Immunity, Inflammation and Allergy in Autism |
|
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
|
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.
Return
to Home Page
Return to Top of Page
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).
Return
to Home Page
Return to Top of Page
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.
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 Republic of Macedonia: retrospective study. Croat Med J. 2004 Dec;45(6):746-9. (they found an excess but they could not say whether it was the autism that caused the gamma globulin rise or vice versa).
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)
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.
Return
to Home Page
Return to Top of Page
Macrophage changes
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)
Return
to Home Page
Return to Top of Page
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).
Return
to Home Page
Return to Top of Page
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.
Return to Home Page Return to Top of Page
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)
Return
to Home Page
Return to Top of Page
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)
Return
to Home Page
Return to Top of Page
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.
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
Return
to Home Page
Return to Top of Page