FINDING IN IMMUNOLOGY

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  source : http://www.taap.info/immunology.htm


Dr. V. K. Singh received his doctorate from the University of British Columbia, Vancouver, Canada. His post-doctoral fellowship was completed in neurochemistry and neuroimmunology. Spanning over twenty years’ experience in neurobiology and immunology research, Dr. Singh studied brain diseases, particularly infantile autism and Alzheimer’s disease. Having authored over a hundred scientific publications, he is both a pioneer and an international authority on autoimmunity in autism. Dr. Singh is a member of the American Association for the Advancement of Sciences, the American Association of Immunologists, and the New York Academy of Sciences. He is listed in American Men and Women in Science (United States, R. R. Bowker, publisher) and The International Who’s Who of Intellectuals (Cambridge, England, International Biographical Centre).

 

Selected Research on Autism

Serological Detection of Measles Virus in Relation to Autoimmunity in Autism,” 102nd General Meeting of the American Society for Microbiology, May 19-23, 2002, Salt Lake City, Utah, Presentation V-5.  Autoimmunity to brain myelin protein (MBP) secondary to a measles infection may cause autistic regression in some children with this neurodevelopmental disorder. …there is a strong correlation between MMR antibodies and MBP autoantibodies in autism.  By using monoclonal antibodies, we characterized that the MMR antibodies are due to the measles subunit, but not due to mumps or rubella subunits, of the polyvalent vaccine.  In light of the new evidence presented here, we suggest that the MMR vaccine in some cases of autism might cause autoimmunity and it might do so by bringing on an atypical measles infection that does not produce a typical measles rash but manifests neurological symptoms upon immunization.  It is confirmed here (in an additional population) that this antibody is not typically produced during normal immune response to the vaccine.

Abnormal Measles Serology and Autoimmunity in Autistic Children,Journal of Allergy and Clinical Immunology, vol. 109, no. 1, S232, January 2002 (abstract #702).  Immunoblotting analysis in recent work showed the presence of an unusual MMR antibody in 60% (75 of 125) of autistic children, but in none of 92 normal children.  By using MMR blots and monoclonal antibodies, we found that the specific increase of MV antibodies or MMR antibodies was related to measles hemagglutinin antigen (MV-HA), but not to the mumps or rubella viral proteins within the MMR vaccine. In addition, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a causal association between MMR and brain autoimmunity in autism.  Stemming from this evidence, we suggest that an “atypical” measles infection in the absence of a rash but with neurological symptoms might be etiologically linked to autoimmunity in autism.

Serological Association of Measles Virus and Human Herpesvirus-6 With Brain Autoantibodies in Autism.” Clinical Immunology and Immunopathology, vol. 89, number 1, October 1998, pp. 105-8. This study is the first to report an association between virus serology and brain autoantibody in autism; it supports the hypothesis that a virus-induced autoimmune response may play a causal role in autism.

Positive Titers of Measles and Measles-Mumps-Rubella Antibody Are Related to Myelin Basic Protein Autoantibody in Autism.” Abstract of study prepared for the annual meeting of the American Association of Immunologists (AAI) / Federation of American Societies for Experimental Biology (FASEB), San Francisco, April 1998. A significant number of autistic children exhibit positive titers of measles and MMR [measles-mumps-rubella] antibody, which in a vast majority of cases is associated with the presence of MBP [myelin basic protein, or brain] autoantibody. A measles- and/or MMR-triggered autoimmune response to myelin may play a pathogenesis role in autism.

Association of Anti-MBP and Anti-NAFP Antibodies With HHV-6 Antibodies in a Child With Autism Regression.” Journal of Allergy and Clinical Immunology, vol. 101, no. 1, part 2, S122, January 1998 (in section entitled, “Program and Abstracts of Papers to Be Presented During Scientific Sessions [at the] 54th Annual Meeting, March 13-18, 1998”).  Children with autism have been shown to have a high incidence of circulating autoantibodies to myelin basic protein (MBP) and to neuron-axon filament protein (NAFP) compared with healthy controls or controls with other disabilities.  Subacute viral infections of the central nervous system have been postulated to play a role in children who develop normally before undergoing autistic regression.  In this instance, a healthy boy having a typical case of roseola (HHV-6) at 15 months experienced severe regressions of language and social behavior soon afterward.  “The presence of antibodies against MBP and NAFP along with the clinical course and elevated levels of HHV-6 antibodies suggest an autoimmune response to this neurotropic virus[,] resulting in the autistic regression.”

Circulating Autoantibodies to Neuronal and Glial Filament Proteins in Autism.” Pediatric Neurology, vol. 17, number 1, July 1997, pp. 88-90. A significant increase in incidence of anti-NAFP [neuron-axon-filament-protein] and anti-GFAP was seen in autistic subjects, but not in mentally retarded subjects. Clinically, these autoantibodies may be related to autoimmune pathology in autism.

Hyperserotoninemia and Serotonin Receptor Antibodies in Children With Autism but Not Mental Retardation.” Biological Psychiatry, vol. 41, number 6, March 15, 1997, pp. 753-5.

Elevated Serotonin Levels in Autism: Association With the Major Histocompatibility Complex.” Neuropsychobiology, vol. 34, number 2, 1996, pp. 72-5. Two of the most consistently observed biological findings in autism are increased serotonin levels in the blood and immunological abnormalities (including autoreactivity with tissues of the central nervous system). The major histocompatibility complex (MHC) regulates the immune system, and is associated with autoimmune disorders. In this study, a positive relationship was observed between elevated serotonin levels and the MHC types previously associated with autism.

Plasma Increase of Interleukin-12 and Interferon-gamma. Pathological Significance in Autism.Journal of Neuroimmunology, vol. 66, numbers 1-2, May 1996, pp. 143-5. Immune factors such as autoimmunity have been implicated in the genesis of autism, a neurodevelopmental disorder. Since autoimmune response involves immune activation, the plasma levels of interferon-alpha (IFN-alpha), IFN-gamma, interleukin-12 (IL-12), and IL-6 were measured, along with tumor necrosis factor (TNF-alpha) and soluble intercellular adhesion molecule-1 (sICAM-1). The levels of IL-12 and IFN-gamma were significantly higher in autistic patients than in controls (the remaining measures were not significantly different). It is suggested that IL-12 and IFN-gamma increases may indicate antigenic stimulation of Th-1 cells pathogenetically linked to autoimmunity in autism.

Immunogenetic Studies in Autism and Related Disorders.” Molecular Chemistry and Neuropathology, vol. 28, numbers 1-3, May-August 1996, pp. 77-81. The major histocompatibiligy complex comprises a number of genes that control the function and regulation of the immune system. One of these, the C4B gene, encodes a product that is involved in eliminating pathogens such as viruses and bacteria from the body. A deficient form of the C4B gene, termed the C4B null allele (no C4B protein produced) was previously seen to have an increased frequency in autism. In this study, this finding was confirmed, and this same condition was detected in related [neurodevelopmental] disorders as well. In addition, two alleles of the DR beta 1 gene also had significantly increased representation in autistic subjects.

Antibodies to Myelin Basic Protein in Children With Autistic Behavior.” Brain, Behavior and Immunity, vol. 7, number 1, March 1993, pp. 97-103. Approximately 58% of the sera of autistic children were found to be positive for anti-MBP [anti-brain antibodies]. This result was significantly different from that of the controls, among whom were children with normal health, idiopathic mental retardation, and Down syndrome. It is possible that anti-MBP antibodies are associated with the development of autistic behavior.

Possible Association of the Extended MHC Haplotype B44-SC30-DR4 With Autism.Immunogenetics, vol. 36, number 4, 1992, pp. 203-7. The complement C4B null allele appears to be associated with infantile autism. In this study, the incidence of B44-SC30-DR4 was increased by almost six-fold in the autistic subjects as compared with healthy controls. Moreover, the total number of extended haplotypes expressed on chromosomes of autistic subjects was significantly increased as compared with those expressed on chromosomes of healthy subjects. Conclusion: a gene related to, or included in, the extended major histocompatibility complex may be associated with autism.

Increased Frequency of the Null Allele at the Complement C4b Locus in Autism.” Clinical Experiments in Immunology, vol. 83, number 3, March 1991, pp. 438-40. Associations between C4 deficiency and autoimmune disorders have been found over the past several years. In this study, autistic subjects and their mothers had significantly increased phenotypic frequencies of the C4B null allele, compared with controls. The siblings of the autistic subjects also had an increased frequency of the C4B null allele, but this was not significant. The fathers did not display this allele. All family members had normal frequencies of the C4A null allele, all normal C4A and C4B alleles and all BF and C2 alleles.

Changes of Soluble Interleukin-2, Interleukin-2 Receptor, T8 Antigen, and Interleukin-1 in the Serum of Autistic Children.” Clinical Immunology and Immunopathology, vol. 61, number 3, December 1991, pp. 448-455. Findings indirectly indicated that the activation of a subpopulation of T cells occurs in some children with autism, as opposed to healthy children or children with mental retardation (non-Down’s syndrome).

Deficiency of Suppressor-inducer (CD4+CD45RA+) T Cells in Autism.” Immunological Investigations, vol. 19, number 3, June 1990, pp. 245-51. Autistic subjects as compared to a group of 35 healthy age-matched subjects had a significantly reduced number of lymphocytes, a decreased number of CD2+ T cells and reduced numbers of CD4+ and CD4+CD45RA+ lymphocytes. Results suggest that an alteration in the suppressor-inducer T-cell subset is associated with autism.

CD4+ Helper T Cell Depression in Autism.” Immunology Letters, vol. 25, number 4, September 1990, pp. 341-5.  Autistic subjects had a significantly lower percentage and number of CD4+ cells, a lower number of T cells (CD2+ cells) and B cells (CD20+ cells), and a lower percentage and number of total lymphocytes than siblings and normal subjects.  The level of blood values for female subjects appeared lower than those for males as compared to normal subjects of the same sex.  Results suggest that a decrease in CD4+ cells is associated with autism.
 




The Causes of Autism and the Need for Immunological Research:  Excerpts from the Autism Literature


 Autism is often referred to as a genetic disorder which begins before birth. Yet many parents observe a period of initial normality in their children. Differentiation between typical, or “Kanner’s,” autism and atypical or regressive autism, and childhood disintegrative disorder—or any of the other pervasive developmental disorders—would seem to be imperative. The supposition that only a single causative factor for autism exists—simple genetics—is proving increasingly flawed. In fact, the only proven genetic causes of autism to date are well-defined syndromes like the Fragile X chromosome anomaly. Study of simple genetic inheritance factors fails to explain the condition of children with regressive autism. The long-standing genetic model in autism is contradicted, in fact, in important works from the autism literature:
 

Diagnostic and Statistical Manual of Mental Disorders: DSM-IV, fourth edition, 1994, pages 66 and 69. DSM-IV specifies that “Autistic Disorder (defined as “early infantile autism…or Kanner’s autism”) must be differentiated from other Pervasive Developmental DisordersAutistic disorder differs from Childhood Disintegrative Disorder, which has a distinctive pattern of developmental regression following at least 2 years of normal development. In Autistic Disorder, developmental abnormalities are usually noted within the first year of life,” pages 66 and 69. [It is important to note that DSM-IV’s definition of autistic disorder differs markedly from earlier definitions, and that autistic spectrum subtypes are still very much in the definition stage.]


Cohen and Volkmar, eds., Handbook of Autism and the Pervasive Developmental Disorders, 2nd edition, 1997: Chapter 18, MEDICAL CONDITIONS[:] InfectionsImmunological Association[:] The claim has been made that a small but significant proportion of children develop autism as a result of pre-or post-natal infections—for example, with rubella, cytomegalovirus, herpes simplex, HIV, and so on…Interest in the immune system and autism arises from the various case reports in which infections (and possibly altered immune response) are associated with the development of autism or autistic features” (p. 398).

Margaret L. Bauman and Thomas Kemper’s The Neurobiology of Autism (Johns Hopkins Press), 1994: the Introduction to Neurobiology, written by Isabelle Rapin, states, “missing from this book, because of the dearth of prospective information, is a focus on the many potential nongenetic etiologies of the autistic spectrum…Another topic of interest, because of its potential therapeutic implications, that is not considered as such in this book is autistic regression.At least 40 percent of parents report that their infant or toddler, whose development may or may not have been entirely normal up to then, experienced a regression, usually insidious but occasionally abrupt, in language, sociability, and play… Development resumes after a plateau…but, in most cases, never returns to its previous levelMany speculations have been offered…to explain autistic regression: slow viral infection, autoimmune phenomenon, lack or insufficiency of a growth factor at a particular time in developmentData need to be collected to investigate these speculations” (pages 13-14). Bauman and Kemper resume, in chapter 2, “The Genetics of Autism,” with the following passages occurring on pages 30 to 31 of Neurobiology:
 

Environmental Factors[:] In examining the importance of genetic factors in the etiology of autism, evidence for environmental factors should be reviewed as well. Unfavorable pre-, peri-, and neonatal factors have been shown to occur more commonly in autistic individuals than normal controls….. Modes of Inheritance[:] Although the importance of hereditary factors in the etiology of idiopathic autism is well established, particularly genetic mechanisms have not yet been identified…it is almost certain that autism is an etiologically heterogeneous [multi-causal] disorder. It is known, for example, that autism can develop in association with etiologies as diverse as congenital rubella, tuberous sclerosis, and the fragile x anomaly, as well as in the absence of any identifiable, co-occurring, etiologically defined condition [emphases mine]. Among autistic individuals without identifiable, associated etiologic conditions, several points suggest that there may also be genetic heterogeneity.



Journal of Autism and Developmental Disorders, vol. 28, no. 5. 1998 (entirely devoted to the genetics of autism; preface by Eric Fombonne): as one would surmise, the general tone of the separate contributions indicate the strong possibility of a genetic component in autism (though the writers rarely differentiate between subtypes), but this research is far from finished, and does not exclude other factors, as London implies. In P. Szatmari, et al., “Genetics of Autism: Overview and New Directions,” the authors observe that the genetics of autism in its various manifestations is likely to involve the complex interaction of multiple genes, but even in this event “it is too early to say what type of complex genetic disease autism/PDD represents.” A variety of factors may interact to produce these conditions (pages 355; 365)—possibly different mechanisms for each ‘type’ of autism (page 365). The authors venture so far as to say that “certain severe insults” during pregnancy and birth might “play a causative role in the development of PDD: “For some children, genetic vulnerability may interact with insults on the developing nervous system to lead to autism.” Such insults might lead to PDD even in the absence of genetic factors—for instance, thalidomide exposure or congenital rubella (page 364). The authors do not examine the period of development after birth, but it is likely that the same reasoning could apply to the developing nervous system during the first three years of life—or even later.

Marian Sigman and Lisa Capps’ Children With Autism: a Developmental Perspective (Harvard University Press), 1997 asks, in Chapter 8, In Search of Core Deficits and Causes: “What Are the Causes of Autism?Autism is not a unitary disease with a single etiology,” the authors state. “It is a heterogeneous behavioral syndrome found in association with many etiologies…Complications in any part of… development… could cause damage that leads to autism. Infections affecting the central nervous system in early life could also have this effect (pp. 171-2). Evidence for genetic factors is mounting, they note, but “it is not clear, however, whether all forms of autism are genetically transmitted in the same way (pp. 172-3).” Evidence suggests that multiple genes are involved (pp. 173-4).

C. Gillberg and M. Coleman, The Biology of the Autistic Syndromes—second edition, 1992. Chapter 8, GENETIC FACTORS[:] “It is currently believed that a genetic disease underlies 10 to 20 percent of all autism cases…” (page 96); “There is another autism subgroup in which the autistic symptomatology is linked to disease processes currently thought to be, in many instances, of a non-genetic (or at least ‘non-inherited’) character” (page 103). Chapter 18, INFECTIOUS DISEASES[:] Postnatal infections[:] …Can an infection after birth cause an autistic syndrome? “…In summary… infectious agents in the prenatal or postnatal period may be a factor in the development of autism. The most common mechanism appears to be a direct toxic effect on brain cells from the infection (encephalitis)… It is of interest that, in reports concerning both rubella and HSV infections, cases with late onset are found. An infectious aetiology is a strong contender in the differential diagnosis of autistic symptoms…” (pages 222-4).

Schopler and Mesibov, eds., Diagnosis and Assessment in Autism (1988). Chapter authors Schopler and Michael Rutter note on page 28, “[Considering] the very fact that the clinical picture of autism can arise from diseases as diverse as congenital rubella, tuberous sclerosis, encephalopathy…cerebral lipoidosis, and neurofibromatosis…it remains quite uncertain whether the…cases with a known pathologic cause represent phenocopies of some other unitary disorder with (an as yet undiscovered) single etiology….“Page 86 quotes Volkmar and Cohen, “…it is clear that the preponderance of available evidence suggests the importance of multiple biologic factors acting through one or more mechanisms to produce the autistic syndrome.” On pages 295-6, chapter authors Watson and Marcus note the importance of a medical assessment paralleling psychological and other testing: “it is important to recognize the possible medical factors associated with autism. A variety of biologic conditions have been documented including… certain viral infections, abnormalities in purine metabolism and intestinal absorption…” The authors refer readers to Coleman and Gillberg, quoted above, for comprehensive information on the medical aspects of autism.

Shirley Cohen, Targeting Autism, 1998, pages 139 and 140: “There is increasing evidence of immune system abnormalities in autism. A substantial number of reports of research on this subject have appeared in medical journals since the 1980s, and most of these articles present data that appear to support the theory of a connection between immune system dysfunction and some cases of autism…study of immune system abnormalities in autism has attained the status of mainstream medical research.”

The Centers for Disease Control, [1998], “Vaccines and Autism: Is There a Relationship?” (http://www.cdc.gov/nip/vacsafe/vac4autism.htm): Notoriously pro-vaccine, the CDC nevertheless says, of autism, “Some prenatal factors included intrauterine rubella; tuberous sclerosis; chromosomal abnormalities, such as Down’s Syndrome, as well as brain abnormalities, like hydrocephalus. …postnatal conditions associated with autism are untreated phenylketonuria, infantile spasms, and herpes simplex encephalitis. …Evidence that genetics is an important, but not exclusive, cause of autism includes a three to eight percent risk of recurrence in families with one affected child. An issue unresolved [by a working group convened by the National Institutes of Health in 1995] was the role of immune factors in autism spectrum disorders; it was suggested that studies to clarify the situation are needed.”

Uta Frith, Autism: Explaining the Enigma, 1989/1994, p. 79, “the theory that psychotic illness can be due to immune dysfunction and/or viral infection has particular justification in the area of Autism.  It has been shown …that a virus infection in a young child preceded the onset of typical symptoms of Autism, before which there was a period of apparently normal development…If the central nervous system becomes infected at a critical time, either before or after birth, Autism may result… Of special interest are certain types of virus called retrovirus, which totally integrate themselves in genetic material in the body cells…These can remain dormant for years but from time to time can be reactivated.”

Van Gent, et al. present a review of the literature in the emerging field of “psychoneuroimmunology” through 1997 in “Autism and the Immune System,Journal of Child Psychology and Psychiatry, vol. 38 no. 3, March 1997, pp. 337-349. “Over the last 30 years increasing evidence has been found for the existence of complex links between the immune system, the central nervous system and the endocrine system on the one hand, and psychological phenomena…on the other…:   prenatal and early childhood experiences could have prominent effects on the development of the responsiveness of the immune system, with far-reaching and long-lasting consequences for the immune capacity at a later age.  Conversely, early derailments in the normal development of immune function, as, for instance, in the induction of autoimmunity in an early phase of the immunological developmental traject, could have important effects on the development of the nervous and endocrine systems… [Regarding autism,] two etiologically relevant immune hypotheses in particular have emerged:   a viral and an autoimmune hypothesis, which are interrelated (p.345). The basic neuroimmunologic premise of these hypotheses is that autoimmune and/or viral processes in some way affect the nervous system and alter central nervous system activity” (pages 337-8).

M.V. Pletnikov, T. H. Moran, and K. M. Carbone, “Borna Disease Virus Infection of the Neonatal Rat: Developmental Brain Injury Model of Autism Spectrum Disorders,Frontiers in Bioscience, March 1, 2002, vol. 7, pages D593-607.  Researchers at the Johns Hopkins University School of Medicine note, “Autism spectrum disorders (ASD) have been the focus of a great deal of research and clinical speculation. This intense interest relates to both the perplexing pathogenesis and devastating consequences of these disorders. One of the obstacles to understanding the pathogenesis of autism and its efficient treatment has been the paucity of animal models that could be used for hypotheses-driven mechanistic studies of abnormal brain and behavior development and for the pre-clinical testing novel pharmacological treatments. The present review provides a detailed analysis of a new animal model of ASD. This model utilizes neonatal Borna disease virus (BDV) infection of the rat brain as a unique experimental teratogen to study the pathogenesis of neurodevelopmental damage…  The most recent experiments demonstrate the utility of the BDV model for studying the pathophysiological mechanisms of the gene-environment interaction that determines differential disease outcomes and variability in responses to treatments.”

M. Hornig, W. I. Lipkin, et al., “An Infection-based Model of Neurodevelopmental Damage,” Proceedings of the National Academy of Sciences, vol. 96, no. 21, pp. 12102-12107, Oct. 12, 1999 (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=10518583):  perinatal exposure to infectious agents and toxins is linked to the pathogenesis of neuropsychiatric disorders.  The authors create a model for examining the effect of infection on the developing immune and nervous system, using Borna disease virus.  The resulting functional and neuropathologic abnormalities thus triggered in rats were applicable to human neurodevelopmental disorders.

M. Hornig, W. I. Lipkin, “Infectious and Immune Factors in the Pathogenesis of Neurodevelopmental Disorders: Epidemiology, Hypotheses, and Animal Models,” Mental Retardation and Developmental Disabilities Research Reviews, vol. 7, no. 3, 2001, pp. 200-210 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11553936&dopt=Abstract):  both genetic and environmental factors contribute to the pathogenesis of a variety of neurodevelopmental disorders, including autism, mental retardation and schizophrenia.  Subtle aspects of clinical disease expression may be influenced by the environment, even in highly heritable disorders.  In other disorders with genetic influences, exogenous factors, and the timepoint(s) during nervous system development at which they are introduced, modulate expression of disease.   The authors review the evidence that infectious and immune factors may contribute to the pathogenesis of neurodevelopmental disorders, while describing an animal model based on viral infection, identifying processes by which neural circuitry may be compromised.

William Shaw, Biological Treatments for Autism and PDD, 1998. Shaw reports finding in children with autism and PDD none of the signs characteristic of known, inborn (genetic) conditions causing metabolic disorders (pages 31; 35-37; 68-9; 129). On pages 103-4 Shaw notes, “In several cases, electron microscopy has revealed live measles virus in the intestinal lining of children with the gastrointestinal abnormalities common in children with autism.” Shaw also notes “some interesting parallels between autism and tetanus,” citing Ellen Bolte’s paper, “Autism and Clostridium Tetani: An Hypothesis” [Medical Hypotheses, vol. 51, 1998, pages 133-144; Shaw 22].

H. H. Fudenberg, NeuroImmuno Therapeutics Research Foundation, “Classic Infantile Onset Autism is an Autoimmune Disease,” http://members.aol.com/nitrf/autism1.htm, accessed May 20, 1998:2 In the process of describing transfer factor therapy studied in 40 autistic patients, Fudenberg notes, “The gene for classic autism has been localized to human chromosome-6, the site of human immune response genes and [is] linked to haplotypes containing the C4 null allele.”

Immunogenetic Studies in Autism and Related Disorders.” Molecular Chemistry and Neuropathology, vol. 28, numbers 1-3, May-August 1996, pp. 77-81. The major histocompatibiligy complex comprises a number of genes that control the function and regulation of the immune system. One of these, the C4B gene, encodes a product that is involved in eliminating pathogens such as viruses and bacteria from the body. A deficient form of the C4B gene, termed the C4B null allele (no C4B protein produced) was previously seen to have an increased frequency in autism. In this study, this finding was confirmed, and this same condition was detected in related [neurodevelopmental] disorders as well. In addition, two alleles of the DR beta 1 gene also had significantly increased representation in autistic subjects.

Association of MHC Genes With Autism,” Frontiers in Bioscience, August 1, 2001, vol. 6, d936-943, http://www.bioscience.org/2001/v6/d/torres/2.htm.  Various research groups have reported numerous immune-autism associations over the last 20 years.  This laboratory has published disease-associations with MHC class I, class II and class III genes/proteins.  These associations have been extended to the Major Histocompatibility Complex (MHC), a section of DNA remarkable for the number of encoded proteins with immunological functions.  The C4B null allele in the class III region has the strongest disease association identified thus far.  Low levels of C4 resulting from the null allele may be important in disease pathogenesis especially since C4 has been identified in developing brain neurons.  The DNA region just telomeric to C4 has several genes including tumor necrosis factor which encode proteins with immunological functions, having various roles in inflammation and infection and may therefore be involved in disease pathogenesis. These proteins may act in concert with C4 in disease contribution and the genes should be more closely examined for autism association.  An additional area which should be studied is the function of C4 in the developing brain.

Autoimmune Diseases:  Genes, Bugs and Failed Regulation,” Nature Immunology, vol. 2, no. 9, 2001, September 2001, pp. 759-761 (http://www.nature.com/ni/special_focus/autoimmunity/home_welcome.html):  Stanford University School of Medicine authors Joerg Ermann and C. Garrison Fathman discuss common themes from five articles in this same issue, regarding rheumatoid arthritis, systemic lupus erythematosus, insulin-dependent diabetes, autoimmune thyroid disease and multiple sclerosis.  A unifying concept for the development of these and other autoimmune diseases, said the authors, should incorporate genetic predisposition, environmental factors and immune dysregulation, as they underlie the induction and perpetuation of these and other autoimmune diseases.  Genetically, “one gene cluster stands out among all others in defining genetic susceptibility…the region that encodes the major histocompatibility gene complex (MHC).  The association between MHC products and autoimmune diseases has been known for more than 20 years and…certain MHC alleles [can] be used as markers of genetic predisposition…..  “[D]ata imply that it is the normal allelic variant of the MHC molecule itself, and not some other gene within the MHC complex, that confers the increased risk of developing autoimmune disease…[and] point to a central role for antigen-presentation events in the pathogenesis of these diseases…..  [A] disconcerting fact about genetic predisposition to autoimmune disease is the lack of concordance in identical twin pairs…autoimmune disease becomes manifest in less than 50% of the twin siblings of an affected identical twin; this poses a major problem for any simple explanation of the genetic control of autoimmune disease development.  To explain this…one has to…search for an initiating external event such as the response against an environmental pathogen.”

Role of Immunogenetics in the Diagnosis of Postvaccinal CNS Pathology,” Massimo Montinari, et al., Department of Pediatric Surgery, University of Bari, Italy, presented May 9, 1996 (text available http://www.healthy.net/library/ articles/coulter/biochem.htm):   after thirty children were found to have signs of central nervous system and genetic damage following vaccination, the authors remark, “A study of the disease associated with genes of the HLA system has shown that this genetic complex can be responsible for a particular genetic susceptibility, predisposing to various diseases characterized predominantly by immune-system pathogenesis…”

T. Binstock, Researcher in Developmental & Behavioral Neuroanatomy, www.jorsm.com/~binstock, “Familial does not mandate genetic[:]…Four categories of familial illness or disorder.” “Only one of [the first] three categories is purely genetic [–category A:]” A) familial occurrences indicating an actual gene-mutation that is hereditary; B) familial occurrences reflecting a genetically encoded susceptibility factor; C) familial illness via environmental factors. D) familial clustering of increased small intestinal permeability in families with Crohn’s Disease. In category B, “the mutated gene is not the primary cause but is merely an inborn way that a person is more statistically likely, over time, to experience the primary cause. Genetically encoded immunodeficiencies are an example of ‘susceptibility factor.’ [With autism,] the most common genetic susceptibility factor is having a null allele of complement 4b” (referenced communication to Autism listserv originating at St. Johns, University, New York [autism@maelstrom. stjohns.edu], September 16, 1997, 08:39:13 -0700).

A. M. Comi, et al., “Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism” (Journal of Child Neurology, vol. 14, no. 6, June 1999, pp. 388-94): “Autism is an age-dependent neurologic disorder that is often associated with autoimmune disorders in the patients’ relatives… The most common autoimmune disorders…[are] type 1 diabetes, adult rheumatoid arthritis, hypothyroidism, and systemic lupus erythematosus… An increased number of autoimmune disorders [in patients’ families] suggests that in some families with autism, immune dysfunction could interact with various environmental factors to play a role in autism pathogenesis.”

G. Trottier et al., “Etiology of infantile autism: a review of recent advances in genetic and neurobiological research” (Journal of Psychiatry and Neuroscience, vol. 24, no. 2, March 1999, pp. 103-15): “The etiology of autism is complex, and in most cases the underlying pathologic mechanisms are unknown… Recent research has investigated… immunological factors. On the basis of family and twin studies, there appears to be a genetic basis for a wide ‘autistic syndrome.’ …Autoimmunity also may play a role; antibodies against myelin basic protein are often found in children with autism, who also have increased eosinophil and basophil response to IgE-mediated reactions. In summary, the prevailing view is that autism is caused by a pathophysiologic process arising from the interaction of an early environmental insult and a genetic predisposition.”

Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism” (Clinical Immunology and Immunopathology vol. 89, number 1, October 1998, pp. 105-8): this study is the first to report an association between virus serology and brain autoantibody in autism; it supports the hypothesis that a virus-induced autoimmune response may play a causal role in autism.

Continuing this work in “Abnormal Measles Serology and Autoimmunity in Autistic Children,Journal of Allergy and Clinical Immunology (vol. 109, no. 1, S232, January 2002, abstract #702), Vijendra Singh, Ph.D. and Courtney Nelson of Utah State University, Logan find that immune factors such as autoimmunity may play a causal role in autism:  “we recently showed that many autistic children have autoantibodies to brain myelin basic protein (MBP) as well as elevated levels of measles virus antibodies. To extend this research further, we conducted a serological study of measles virus (MV), mumps virus (MuV), rubella virus (RV), cytomegalovirus (CMV), human herpesvirus-6 (HHV-6), measles-mumps-rubella (MMR), diptheria-pertussis-tetanus (DPT), diptheria-tetanus (DT) and hepatitis B (Hep B) and studied correlations with MBP autoantibodies.  Antibodies were assayed in sera of autistic children (n=125) and normal children (n=92) by ELISA or immunoblotting methods. We found that autistic children have significantly (p=0.001) higher than normal levels of MV and MMR antibodies whereas the antibody levels of MuV, RV, CMV, HHV-6, DPT, DT or Hep B did not significantly differ between autistic and normal children.  Immunoblotting analysis showed the presence of an unusual MMR antibody in 60% (75 of 125) of autistic children, but none of the 92 normal children had this antibody. Moreover, by using MMR blots and monoclonal antibodies, we found that the specific increase of MV antibodies or MMR antibodies was related to measles hemagglutinin antigen (MV-HA), but not to mumps or rubella viral proteins, of the MMR vaccine. In addition, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a causal association between MMR and brain autoimmunity in autism.  Stemming from this evidence, we suggest that an ‘atypical’ measles infection in the absence of a rash but with neurological symptoms might be etiologically linked to autoimmunity in autism.”

Association of Anti-MBP and Anti-NAFP Antibodies With HHV-6 Antibodies in a Child With Autistic Regression.” Journal of Allergy and Clinical Immunology, vol. 101, no. 1, part 2, S122, January 1998 (in section entitled, “Program and Abstracts of Papers to Be Presented During Scientific Sessions [at the] 54th Annual Meeting, March 13-18, 1998“). Children with autism have been shown to have a high incidence of circulating autoantibodies to myelin basic protein (MBP) and to neuron-axon filament protein (NAFP) compared with healthy controls or controls with other disabilities. Subacute viral infections of the central nervous system have been postulated to play a role in children who develop normally before undergoing autistic regression. In this instance, a healthy boy having a typical case of roseola (HHV-6) at 15 months experienced severe regressions of language and social behavior soon afterward. “The presence of antibodies against MBP and NAFP along with the clinical course and elevated levels of HHV-6 antibodies suggest an autoimmune response to this neurotropic virus[,] resulting in the autistic regression.”

Serological Association of Measles Virus and Human Herpesvirus-6 With Brain Autoantibodies in Autism.” Clinical Immunology and Immunopathology, vol. 89, number 1, October 1998, pp. 105-8. This study is the first to report an association between virus serology and brain autoantibody in autism; it supports the hypothesis that a virus-induced autoimmune response may play a causal role in autism.

V. Uhlmann, J. O’Leary et al., “Measles Virus (MV) in Reactive Lympho-nodular Hyperplasia and Ilio-colitis of Children,” from the 180th Meeting of the Pathological Society of Great Britain and Ireland, January 18-21, 2000, chronicles the molecular confirmation of measles virus nucleoprotein (N antigen) detected in association with follicular dendritic (FDC) cells in patients with a newly-described pediatric syndrome, ileo-colonic lymphoid nodular hyperplasia and ileo-colitis (also known as autistic enterocolitis).  Specialized RT-PCR techniques were developed and used by the authors on paraffin-embedded and fresh-frozen tissue sections.  Pediatric controls with Crohn’s Disease, ulcerative colitis and normal biopsies were also analyzed.  Distinct measles virus genome was identified in FDC-reactive follicular centers in 24 out of 25 children with autism and bowel disease.  None of the normal controls showed any evidence of measles.  “The data highlights a possible causal link,” the authors stated, “between measles virus infection and the ileo-colonic l[ympho-]n[odular] h[yperplasia] in affected [autistic] children.”

In “Detection and Sequencing of Measles Virus from Peripheral [Blood] Mononuclear Cells from Patients with Inflammatory Bowel Disease and Autism” (Digestive Diseases and Sciences, vol. 45, no. 4, April 2000, pages 723-9, Kawashima et al. characterize measles strains present in peripheral blood from of eight patients with Crohn’s Disease, three patients with ulcerative colitis, and nine with autistic enterocolitis.  A total of eight controls, both healthy and with other diseases (Subacute Sclerosing Panencephalitis, Systemic Lupus Erythematosus, and HIV-1) were examined in addition.  Results showed all controls negative for measles virus.  Samples of one of eight patients with Crohn’s Disease, one of three with ulcerative colitis, and three of nine children with autism were positive for measles virus.  Of these, Crohn’s Disease patients exhibited viral strains consistent with wild-type measles virus.  Ulcerative colitis and autistic enterocolitis patients’ samples were consistent with vaccinal measles.  In an interview with Reuters Health (Reuters Medical News, June 20, 2000), Dr. Kawashima commented that, while detection of measles virus in Crohn’s patients “are not important, if further cases of autistic enterocolitis are detected after MMR vaccination, our study will be very significant.”

Jyonouchi, “Innate and Adaptive Immune Responses in Children With Regression Autism:  Evaluation of the Effects of Environmental Factors Including Vaccination” (Journal of Allergy and Clinical Immunology, February 2001, Part 2, vol. 107, no. 2).  Presented in entirety at the 57th annual meeting of the American Academy of Asthma, Allergy, and Immunology, March 16-21, Harumi Jyonouchi et al. of the University of Minnesota determined that a high frequency of excessive innate immune responses is seen in children with regressive autism, possibly explaining in part the apparent association between immunization and the onset of regression and autistic behavior.

Jyonouchi, et al., “Proinflammatory and Regulatory Cytokine Production Associated With Innate and Adaptive Immune Responses in Children With Autism Spectrum Disorders and Developmental Regression” (Journal of Neuroimmunology, vol. 120, nos. 1-2, January 11, 2001, pp. 170-9).  Comparing children with developmental regression and autism spectrum disorders with their developmentally normal siblings, plus with controls, results indicate that excessive innate immune responses in autism spectrum children that may result in aberrant adaptive immune responses.  Further exploration of this situation in autism-spectrum children may define a role for immune processes in regressive autism, and indicate possible methods of intervention.

Disordered Metal Metabolism in a Large Autism Population,” William J. Walsh, Ph.D. and Anjum Usman, M.D., 154th Annual Meeting, American Psychiatric Association, New Orleans, May 5-10, 2001 (abstract available at http://www.hriptc.org/APA_abstract.htm).  Drs. William Walsh and Anjum Usman provided a basis for possible mercury poisoning in autism.  A total of 499 of 503 autism-spectrum patients exhibited evidence of a metal-metabolism disorder.  Data suggest that an inborn error of MT (metallothionene) functioning, affecting neuronal development, detoxification of heavy metals, and modulation of the immune response, may be a fundamental cause of autism.

V. K. Singh, “Neuro-immunopathogenesis in Autism,” Chapter 5, Clinical Neuroimmune Biology (vol. VI, New Foundation of Biology series, Elsevier Science, 2001) abstracts the work of Vijendra K. Singh, et al., “Based on our ongoing research of a reciprocal relationship between nervous system and immune system, we studied autism as a neuro-immune dysfunction syndrome in which autoimmunity to brain was strongly implicated…  We found that autoantibodies to M[yelin] B[asic] P[rotein] were selectively present in up to 80 percent of the autistic children, but they were only rarely detected in the controls…  Regarding virus serology, autistic children had a significantly higher level of measles virus antibodies as compared to controls; however, the antibody level of [the] other three viruses [assessed] did not significantly differ between the two groups.  This suggested a temporal link of measles virus with autoimmunity in autism.  This examination of brain autoantibody and virus serology data revealed that there was a serological association between measles virus and MBP autoantibodies, i.e., the higher the measles virus antibody level the greater the chance of MBP autoantibody.   Collectively, these observations led us to speculate that an autoimmune response, presumably secondary to an atypical measles virus infection, may cause autism.  The idea that autism is an autoimmune disorder is further strengthened by the fact that many autistic children respond well to treatment with immune modulating [treatments]…  In conclusion, autism involves a neuroautoimmune response that occurs at the neuro-immune biology interface.  Clinically, therefore, there is enormous potential for restoring brain function in autistic people through immunology. ”
 


The pattern of normality followed by regression, loss of development, or halted development and appearance of odd behavioral features is thus represented in the autism literature. Probing the issue of genetics in autism, an important possibility surfaces: the genetic factor in regressive autisms and PDDs could well be a particular configuration of immune system components—in essence, vulnerabilities in the immune system such that affected children cannot adequately deal with the challenges posed by the current, frequently trivalent live-virus vaccines. Like Fudenberg, Van Gent, et al. observe that “the immune response is regulated by genetic material located mainly on the sixth chromosome.” Failure of components of this system can lead to disruption of normal cell-mediated cellular immune responses. Virus infections may induce autoimmunity, and autoimmunity may result in increased susceptibility to infections and subsequent damage to the CNS. Besides viral infections as a cause, it is possible that “a genetic predisposition to a relative deficiency of specific immune cells may be involved” (pp. 344-5).


To date, there has been no concerted national effort to monitor the actual incidence of autism–one of the many disabilities/ diseases that can be caused by immunization–since it was described by Kanner in the 1940s. The most frequently quoted incidence figure, based on large-scale surveys in the United States in England, is 4.5 in 10,000–not including other autism spectrum disorders.1 Presently the CDC admits to an estimated autism incidence of 1 in 500 (contrasted with an earlier estimate of 1 in 10,000). The actual incidence is suspected by the autism community to be at least this high, perhaps higher than 1 in 200, and to be increasing exponentially [coincidentally or not, the number of mandated or recommended immunizations is also rapidly expanding].2 In response to a recent inquiry, the Assessment, Evaluation and Support Unit of the California Department of Education’s Special Education Division gave the following statement about increases in the numbers of special education students with autism:

“…the only info I can provide on Autism is the number of students, ages 0-22, with IEPs receiving special education services in California. We first started collecting enrollments count on Autism in the 1992-93 school year. On April 1, 1993, there were 2,157 students (out of 540,472) reported [to have autism]. Five years later, on April 1, 1998, there were 8,084 students (out of 632,238) reported.3


The California Department of Developmental Services recently produced A Report to the Legislature: Changes in the Population of Persons with Autism and Pervasive Developmental Disorders in California’s Developmental Services System: 1987 through 1998 (text available at http://www.dds.ca.gov/autismreport.cfm). In 1987 there were 3,864 autistic children enrolled in the department’s twenty-one regional programs; in 1998, 11,995 autistic children were counted–a 210% increase. Children with other disorders such as cerebral palsy and epilepsy increased at a rate consistent with the state’s population growth (from 30-48%). The Illinois State Board of Education lists figures for the incidence of both autism and learning disabilities: autism cases on hand were 317 in 1991, and 2,305 in 1997. The number of children with learning disabilities was, in 1991, 111,326, and in 1997, 126, 065.4 The text to a study analyzing these statistics, together with those of other states, can be found at http://www.garynull.com/ Documents/autism_99.htm. Another study was published recently in Copenhagen, Denmark:

Autism: not an extremely rare disorder” (Acta Psychiatrica [et Neurologica] Scandinavica, vol. 99, no. 6, June 1999, pp. 399-406): Authors studied autism prevalence over time, to determine whether there has been an increase in its prevalence in recent years. Early studies yielded prevalence rates of under 0.5 in 1000 children, whereas the later ones showed a mean rate of about 1 in 1000. “There was a marked difference in prevalence rates between those studies that included some children born in 1970 and after (high rates)…There was a highly significant estimated increase with calendar year in the non-US studies (3.8% per year)…it is concluded that autism is considerably more common than was previously believed.”


References


1 A Report to the Legislature: Changes in the Population of Persons With Autism and Pervasive Developmental Disorders in California’s Developmental Services System: 1987 Through 1998 (Department of Developmental Services, California Health and Human Services Agency, Sacramento, CA: March 1, 1999), section IV, Rates of Occurrence, p. 5, http://www.dds.ca.gov/autismreport.cfm. see also http://www.garynull.com/Documents/autism_99.htm

2 Post to the Autism electronic mail discussion list originating from St. John’s University, New York [listserv@maelstrom.stjohns.edu], April 12, 1999, 19:09:49 -0700, subject lined “Is Autism a Public Health Problem?”

3 Barbara McDonald, Assessment, Evaluation and Support Unit, Special Education Division, California Department of Education (Bmcdonal@cde.ca.gov), to Raymond Gallup (truegrit@gti.net) via electronic mail, April 9, 1999, 10:10 a.m.

4 Statistics extracted from correspondence between Ray Gallup and the Illinois State Board of Education, posted to Vaccine Information and Awareness (VIA) discussion list [via@access1.net] April 28, 1999, 4:12 p.m.


 


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