Vijendra Singh----IOM Presentation----Autism, Vaccines and Immune Reactions

[Guest guest]

On our web site at http://autismautoimmunityproject.org/

Autism, Vaccines, and Immune Reactions

Vijendra K. Singh, Ph.D.

Research Associate Professor of Neuroimmunology

Department of Biology, Center for Integrated Biosystems

Utah State University

Logan, Utah, USA

1. Introduction

Autism is the fastest-growing developmental disability in children

today. Millions are affected worldwide, and the numbers are rising

sharply to epidemic levels. Autism causes neurological and behavioral

deficits in children, impairing their ability for social interaction,

language, communication, cognition, and imagination. Autism is an

idiopathic disorder of unknown etiology. Current theories include

genetic factors, immune factors, viral factors, neural factors, and yet

other unidentified factors. For last 10-12 years, I focused on

autoimmune mechanism of pathogenesis and autoimmune therapy for patients

affected with the disorder. I started out working on autism with the

idea of Autism as an Autoimmune Disorder and my hope was to use

autoimmunity as a target of drug development for treating autism [1-3].

Indeed, this is happening today [4-6]. In my presentation today, I will

be speaking on the topic of autism, vaccines, and immune reactions and

to examine the possibility of a causal link between vaccines and autism.

I view autism as a very complex disorder with different subsets and one

such subset might be autoimmune in origin. I have studied autism as an

autoimmune disorder, in which viral-autoimmune interplay may lead to

pathological changes in the central nervous system (CNS). The essence of

my Autoimmune Hypothesis is that a virus-induced autoimmune response

to developing brain myelin may impair anatomical development of neural

pathways in autistic children [3,4]. This line of thinking relies on the

fact that the speed of nerve-impulse transmission depends essentially on

structural properties of the insulating myelin sheath, connecting nerve

fibers, and axon diameter. The anatomical changes could ultimately lead

to life-long disturbances of higher mental functions such as learning,

memory, communication, social interaction, etc. Fundamentally,

therefore, I think that autism can be treated successfully using some of

the therapies proven effective in treating other autoimmune diseases. To

that end, however, the complete identification and characterization of

autoimmune pathology in autism is of utmost importance today.

Autoimmune Hypothesis

Environmental Factors (viruses/vaccines) à Immune Dysfunction à

Autoimmunity to Brain à Autism

2. Viruses as causal factors in autism: Measles is likely an etiological

agent.

Leading scientists in the field commonly believe that the viral

infections trigger autoimmune responses and eventually lead to

organ-specific autoimmune diseases. In autism, the trigger mechanism is

not known but viral infections have been suspected. Viruses can enter

the brain through the nasopharyngeal membranes or induce an autoimmune

response against the brain, thereby impact the development of the

central nervous system (CNS). Since the onset of the disorder is quite

early on in life, viruses might serve as teratogens (agents that cause

developmental malfunctions) etiologically linked to autism. Children

with congenital rubella had certain autistic-like behaviors. Some

autistic children did not make antibodies to rubella vaccine even after

the repeated rubella immunization. Few cases of autism have also been

described among children with congenital cytomegalovirus (CMV) infection.

Recently, we took a novel approach of studying viral etiology in autism

[7-9]. We raised two simple questions: First, do autistic children

harbor abnormal virus serology (antibody levels) and, secondly, is there

a correlation between virus serology and brain antibodies. We studied

immune response to viruses by measuring the level of their antibodies.

For this purpose, we measured antibodies to five viruses: Measles virus,

mumps virus, rubella virus, CMV, and human herpesvirus-6 (HHV-6). To our

surprise, we found that the antibody level of only the measles virus,

but not of the other viruses tested, was significantly higher in

autistic children than the normal children [reference #4 and #9; Table 1

and Fig. 1]. In addition, we found an interesting correlation between

measles antibody and brain autoimmunity, which was marked by myelin

basic protein (MBP) antibodies. These two immune markers correlated in

90% or greater autistic children, suggesting a causal link of measles

virus with autoimmunity in autism. But the serology to other viruses and

other brain autoantibodies did not show this correlation. This was a

very important finding that prompted us to postulate a temporal link of

measles virus in the etiology of the disorder [singh et al., 1998;

reference #7]. To that end, it is also noteworthy that the immune

manifestations of measles virus infection are quite similar to the

immune abnormalities in autistic children, indirectly pointing to an

etiological link of measles infection in autism.

Table 1. Viral antibodies in the sera of autistic children

Virus antibody Subject group EIA Units (mean ± SD) p value

CMV-IgG Autistic (n=30) 0.23 ± 0.32 0.37

Normal (n=30) 0.28 ± 0.46

HHV-6-IgG Autistic (n=45) 2.18 ± 5.35 0.459

Normal (n=37) 1.52±0.64

Rubella-IgG Autistic (n=31) 3.59 ± 1.19 0.076

Normal (n=12) 2.90 ± 0.81

Mumps-IgG Autistic (n=30) 2.57 ± 1.50 0.759

Normal (n=32) 2.46 ± 1.31

Measles-IgG Autistic (n=42) 3.83 ± 1.23 0.004

Normal (n=26) 3.08 ± 0.45 (Significant)

Figure 1. Viral antibody levels are shown for measles virus, mumps virus

and rubella virus in autistic children (n=87, dotted bars), normal

children (n=32, solid bars) and siblings of autistic children (n=14,

shaded bars). Note: As evaluated by the Students t test, the measles

antibody level was significantly (p?0.05) increased in autistic children.

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3. Vaccines as risk factors in autism: MMR could potentially cause

autism via an autoimmune mechanism.

Although there is very little experimental data, parents of autistic

children commonly report the onset of autistic characteristics shortly

after immunization with measles-mumps-rubella (MMR) and/or

diphtheria-pertussis-tetanus (DPT) vaccines. This subset is sometimes

referred to as Autistic Regression. This population includes

approximately 85% of autistic children quite commonly with a new

diagnosis of the disorder. The remainder 15% of children either does not

have any history of adverse vaccine reaction or they have diagnosis of

autism without the vaccines. This information, albeit anecdotal, was

quite important when we expanded our investigation further by using the

MMR vaccine (see below).

To examine vaccines as risk factors in autism, we conducted a study of

serology (antibody levels) to three vaccines: MMR, DPT and DT

(diphtheria-tetanus). Once again, we raised the same two questions:

First, do autistic children harbor abnormal vaccine serology (antibody

levels) and, secondly, is there a correlation between vaccine serology

and brain autoantibodies. Through our experimental research [8], we

found that the level of MMR antibodies was significantly higher in

autistic children as compared to normal children or other disease

children [Fig. 2]. Moreover, it is noteworthy that autistic children

exhibited a very high degree of specificity for MMR antibodies, similar

to our previous finding for measles antibodies, which is of paramount

importance in establishing an etiological role of MMR in autism.

Furthermore, we characterized that this abnormal MMR serology was due to

antibodies to measles subunit but not the mumps or rubella subunit of

the trivalent vaccine MMR [8]. The same result was also found when we

used monovalent measles vaccine in lieu of the trivalent MMR vaccine,

furthermore pointing to a problem of only the measles subunit [9]. Once

again, there was a positive correlation (90% or greater) between MMR

antibody and MBP autoantibody [Fig. 3; reference #8]. These findings led

me to speculate that the measles subunit of the MMR vaccine might

trigger an autoimmune reaction in a significant number of autistic

children [7-9]. While more research is necessary, I think this is an

excellent working hypothesis to explain autoimmune subset of autism and

it may also help us understand why some children show autistic

regression after MMR immunization. To that end, it is also important to

note that the MMR vaccine induces a Th-1 cellular response [10], an

immune response that is also found in autistic children [6,11].

Figure 2. MMR antibodies in autism. At four serum dilutions, the MMR

antibody levels are shown for autistic children (n=24, solid circles),

normal children (n=14, solid squares), and other disease children (n=16,

solid triangles). Note: MMR antibody level was significantly (p?0.05)

increased in autistic children.

Figure 3. MMR and MBP antibodies in autistic children. Note that 90% or

more correlation was found between MMR and MBP antibodies in autistic

children (vertical bars) but not in controls that included normal

children (baseline box 1), normal siblings (baseline box 2), and other

disease children (baseline box 3).

__________________________________________

4. Immune reactions in autism: Autoimmunity is the core of the problem.

Several groups have demonstrated abnormal immune reactions, in

particular autoimmunity, in children with autism and related spectrum

disorders. Autoimmunity is an abnormal immune reaction in which the

immune system goes haywire and reacts abnormally against bodys own

organs, and the end result is an autoimmune disease. Several factors

contribute to autoimmune diseases. Microbes such as viruses can trigger

autoimmune diseases. They are generally linked to certain genes that

control immune responses. They cause immune abnormalities of white blood

cells (WBC), in particular that of T cells, B cells and NK cells. They

induce the production of pathogenic antibodies, especially the

organ-specific autoantibodies. They involve hormonal factors. And they

generally show a gender preference. This is also the case with autism,

which means that several autoimmune factors have also been found in

autistic children [for various citations see references 1-9]. Some of

the important autoimmune factors in autism are:

1. Autism is commonly associated with microbial infections, in

particular viral infections.

2. Autistic patients have immune abnormalities, especially those that

characterize an autoimmune reaction in a disease.

3. Autism shows inappropriate immune responses to vaccines, in

particular MMR.

4. Autism displays increased frequency for immune response genes (e.g.,

HLA, C4B null allele or extended haplotypes) that render susceptibility

to autoimmune diseases.

5. Autism involves a gender factor as it affects males about four times

more than females.

6. Autism has a family history of autoimmune diseases such as multiple

sclerosis, rheumatoid arthritis, and diabetes.

7. Autism also involves a hormonal factor, for example secretin and

endorphins.

8. Autistic patients respond well to immune modulation therapy (IMT).

5. Mercury and autism: Mercury is not related to autoimmunity.

Because both autism and mercury exposure involve autoimmunity, mercury

has recently been proposed as an environmental risk factor in autism.

However, the laboratory analysis showed that the blood levels of mercury

do not rise above safe levels in infants and children receiving

thimerosal-containing vaccines [12]. We hypothesized that if autism

involved a connection between mercury exposure and autoimmunity then

autistic children should harbor elevated levels of mercury-induced

autoimmune markers, namely the antinucleolar antibodies and antilaminin

antibodies. So, we recently conducted a pilot study of these two

autoimmune markers in autistic children and normal children. The results

of our experimental study, for the first time, showed that the

distribution of these two markers did not change in autistic children.

Quite plainly, mercury is not a risk factor for autoimmunity in autism

[Our research in progress].

6. Immune Modulation Therapy (IMT) in Autism

Accumulating evidence suggest that autoimmunity plays a key role in the

pathogenesis of autism. The idea that autism is an autoimmune disorder

is further strengthened by the fact that autistic patients respond well

to treatment with immune modulating drugs [4-6]. Immune interventions

can produce immune modulation - a state of suppression or stimulation.

Since autistic patients do not show a classical primary

immunodeficiency, simply boosting their immunity is not a good strategy.

However, they do have immune abnormalities and therefore, depending on

the nature of the immune abnormality, the goal of IMT should be to

normalize or reconstitute the immune function. This will permit a more

balanced immune response, avoiding major fluctuations of overt immune

activity that could be detrimental to the patient. The IMT should always

be given in consultation with a physician, preferably a clinical

immunologist, allergist or hematologist. For autism, the recommended

list of IMT includes steroid therapy, immunoglobulin therapy, oral

autoantigen therapy, transfer factor therapy, immunomodulating drugs,

and plasmapheresis.

7. Summary and concluding remarks

1. Considering an estimated population of 500,000 Americans with autism

(not including all spectrum disorders), I think that between 250,000 to

350,000 autistic patients could benefit directly from autoimmunity

research today.

2. The current genetic research estimates that no more than 10% of all

autistic cases are genetic in origin. Simply put, the remainder 90% of

autistic cases is sporadic with a non-genetic etiology. I tend to think

that the sporadic form is by and large an acquired subset involving

autoimmunity. This subset is likely triggered by a virus, possibly

measles virus or MMR vaccine. I recently designated this subset as an

Autoimmune Autistic Disorder (AAD) - a term coined to describe

autoimmune subset of autism (Singh VK: May 1, 2003). I think that the

autoimmunity research has a global impact for treating autism worldwide

hence the physicians and researchers should pay a closer attention to

autoimmunity research in autism.

3. Based upon our experimental research, it is plausible to postulate

that an atypical measles infection that does not produce a typical

measles rash but manifests neurological symptoms might be etiologically

linked to autoimmunity in autism. The source of measles virus could

potentially be MMR vaccine or a mutant measles strain, but more research

is necessary to establish either of these two possibilities.

4. Fundamentally, I tend to think that autistic children have a problem

of their immune system, which is the faulty immune regulation. Hence

they have abnormal immune reactions to measles virus and/or MMR vaccine.

5. I am a strong advocate of immunization program worldwide, chiefly

because the vaccines are the best preventive measures against deadly

infections available to mankind today. So, I am not an anti-vaccine

person. I do believe however that the safety of vaccines must be as

absolute as humanly possible because they are administered into healthy

children, adults and elderly.

6. To conclude, since everything changes with time, I firmly believe

that it is time to re-evaluate the safety of vaccines and the manner in

which we practice immunizations. Vaccines are well known to cause

numerous adverse reactions in humans and no matter how rare they might

be it is time to pay a closer attention to them. I dont think the

epidemiological studies will suffice the purpose but the

laboratory-based experimental research is urgently needed. We need new

policies simply because the existing policies are not in line with our

modern knowledge of human immunology, virology, and genomics. This is

clearly exemplified by our experimental approach involving laboratory

techniques that did not exist 30-40 years ago when the vaccines were

originally developed. Indeed, there is persuasive evidence to suggest

that the MMR vaccine could potentially cause autism or a regressive form

thereof in a significant number of children. At this juncture, I would

also like to recommend a new policy of Testing immunity before

vaccination or immunization that should help identify immunocompromised

children who otherwise might react adversely to vaccines. The cost

should not deter us from implementing this policy especially when the

lives of hundreds and thousands of children and their families are

concerned.

8. Financial support disclosure

The experimental research in this report was supported by seed grants

and charitable donations from the BHARE, Yorio, Unanue, Mellanby,

Lattner and Dougherty Foundations and the Autism Autoimmunity Project.

There was no conflict of interest between these 501© private

organizations and the principal investigator of this research project.

9. Relevant references

1. Singh VK. Brain, Autoimmunity and autism. Invited presentation at the

Annual Conference of the Long Beach Chapter of Autism Society of America

(ASA), Long Beach, California; October 13-14, 1995.

2. Singh VK, et al. Immunodiagnosis and immunotherapy in autistic

children. Presented at the International Congress of Neuroimmunology,

Philadelphia, Pennsylvania; Sept. 8-11, 1987.

3. Singh VK, et al. Antibodies to myelin basic protein in children with

autistic disorder. Brain Behavior and Immunity 7: 97-103 (1997).

4. Singh VK. Neuro-immunopathogenesis in autism. In: NeuroImmune

Biology: New Foundation of Biology, Vol. 1: 443-454 (2001).

5. Singh VK. Immunotherapy for brain disease and mental illnesses.

Progress in Drug Research 48: 129-146 (1997).

6. Singh VK. Cytokine regulation in autism. In: Cytokines and Mental

Health, Edited by Z. Kronfol (2003) pp. 369-383, Kluwer Acad.

Publishers, Boston, MA.

7. Singh VK, et al. Serological association of measles virus and human

herpesvirus-6 with brain autoantibodies in autism. Clin. Immunol.

Immunopathol. 89: 105-108 (1998).

8. Singh VK, et al. Abnormal measles-mumps-rubella antibodies and

autoimmunity in children with autism. Journal of Biomedical Science 9:

359-364 (2002).

9. Singh VK and Jensen RL. Elevated levels of measles antibodies in

children with autism. Pediatric Neurology 28: 292-294 (2003).

10. Pabst HF, et al. Kinetics of immunologic responses after primary MMR

vaccination. Vaccine 15: 10-14 (1997).

11. Singh VK. Plasma increase ofinterleukin-12 and interferon-gamma:

Pathological significance in autism. Journal of Neuroimmunology 66:

143-145 (1996).

12. Pichichero ME, et al. Mercury concentrations and metabolism in

infants receiving vaccines containing thiomersal: a descriptive study.

Lancet 360: 1737-1741 (2001).

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