IMMUNE RESPONSE TO BRAIN MYELIN IN
AUTISTIC CHILDREN
by Vijendra K. Singh, Reed P. Warren, Dennis Odell
Utah State University, July 1992

Autism is generally believed to be a behavioral syndrome that includes abnormalities of language and thinking skills; repetitive behavior such as rocking; abnormal
responses to sensations, people, events and objects; and self- injurious behavior. What causes the syndrome is not known. A few years ago, we hypothesized that
one possible cause of autism may involve faulty immune regulation, in particular, autoimmunity ( 1,2 ). To further understand the role of immune factors, we have
recently studied immune response ( or antibodies ) to myelin basic protein ( MBP ), which is a protein component of the brain myelin. The myelin is a covering sheath
that is necessary for the normal flow of nerve impulses from one nerve cell to another, and defects in this function would dramatically alter brain activity and behavior.
In this study, the testing of 33 autistic children ( less than or equal to 10 years of age ) was compared with that of 18 age- matched normal children. The diagnosis of
autism was made by at least one pediatric psychiatrist and one clinical child psychologist using the DSM-III-R guidelines of the American Psychiatric Association,
Washington, D.C. Since nearly 60% of autistic children show mental retardation ( MR ) ( IQ of 70 or lower ), 20 children with MR due to unknown causes and 12
children with Down syndrome ( DS ) were also studied as the disease controls. From each donor a blood sample ( 5 ml ) was drawn and the serum separated from
the blood cells. The testing for serum antibodies to MBP was performed with the technique of protein-immunoblotting. When the serum contained antibodies to
MBP, a positive reaction was seen by a protein band. Screening for these antibodies showed that they were found in 19 of 33 ( 58% ) sera from autistic children as
compared to only 7 of 50 ( 7% ) sera from the control children. This result indicated that the autistic children have about 8.3 times greater incidence of antibodies to
MBP than the control children. Since none of the 12 DS children and only 3 of 20 MR children showed this antibody- positive reaction, it may be concluded that the
mental retardation in autistic children is not related to the production of antibodies to MBP.
Immunological testing of autistic children has shown certain features that are also found in patients with autoimmune diseases such as systemic lupus erythematosus (
SLE ), thyroid disease ( TD ), ankylosing spondylitis ( AS ), rheumatoid arthritis ( RA ), insulin-dependent diabetes ( IDD ), and multiple sclerosis ( MS ). These are:
( a ) genetic predisposition-autism shows a greater concordance rate in monozygotic twins than in the normal population; ( b ) gender factor-autism is 4 or 5 times
more common in boys than in girls; ( c ) triggering by microorganisms-rubella virus and cytomegalovirus infections have been indirectly linked to autism; ( d ) maternal
factors-maternal antibodies in autism were detected by us ( 3 ); ( e ) major histocompatibility ( MHC ) association- autism displays genetic linkage with
immunogenetic factors located on chromosome 6, as recently discovered by our group ( 4 ); and ( f ) immune activation-this was recently observed by us in autism (
5 ). Taken collectively, the aforementioned parallels between autism and other autoimmune diseases suggest that autoimmunity may be a critical factor in the cause of
autism. An essential part of the autoimmune mechanism should involve antibody-mediated immune response or antibodies against brain, the affected organ in autism.
In this respect, a few recent studies in autism have found evidence of antibodies to brain tissue antigens, e.g., MBP ( this report ), neurofilament proteins ( 2 ), and
serotonin receptor ( 6; our unpublished data ). Antibodies to MBP may have some pathological relevance since abnormal cell-mediated immune response ( involving
a soluble factor but not antibodies ) to this protein was previously detected by another group of researchers ( 7 ), suggesting that autistic children somehow develop
inappropriate immune responses to this brain protein. Brain-reactive antibodies and the increased serum levels of IgG3 antibody ( 8 ), which selectively activates
complement function via classical pathway ( another type of immunity ), could be an important first step in the activation of complement-mediated nerve cell damage,
thereby altering their ability to perform normal function of nerve impulse transmission. Despite numerous behavioral problems, research into the brains of autistic
children has been hampered by the lack of available brain biopsies or autopsies. Based on a very limited number of case studies, anatomical abnormalities in certain
parts of the brain have been found, but the findings are not suffiently consistent to permit any firm conclusion. While the pathological data are scarce, we know
virtually nothing about the neurochemistry ( neurotransmitter function ) of the autistic brain. Whatever the pathological abnormalities might be, it is generally believed
that the anatomical defects are the results of abnormal development rather than damage following full development of the brain in autistic children ( 9 ). At present,
the relationship between antibodies to MBP and autism is not understood. However, we hypothesize that the development of this immune response may be the basis
of autoimmune pathogenesis in some cases of autism. At birth, there is very little myelin in the brain, and the synthesis of myelin may not be complete until the age of
10 years or older in the normal child ( 10 ). Moreover, it has been suggested that some children with learning disabilities ( LD ) may have delayed or incomplete
myelin development ( 11 ). In light of the above, it is conceivable that if an immunological assault were to occur before birth or during infancy or childhood, it could
lead to poor myelin development or abnormal function of the nerve fiber myelin. This line of thinking, as we postulate in this report, may be an important step in the
future understanding of the pathological basis of autism. ( We thank Mrs. Edith Singh for her skilled technical assistance. This study was supported by grants from the
National Institute of Mental Health and the Willard L. Eccles Charitable Foundation. ) REFERENCES ( 1 ) Warren,R.P.,et.al., Immune abnormalities in patients
with autism. J. Aut. Devlopm. Disord. 16:189-197 ( 1986 ). ( 2 ) Singh,V.K.,et.al., Immunodiagnosis and immunotherapy in autistic children. Ann. N Y Acad Sci
540:602-604 ( 1988 ). ( 3 ) Warren,R.P.,et.al., Detection of maternal antibodies in infantile autism. J. Am. Acad. Child. Adolesc. Psychiat. 29:873-877 ( 1990 ). (
4 ) Warren,R.P.,et.al., Possible association of the extended MHC haplotype B44-SC30-DR4 with autism. Immunogenetics ( 1992, in press ). ( 5 )
Singh,V.K.,et.al., Changes of soluble interleukin-2, interleukin-2 receptor, t8 antigen, and interleukin- 1 in the serum of autistic children. Clin. Immunol.
Immunopathol. 61:448-455 ( 1991 ). ( 6 ) Todd,R.D. and Ciarnello,R.D., Demonstration of inter- and intraspecies differences in serotonin binding sites by
antibodies from an autistic child. Proc. Natl. Acad. Sci., USA 82:612-616 ( 1985 ). ( 7 ) Weizman,A.,et.al., Abnormal immune response to brain tissue antigen in
the syndrome of autism. Am. J. Psychiat. 7:1462-1465 ( 1982 ). ( 8 ) Singh,V.K.,et.al., Abnormalities of interleukin-2 production and levels of IgG isotypes in
autistic patients. The FASEB J. 3:A496 ( 1989 ). ( 9 ) Bauman,M.L., Microscopic neuroanatomic abnormalities in autism. Pediatrics ( Suppl. ) 87:791-796 ( 1991
). (10) Trevarthen,C., Cerebal embryology and the split brain. In: Hemispheric Disconnection and Cerebral Function ( M. Kinsbourne & W. Smith,eds. ). pp.
208-236 (1974), Charles C. Thomas Publ., Springfield, Ill. (11) Musiek,F.E.,et.al., Myelination of the corpus callosum and auditory processing problems in children:
theoretical and clinical correlates. Seminars in Hearing 5:231-241 ( 1989 ).

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Brief excerpt:


Immunological testing of autistic children has shown certain features that are also found in patients with autoimmune diseases such as systemic lupus erythematosus (
SLE ), thyroid disease ( TD ), ankylosing spondylitis ( AS ), rheumatoid arthritis ( RA ), insulin-dependent diabetes ( IDD ), and multiple sclerosis ( MS ). These are:
( a ) genetic predisposition-autism shows a greater concordance rate in monozygotic twins than in the normal population;
( b ) gender factor-autism is 4 or 5 times more common in boys than in girls;
( c ) triggering by microorganisms-rubella virus and cytomegalovirus infections have been indirectly linked to autism;
( d ) maternal factors-maternal antibodies in autism were detected by
us (3);
( e ) major histocompatibility ( MHC ) association- autism displays genetic linkage with immunogenetic factors located on chromosome 6, as recently discovered by our group ( 4 ); and
( f ) immune activation-this was recently observed by us in autism (5 ). Taken collectively, the aforementioned parallels between autism and other autoimmune diseases suggest that autoimmunity may be a critical factor in the cause of autism.

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