Immunity, Inflammation and Allergy in Autism |
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Immunity in autism cases: complexOne of the major problems with trying to understand the complexity of inflammation is that so many factors may affect each other. As a result it is difficult to work out what is the underlying cause for any complex change as seen in autism. Mostly it is found to be normal but many researchers found reliable, repeatable results that it is specific changes are present. Reviews in autism immunity
There have been a large group of reviewers. In a way this is necessary simply for anyone that is new in the field to somehow get their head around what has taken place so far. Can I recommend the review by Ashwood in 2006. Changes that have been reported to the immune system
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From the top…dendritic cells show the antigens to young lymphocytes,
which should then decide as to whether to form the Th1 or the Th2 format. As
you see, the different types cause either the cell mediated or the antibody
mediated type of immunity. |
It is clear that researchers have been looking hard at this for some time. Warren, Ashwood and Singh deserve a lot for the work.
van Gent T, Heijnen CJ, Treffers PD. Autism and the immune system. J Child Psychol Psychiatry. 1997 Mar;38(3):337-49. Review.
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.
Ashwood P, Wills S, Van de Water J. The immune response in autism: a new frontier for autism research. J Leukoc Biol. 2006 Jul;80(1):1-15. a review. He is suggesting that the immune response is different in autistics compared with controls and hence this permits infection to cause the illness. A wide range. (although this is not really a new frontier in that various researchers have been trying hard in this direction since the 1970s, it is becoming at lease possible due to the
Cohly HH, Panja A. Immunological findings in autism. Int Rev Neurobiol. 2005;71:317-41. Review. (particularly in the brain itself)
van Gent T, Heijnen CJ, Treffers PD. Autism and the immune system. J Child Psychol Psychiatry. 1997 Mar;38(3):337-49. Review.
Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry. 2005 Dec;17(6):485-95. Review. (particularly within the brain: they go into the neuroglial and innate neuroimmune system activation in brain tissue and cerebrospinal fluid of patients with autism)
Krause I, He XS, Gershwin ME, Shoenfeld Y. Brief report: immune factors in autism: a critical review. J Autism Dev Disord. 2002 Aug;32(4):337-45.
Warren RP, Margaretten NC, Pace NC, Foster A. Immune abnormalities in patients with autism. J Autism Dev Disord. 1986 Jun;16(2):189-97.
Autism: an emerging 'neuroimmune
disorder' in search of therapy.
Theoharides TC, Kempuraj
D, Redwood L. Expert Opin Pharmacother.
2009 Sep;10(13):2127-43. This is a large document aimed at trying to
work out what aspects of the immune changes that have been seen may give an
idea as to how treatment might be altered.
Autism and immunity: revisited study. Castellani ML, Conti CM, Kempuraj DJ, Salini V, Vecchiet J, Tete S, Ciampoli C, Conti F, Cerulli G, Caraffa A, Antinolfi P, Galzio R, Shaik Y, Theoharides TC, De Amicis D, Perrella A, Cuccurullo C, Boscolo P, Felaco M, Doyle R, Verrocchio C, Fulcheri M. Int J Immunopathol Pharmacol. 2009 Jan-Mar;22(1):15-9. Review
Immune-glutamatergic
dysfunction as a central mechanism of the autism spectrum disorders. Blaylock RL, Strunecka
A. Curr Med
Chem. 2009;16(2):157-70. this is a review in
which they try to fit everything together that might fit a genetic, toxic,
anatomical etc format and they create an idea that it will involve the immune
and glutamate pathways.
Immunologic and neurodevelopmental
susceptibilities of autism. Pessah
IN, Seegal RF, Lein PJ,
LaSalle J, Yee BK, Van De Water J, Berman RF. Neurotoxicology. 2008 May;29(3):532-45.
Impact of innate immunity in a subset of children with
autism spectrum disorders: a case control study. Jyonouchi
H, Geng L, Cushing-Ruby A, Quraishi
H. J Neuroinflammation.
2008 Nov 21;5:52 This study assessed
whether these clinical features of this ASD subset are associated with atopy, asthma, food allergy (FA), primary immunodeficiency
(PID), or innate immune responses important in viral infections. Innate immune responses were assessed by
measuring production of proinflammatory and
counter-regulatory cytokines by peripheral blood mononuclear cells (PBMCs) in response to agonists of Toll-like receptors (TLRs), with or without pre-treatment of lipopolysaccharide
(LPS), a TLR4 agonist. Clinical features
of the ASD test group were not associated with atopy,
asthma, FA, or PID in our study but may be associated with altered TLR
responses mediating neuro-immune interactions.
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Abnormal Indices: Lymphocytic
These cells are produced in the bone marrow, and are modified into different types to act in specific ways in modifying the immune response to antigens. The finding that such types of lymphocyte act differently, and that they can now be identified has given an opportunity to test to see any difference in autism. Claims are that the lymphocytes show a poor response to mitogens, there is a relatively low level of natural killer (NK cells), which are commonly involved in cytokine release. The suggestion of the lower numbers of NK cells might be that viruses are difficult to remove or infected cells be destroyed. If you read the data below you will see how complex the findings have become.
Warren RP, Foster A, Margaretten NC. Reduced natural killer cell activity in autism. J Am Acad Child Adolesc Psychiatry. 1987 May;26(3):333-5. (little data available)
Fiumara A, Sciotto A, Barone R, D'Asero G, Munda S, Parano E, Pavone L. Peripheral lymphocyte subsets and other immune aspects in Rett syndrome. Pediatr Neurol. 1999 Sep;21(3):619-21. (in fact this is a change in the subsets seen in Rett’s syndrome)
Low C4B levels (Clin Exp Immunol 83: 438-440 1991)
Yonk LJ, Warren RP, Burger RA, Cole P, Odell JD, Warren WL, White E, Singh VK. CD4+ helper T cell depression in autism. Immunol Lett. 1990 Sep;25(4):341-5. (this decrease is difficult to understand but appears to be present regularly. Notably T cell deficiency in mice will give rise to memory and learning impairment, which is put right with the infusion of them)
Ashwood P, Wakefield AJ. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol. 2006 Apr;173(1-2):126-34. (this really follows the finding in the tissues)
Ashwood P,
Anthony A, Pellicer AA, Torrente
F, Walker-Smith JA, Wakefield AJ. Intestinal lymphocyte populations
in children with regressive autism: evidence for extensive mucosal immunopathology. J Clin
Immunol. 2003 Nov;23(6):504-17
Hunter LC, O'Hare A, Herron WJ, Fisher LA, Jones GE. Opioid peptides and dipeptidyl peptidase in autism. Dev Med Child Neurol. 2003 Feb;45(2):121-8. Children with autism had a significantly lower percentage of cells expressing CD3 and CD26, suggesting that they had lower T-cell numbers than their siblings. (Could not find any excess opioid in plasma of autistic children but the CD26/dipeptidyl peptidase antigen was low indicating that T cells were low)
Denney DR, Frei BW, Gaffney GR. Lymphocyte subsets and interleukin-2 receptors in autistic children. J Autism Dev Disord. 1996 Feb;26(1):87-97. A lower percentage of lymphocytes expressing bound interleukin-2 receptors following mitogenic stimulation was also noted, and this too was inversely related to the severity of autistic symptoms. The children with autism had a lower percentage of helper-inducer cells and a lower helper:suppressor ratio
Scifo R, Cioni M, Nicolosi A, Batticane N, Tirolo C, Testa N, Quattropani MC, Morale MC, Gallo F, Marchetti
B. Opioid-immune interactions in autism:
behavioural and immunological assessment during a double-blind treatment with naltrexone. Ann Ist
Super Sanita. 1996;32(3):351-9
The behavioural improvement (naltrexone)
was accompanied by alterations in the distribution of the major lymphocyte
subsets, with a significant increase of the T-helper-inducers (CD4+CD8-) and a
significant reduction of the T-cytotoxic-suppressor
(CD4-CD8+) resulting in a normalization of the CD4/CD8 ratio. Changes in
natural killer cells and activity were inversely related to plasma
beta-endorphin levels.
Yonk LJ, Warren RP, Burger RA, Cole P, Odell JD, Warren WL, White E, Singh VK. CD4+ helper T cell depression in autism. Immunol Lett. 1990 Sep;25(4):341-5. The 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
Gupta S, Aggarwal S, Rashanravan B, Lee T. Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. J Neuroimmunol. 1998 May 1;85(1):106-9. (Intracellular production of cytokines were measured using specific antibodies to various cytokines and anti-CD4 or anti-CD8 monoclonal antibodies by FACScan. Proportions of IFN-gamma+CD4+ T cells and IL-2+CD4+ T cells (Th1), and IFN-gamma+CD8+ and IL-2+CD8+ T cells (TC1) were significantly lower in autistic children as compared to healthy controls. In contrast, IL-4+CD4+ T cells (Th2) and IL-4+CD8+ T cells (TC2) were significantly increased in autism. The proportions of IL-6+ CD4+, IL-6+CD8+ and IL-10+CD4+, IL-10+CD8+ T cells were comparable in autism and control group. This is the method to show the different Th1 and Th2 forms)
Stubbs EG, Crawford ML. Depressed lymphocyte responsiveness in autistic children. J Autism Child Schizophr. 1977 Mar;7(1):49-55. (a poor response to a phytohaemaglutinin as a mitogen)
Warren RP, Margaretten NC, Pace NC, Foster A. Immune abnormalities in patients with autism. J Autism Dev Disord. 1986 Jun;16(2):189-97. (also shows a poor response to mitogens)
T-cell Deficiency (J Autism Child Schizo 7:49-55 1977)
Cohly HH, Panja A. Immunological findings in autism. Int Rev Neurobiol. 2005;71:317-41. (this states specific changes, and goes into the altered ratio of Th1/Th2 lymphocyte subtypes and how this is relatively reliable. The article is a review, however.)
Ferrante P, Saresella M, Guerini FR, Marzorati M, Musetti MC, Cazzullo AG. Significant association of HLA A2-DR11 with CD4 naive decrease in autistic children. Biomed Pharmacother. 2003 Oct;57(8):372-4. (what they are saying is that the cells demonstrating the HLA are much more likely to be CD4 naive (indeed, because their numbers are so low they must have found quite a difference between the autistic and the control groups). They say that this agrees with the idea that an immune imbalance is involved in autism).
Gene expression
profiling of lymphoblasts from autistic and nonaffected sib pairs: altered pathways in neuronal
development and steroid biosynthesis. Hu VW, Nguyen A, Kim KS, Steinberg ME,
Sarachana T, Scully MA, Soldin
SJ, Luu T, Lee NH. PLoS One. 2009
Jun 3;4(6):e5775.
The way this is done is to look and see which genes on the lymphocytic population of autistic children are expressed
as proteins, and compare this with the ones in a control group. They found several genes being used involve
1. Steroid biochemical formation pathway
(including testerone and female hormones), 2 cholesterol
importation into the cell (SCARB1 and SRD5A1 genes), plus a list more. What does not come out is a gene that is a
reliable diagnostic, but it does give an insight into the reasons why other
biochemical changes are seen in the body and brain. They are going particularly into the effect
of the genes, the proteins, and hence the formation of hormones that is
involved. This is a complex article.
MET and autism susceptibility: family and case-control
studies. Sousa I, Clark TG, Toma C, Kobayashi K, Choma M,
Holt R, Sykes NH, Lamb JA, Bailey AJ, Battaglia A, Maestrini E, Monaco AP; International Molecular Genetic
Study of Autism Consortium (IMGSAC). Eur J Hum Genet. 2009 Jun;17(6):749-58. The International Molecular Genetic Study of
Autism Consortium (IMGSAC) genome screen for linkage in affected sib-pair
families identified a chromosome 7q susceptibility locus (AUTS1), that has subsequently shown evidence of increased sharing
in several independent multiplex samples and in two meta-analyses. Taking into
account the location of the MET gene under this linkage peak, and the fact that
it has recently been reported to be associated with autism. Significant results were obtained in both
single locus and haplotype approaches with a single
nucleotide polymorphism in intron 1 (rs38845,
P<0.004) and with one intronic haplotype
(AAGTG, P<0.009) in 325 multiplex IMGSAC families and 10 IMGSAC trios. MET gene is associated with immunesystem regulation,
Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2
and IL-15. Vojdani A, Mumper E, Granpeesheh D, Mielke L, Traver D, Bock K, Hirani K, Neubrander J, Woeller KN, O'Hara N, Usman A,
Schneider C, Hebroni F, Berookhim
J, McCandless J. J Neuroimmunol. 2008 Dec 15;205(1-2):148-54.
we explored the measurement of NK cell activity in
1027 blood samples from autistic children obtained from ten clinics and
compared the results to 113 healthy controls. This counting of NK cells and the
measurement of their lytic activity enabled us to
express the NK cell activity/100 cells. At the cutoff
of 15-50 LU we found that NK cell activity was low in 41-81% of the patients
from the different clinics. Overall, after this correction factor, 45% of the
children with autism still exhibited low NK cell activity, correlating with the
intracellular level of glutathione. Finally, we cultured lymphocytes of
patients with low or high NK cell activity/cell with or without glutathione,
IL-2 and IL-15. The induction of NK cell activity by IL-2, IL-15 and
glutathione was more pronounced in a subgroup with very low NK cell activity.
We conclude that that 45% of a subgroup of children with autism suffers from
low NK cell activity, and that low intracellular levels of glutathione, IL-2
and IL-15 may be responsible.
Altered gene expression and function of
peripheral blood natural killer cells in children with autism. Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen RL, Pessah
IN, Hertz-Picciotto I, Van de Water JA, Sharp FR, Ashwood P. Brain Behav Immun. 2009
Jan;23(1):124-33. Flow cytometric analysis of NK
cells demonstrated increased production of perforin, granzyme B, and interferon gamma (IFNgamma)
under resting conditions in children with ASD (p<0.01). Following NK cell
stimulation in the presence of K562 target cells, the cytotoxicity
of NK cells was significantly reduced in ASD compared with controls
(p<0.02). Furthermore, under similar stimulation conditions the presence of perforin, granzyme B, and IFNgamma in NK cells from ASD children was significantly
lower compared with controls (p<0.001).
Serum levels of P-selectin in
men with high-functioning autism. Iwata Y, Tsuchiya KJ, Mikawa S, Nakamura K, Takai Y, Suda S, Sekine Y, Suzuki K, Kawai
M, Sugihara G, Matsuzaki H, Hashimoto K, Tsujii M, Sugiyama T, Takei N, Mori N. Br J Psychiatry. 2008 Oct;193(4):338-9. The selectin family
of adhesion molecules plays a prominent role in immune/inflammatory responses.
We determined the serum levels of three types of soluble-form selectin (sP, sL and sE) in 15 men with
high-functioning autism and 22 age-matched healthy controls by enzyme-linked immunosorbent assay. Levels of sP-selectin
and sL-selectin were significantly lower in patients
than in controls. Selectins
are involved in the rolling of lymphocytes and their migration.
Cellular and
mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism.
James SJ, Rose S, Melnyk S, Jernigan S, Blossom S, Pavliv O, Gaylor DW. FASEB J.
2009 Aug;23(8):2374-83.
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Abnormal indices: cytokines and antibodies
The
worry has been for some time that the cytokines (peptides that are produced by
the immune system for the modulation of other cells) are also active in the
brain as modulators of neurological function. E.g. interferon gamma, and tumour necrosis factor alpha. Similarly neuropeptides
may work the other way. Also there
have been demonstrations of changes in antibody levels but they are not
enormous, and are not expected to cause lack of immunity. The claim of T1/T2 ratio types being more towards the T2
than in the normal blood seems to be repeated by other workers. The cytokines being involved
in brain development (in animal experiments) give some insight into the
potential involvement possible in autism.
The depressingly variant levels of immunoglobulin in
autistics compared with controls is still under argument. Possibly one of the best look into this is
done by Heuer et al in 2009 (see below). Genetic alterations to the immunoglobulin
pathway have been pointed out but are not reliable: PTEN (a negative regulator of
the PI3K/AKT pathway) [Boccone et al., 2006; Butler et al., 2005; Goffin,
Hoefsloot, Bosgoed, Swillen, & Fryns, 2001; Kwon
et al., 2006], MET (a receptor tyrosine kinase) [Campbell et al., 2006, 2007], and Ca(V)1.2 (an L-type calcium channel) [Splawski
et al., 2004].
Singh VK. Plasma increase of interleukin-12 and interferon-gamma. Pathological significance in autism. J Neuroimmunol. 1996 May;66(1-2):143-5. The levels of IL-12 and IFN-gamma were significantly (P < or = 0.05) higher in patients as compared to controls. However, IFN-alpha, IL-6, TNF-alpha, and sICAM-1 levels did not significantly differ between the two groups. Because macrophage-derived IL-12 is known to selectively induce IFN-gamma in T helper type-1 (Th-1) cells, it is suggested that IL-12 and IFN-gamma increases may indicate antigenic stimulation of Th-1 cells pathogenetically linked to autoimmunity in autism.
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)
Low or absent IgA (Autism Develop Dis 16: 189-197 1986)
Zimmerman A, Hyonouchi H, Comi A et al. Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol 2005 Sep;33(3):195-201. Blood cytokines. No difference was found between autism and control except with TNF receptor II elevated (P<0.02). See CSF
Jyonouchi H, Sun S, Le H. Proinflammatory and
regulatory cytokine production associated with innate and adaptive immune
responses in children with autism spectrum disorders and developmental
regression. J Neuroimmunol.
2001 Nov 1;120(1-2):170-9. Non-specific immune stimulants (in vitro) of
polymorphs or macrophages produced several cytokines to much higher levels than
controls.
Croonenberghs J, Wauters A, Devreese K, Verkerk R, Scharpe S, Bosmans E, Egyed B, Deboutte D, Maes M. Increased serum albumin, gamma globulin, immunoglobulin IgG, and IgG2 and IgG4 in autism. Psychol Med. 2002 Nov;32(8):1457-63. (increased serum albumin and IgG, and by a specific IgG subclass profile, i.e. increased serum IgG2 and IgG4. The increased serum concentrations of IgGs in autism may point towards an underlying autoimmune disorder and/or an enhanced susceptibility to infections resulting in chronic viral infections, whereas the IgG subclass skewing may reflect different cytokine-dependent influences on autoimmune B cells and their products.)
Trajkovski V, Ajdinski L, Spiroski M. Plasma concentration of immunoglobulin
classes and subclasses in children with autism in the
Ashwood P, Wakefield AJ. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol. 2006 Apr;173(1-2):126-34.
Ashwood P, Anthony A, Torrente F, Wakefield AJ. Spontaneous mucosal lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms: mucosal immune activation and reduced counter regulatory interleukin-10. J Clin Immunol. 2004 Nov;24(6):664-73. (these last three basically show that there is a specific change in the cytokines, leukocytes and interleukins in the mucosal walls of biopsies taken from symptomatic autistic children)
Engstrom, A, Ohlston S, Stubbs et al. Decrease expression of CD95 (FAS/APO-1) on CD4+ T-lymphocytes from participants with autism. J. Dev. Phys. Disabil. 2003;15:155-63.
Sweeten TL, Posey DJ, Shankar S, McDougle CJ. High nitric oxide production in autistic disorder: a possible role for interferon-gamma. Biol Psychiatry. 2004 Feb 15;55(4):434-7. These results confirm that plasma NO is high in some children with autism and suggest that this elevation may be related to IFN-gamma activity.
Gupta S, Aggarwal S, Rashanravan B, Lee T. Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism. J Neuroimmunol. 1998 May 1;85(1):106-9. (Intracellular production of cytokines were measured using specific antibodies to various cytokines and anti-CD4 or anti-CD8 monoclonal antibodies by FACScan. Proportions of IFN-gamma+CD4+ T cells and IL-2+CD4+ T cells (Th1), and IFN-gamma+CD8+ and IL-2+CD8+ T cells (TC1) were significantly lower in autistic children as compared to healthy controls. In contrast, IL-4+CD4+ T cells (Th2) and IL-4+CD8+ T cells (TC2) were significantly increased in autism. The proportions of IL-6+ CD4+, IL-6+CD8+ and IL-10+CD4+, IL-10+CD8+ T cells were comparable in autism and control group. This was done in cell culture)
Molloy
CA, Morrow AL, Meinzen-Derr J, Schleifer
K, Dienger K, Manning-Courtney P, Altaye
M, Wills-Karp M. Elevated cytokine levels in children with autism spectrum
disorder. J Neuroimmunol. 2006 Mar;172(1-2):198-205.
Epub 2005 Dec 19.
(This study compared production of IL-2, IFN-gamma, IL-4, IL-13, IL-5
and IL-10 in peripheral blood mononuclear cells from 20 children with autism
spectrum disorder to those from matched controls. Levels of all Th2 cytokines
were significantly higher in cases after incubation in media alone, but the
IFN-gamma/IL-13 ratio was not significantly different between cases and
controls. Cases had significantly higher IL-13/IL-10 and IFN-gamma/IL-10 than
controls. Conclusion: Children with ASD had increased activation of both Th2
and Th1 arms of the adaptive immune response, with a Th2 predominance, and
without the compensatory increase in the regulatory cytokine IL-10. The problem with this is the interpretation,
which is better described in the paper itself)
Possible immunological disorders in
autism: concomitant autoimmunity and immune tolerance.
Kawashti MI, Amin OR,
Rowehy NG.
Egypt J Immunol.
2006;13(1):99-104 They used simple elisa methods to measure the antibody levels against common
conditions in autistic children compared to controls. Results revealed high seropositivity
for autoantibodies to casein and gluten: 83.3% and
50% respectively in autistic children as compared to 10% and 6.7% positivity in the control group. Surprisingly, circulating
anti-measles, anti-mumps and anti-rubella IgG were
positive in only 50%, 73.3% and 53.3% respectively as compared to 100% positivity in the control group. Anti-CMV IgG was positive in 43.3% of the autistic children as
compared to 7% in the control group.
Okada K, Hashimoto K, Iwata Y, Nakamura K, Tsujii M, Tsuchiya KJ, Sekine Y, Suda S, Suzuki K, Sugihara G, Matsuzaki H, Sugiyama T, Kawai M, Minabe Y, Takei N, Mori N. Decreased serum levels of transforming growth factor-beta1 in patients with autism.
Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jan 30;31(1):187-90. Epub 2006 Oct 6 (TGF-beta 1 is involved in the modification of lymphocytes and other immune cells. They looked for various cytokines).
Zhao B, Schwartz JP. Involvement of cytokines in normal CNS development and neurological diseases: recent progress and perspectives. J Neurosci Res. 1998 Apr 1;52(1):7-16. They worked on transgenic mice in which specific cytokines were in the genetics of the animal or not. They then looked for changes in the brain tissue. What they found was that small changes in cytokines could make a difference in neurological development. What we are unclear about at this point is whether many of the cytokines in the periphery of an autistic person are actually being produced incorrectly…and why this would be associated with autism increasing since the early 1990s.
Reduced levels of immunoglobulin in
children with autism correlates with behavioral
symptoms. Heuer L, Ashwood P, Schauer J, Goines P, Krakowiak P, Hertz-Picciotto I, Hansen R, Croen LA, Pessah IN, Van de Water J. Autism
Res. 2008 Oct;1(5):275-83.
Children with autism had a reduced level of plasma IgM
(0.670.06 mg/mL) compared to TD (0.79+/-0.05 mg/mL; P<0.05). Ig levels were
negatively correlated with ABC scores for all children (IgG:
r=-0.334, P<0.0001; IgM: r=-0.167, P=0.0285).
CONCLUSION: Children with AU have significantly reduced levels of plasma IgG and IgM compared to both
developmental delay and typical delay controls, suggesting an underlying defect
in immune function. This reduction in specific Ig
levels correlates with behavioral severity, where
those patients with the highest scores in the behavioral
battery have the most reduced levels of IgG and IgM. Children with
AU have a significantly reduced level of plasma IgG
(5.39+/-0.29 mg/mL) compared to the TD (7.72+/-0.28
mg/mL; P<0.001) and DD children (8.23+/-0.49 mg/mL; P<0.001).
Preliminary evidence of the in vitro
effects of BDE-47 on innate immune responses in children with autism spectrum
disorders. Ashwood P, Schauer J, Pessah IN, Van de
Water J. J Neuroimmunol.
2009 Mar 31;208(1-2):130-5. They tried
to see if the compound 2,2',4,4'-tetrabrominated biphenyl, which is apparently
a common environmental contaminant, had any in vitro effect on cytokine
production. It did, and they discussed
to see if this could be involved in autism.
Elevated immune response in the brain
of autistic patients.
Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Ji L, Brown T, Malik M. J Neuroimmunol. 2009 Feb
15;207(1-2):111-6. They looked at the
levels of cytokines in the brains of autistic vs
control patients. They showed that proinflammatory cytokines (TNF-alpha, IL-6 and GM-CSF), Th1
cytokine (IFN-gamma) and chemokine (IL-8) were
significantly increased in the brains of ASD patients compared with the
controls. However the Th2 cytokines (IL-4, IL-5 and IL-10) showed no
significant difference. The Th1/Th2 ratio was also significantly increased in
ASD patients. Conclusion: ASD patients displayed an increased innate and
adaptive immune response through the Th1 pathway. This is the finding that would be expected if
there was an increase in the immune and autoimmune pathways.
Increased IgG4 levels in children with
autism disorder. Enstrom A, Krakowiak P, Onore C, Pessah IN, Hertz-Picciotto I, Hansen RL, Van de Water JA, Ashwood P. Brain Behav Immun. 2009
Mar;23(3):389-95.
Low-dose naltrexone
for disease prevention and quality of life. Brown N, Panksepp J. Med Hypotheses. 2009 Mar;72(3):333-7. Accumulating evidence suggests that low dose naltrexone can promote health supporting immune-modulation
which may reduce various oncogenic and inflammatory
autoimmune processes. That is not really
surprising and it is interesting in this hypothesis that they are connecting up
the effects seen with various aspects of the disease and how LDN may actually
be the answer.
Impact of innate immunity in a subset of children with
autism spectrum disorders: a case control study. Jyonouchi
H, Geng L, Cushing-Ruby A, Quraishi
H. J Neuroinflammation.
2008 Nov 21;5:52. In ASD there seems to
be a subset that can be clinically distinguished from other ASD children
because of frequent infections (usually viral) accompanied by worsening
behavioural symptoms and/or loss/decrease in acquired skills. They compared the group apparently without
the increase in infections with the ASD patients without this. Clinical features of the ASD test group were
not associated with atopy, asthma, FA, or PID in our
study but may be associated with altered TLR responses mediating neuro-immune interactions.
Chemistry, and tests also did not appear to show any association.
Decreased transforming growth factor beta1 in autism: a
potential link between immune dysregulation and
impairment in clinical behavioral outcomes.
Ashwood P, Enstrom A, Krakowiak P, Hertz-Picciotto I,
Hansen RL, Croen LA, Ozonoff
S, Pessah IN, Van de Water J. J Neuroimmunol. 2008 Nov
15;204(1-2):149-53.
Elevated immune response in the brain
of autistic patients. Li X, Chauhan
A, Sheikh AM, Patil S, Chauhan
V, Li XM, Ji L, Brown T, Malik
M. J Neuroimmunol.
2009 Feb 15;207(1-2):111-6. Our results
showed that proinflammatory cytokines (TNF-alpha,
IL-6 and GM-CSF), Th1 cytokine (IFN-gamma) and chemokine
(IL-8) were significantly increased in the brains of ASD patients compared with
the controls. However the Th2 cytokines (IL-4, IL-5 and IL-10) showed no
significant difference. The Th1/Th2 ratio was also significantly increased in
ASD patients
Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2
and IL-15. Vojdani A, Mumper E, Granpeesheh D, Mielke L, Traver D, Bock K, Hirani K, Neubrander J, Woeller KN, O'Hara N, Usman A,
Schneider C, Hebroni F, Berookhim
J, McCandless J. J Neuroimmunol. 2008 Dec 15;205(1-2):148-54.
Serum anti-nuclear antibodies as a
marker of autoimmunity in Egyptian autistic children.
Association of family history of
autoimmune diseases and autism spectrum disorders. Atladóttir HO, Pedersen MG, Thorsen
P, Mortensen PB, Deleuran B, Eaton WW, Parner ET. Pediatrics.
2009 Aug;124(2):687-94. A total of 3325 children were
diagnosed with ASDs, of which 1089 had an infantile
autism diagnosis. Increased risk of ASDs was observed
for children with a maternal history of rheumatoid arthritis and celiac
disease. Also, increased risk of infantile autism was observed for children
with a family history of type 1 diabetes.
Tight junctions, intestinal permeability, and
autoimmunity: celiac disease and type 1 diabetes
paradigms. Visser J, Rozing
J, Sapone A, Lammers K, Fasano A. Ann N Y Acad Sci. 2009
May;1165:195-205. In this respect, CD
represents a unique autoimmune disorder because a close genetic association
with HLA-DQ2 or HLA-DQ8 haplotypes and, more
importantly, the environmental trigger (the gliadin
fraction of gluten-containing grains wheat, barley, and rye) are known.
Conversely, the trigger for autoimmune destruction of pancreatic ss cells in T1D is unclear.
This is an attempt to suggest that other autoimmune diseases may be
associated with gliadin sensitivity.
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Macrophage changes (beware! Some publications talks about ‘mononuclear cells’ and may be meaning lymphocytes!)
Elevated number of circulating monocytes (macrophages in tissue) with increased monocyte numbers correlating with plasma interferon gamma and neopterins. Also see the page on pterins and peridines. Macrophages are involved with the uptake into the cells and destruction of complex, often large items in blood and tissues. They are designed to be directed to them by cytokines and the presence of antibodies on the surface of the items to be destroyed. There is little data on turnover of the monocytes except for the neopterins.
Sweeten
TL, Posey DJ, McDougle CJ.
High blood monocyte counts and neopterin
levels in children with autistic disorder. Am J Psychiatry. 2003 Sep;160(9):1691-93. (They basically took the numbers of various
white cells in the blood of a range of autistic patients. The interpretation is difficult. The higher
plasma monocyte counts and neopterin
levels reported here in autism are similar in magnitude to those seen in
multiple sclerosis. Serum neopterin levels have also
been found to be high in neuropsychiatric disorders
in which inflammatory processes may be active, such as Alzheimer’s disease.
Brambilla F, Guareschi-Cazzullo A, Tacchini C, Musetti C, Panerai AE, Sacerdote P. Beta-endorphin and cholecystokinin 8 concentrations in peripheral blood mononuclear cells of autistic children. Neuropsychobiology. 1997;35(1):1-4. (Mean beta-EP values were significantly higher in AU than in PDD and control no differences in CCK-8 values. These are peptides with activity in the brain)
Differential monocyte
responses to TLR ligands in children with autism
spectrum disorders. Enstrom AM, Onore CE, Van de Water JA, Ashwood
P. Brain Behav Immun. 2009 Aug 8.
we isolated peripheral blood monocytes from 17
children with ASD and 16 age-matched typically developing (TD) controls and
stimulated these cell cultures in vitro with distinct toll-like receptors (TLR)
ligands: TLR 2 (lipoteichoic
acid; LTA), TLR 3 (poly I:C), TLR 4 (lipopolysaccharide;
LPS), TLR 5 (flagellin), and TLR 9 (CpG-B). Supernatants were harvested from the cell cultures
and pro-inflammatory cytokine responses for IL-1beta, IL-6, IL-8, TNFalpha, MCP-1, and GM-CSF were determined by multiplex Luminex analysis. After in vitro challenge with TLR ligands, differential cytokine responses were observed in monocyte cultures from children with ASD compared with TD
control children. In particular, there was a marked increase in
pro-inflammatory IL-1beta, IL-6, and TNFalpha
responses following TLR 2, and IL-1beta response following TLR 4 stimulation in
monocyte cultures from children with ASD (p<0.04).
Conversely, following TLR 9 stimulation there was a decrease in IL-1beta, IL-6,
GM-CSF, and TNFalpha responses in monocyte
cell cultures from children with ASD compared with controls (p<0.05). This is an interesting finding but it is
difficult to work out what it will do in vivo
Impact of innate immunity in a subset of children with
autism spectrum disorders: a case control study. Jyonouchi
H, Geng L, Cushing-Ruby A, Quraishi
H. J Neuroinflammation.
2008 Nov 21;5:52 This study assessed
whether these clinical features of this ASD subset are associated with atopy, asthma, food allergy (FA), primary immunodeficiency
(PID), or innate immune responses important in viral infections. Innate immune responses were assessed by
measuring production of proinflammatory and
counter-regulatory cytokines by peripheral blood mononuclear cells (PBMCs) in response to agonists of Toll-like receptors (TLRs), with or without pre-treatment of lipopolysaccharide
(LPS), a TLR4 agonist. Clinical features
of the ASD test group were not associated with atopy,
asthma, FA, or PID in our study but may be associated with altered TLR
responses mediating neuro-immune interactions.
Preliminary evidence of the in vitro
effects of BDE-47 on innate immune responses in children with autism spectrum
disorders. Ashwood P, Schauer J, Pessah
IN, Van de Water J. J Neuroimmunol.
2009 Mar 31;208(1-2):130-5. A common environmental contaminant,
2,2',4,4'-tetrabrominated biphenyl (BDE-47), was tested for differential
effects on the immune response of peripheral blood mononuclear cells (PBMC)
isolated from children with ASD (n=19) and age-matched typically developing
controls (TD, n=18). PBMC were exposed in vitro to either 100 nM or 500 nM BDE-47, before
challenge with bacterial lipopolysaccharide (LPS), an
innate immune activator, with resultant cytokine production measured using the Luminex multiplex platform. Preincubation
with 500 nM BDE-47 significantly increased the
stimulated release of the inflammatory chemokine IL-8
(p<0.04) in cells cultured from subjects with ASD but not in cells from typically
developing controls. These data suggest that in vitro exposure of PBMC to
BDE-47 affects cell cytokine production in a pediatric
population. Moreover, PBMC from the ASD subjects were differentially affected
when compared with the TD controls suggesting a biological basis for altered
sensitivity to BDE-47 in the ASD population.
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Immunoglobulin
treatment produced
improvement clinically
Immunoglobulins (antibodies) might be
injected into a patient as a treatment for a non-specific condition; almost as
if there was an ongoing infection that could either be prevented or got rid of
in some way. This sort of treatment has
been used in the past as an experimental method of discovering new illnesses
because, if it works, then it would be possible to work out the sort of immune
mistake the body is making. It must
always be remembered that long term immunoglobulin treatment has side effects
basically due to antibodies being produced by the body against some of the
factors in the injection. The recent
work by Boris et al agrees with Gupta,
who seems to be the major doctor in the field that is happy with its advantage but one study by Niedhofer et al could find no
advantage to the treatment.
Koski CL, Patterson JV. Intravenous immunoglobulin use for neurologic diseases. J Infus Nurs. 2006 May-Jun;29(3 Suppl):S21-8. Review (this shows that Ig has been used in many different conditions…and many have been claimed to be an advantage)
Gupta et al., Treatment of children with autism with intravenous immunoglobulin. J Child Neurol. 1999 Mar;14(3):203-5. No abstract available.
Gupta et al., found IVIG benefited 4 of 10 children, with 1 case of marked improvement. This is an expensive treatment, as the immunoglobulins need to be collected from hundreds or thousands of human donors.
Boris m, Goldblatt A, Edelson SM; Improvement in children with autism treated with intravenous gamma globulin. Journal of Nutritional & Environmental Medicine, Dec 2005; 15(4): 169-176. Twenty six autistic children received intravenous gamma globulin (IVIG) every 4 weeks for 6 months at a dose of 400mg/Kg. Aberrant behaviours, speech, hyperactivity, inappropriate actions and social interactions significantly improved. However 22 of the 26 children regressed within 4 months after discontinuing IVIG. The finding is in itself exceptionally interesting and should be retested using a blind study.
Gupta S, Aggarwal S, Heads C. Dysregulated immune system in children with autism: beneficial effects of intravenous immune globulin on autistic characteristics. J Autism Dev Disord. 1996 Aug;26(4):439-52.
Gupta S. Immunological treatments for autism. J Autism Dev Disord. 2000 Oct;30(5):475-9. (a brief review of various immunological treatments).
Schneider CK, Melmed RD, Barstow LE, Enriquez FJ, Ranger-Moore J, Ostrem JA. Oral human immunoglobulin for children with autism and gastrointestinal dysfunction: a prospective, open-label study. J Autism Dev Disord. 2006 Nov;36(8):1053-64. (the idea is that the antibodies will protect the gut from some unknown factor. The claim is that 50% of children improved but this form of study is inadequate and requires double blind studies to show definite improvement).
Niederhofer H, Staffen W, Mair A.
Immunoglobulins as an alternative strategy
of psychopharmacological treatment of children with autistic disorder. Neuropsychopharmacology.
2003 May;28(5):1014-5. Epub 2003 Mar 26. (In a
cross over blind trial they could show no advantage to the use of immunoglobulins but were only using 12 ASD patients. They warn that only specific cases may
respond to the treatment).
Fugenberg HH, Singh VK, Emerson D. Immunodiagnosis and
immunotherapy in autistic children. J Neuroimmunol 1987;16:58-9.
Plioplys AV. Intravenous
immunoglobulin treatment of children with autism. J Child Neurol. 1998 Feb;13(2):79-82. (this shows only a minor improvement and
then goes into the costs and potential risks making it difficult to justify
except as part of a scientific study)
DelGiudice-Asch G, Simon L, Schmeidler J, Cunningham-Rundles C, Hollander E. Brief report: a pilot open clinical trial of intravenous immunoglobulin in childhood autism. J Autism Dev Disord. 1999 Apr;29(2):157-60. (no full report).
A double-blind, placebo-controlled
trial of oral human immunoglobulin for gastrointestinal dysfunction in children
with autistic disorder. Handen BL, Melmed RD, Hansen RL, Aman MG,
Burnham DL, Bruss JB, McDougle
CJ. J Autism Dev
Disord. 2009 May;39(5):796-805. A randomized,
double-blind, placebo-controlled, parallel groups, dose-ranging study of oral,
human immunoglobulin (IGOH 140, 420, or 840 mg/day) was utilized with 125
children (ages 2-17 years) with autism and persistent GI symptoms. Endpoint
analysis revealed no significant differences across treatment groups on a
modified global improvement scale. The
fact that no effect was found in this study is important.
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Inflammatory response to dietary and bacterial proteins in autism
Always the idea of the ‘leaky gut’ is that proteins enter the gut wall and an immune and inflammatory response takes place to them. This is the sort of thing that is presumed to be taking place in other inflammatory bowel diseases. However, histopathologically the changes seen in the gut wall in autism are different to the other IBDs and hence this cannot be assumed. The lack of calprotectin appearing in the faeces (it is found there in UC) suggests that the response is not an acute inflammatory response in autism. Vojdani and Jyonouchi’ groups tended to do their tests in vitro but their ability to show a difference between autistic groups and controls is interesting. The cross reaction between Purkinje cells and the immune response to diet proteins gliadin in autism was only found in a subsection of autism cases. Experiments looking for antibodies are always difficult in that the sensitivity of the tests can be made extremely high and the finding of cross reactive antibodies between various factors must be repeated with titres as an important factor. They checked to see if the patients with no histopathology changes had the same immune changes as the ones that did, they could show an association between the histopathology and the immune response to the food.
Jyonouchi H, Sun
S, Itokazu N. Innate immunity associated with inflammatory
responses and cytokine production against common dietary proteins in patients
with autism spectrum disorder. Neuropsychobiology. 2002;46(2):76-84. (They showed an inflammatory response in vitro
to the dietary proteins and they suggest that this may be the cause of the
inflammatory changes in the gut wall).
Vojdani A, O'Bryan T, Green JA, Mccandless
J, Woeller KN, Vojdani E, Nourian AA, Cooper EL. Immune response to dietary
proteins, gliadin and cerebellar
peptides in children with autism. Nutr Neurosci. 2004 Jun;7(3):151-61.
A subgroup of patients with autism produce antibodies against Purkinje
cells and gliadin peptides and these cross reacted
i.e. they appeared to interact with the same antigenic site.
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. They used casein, gliadin, streptokinase and ethylmercury in vitro to show interaction with lymphocyte sites CD26 and DPP IV and suggest this will create an immune reaction in vivo.
Vojdani A, Bazargan M, Vojdani E, Samadi J, Nourian AA, Eghbalieh N, Cooper EL. Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease. Clin Diagn Lab Immunol. 2004 May;11(3):515-24. They are talking about the dipeptidyl peptidase IV present on the surface of the lymphocyte. They show that the gliadin and the HSP60 (which gives all immunity a push) increase antibodies to DPP.
Vojdani A, Campbell AW, Anyanwu E, Kashanian A, Bock K, Vojdani E. Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A. J Neuroimmunol. 2002 Aug;129(1-2):168-77. Erratum in: J Neuroimmunol 2002 Sep;130(1-2):248. Using autism plasma and healthy controls by means of enzyme-linked immunosorbent assay (ELISA) testing. The antigens were myelin basic protein (MBP), myelin-associated glycoprotein (MAG), ganglioside (GM1), sulfatide (SULF), chondroitin sulfate (CONSO4), myelin oligodendrocyte glycoprotein (MOG), alpha,beta-crystallin (alpha,beta-CRYS), neurofilament proteins (NAFP), tubulin and three cross-reactive peptides, Chlamydia pneumoniae (CPP), streptococcal M protein (STM6P) and milk butyrophilin (BTN). Autistic children showed the highest levels of IgG, IgM and IgA antibodies against all neurologic antigens as well as the three cross-reactive peptides. (beware!!)
Jyonouchi H, Geng L, Ruby A, Reddy C, Zimmerman-Bier B. Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders. J Pediatr. 2005 May;146(5):605-10. Complex demonstration of dietary proteins causing the release of cytokines (in vitro). TNF alpha release autism vs control
Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology. 2005;51(2):77-85. (findings indicate intrinsic defects of innate immune responses in gastrointestinal histopathology(+) ASD children but not in non-allergic food hypersensitive or gastrointestinal histopathology(-) ASD children, suggesting a possible link between GI and behavioural symptoms mediated by innate immune abnormalities.)
Lucarelli S, Frediani T, Zingoni AM, Ferruzzi F, Giardini O, Quintieri F, Barbato M, D'Eufemia P, Cardi E. Food allergy and infantile autism. Panminerva Med. 1995 Sep;37(3):137-41Lucarelli et al, Food allergy and infantile autism. Panminerva Med. 1995 Sep;37(3):137-41. (avoiding foods to which allergy is present improves clinical symptoms). They noticed a marked improvement in the behavioural symptoms of patients after a period of 8 weeks on an elimination diet and we found high levels of IgA antigen specific antibodies for casein, lactalbumin and beta-lactoglobulin and IgG and IgM for casein. It was not clear how they were sure that this was an allergic response.
Murch S. Diet, immunity, and autistic spectrum disorders. J Pediatr. 2005 May;146(5):582-4. (a short review).
Latcham F, Merino F, Lang A, Garvey J, Thomson MA, Walker-Smith JA, Davies SE, Phillips AD, Murch SH. A consistent pattern of minor immunodeficiency and subtle enteropathy in children with multiple food allergy. J Pediatr. 2003 Jul;143(1):39-47.
Possible immunological disorders in
autism: concomitant autoimmunity and immune tolerance
Kawashti MI, Amin OR, Rowehy NG. Egypt J Immunol. 2006;13(1):99-104 They used simple elisa methods to measure the antibody levels against common conditions in autistic children compared to controls. Results revealed high seropositivity for autoantibodies to casein and gluten: 83.3% and 50% respectively in autistic children as compared to 10% and 6.7% positivity in the control group. Surprisingly, circulating anti-measles, anti-mumps and anti-rubella IgG were positive in only 50%, 73.3% and 53.3% respectively as compared to 100% positivity in the control group. Anti-CMV IgG was positive in 43.3% of the autistic children as compared to 7% in the control group.
Food allergy and autism spectrum disorders: is there a
link? Jyonouchi H. Curr Allergy Asthma Rep.
2009 May;9(3):194-201. The group says they have found an increase in food
allergy in autistics…and in this article they suggest that one causes the other.
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Immune response (non specific)
This goes through the complex interactions between food, and other antigens in the autistic child. The suggestion is that elements of the disease are caused by the immune response and, as this will vary from patient to patient, a varying clinical condition will result. It is clear that Mantoux tests are valid in autistic children, that they do respond to vaccines, that they produce pus, and their white cell response (and C-RP) is normal following infective or inflammatory conditions. Hence it is not surprising that non-specific responses are not particularly odd in autistic children and that changes are as if there is an immune stimulation taking place already in some way. See normal indices below.
Ashwood P, Wills S, Van de Water J. The immune response in autism: a new frontier for autism research. J Leukoc Biol. 2006 Jul;80(1):1-15. a review. He is suggesting that the immune response is different in autistics compared with controls and hence this permits infection to cause the illness. The article discusses the interaction between neuropeptides and cytokines, autoantibodies and brain tissue, and other factors. An excellent article.
Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology. 2005;51(2):77-85.
Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M. Activation of the inflammatory response system in autism. Neuropsychobiology. 2002;45(1):1-6. (Measured the production of interleukin (IL)-6, IL-10, the IL-1 receptor antagonist (IL-1RA), interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha by whole blood and the serum concentrations of IL-6, the IL-2 receptor (IL-2R) and IL-1RA. RESULTS: This study showed a significantly increased production of IFN-gamma and IL-1RA and a trend toward a significantly increased production of IL-6 and TNF-alpha)
Stubbs EG. Autistic children exhibit undetectable hemagglutination-inhibition antibody titers despite previous rubella vaccination. J Autism Child Schizophr. 1976 Sep;6(3):269-74. (This has not been repeated and indeed autistic patients did appear to respond to MMR vaccine. There has not been a report of rubella cases in the autistic cases that have received the vaccines)
Impact of innate immunity in a subset of children with autism spectrum disorders: a case control study. Jyonouchi H, Geng L, Cushing-Ruby A, Quraishi H. J Neuroinflammation. 2008 Nov 21;5:52 They found no major difference between the autistic children and controls in clinical allergic aspects. This is except for a specific Toll like receptor on mononuclear cells in blood.
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Normal Indices in autistic children.
Stern L, Francoeur MJ, Primeau MN, Sommerville W, Fombonne E, Mazer BD. Immune function in autistic children. Ann Allergy Asthma Immunol. 2005 Dec;95(6):558-65. (Most of the autistic children studied had normal immune function, suggesting that routine immunologic investigation is unlikely to be of benefit in most autistic children and should be considered only when there is a history suggestive of recurrent infections. They did not try to copy any of the findings from elsewhere e.g. autoantibodies or Th1/Th2 ratios. Their samples had been in the fridge for 7-8 years before testing)
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Leptins increased in blood in autism
Ashwood P, Kwong C, Hansen
R, Hertz-Picciotto I, Croen L, Krakowiak P, Walker
W, Pessah IN, Van
de Water J. Brief report: plasma leptin levels are elevated in autism: association with
early onset phenotype? J Autism Dev Disord.
2008 Jan;38(1):169-75. Epub 2007 Mar 9 (Children with autism had significantly higher
plasma leptin levels compared with typically
developing controls (p<.006). When further sub-classified into regression or
early onset autism, children with early onset autism had significantly higher
plasma leptin levels compared with children with regressive
autism (p<.042), typically developing controls (p<.0015), and
developmental disability controls (p<.004).
Remember that leptins are proteins that are
found on the surface of cells that are directly involved in the interaction
between cells and the immune response of the cells)
Brain Inflammatory Markers
It
would be expected if there was infection, irritation, autoimmunity and many
other factors, to see inflammation in the brain. Many factors are simply not seen as
alterations in standard structure or major CSF changes. While earlier studies did not show evidence of astrogliosis
or microglial activation more recent work has
suggested a role for neuroglial activation and neuroinflammation in autism (for review, see Laurence and Fatemi, 2005; Pardo et al.,
2005). A role for neuroglial activation in autism is
suggested by altered expression of glial fibrillary acidic protein (GFAP), a marker of astroglial activation, in brain (Ahlsen
et al., 1993; Vargas et al., 2005) and cerebral spinal fluid (Ahlsen et al., 1993; Rosengren et
al., 1992) of subjects with autism. Furthermore, antibodies against GFAP have
been shown to be increased in the
plasma of subjects with autism (Singh et al,
1997). Vargas et al (2005) also demonstrated an altered pattern of cytokine
expression in brains from subjects with autism including increased expression
of pro-inflammatory chemokines macrophage chemoattractant protein-1 and thymus and activation
regulated chemokine and pro-inflammatory cytokines
including interleukin-6 and interleukin-10 (Pardo et
al., 2005) suggesting neuroinflammation is also
associated with autism.
Glial fibrillary acidic protein in the cerebrospinal fluid of children with autism and other neuropsychiatric disorders. Ahlsén G, Rosengren L, Belfrage M, Palm A, Haglid K, Hamberger A, Gillberg C. Biol Psychiatry. 1993 May 15;33(10):734-43
A sensitive ELISA for glial fibrillary acidic protein: application in CSF of children. Rosengren LE, Ahlsén G, Belfrage M, Gillberg C, Haglid KG, Hamberger A. J Neurosci Methods. 1992 Sep;44(2-3):113-9
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 Jan;57(1):67-81. Erratum in: Ann Neurol. 2005 Feb;57(2):304. (To investigate whether immune-mediated mechanisms are involved in the pathogenesis of autism, we used immunocytochemistry, cytokine protein arrays, and enzyme-linked immunosorbent assays to study brain tissues and cerebrospinal fluid (CSF) from autistic patients and determined the magnitude of neuroglial and inflammatory reactions and their cytokine expression profiles. Brain tissues from cerebellum, midfrontal, and cingulate gyrus obtained at autopsy from 11 patients with autism were used for morphological studies. Immunocytochemical studies showed marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and tumor growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. CSF showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1.)
Pardo CA, Vargas
DL, Zimmerman
AW. Immunity, neuroglia and neuroinflammation
in autism. Int Rev Psychiatry. 2005 Dec;17(6):485-95
Bradl M, Hohlfeld R. Molecular pathogenesis of neuroinflammation. J Neurol Neurosurg Psychiatry. 2003 Oct;74(10):1364-70. Review. (this gives some idea into the inflammation in the brain. However, similarly to inflammation in other parts of the body, many factors are either unknown or there are too many arrows of what causes what!)
Vega JA, García-Suárez O, Hannestad J, Pérez-Pérez M, Germanà A. Neurotrophins and the immune system. J Anat. 2003 Jul;203(1):1-19. Review. (going through the major markers)
Expression of astrocytic
markers aquaporin 4 and connexin
43 is altered in brains of subjects with autism. Fatemi
SH, Folsom TD, Reutiman TJ, Lee S. Synapse. 2008 Jul;62(7):501-7. Aquaporin 4 is
associated with astrocytes and ependymal
cells. Connexins are involved in the formation of the
formation of gap junctions between glial cells. The changes were found in specific parts of
the brain.
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