Furthermore, behaviorally abnormal MIA offspring that have been

> irradiated and transplanted with immunologically normal bone marrow from

> either MIA or control offspring no longer exhibit deficits in

> stereotyped/repetitive and anxiety-like behaviors, suggesting that immune

> abnormalities in MIA offspring can contribute to ASD-related behaviors.

> These studies support a link between cellular immune dysregulation and

> ASD-related behavioral deficits in a mouse model of an autism risk factor.

>

> ____________________________________________________________ You received

> this message as a subscriber on the list:

> cheautism@... To be removed from the list, send

> any message to: cheautism-unsubscribe@... For all

> list information and functions, see:

> http://lists.healthandenvironment.org/lists/info/cheautism Please remember

> that CHE Working Group correspondence may only be forwarded or posted

> elsewhere if all personal commentary has been removed from the original

> post. To forward personal commentary explicit permission of the author must

> first be obtained.

>

July 18, 2012

I think it is both, as bad gut bugs would not be there for no reason. Imo the viral infection in pregnancy lays the ground, throws the system off balance enough that it later goes completely nuts on vaccines or on exposure to gut pathogens. If immune system is dysregulated in fetus during pregnancy then offspring will both be less able to ward of pathogens (hence dysbiosis) and secondly their will 'over-react' in terms of producing excess inflammation (but not really controlling the pathogens very well --- sort of like a very loud barking small dog)And lastly the 'switch off system' -- the feedback that allows immune/inflammatory system to cool down and switch off after the acute attack does not work well in this scenario. Also viral attack in pregnancy can dysregulate autonomic nervous system long term, which also links in to immune dysregulation and especially the lack of immune defences in the GUT (where ANS rules). This all comes from animal studies and is well known to happen in animals but no reason to believe that very similar things don't happen in humans. One more thing if there is immune dysregulation of such kind (and it seem this IS exactly what happens in autism, according to latest German/Danish study where newborns who are later diagnosed with autism did have those immune/inflammatory markers in their blood, as well as placenta… ) vaccinating them with live virus vaccines, esp multiple vaccines on the same day, is the last thing you want to do. Hence regressions and higher rates of autism today than in the past imo, live vaccine strains of viruses reverting to virulence in the gut (wakefield's 'controversial' findings :-x etc) --- this also is well known to happen in immunocompromised humans … So I expect there will be big resistance by the establishment to accept and admit that there is immune dysregulation in autism, because the vaccine elephant in the room will become impossible to ignore. Imo this is also where we should focus all fight and advocacy with the mainstream. Reply-To: "Autism-Biomedical-Europe " <Autism-Biomedical-Europe >Date: Wed, 18 Jul 2012 16:25:13 -0000To: "Autism-Biomedical-Europe " <Autism-Biomedical-Europe >Subject: Re: Reversal of autism through immune modulation: evidence of link btw mmune irregularities and Autism

Hi,

Surely there can't have been that big an increase in the number of mothers getting a viral infection in the first three months of pregnancy to account for the vast increase in the incidence of autism?

I suspect the answer lies right at the end of the piece - the effect of gut bugs on the immune system.

Patience

>

> Autism, immune irregularities linked in new research

>

> Posted on July 17, 2012

> <http://www.stonehearthnewsletters.com/autism-immune-irregularities-linked-i

> n-new-research/autism/> by Stone Hearth News

> <http://www.stonehearthnewsletters.com/author/admin/>

> Scientists at the California Institute of Technology (Caltech) pioneered the

> study of the link between irregularities in the immune system and

> neurodevelopmental disorders such as autism a decade ago. Since then,

> studies of postmortem brains and of individuals with autism, as well as

> epidemiological studies, have supported the correlation between alterations

> in the immune system and autism spectrum disorder.

>

> What has remained unanswered, however, is whether the immune changes play a

> causative role in the development of the disease or are merely a side

> effect. Now a new Caltech study suggests that specific changes in an

> overactive immune system can indeed contribute to autism-like behaviors in

> mice, and that in some cases, this activation can be related to what a

> developing fetus experiences in the womb.

>

> The results appear in a paper this week in the Proceedings of the National

> Academy of Sciences (PNAS).

>

> Â¡Â§We have long suspected that the immune system plays a role in the

> development of autism spectrum disorder,Â¡Â¨ says , the Anne P.

> and F. Biaggini Professor of Biological Sciences at Caltech, who

> led the work. Â¡Â§In our studies of a mouse model based on an environmental

> risk factor for autism, we find that the immune system of the mother is a

> key factor in the eventual abnormal behaviors in the offspring.Â¡Â¨

>

> The first step in the work was establishing a mouse model that tied the

> autism-related behaviors together with immune changes. Several large

> epidemiological studiesÂ¡Xincluding one that involved tracking the medical

> history of every person born in Denmark between 1980 and 2005Â¡Xhave found a

> correlation between viral infection during the first trimester of a motherÂ¡Â¦s

> pregnancy and a higher risk for autism spectrum disorder in her child. To

> model this in mice, the researchers injected pregnant mothers with a viral

> mimic that triggered the same type of immune response a viral infection

> would.

>

> Â¡Â§In mice, this single insult to the mother translates into autism-related

> behavioral abnormalities and neuropathologies in the offspring,Â¡Â¨ says Elaine

> Hsiao, a graduate student in Â¡Â¦s lab and lead author of the PNAS

> paper.

>

> The team found that the offspring exhibit the core behavioral symptoms

> associated with autism spectrum disorderÂ¡Xrepetitive or stereotyped

> behaviors, decreased social interactions, and impaired communication. In

> mice, this translates to such behaviors as compulsively burying marbles

> placed in their cage, excessively self grooming, choosing to spend time

> alone or with a toy rather than interacting with a new mouse, or vocalizing

> ultrasonically less often or in an altered way compared to typical mice.

>

> Next, the researchers characterized the immune system of the offspring of

> mothers that had been infected and found that the offspring display a number

> of immune changes. Some of those changes parallel those seen in people with

> autism, including decreased levels of regulatory T cells, which play a key

> role in suppressing the immune response. Taken together, the observed immune

> alterations add up to an immune system in overdriveÂ¡Xone that promotes

> inflammation.

>

> Â¡Â§Remarkably, we saw these immune abnormalities in both young and adult

> offspring of immune-activated mothers,Â¡Â¨ Hsiao says. Â¡Â§This tells us that a

> prenatal challenge can result in long-term consequences for health and

> development.Â¡Â¨

>

> With the mouse model established, the group was then able to test whether

> the offspringÂ¡Â¦s immune problems contribute to their autism-related

> behaviors. In a revealing test of this hypothesis, the researchers were able

> to correct many of the autism-like behaviors in the offspring of

> immune-activated mothers by giving the offspring a bone-marrow transplant

> from typical mice. The normal stem cells in the transplanted bone marrow not

> only replenished the immune system of the host animals but altered their

> autism-like behavioral impairments.

>

> The researchers emphasize that because the work was conducted in mice, the

> results cannot be readily extrapolated to humans, and they certainly do not

> suggest that bone-marrow transplants should be considered as a treatment for

> autism. They also have yet to establish whether it was the infusion of stem

> cells or the bone-marrow transplant procedure itselfÂ¡Xcomplete with

> irradiationÂ¡Xthat corrected the behaviors.

>

> However, says, the results do suggest that immune irregularities

> in children could be an important target for innovative immune manipulations

> in addressing the behaviors associated with autism spectrum disorder. By

> correcting these immune problems, he says, it might be possible to> ameliorate some of the classic developmental delays seen in autism.

>

> In future studies, the researchers plan to examine the effects of highly

> targeted anti-inflammatory treatments on mice that display autism-related

> behaviors and immune changes. They are also interested in considering the

> gastrointestinal (GI) bacteria, or microbiota, of such mice. Coauthor Sarkis

> Mazmanian, a professor of biology at Caltech, has shown that gut bacteria

> are intimately tied to the function of the immune system. He and

> are investigating whether changes to the microbiota of these mice might also

> influence their autism-related behaviors.

>

> ###

> Along with , Hsiao, and Mazmanian, additional Caltech coauthors on

> the PNAS paper, Â¡Â§Modeling an autism risk factor in mice leads to permanent

> immune dysregulation,Â¡Â¨ are Mazmanian lab manager Sara McBride and former

> graduate student Janet Chow. The work was supported by an Autism Speaks

> Weatherstone Fellowship, National Institutes of Health Graduate Training

> Grants, a Weston Havens Foundation grant, a O. and W.

> Caltech Innovation Fellowship, a Caltech Innovation grant, and a

> Congressionally Directed Medical Research Program Idea Development Award.

>

> Source <http://www.eurekalert.org/pub_releases/2012-07/ciot-crf071712.php>

>

> PNAS <http://www.pnas.org/>

> Proceedings of the National Academy of Sciences of the United States of

> America <http://www.pnas.org/>

>

> Skip to main page content

> <http://www.pnas.org/content/early/2012/07/10/1202556109.abstract#content-bl

> ock>

> * Info for Authors <http://www.pnas.org/misc/iforc.shtml>

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> .pnas.org%2Fsite%2Fmisc%2Fpodcasts.shtml>

> * <http://www.pnas.org/content/early/2012/07/10/1202556109.abstract#>

> Modeling an autism risk factor in mice leads to permanent immune

> dysregulation

> 1. Elaine Y. Hsiao

> <http://www.pnas.org/search?author1=Elaine+Y.+Hsiao & sortspec=date & submit=Sub

> mit> 1

> <http://www.pnas.org/content/early/2012/07/10/1202556109.abstract#corresp-1>

> ,

> 2. Sara W. McBride

> <http://www.pnas.org/search?author1=Sara+W.+McBride & sortspec=date & submit=Sub

> mit> ,

> 3. Janet Chow

> <http://www.pnas.org/search?author1=Janet+Chow & sortspec=date & submit=Submit>

> ,

> 4. Sarkis K. Mazmanian

> <http://www.pnas.org/search?author1=Sarkis+K.+Mazmanian & sortspec=date & submit

> =Submit> , and

> 5. H.

> <http://www.pnas.org/search?author1=+H.+ & sortspec=date & submit=S

> ubmit>

> + <http://www.pnas.org/content/early/2012/07/10/1202556109.abstract#>

> Author Affiliations

> 1. Biology Division, California Institute of Technology, Pasadena, CA

> 91125

> 2.

> 3.

> 4. Edited by Carla J. Shatz, Stanford University, Stanford, CA, and

> approved June 19, 2012 (received for review February 15, 2012)

>

> Abstract

> Increasing evidence highlights a role for the immune system in the> pathogenesis of autism spectrum disorder (ASD), as immune dysregulation is

> observed in the brain, periphery, and gastrointestinal tract of ASD

> individuals. Furthermore, maternal infection (maternal immune activation,

> MIA) is a risk factor for ASD. Modeling this risk factor in mice yields

> offspring with the cardinal behavioral and neuropathological symptoms of

> human ASD. In this study, we find that offspring of immune-activated mothers

> display altered immune profiles and function, characterized by a systemic

> deficit in CD4+ TCRÂ£]+ Foxp3+ CD25+ T regulatory cells, increased IL-6 and