Antibodies against the foetal brain in the serum of the mother of the child that develops autism, the family and the autistic child itself |
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Immunofluorescence of brain tissue in which antibodies
(e.g. auto-antibodies) against the tissue are themselves stained |
Antibodies against foetal brain in the mother’s serum
It should be noted that antibodies derived from the mother may have activity in the foetus in causing damage because they can cross the placenta into the blood of the foetus. They will only do this test in the blood of the mothers when the child developed autism. These antibodies will be expected to disappear from the blood of the child over the 6 months after the birth. Some of the researchers suggest that these antibodies may cause the damage to the brain. It does seem clear that the antibodies found in the mother’s serum do indeed cause damage to brain tissue, as this has been demonstrated by injecting them into animal models but clearly these experiments cannot be done in humans. Autoantibodies in the child’s serum However, autoantibodies against brain tissue and neuronal tissue are found in a large number of autistic children well after the period in which a mother’s antibodies may have left. The reason for these antibodies is unclear and it is never easy to prove whether damage to the tissue allows new brain proteins to expose themselves to the immune system (and hence antibodies are produced) or the other way around and it is the antibodies that cause the damage in the first place…in which case we have no clear cause for the antibodies to be produced originally. Families that seem to have an excess of autoantibodies Certain families, and particularly the women in them sometimes have an excess of autoimmune disease. The feeling by some researchers was that it was this excess tendency to produce damaging antibodies that cause the child to have a tendency to produce autoantibodies and hence damage its own nervous tissue. They found, however that there was less autoantibodies than expected in these children. In fact the difference was quite wide and a reason should be looked on for this as well. . :
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Prenatal Stress
It is
difficult to be sure what is the actual association and what is the cause when
looking for the antibodies. All of the
effects may be working through a stress syndrome. Perhaps this is infection but it may be due
to other effects on the mother…currently unclear.
Kinney DK, Munir KM, Crowley DJ, Miller AM. Prenatal stress and risk for autism. Neurosci Biobehav Rev. 2008 Jun 13. [Epub ahead of print]
Singh’s
group have worked on this field for some time and I would recommend working
through their research in that it simply cannot be denied and should not be
ignored. What is important to remember
is that the proportion of children, mothers or relatives that actually don’t
have autoantibodies; as such, what is causing (or resulting from) the
damage? Does this suggest that the
autoimmune associated cases are different in some way from the others? In adequate research is currently available
to know. The finding that steroid drugs,
which tend to decrease the damaging effect of antibodies have not been
adequately tested in treatment, should by rights be followed up
Autoantibodies in the serum of autistic
children
Singh VK, Rivas WH. Prevalence of serum antibodies to caudate nucleus in autistic children. Neurosci Lett. 2004 Jan 23;355(1-2):53-6. In 30 normal and 68 autistic children. Autistic children, but not normal children, had antibodies to caudate nucleus (49% positive sera), cerebral cortex (18% positive sera) and cerebellum (9% positive sera). Brain stem and hippocampus were negative. Antibodies to caudate nucleus were directed towards three proteins having 160, 115 and 49 kD.
Singh VK, Warren R, Averett R, Ghaziuddin M. Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr Neurol. 1997 Jul;17(1):88-90.
Singh VK, Singh EA, Warren RP. Hyperserotoninemia and serotonin receptor antibodies in children with autism but not mental retardation. Biol Psychiatry. 1997 Mar 15;41(6):753-5.
Singh VK, Lin SX, Newell E, Nelson C. Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism. J Biomed Sci. 2002 Jul-Aug;9(4):359-64. (as suggestion that the MMR vaccine response in the autistic child may have activity in the brain)
Singh VK, Lin SX, Yang VC. Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Clin Immunol Immunopathol. 1998 Oct;89(1):105-8. (anti-measles and anti-HHV6 acting as also anti-brain in autistic child)
Singh VK, Warren RP, Odell JD, Warren WL, Cole P. Antibodies to myelin basic protein in children with autistic behaviour. Brain Behav Immun. 1993 Mar;7(1):97-103.
Vojdani A, Pangborn JB, Vojdani E, Cooper EL. Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. Int J Immunopathol Pharmacol. 2003 Sep-Dec;16(3):189-99. (in fact all he is showing is that very specific proteins of various simple sources may stimulate autism lymphocytes in vitro).
Connolly AM, Chez MG, Pestronk A, Arnold ST, Mehta S, Deuel RK. Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Pediatr. 1999 May;134(5):607-13. (The immunoglobulin called IgG anti-brain autoantibodies were present in 45% of sera from children with Landau-Kleffner variant, 27% with ASD, and 10% with ONDs compared with 2% from healthy children and control children with non-neurological illnesses. IgM autoantibodies were present in 36% of sera from children with ASD, 9% with Landau-Kleffner variant, and 15% with ONDs compared with 0% of control sera.)
Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D, Van de Water J. Autoantibodies in autism spectrum disorders (ASD). Ann N Y Acad Sci. 2007 Jun;1107:79-91. Review.
Cabanlit M, Wills S, Goines P, Ashwood P, Van de Water J. Brain-specific autoantibodies in the plasma of subjects with autistic spectrum disorder. Ann N Y Acad Sci. 2007 Jun;1107:92-103. (Reactivity to three brain proteins (42-48 kDa MW), in particular in the hypothalamus, were observed with increased incidence in 37% of subjects with autism compared to 13% TD controls (P = 0.004). Multiple brain-specific autoantibodies are present at significantly higher frequency in children with autism).
Libbey JE, Coon HH, Kirkman NJ, Sweeten TL, Miller JN, Stevenson EK, Lainhart JE, McMahon WM, Fujinami RS. Are there enhanced MBP autoantibodies in autism? J Autism Dev Disord. 2008 Feb;38(2):324-32. Epub 2007 Jun 22. Myelin basic protein (MBP). They measured autoantibody titers to MBP in children with autism, both classic onset and regressive onset forms, controls (healthy age- and gender-matched) and individuals with Tourette syndrome via enzyme-linked immunosorbent assays. We found a significant difference in autoantibody titers to MBP, not accounted for by age or medication, between Tourette and classic autism (both significantly lower) when compared to regressive autism, but not when compared to controls. They say that autoantibody responses against MBP are unlikely to play a pathogenic role in classical autism. I am not sure that this can be said to regressive autism where they found higher titres than those found in classical autism or Tourettes or controls. This article probably should be read completely for understanding.
Kirkman NJ, Libbey JE, Sweeten TL, Coon HH, Miller JN, Stevenson EK, Lainhart JE, McMahon WM, Fujinami RS. How relevant are GFAP autoantibodies in autism and Tourette Syndrome? J Autism Dev Disord. 2008 Feb;38(2):333-41. Epub 2007 Jun 20. (They tried quite hard to show a statistical difference between the titres of glial fibrilliary acid protein autoantibodies of autistics and controls but found none. They questioned the significance of these autoantibodies in pathogenicity).
Molloy CA, Morrow AL, Meinzen-Derr J, Dawson G, Bernier R, Dunn M, Hyman SL, McMahon WM, Goudie-Nice J, Hepburn S, Minshew N, Rogers S, Sigman M, Spence MA, Tager-Flusberg H, Volkmar FR, Lord C. Familial autoimmune thyroid disease as a risk factor for regression in children with Autism Spectrum Disorder: a CPEA Study. J Autism Dev Disord. 2006 Apr;36(3):317-24. The only specific autoimmune disorder found to be associated with regression was autoimmune thyroid disease (adjusted OR=2.09; 95% CI: 1.28, 3.41).
Havarinasab S, Hultman P. Organic mercury compounds and autoimmunity.. Autoimmun Rev. 2005 Jun;4(5):270-5. Epub 2005 Jan 5.
Folate receptor autoimmunity and cerebral folate
deficiency in low-functioning autism with neurological deficits.
Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral DG, Van de Water J. Brain Behav Immun. 2009 Jan;23(1):64-74. In addition, the presence of cerebellar specific antibodies was assessed by immunohistochemical staining of sections from Macaca fascicularis monkey cerebellum. Western blot analysis revealed that 13/63 (21%) of subjects with ASD possessed antibodies that demonstrated specific reactivity to a cerebellar protein with an apparent molecular weight of approximately 52 kDa compared with only 1/63 (2%) of the typically developing controls (p=0.0010). Intense immunoreactivity, to what was determined morphologically to be the Golgi cell of the cerebellum, was noted for 7/34 (21%) of subjects with ASD, compared with 0/23 of the typically developing controls. This can hardly be ignored in that a titre was assessed. If simple immunoreactivity to tissues carried out using histochemistry is always difficult because by altering the method it can suggest that almost all cases are positive. In this study, however, this is not possible.
Serum anti-nuclear antibodies as a marker of autoimmunity
in Egyptian autistic children.
Autoimmunity in autism. Enstrom AM, Van de
Water JA, Ashwood P. Curr
Opin Investig Drugs. 2009 May;10(5):463-73. This is a review
of how Increasing
evidence of autoimmune phenomena in individuals with autism could represent the
presence of altered or inappropriate immune responses in this disorder, and
this immune system dysfunction may represent novel targets for treatment.
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Autoantibodies present in mother’s serum
Warren RP, Cole P, Odell JD, Pingree CB, Warren WL, White E, Yonk J, Singh VK. Detection of maternal antibodies in infantile autism. J Am Acad Child Adolesc Psychiatry. 1990 Nov;29(6):873-7. (antibodies to antigens present on the baby’s lymphocytes. Mother also often had problems with pregnancy)
Dalton P, Deacon R, Blamire A, Pike M, McKinlay I, Stein J, Styles P, Vincent A. Maternal neuronal
antibodies associated with autism and a language disorder. Ann Neurol.
2003 Apr;53(4):533-7. (they took the
serum from a mother of an autistic child and inocualated it into a mouse before
birth. Changes were seen neurologically in the mouse after birth)
Braunschweig D, Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, Pessah IN, Van de Water J. Autism: Maternally derived antibodies specific for fetal brain proteins. Neurotoxicology. 2007 Nov 6; now: 2008 Mar;29(2):226-31. (maternal plasma antibodies against human fetal and adult brain proteins were analyzed by western blot in 61 mothers of children with autistic disorder and 102 controls matched for maternal age and birth year (62 mothers of typically developing children (TD) and 40 mothers of children with non-ASD developmental delays (DD)). We observed reactivity to two protein bands at approximately 73 and 37kDa in plasma from 7 of 61 (11.5%) mothers of children with autism (AU) against fetal but not adult brain, which was not noted in either control group (TD; 0/62 p=0.0061 and DD; 0/40 p=0.0401). Further, the presence of reactivity to these two bands was associated with parent report of behavioral regression in AU children when compared to the TD (p=0.0019) and DD (0.0089) groups. Individual reactivity to the 37kDa band was observed significantly more often in the AU population compared with TD (p=0.0086) and DD (p=0.002) mothers, yielding a 5.69-fold odds ratio (95% confidence interval 2.09-15.51) associated with this band. The presence of these antibodies in the plasma of some mothers of children with autism, as well as the differential findings between mothers of children with early onset and regressive autism may suggest an association between the transfer of IgG autoantibodies during early neurodevelopment and the risk of developing of autism in some children.)
Zimmerman AW, Connors SL, Matteson KJ, Lee LC, Singer HS, Castaneda JA, Pearce DA. Maternal antibrain antibodies in autism. Brain Behav Immun. 2007 Mar;21(3):351-7. Epub 2006 Oct 6. (Specific patterns of antibody reactivity were present in sera from the autism mothers, from 2 to 18 years after the birth of their affected children and were unrelated to birth order. Immunoblotting using specific antigens for myelin basic protein (MBP) and glial acidic fibrillary protein (GFAP) suggests that these proteins were not targets of the maternal antibodies. The identification of specific serum antibodies in mothers of children with autism that recognize prenatally expressed brain antigens suggests that these autoantibodies could cross the placenta and alter fetal brain development.)
Martin LA, Ashwood P, Braunschweig D, Cabanlit M, Van de Water J, Amaral DG. Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism. Brain Behav Immun. 2008 Feb 7; (unpublished at this point) Four rhesus monkeys were exposed prenatally to human IgG collected from mothers of multiple children diagnosed with ASD. Four control rhesus monkeys were exposed to human IgG collected from mothers of multiple typically developing children. Five additional monkeys were untreated controls. Rhesus monkeys gestationally exposed to IgG class antibodies from mothers of children with ASD consistently demonstrated increased whole-body stereotypies across multiple testing paradigms. These monkeys were also hyperactive compared to controls.
Dalton P, Deacon R, Blamire A, Pike M, McKinlay I, Stein J, Styles P, Vincent A. Maternal neuronal antibodies associated with autism and a language disorder. Ann Neurol. 2003 Apr;53(4):533-7. (They detected serum antibodies binding to rodent Purkinje cells and other neurons in a mother of three children: the first normal, the second with autism, and the third with a severe specific language disorder. We injected the serum (0.5-1.0 ml/day) into pregnant mice during gestation and found altered exploration and motor coordination and changes in cerebellar magnetic resonance spectroscopy in the mouse offspring)
Singer HS, Morris CM, Gause CD, Gillin PK, Crawford S, Zimmerman AW. Antibodies against fetal brain in sera of mothers with autistic children. J Neuroimmunol. 2008 Feb;194(1-2):165-72. Epub 2008 Feb 21. (Mothers of autistically affected children (MCAD) had significantly more individuals with Western immunoblot bands at 36 kDa in human fetal and rodent embryonic brain tissue than controls. The density of bands was greater in fetal brain at 61 kDa. If the child had developmental regression then greater reactivity against human fetal brain was seen at 36 and 39 kDa.).
Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN. Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol. 1999 Jun;14(6):388-94. (this article is mainly about the autoimmune excess in the familial group but goes over the familial clusters seen. The statistics are difficult in that the many aspects of disease are included)
Croen LA, Braunschweig D, Haapanen L, Yoshida CK, Fireman B, Grether JK, Kharrazi M, Hansen RL, Ashwood P, Van de Water J. Maternal Mid-Pregnancy Autoantibodies to Fetal Brain Protein: The Early Markers for Autism Study. Biol Psychiatry. 2008 Jun 19. The pattern of maternal mid-gestation antibody reactivity to human fetal brain protein varied by study group and by autism onset type, although most differences did not reach statistical significance. Reactivity to a band at 39 kDa was more common among mothers of children with autism (7%) compared with mothers of mental retardation (0%; p = .09) and general practice control subjects (2%; p = .07), and simultaneous reactivity to bands at 39 kDa and 73 kDa was found only in mothers of children with early onset autism (n = 3).
Russo AF. Anti-metallothionein IgG and levels of metallothionein in autistic families. Swiss Med Wkly. 2008 Feb 9;138(5-6):70-7. (they showed that there was a large excess compared with controls of antibodies to metallothioneins in blood…but this did not seem to correalate with the type of autism or other factors. They take this as indicating that it was not the cause itself but may actually be secondary in some way)
Autoimmunity in autism. Enstrom
AM, Van de Water JA, Ashwood P. Curr Opin Investig Drugs. 2009 May;10(5):463-73.
Activation of the maternal immune system alters
cerebellar development in the offspring. Shi L, Smith SE, Malkova N,
Tse D, Su Y, Patterson PH. Brain Behav Immun.
2009 Jan;23(1):116-23.
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Autoantibodies
found in the family of an autistic child
Silva SC, Correia C, Fesel C, Barreto M, Coutinho AM, Marques C, Miguel TS, Ataide A, Bento C, Borges L, Oliveira G, Vicente AM. Autoantibody repertoires to brain tissue in autism nuclear families. J Neuroimmunol. 2004 Jul;152(1-2):176-82. (plasma of 171 autism children, their parents, and 54 controls, by quantitative immunoblotting. Multiparametric analysis revealed significant differences between patients and controls, and showed that one single reactivity in Section 32 of the blot had the most power to discriminate between these samples. Family correlation coefficients and heritability estimates did not provide any evidence that this reactivity was genetically determined.)
Valicenti-McDermott M, McVicar K, Rapin I, Wershil BK, Cohen H, Shinnar S. Frequency of gastrointestinal symptoms in children with autistic spectrum disorders and association with family history of autoimmune disease. J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S128-36. Family history of autoimmune disease was reported in 38% of the ASD group and 34% of controls and was not associated with a differential rate of GI symptoms.
Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN. Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol. 1999 Jun;14(6):388-94. (surveyed the families of 61 autistic patients and 46 healthy controls using questionnaires. The mean number of autoimmune disorders was greater in families with autism; 46% had two or more members with autoimmune disorders. As the number of family members with autoimmune disorders increased from one to three, the risk of autism was greater, with an odds ratio that increased from 1.9 to 5.5, respectively. In mothers and first-degree relatives of autistic children, there were more autoimmune disorders (16% and 21%) as compared to controls. The most common autoimmune disorders in both groups were type 1 diabetes, adult rheumatoid arthritis, hypothyroidism, and systemic lupus erythematosus. Thirty-nine percent of the controls, but only 11% of the autistic, group, reported allergic symptoms that might cause these illnesses themselves i.e. there is an excess of autoantibodies expected to be associated with various conditions but relatively few symptoms)
Gurney JG, McPheeters ML, Davis MM. Parental report of health conditions and health care use among children with and without autism: National Survey of Children's Health. Arch Pediatr Adolesc Med. 2006 Aug;160(8):825-30 (this looks into the many illnesses of the child, and considers the illnesses of the family)
Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ. Increased prevalence
of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics.
2003 Nov;112(5):e420. (This was mainly autoimmune thyroidism, and rheumatic
fever but also there was an increase in multiple sclerosis but not to a
significant level).
Money J, Bobrow NA, Clarke FR. Autism and autoimmune disease: a family study. J Autism child. Schizophr. 1971:1;146-60.
Cook EH Jr, Perry BD,
Russo AF. Anti-metallothionein IgG and levels of metallothionein in autistic families. Swiss Med Wkly. 2008 Feb 9;138(5-6):70-7. (they showed that there was a large excess compared with controls of antibodies to metallothioneins in blood…but this did not seem to correalate with the type of autism or other factors. They take this as indicating that it was not the cause itself but may actually be secondary in some way)
HLA-DR4 as a risk allele for autism acting in mothers of
probands possibly during pregnancy.
Johnson WG, Buyske S, Mars AE, Sreenath M, Stenroos ES, Williams TA,
Stein R, Lambert GH. Arch Pediatr Adolesc Med. 2009 Jun;163(6):542-6. They found that there was an excess of the
gene in the mothers of the children with autism and suggested a mechanism by
which this might have taken place (causing the production of decreased neuronal
development in the child).