RE: Re: immune dysr. in autism

[Guest guest]

Not - but I did genetic testing on my son and it showed normal

IL-10, but a double mutation on IL-6. I am assuming this was a genetic

test ?

Re: immune dysr. in autism

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

>

>

>