Re: immune dysr. in autism

[Guest guest]

My son has one mutation on each the following TH-2 Cytokines: IL-4. IL-6 and

IL-10, similar to what the article states.

-

Doris and Steve <sjsmith@...> wrote:

Study Finds Children with Autism Have More Active Adaptive Immune System

New Research May Also Identify Potential Mechanism for Immune

Dysregulation in Autism

With support from Cure Autism Now, a study recently published in the

Journal of Neuroimmunology has found that children with autism have a

more active immune system. The research, led by Molloy, MD, also

identified a potential mechanism for this immune dysregulation. The

authors suggest that a cytokine called interleukin-10 (IL-10) could be a

key part of the mechanism that leads to alterations in the adaptive

immune response in individuals with autism. This new finding about the

role of IL-10 provides another piece of the puzzle in understanding the

complex nature of immune dysfunction in autism.

As early as the 1970's, immunological factors were identified in autism.

Over time, a growing body of evidence has indicated a role of immune

dysfunction in individuals with autism, but the exact nature is not

fully clear, and no causal function has been established. One potent

area of research has been the study of cytokines, chemicals in the body

that serve as signaling molecules and play a crucial role in mediating

specific types of immune responses. Cytokines are essential components

of both the innate immune system (immune defense mechanisms that are the

first line of defense against any kind of invading substance, and

present from birth) and the adaptive immune system (immune defense

mechanisms that develop in response to specific invading substances,

built up as immunities to infection from diseases we have been exposed

to over our lifetimes.) These important messengers control the strength,

length, and direction of immune responses, and are essential in

regulating the repair of tissue after injury. The many individual

cytokines play different roles; some act as stimulators of immune system

activation, while others provide inhibitory functions. Together, the

various cytokines work in an intricately coordinated system, the success

of which is dependent on their well-timed production by the various cell

types of the immune system.

Interested in the impact of immune regulation on the development of

autism, in 2003 Dr. Molloy received a pilot project grant from CAN. Dr.

Molloy is an Assistant Professor of Pediatrics at the Center for

Epidemiology and Biostatistics at Cincinnati Children's Hospital Medical

Center, and is also the mother of a 13 year-old daughter with autism.

While she began her career in pediatric emergency medicine, the emphasis

of her work changed in 1999, when Dr. Molloy started a research

fellowship in developmental disabilities at Cincinnati Children's

Hospital Medical Center. She joined the faculty in 2003, where her

research currently focuses on immune phenotypes and the contribution of

genes on chromosome 21 to autism. Dr. Molloy highlights the benefits of

teamwork at Cincinnati Children's Hospital, where she works closely with

Marsha Wills-Karp, Ph.D. " I have been fortunate to collaborate with an

exceptional immunobiologist to work on understanding the extent to which

the immune system contributes to the pathogenesis of autism. "

In this study, Dr. Molloy and her colleagues were interested in the

levels of certain cytokines that are produced by a specific type of

immune cell in the adaptive immune system, called helper T cells (T

cells are a type of white blood cell). Helper T cells contribute to the

immune response by promoting the production of other types of T and

immune cells. The research team studied two types of helper T cells that

work as a system: Th1 and Th2. Under normal circumstances, the Th1 and

Th2 systems balance one another by inhibiting each other's activity.

Each type of helper T cell produces different kinds of cytokines, with

the T cell types defined by the cytokines they produce. These cytokines

are termed interferons and interleukins, and the research group

concentrated on a certain subset. Within the Th1 system, the dominant

cytokine is interferon gamma (IFN-gamma), which is responsible primarily

for reactions against viruses and intra-cellular microbes, and is

pro-inflammatory. Among others, Th2 cells produce interleukins IL-4,

IL-5, and IL-13. These interleukins are important for stimulating

production of antibodies (immune proteins that identify specific foreign

substances for destruction) and often have multiple functions. As part

of the Th2 system, IL-4 and IL-13 are primarily anti-inflammatory (by

inhibiting Th1 cells), but they also promote the growth and

differentiation of other immune cells. IL-4 also has the very important

role of producing the regulatory cytokine IL-10, which helps maintain

the balance between the Th1- and Th2- produced cytokines.

Historically, the role of cytokines in the immune system dysregulation

observed in studies of individuals with autism has not been conclusive,

because different patterns of cytokine activation have been found. Some

studies of the adaptive immune system in autistic individuals have shown

that the cytokines of the Th1 cells are elevated, while other studies

have found elevations in the cytokines of the Th2 system. Interestingly,

a study of patient registries in Europe found that many individuals

suffered from both allergies (generally Th2 driven) and autoimmune

disorders (generally Th1 driven). Typically, autoimmune diseases and

allergies are not seen together in an individual, because both Th

systems are not usually overactive at the same time. One goal of Dr.

Molloy's study was to determine if direct measures of the cytokine

levels themselves (as opposed to measures of the allergic/autoimmune

disorders produced by imbalances in these systems) would show the same

simultaneous hyper-activation in individuals with autism.

To examine the adaptive immune system, Dr. Molloy's team measured

cytokine production of children's immune cells in a cell culture, both

at a baseline level and after stimulation by an allergen and a toxin.

The team compared individual cytokine levels in blood samples from

twenty children with autism and twenty unaffected controls matched on

the basis of age, race, gender and date of study visit; this careful

one-to-one matching was important for controlling some of the

variability that has made previous studies of immune function in autism

hard to interpret.

At baseline, the researchers found that immune cells of children with

autism produced higher levels of both the Th1 and Th2 cytokines,

including IFN-gamma and IL-4, -5, -13, than the cells cultured from the

control group. In contrast, in the experiment using stimulation by an

allergen or toxin, there was no difference between cases and controls,

indicating that the cells in both groups were equally capable of

producing the cytokines and generating an immune response.

These findings demonstrate that, in children with autism, both the Th1

and Th2 cytokines are more highly activated in the immune system's

resting state, indicating potential underlying hypersensitivity to

exposures in the general environment. Dr. Molloy's study shows that

immune dysregulation is found in the adaptive immune system, as has been

previously shown for the innate immune system, confirming that children

with autism exhibit hyper-sensitivity in both innate and adaptive

systems. Dr. Molloy's research has found increases in both pro- and

anti- inflammatory cytokines in the Th1 and Th2 system which is

indicative of dysregulation in the two systems. Instead of focusing on

the exact role of the anti- or pro- inflammatory cytokines, the study

highlights the importance of balanced regulation between these two

systems in the adaptive immune system.

In an intriguing twist, although baseline levels of almost all the

cytokines measured were higher in children with autism than in control

individuals, Dr. Molloy found an exception in the relatively lower

levels of the critical regulatory cytokine, IL-10, in individuals with

autism. If both Th1 and Th2 cells are just generally overactive in

individuals with autism, elevated IL-10 production would have been

predicted as well. Dr. Molloy explains that " it is unusual to see both

the Th1 and Th2 arms of the adaptive immune response so active at the

same time; it is even more unusual to see this increased activation

without a proportional increase in the regulatory cytokine IL-10, which

is involved in Th1 and Th2 system regulation. " Although previous

research has shown that IL-10 regulates the Th1 and Th2 systems, the

exact mechanisms contributing to the balance within the two systems is

currently not known. Dr. Molloy proposes that " many of the paradoxical

findings that have been reported about immune responses in autism could

possibly be explained by the general dysfunction of IL-10. " The finding

that IL-10 levels were not elevated in individuals with autism, even

when the levels of both Th1 and Th2 cytokines were elevated, suggests

that the immune response dysfunction seen in autism may be a problem

with regulating the cytokine system. Dr. Molloy hypothesizes that

" children with autism may not be able to down-regulate their Th1 and Th2

systems " either because of a dysfunction in the production of IL-10 or

because of a dysfunction with the activity of IL-10 itself.

Dr. Molloy's research contributes a crucial piece of information to the

ability to determine how these cytokines function within the complex

interactions of an adaptive immune system response. Further study of

IL-10 is needed to determine how it contributes to the balance between

the Th1 and Th2 systems. Therefore, Dr. Molloy plans to follow-up her

CAN-funded project with a study that investigates the function of IL-10,

as well as Transforming Growth Factor (TGF ), another regulatory

cytokine shown to mediate the balance of the Th1 and Th2 systems through

unknown mechanisms.

Dr. Molloy's research is complemented by other CAN-funded projects which

are currently examining cytokine activity. A 2006 CAN pilot project by

Ashwood, Ph.D. from the University of California, will

examine plasma cytokine levels in autistic individuals, in order to

develop an immunological marker that can be used as a diagnostic

bio-marker. In his study, Dr. Ashwood will measure several types of

cytokines and compare their levels of production in typically developing

children and in autistic children who have different clinical and

behavioral symptoms. Dr. Ashwood's study may help define phenotypic

subgroups within the spectrum and explain why we see different patterns

of cytokine elevation in different studies. In addition, several other

CAN-funded researchers are studying how elevated cytokine levels in the

blood may affect brain development. Boulanger, Ph.D. of the

University of California, San Diego is examining the effects of

cytokines on the expression of immune genes in the brain, and CAN

Scientific Advisory Board member , Ph.D. of the California

Institute of Technology is examining how a maternal infection during

pregnancy may alter cytokine levels and contribute to development of autism.

Cytokines, and the immune system overall, may play a very important role

in the development of autism. These cellular and molecular studies are

vital, both for identifying the function of cytokines in autistic

individuals and for understanding how the cells that produce these

cytokines may play a factor in immune dysfunction. A better

understanding of underlying biology can inform studies examining how

these structures contribute to the immune impairments that are observed

in individuals with autism. Dr. Molloy emphasizes this point, " If the

cells that contribute to the dysregulation can be identified, then from

this, models can be developed that identify how these cells work in the

active immune system to give rise to the dysregulation in autism. " Such

studies are also critical to the development of treatments. By

documenting specific changes in the immune system and when they might

occur, these researchers studying the immune system can provide the

foundation for the development of preventive measures and treatments

that can target the dysfunctions in the underlying biology.

Reference: Molloy, C., Morrow, A., Meinzen-Derr, J., Schleifer, K.,

Dienger, K., Manning-, P., Altaye, M., & Wills-Karp, M. (2006).

Elevated cytokine levels in children with autism spectrum disorder.

Journal of Neuroimmunology, 172, 198-205

[Guest guest]

that is very interesting..what were the specific tests you did

to determine this?

thanks

> Study Finds Children with Autism Have More Active Adaptive

Immune System

>

> New Research May Also Identify Potential Mechanism for Immune

> Dysregulation in Autism

>

> With support from Cure Autism Now, a study recently published in

the

> Journal of Neuroimmunology has found that children with autism

have a

> more active immune system. The research, led by Molloy,

MD, also

> identified a potential mechanism for this immune dysregulation.

The

> authors suggest that a cytokine called interleukin-10 (IL-10)

could be a

> key part of the mechanism that leads to alterations in the

adaptive

> immune response in individuals with autism. This new finding about

the

> role of IL-10 provides another piece of the puzzle in

understanding the

> complex nature of immune dysfunction in autism.

>

> As early as the 1970's, immunological factors were identified in

autism.

> Over time, a growing body of evidence has indicated a role of

immune

> dysfunction in individuals with autism, but the exact nature is

not

> fully clear, and no causal function has been established. One

potent

> area of research has been the study of cytokines, chemicals in the

body

> that serve as signaling molecules and play a crucial role in

mediating

> specific types of immune responses. Cytokines are essential

components

> of both the innate immune system (immune defense mechanisms that

are the

> first line of defense against any kind of invading substance, and

> present from birth) and the adaptive immune system (immune defense

> mechanisms that develop in response to specific invading

substances,

> built up as immunities to infection from diseases we have been

exposed

> to over our lifetimes.) These important messengers control the

strength,

> length, and direction of immune responses, and are essential in

> regulating the repair of tissue after injury. The many individual

> cytokines play different roles; some act as stimulators of immune

system

> activation, while others provide inhibitory functions. Together,

the

> various cytokines work in an intricately coordinated system, the

success

> of which is dependent on their well-timed production by the

various cell

> types of the immune system.

>

> Interested in the impact of immune regulation on the development

of

> autism, in 2003 Dr. Molloy received a pilot project grant from

CAN. Dr.

> Molloy is an Assistant Professor of Pediatrics at the Center for

> Epidemiology and Biostatistics at Cincinnati Children's Hospital

Medical

> Center, and is also the mother of a 13 year-old daughter with

autism.

> While she began her career in pediatric emergency medicine, the

emphasis

> of her work changed in 1999, when Dr. Molloy started a research

> fellowship in developmental disabilities at Cincinnati Children's

> Hospital Medical Center. She joined the faculty in 2003, where her

> research currently focuses on immune phenotypes and the

contribution of

> genes on chromosome 21 to autism. Dr. Molloy highlights the

benefits of

> teamwork at Cincinnati Children's Hospital, where she works

closely with

> Marsha Wills-Karp, Ph.D. " I have been fortunate to collaborate

with an

> exceptional immunobiologist to work on understanding the extent to

which

> the immune system contributes to the pathogenesis of autism. "

>

> In this study, Dr. Molloy and her colleagues were interested in

the

> levels of certain cytokines that are produced by a specific type

of

> immune cell in the adaptive immune system, called helper T cells

(T

> cells are a type of white blood cell). Helper T cells contribute

to the

> immune response by promoting the production of other types of T

and

> immune cells. The research team studied two types of helper T

cells that

> work as a system: Th1 and Th2. Under normal circumstances, the Th1

and

> Th2 systems balance one another by inhibiting each other's

activity.

> Each type of helper T cell produces different kinds of cytokines,

with

> the T cell types defined by the cytokines they produce. These

cytokines

> are termed interferons and interleukins, and the research group

> concentrated on a certain subset. Within the Th1 system, the

dominant

> cytokine is interferon gamma (IFN-gamma), which is responsible

primarily

> for reactions against viruses and intra-cellular microbes, and is

> pro-inflammatory. Among others, Th2 cells produce interleukins IL-

4,

> IL-5, and IL-13. These interleukins are important for stimulating

> production of antibodies (immune proteins that identify specific

foreign

> substances for destruction) and often have multiple functions. As

part

> of the Th2 system, IL-4 and IL-13 are primarily anti-inflammatory

(by

> inhibiting Th1 cells), but they also promote the growth and

> differentiation of other immune cells. IL-4 also has the very

important

> role of producing the regulatory cytokine IL-10, which helps

maintain

> the balance between the Th1- and Th2- produced cytokines.

>

> Historically, the role of cytokines in the immune system

dysregulation

> observed in studies of individuals with autism has not been

conclusive,

> because different patterns of cytokine activation have been found.

Some

> studies of the adaptive immune system in autistic individuals have

shown

> that the cytokines of the Th1 cells are elevated, while other

studies

> have found elevations in the cytokines of the Th2 system.

Interestingly,

> a study of patient registries in Europe found that many

individuals

> suffered from both allergies (generally Th2 driven) and autoimmune

> disorders (generally Th1 driven). Typically, autoimmune diseases

and

> allergies are not seen together in an individual, because both Th

> systems are not usually overactive at the same time. One goal of

Dr.

> Molloy's study was to determine if direct measures of the cytokine

> levels themselves (as opposed to measures of the

allergic/autoimmune

> disorders produced by imbalances in these systems) would show the

same

> simultaneous hyper-activation in individuals with autism.

>

> To examine the adaptive immune system, Dr. Molloy's team measured

> cytokine production of children's immune cells in a cell culture,

both

> at a baseline level and after stimulation by an allergen and a

toxin.

> The team compared individual cytokine levels in blood samples from

> twenty children with autism and twenty unaffected controls matched

on

> the basis of age, race, gender and date of study visit; this

careful

> one-to-one matching was important for controlling some of the

> variability that has made previous studies of immune function in

autism

> hard to interpret.

>

> At baseline, the researchers found that immune cells of children

with

> autism produced higher levels of both the Th1 and Th2 cytokines,

> including IFN-gamma and IL-4, -5, -13, than the cells cultured

from the

> control group. In contrast, in the experiment using stimulation by

an

> allergen or toxin, there was no difference between cases and

controls,

> indicating that the cells in both groups were equally capable of

> producing the cytokines and generating an immune response.

>

> These findings demonstrate that, in children with autism, both the

Th1

> and Th2 cytokines are more highly activated in the immune system's

> resting state, indicating potential underlying hypersensitivity to

> exposures in the general environment. Dr. Molloy's study shows

that

> immune dysregulation is found in the adaptive immune system, as

has been

> previously shown for the innate immune system, confirming that

children

> with autism exhibit hyper-sensitivity in both innate and adaptive

> systems. Dr. Molloy's research has found increases in both pro-

and

> anti- inflammatory cytokines in the Th1 and Th2 system which is

> indicative of dysregulation in the two systems. Instead of

focusing on

> the exact role of the anti- or pro- inflammatory cytokines, the

study

> highlights the importance of balanced regulation between these two

> systems in the adaptive immune system.

>

> In an intriguing twist, although baseline levels of almost all the

> cytokines measured were higher in children with autism than in

control

> individuals, Dr. Molloy found an exception in the relatively

lower

> levels of the critical regulatory cytokine, IL-10, in individuals

with

> autism. If both Th1 and Th2 cells are just generally overactive

in

> individuals with autism, elevated IL-10 production would have been

> predicted as well. Dr. Molloy explains that " it is unusual to see

both

> the Th1 and Th2 arms of the adaptive immune response so active at

the

> same time; it is even more unusual to see this increased

activation

> without a proportional increase in the regulatory cytokine IL-10,

which

> is involved in Th1 and Th2 system regulation. " Although previous

> research has shown that IL-10 regulates the Th1 and Th2 systems,

the

> exact mechanisms contributing to the balance within the two

systems is

> currently not known. Dr. Molloy proposes that " many of the

paradoxical

> findings that have been reported about immune responses in autism

could

> possibly be explained by the general dysfunction of IL-10. " The

finding

> that IL-10 levels were not elevated in individuals with autism,

even

> when the levels of both Th1 and Th2 cytokines were elevated,

suggests

> that the immune response dysfunction seen in autism may be a

problem

> with regulating the cytokine system. Dr. Molloy hypothesizes that

> " children with autism may not be able to down-regulate their Th1

and Th2

> systems " either because of a dysfunction in the production of IL-

10 or

> because of a dysfunction with the activity of IL-10 itself.

>

> Dr. Molloy's research contributes a crucial piece of information

to the

> ability to determine how these cytokines function within the

complex

> interactions of an adaptive immune system response. Further study

of

> IL-10 is needed to determine how it contributes to the balance

between

> the Th1 and Th2 systems. Therefore, Dr. Molloy plans to follow-up

her

> CAN-funded project with a study that investigates the function of

IL-10,

> as well as Transforming Growth Factor (TGF ), another regulatory

> cytokine shown to mediate the balance of the Th1 and Th2 systems

through

> unknown mechanisms.

>

> Dr. Molloy's research is complemented by other CAN-funded projects

which

> are currently examining cytokine activity. A 2006 CAN pilot

project by

> Ashwood, Ph.D. from the University of California, will

> examine plasma cytokine levels in autistic individuals, in order

to

> develop an immunological marker that can be used as a diagnostic

> bio-marker. In his study, Dr. Ashwood will measure several types

of

> cytokines and compare their levels of production in typically

developing

> children and in autistic children who have different clinical and

> behavioral symptoms. Dr. Ashwood's study may help define

phenotypic

> subgroups within the spectrum and explain why we see different

patterns

> of cytokine elevation in different studies. In addition, several

other

> CAN-funded researchers are studying how elevated cytokine levels

in the

> blood may affect brain development. Boulanger, Ph.D. of the

> University of California, San Diego is examining the effects of

> cytokines on the expression of immune genes in the brain, and CAN

> Scientific Advisory Board member , Ph.D. of the

California

> Institute of Technology is examining how a maternal infection

during

> pregnancy may alter cytokine levels and contribute to development

of autism.

>

> Cytokines, and the immune system overall, may play a very

important role

> in the development of autism. These cellular and molecular studies

are

> vital, both for identifying the function of cytokines in autistic

> individuals and for understanding how the cells that produce these

> cytokines may play a factor in immune dysfunction. A better

> understanding of underlying biology can inform studies examining

how

> these structures contribute to the immune impairments that are

observed

> in individuals with autism. Dr. Molloy emphasizes this point, " If

the

> cells that contribute to the dysregulation can be identified, then

from

> this, models can be developed that identify how these cells work

in the

> active immune system to give rise to the dysregulation in

autism. " Such

> studies are also critical to the development of treatments. By

> documenting specific changes in the immune system and when they

might

> occur, these researchers studying the immune system can provide

the

> foundation for the development of preventive measures and

treatments

> that can target the dysfunctions in the underlying biology.

> Reference: Molloy, C., Morrow, A., Meinzen-Derr, J., Schleifer,

K.,

> Dienger, K., Manning-, P., Altaye, M., & Wills-Karp, M.

(2006).

> Elevated cytokine levels in children with autism spectrum

disorder.

> Journal of Neuroimmunology, 172, 198-205

>

>

>