Autism, glutamate, HMGB1

Advances in Autism Research
April 2010

High mobility group box 1

A newly published study (Mar 16, 2010) offers exciting insights regarding immunity in autism. A protein known as High mobility group box 1 (HMGB1) “functions as an activator for inducing the immune response and can be released from neurons after glutamate excitotoxicity.” Furthermore, “ Compared with healthy subjects, serum levels of HMGB1 were significantly higher in patients with autistic disorder” (1)


Whereas the search hmgb1 AND autis* generated only one citation on March 27, 2010, the search HMGB1 generates >1600 citations.

Glutamate: The search glutamate AND autism generated 200 citations (eg, 18-25). Indeed, glutamatergic excitotoxicity as etiologically significant in autism and other autism-spectrum disorders (ASDs) has been elaborated by Russell Blaylock, M.D. (21-24); and clinical significance of glutamate in autism is reported (eg, 20, 25).

Immunity: Cytokine interleukin-1beta induces HMGB1 release from astrocytes (2). An abnormal response of interleukin-1beta in relation to a specific flame-retardant molecule has been described in autism (26). Furthermore, the search hmgb1 AND innate AND (immun*[tw]) generates >90 citations, and autis* AND innate AND (immun*[tw]) generated 17 citations (eg, 27-36), one of which described effects of mercury (27).

Learning about HMGB1. A more focused search -- "High mobility group box 1"[tw] OR HMGB1[tw] – generated >1200 citations, of which >400 are free online. Links are provided for sampling of HMGB1 reviews free online (37-53).

References:

1. Increased serum levels of high mobility group box 1 protein in patients with autistic disorder.
Emanuele E, Boso M, Brondino N, Pietra S, Barale F, di Nemi SU, Politi P.
Prog Neuropsychopharmacol Biol Psychiatry. 2010 Mar 16. [Epub ahead of print]

BACKGROUND: High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein that functions as an activator for inducing the immune response and can be released from neurons after glutamate excitotoxicity. The objective of the present study was to measure serum levels of HMGB1 in patients with autistic disorder and to study their relationship with clinical characteristics. METHODS: We enrolled 22 adult patients with autistic disorder (mean age: 28.1+/-7.7years) and 28 age- and gender-matched healthy controls (mean age: 28.7+/-8.1years). Serum levels of HMGB1 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with healthy subjects, serum levels of HMGB1 were significantly higher in patients with autistic disorder (10.8+/-2.6ng/mL versus 5.6+/-2.5ng/mL, respectively, P<0.001). After adjustment for potential confounders, serum HMGB1 levels were independently associated with their domain A scores in the Autism Diagnostic Interview-Revised, which reflects their impairments in social interaction. CONCLUSIONS: These results suggest that HMGB1 levels may be affected in autistic disorder. Increased HMGB1 may be a biological correlate of the impaired reciprocal social interactions in this neurodevelopmental disorder.

{Pubmed function: See a list of related articles}

2. Role of ERK map kinase and CRM1 in IL-1beta-stimulated release of HMGB1 from cortical astrocytes.
Hayakawa K, Arai K, Lo EH.
Glia. 2010 Mar 10. [Epub ahead of print]

3. RAGE-independent autoreactive B cell activation in response to chromatin and HMGB1/DNA immune complexes.
Avalos AM, Kiefer K, Tian J, Christensen S, Shlomchik M, Coyle AJ, Marshak-Rothstein A.
Autoimmunity. 2010 Feb;43(1):103-10.

4. RAGE-independent autoreactive B cell activation in response to chromatin and HMGB1/DNA immune complexes.
Avalos AM, Kiefer K, Tian J, Christensen S, Shlomchik M, Coyle AJ, Marshak-Rothstein A.
Autoimmunity. 2010 Feb;43(1):103-10.

5. HMGB1 loves company.
Bianchi ME.
J Leukoc Biol. 2009 Sep;86(3):573-6.

6. Native HMGB1 protein inhibits repair of cisplatin-damaged nucleosomes in vitro.
Ugrinova I, Zlateva S, Pashev IG, Pasheva EA.
Int J Biochem Cell Biol. 2009 Jul;41(7):1556-62.

7. Chromatin-specific remodeling by HMGB1 and linker histone H1 silences proinflammatory genes during endotoxin tolerance.
El Gazzar M, Yoza BK, Chen X, Garcia BA, Young NL, McCall CE.
Mol Cell Biol. 2009 Apr;29(7):1959-71.

8. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE.
Urbonaviciute V, Fürnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, Bianchi ME, Kirschning C, Wagner H, Manfredi AA, Kalden JR, Schett G, Rovere-Querini P, Herrmann M, Voll RE.
J Exp Med. 2008 Dec 22;205(13):3007-18.

9. High mobility group box 1 in the pathogenesis of inflammatory and autoimmune diseases.
Voll RE, Urbonaviciute V, Herrmann M, Kalden JR.
Isr Med Assoc J. 2008 Jan;10(1):26-8. Review.

10. High mobility group protein B1 enhances DNA repair and chromatin modification after DNA damage.
Lange SS, Mitchell DL, Vasquez KM.
Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10320-5.

11. The anti-inflammatory effects of heat shock protein 72 involve inhibition of high-mobility-group box 1 release and proinflammatory function in macrophages.
Tang D, Kang R, Xiao W, Wang H, Calderwood SK, Xiao X.
J Immunol. 2007 Jul 15;179(2):1236-44.

12. Hydrogen peroxide stimulates macrophages and monocytes to actively release HMGB1.
Tang D, Shi Y, Kang R, Li T, Xiao W, Wang H, Xiao X.
J Leukoc Biol. 2007 Mar;81(3):741-7.

13. Conformational difference in HMGB1 proteins of human neutrophils and lymphocytes revealed by epitope mapping of a monoclonal antibody.
Ito I, Mitsuoka N, Sobajima J, Uesugi H, Ozaki S, Ohya K, Yoshida M.
J Biochem. 2004 Aug;136(2):155-62.

14. Nucleosome remodeling: one mechanism, many phenomena?
Längst G, Becker PB.
Biochim Biophys Acta. 2004 Mar 15;1677(1-3):58-63

15. ATP-dependent chromatin structural modulation by multiprotein complex including HMGB1.
Yamada M, Ueda T, Sato K, Yoshida M.
J Biochem. 2004 Jan;135(1):149-53.

The search autism AND glutamate generated 144 citations

eg

18. Urinary metabolic phenotyping differentiates children with autism, from their unaffected siblings and age-matched controls.
Yap IK, Angley M, Veselkov KA, Holmes E, Lindon JC, Nicholson JK.
J Proteome Res. 2010 Mar 25. [Epub ahead of print]

19. Increased serum levels of high mobility group box 1 protein in patients with autistic disorder.
Emanuele E, Boso M, Brondino N, Pietra S, Barale F, di Nemi SU, Politi P.
Prog Neuropsychopharmacol Biol Psychiatry. 2010 Mar 16. [Epub ahead of print]

20. Novel and emerging treatments for autism spectrum disorders: a systematic review.
Rossignol DA.
Ann Clin Psychiatry. 2009 Oct-Dec;21(4):213-36. Review.

21. Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders.
Blaylock RL, Strunecka A.
Curr Med Chem. 2009;16(2):157-70. Review.

22. A possible central mechanism in autism spectrum disorders, part 1.
Blaylock RL.
Altern Ther Health Med. 2008 Nov-Dec;14(6):46-53. Review.

23. A possible central mechanism in autism spectrum disorders, part 2: immunoexcitotoxicity.
Blaylock RL.
Altern Ther Health Med. 2009 Jan-Feb;15(1):60-7.

24. A possible central mechanism in autism spectrum disorders, part 3: the role of excitotoxin food additives and the synergistic effects of other environmental toxins.
Blaylock RL.
Altern Ther Health Med. 2009 Mar-Apr;15(2):56-60.

25. Urinary metabolic phenotyping differentiates children with autism, from their unaffected siblings and age-matched controls.
Yap IK, Angley M, Veselkov KA, Holmes E, Lindon JC, Nicholson JK.
J Proteome Res. 2010 Mar 25. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/20337404

Autism is an early-onset developmental disorder with a severe life-long impact on behavior and social functioning that has associated metabolic abnormalities. The urinary metabolic phenotypes of individuals (age range= 3 - 9 years old) diagnosed with autism using the DSM-IV-TR criteria (n=39; male=35; female=4), together with their non-autistic siblings (n=28; male=14; female=14) and age-matched healthy volunteers (n=34, male=17; female=17) have been characterized for the first time using 1H NMR spectroscopy and pattern recognition methods. Novel findings associated with alterations in nicotinic acid metabolism within autistic individuals showing increased urinary excretion of Nmethyl- 4-pyridone-3-carboxamide, N-methyl nicotinic acid and N-methyl nicotinamide, indicate a perturbation in tryptophan-nicotinic acid metabolic pathway. Urinary patterns of the free amino acids glutamate, alanine, glycine and taurine were significantly different between groups with the autistic children showing higher levels of urinary alanine, glycine and taurine and a lower level of urinary glutamate indicating perturbation in sulfur and amino acid metabolism in these children. Additionally, metabolic phenotype (metabotype) differences were observed between autistic and control children, which were associated with perturbations of urinary mammalian-microbial co-metabolites including dimethylamine, hippurate, phenyacetylglutamine and 4-cresol sulfate. These biochemical changes are consistent with the known abnormalities of gut microbiota found in autistic individuals and the associated gastrointestinal dysfunction and may be of value in monitoring the success of therapeutic interventions.

26. . 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.
http://www.ncbi.nlm.nih.gov/pubmed/19211157

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders that manifest in childhood. Immune dysregulation and autoimmune reactivity may contribute to the etiology of ASD and are likely the result of both genetic and environmental susceptibilities. 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. The cytokine responses of LPS stimulated PBMC from ASD and TD subjects diverged in the presence of 100 nM BDE. For example, cells cultured from the TD group demonstrated significantly decreased levels of the cytokines IL-12p40, GM-CSF, IL-6, TNFalpha, and the chemokines MIP-1alpha and MIP-1beta following LPS stimulation of PBMC pretreated with 100 nM BDE-47 compared with samples treated with vehicle control (p<0.05). In contrast, cells cultured from subjects with ASD demonstrated an increased IL-1beta response to LPS (p=0.033) when pretreated with 100 nM BDE-47 compared with vehicle control. 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 TD 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. {See all related articles}

27. Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression.
Jyonouchi H, Sun S, Le H.
J Neuroimmunol. 2001 Nov 1;120(1-2):170-9.

28. Innate immunity associated with inflammatory responses and cytokine production against common dietary proteins in patients with autism spectrum disorder.
Jyonouchi H, Sun S, Itokazu N.
Neuropsychobiology. 2002;46(2):76-84.

29. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention.
Jyonouchi H, Geng L, Ruby A, Zimmerman-Bier B.
Neuropsychobiology. 2005;51(2):77-85.

30. Immunity, neuroglia and neuroinflammation in autism.
Pardo CA, Vargas DL, Zimmerman AW.
Int Rev Psychiatry. 2005 Dec;17(6):485-95.

31. Immune transcriptome alterations in the temporal cortex of subjects with autism.
Garbett K, Ebert PJ, Mitchell A, Lintas C, Manzi B, Mirnics K, Persico AM.
Neurobiol Dis. 2008 Jun;30(3):303-11

32. Macrophage migration inhibitory factor and autism spectrum disorders.
Grigorenko EL, Han SS, Yrigollen CM, Leng L, Mizue Y, Anderson GM, Mulder EJ, de Bildt A, Minderaa RB, Volkmar FR, Chang JT, Bucala R.
Pediatrics. 2008 Aug;122(2):e438-45.

33. 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.

34. 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.

35. 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. 2010 Jan;24(1):64-71

36. Mercury induces inflammatory mediator release from human mast cells.
Kempuraj D, Asadi S, Zhang B, Manola A, Hogan J, Peterson E, Theoharides TC.
J Neuroinflammation. 2010 Mar 11;7(1):20. [Epub ahead of print]PMID: 20222982 [PubMed - as supplied by publisher]

37. New EMBO members' review: the double life of HMGB1 chromatin protein: architectural factor and extracellular signal.
Müller S, Scaffidi P, Degryse B, Bonaldi T, Ronfani L, Agresti A, Beltrame M, Bianchi ME.
EMBO J. 2001 Aug 15;20(16):4337-40

38. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses.
Schmidt AM, Yan SD, Yan SF, Stern DM.
J Clin Invest. 2001 Oct;108(7):949-55.

39. HMGB1 as a DNA-binding cytokine.
Andersson U, Erlandsson-Harris H, Yang H, Tracey KJ.
J Leukoc Biol. 2002 Dec;72(6):1084-91

40. The cytokine activity of HMGB1.
Yang H, Wang H, Czura CJ, Tracey KJ.
J Leukoc Biol. 2005 Jul;78(1):1-8.

41. Membrane repair and immunological danger.
Andrews NW.
EMBO Rep. 2005 Sep;6(9):826-30

42. The cytokine activity of HMGB1--extracellular escape of the nuclear protein.
Sun NK, Chao CC.
Chang Gung Med J. 2005 Oct;28(10):673-82

43. Receptor for advanced glycation end products (RAGE) in a dash to the rescue: inflammatory signals gone awry in the primal response to stress.
Herold K, Moser B, Chen Y, Zeng S, Yan SF, Ramasamy R, Emond J, Clynes R, Schmidt AM.
J Leukoc Biol. 2007 Aug;82(2):204-12.

44. The role of nuclear macromolecules in innate immunity.
Pisetsky DS.
Proc Am Thorac Soc. 2007 Jul;4(3):258-62

45. HMGB1 preconditioning: therapeutic application for a danger signal?
Klune JR, Billiar TR, Tsung A.
J Leukoc Biol. 2008 Mar;83(3):558-63

46. Innate alloimmunity: history and current knowledge.
Land W.
Exp Clin Transplant. 2007 Jun;5(1):575-84

47. High mobility group box 1 in the pathogenesis of inflammatory and autoimmune diseases.
Voll RE, Urbonaviciute V, Herrmann M, Kalden JR.
Isr Med Assoc J. 2008 Jan;10(1):26-8

48. Dendritic cells and cytokines in human inflammatory and autoimmune diseases.
Blanco P, Palucka AK, Pascual V, Banchereau J.
Cytokine Growth Factor Rev. 2008 Feb;19(1):41-52

49. The role of cell death in the pathogenesis of autoimmune disease: HMGB1 and microparticles as intercellular mediators of inflammation.
Ardoin SP, Pisetsky DS.
Mod Rheumatol. 2008;18(4):319-26.

50. HMGB1: endogenous danger signaling.
Klune JR, Dhupar R, Cardinal J, Billiar TR, Tsung A.
Mol Med. 2008 Jul-Aug;14(7-8):476-84. Review.

51. High-mobility group box protein 1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease.
Pisetsky DS, Erlandsson-Harris H, Andersson U.
Arthritis Res Ther. 2008;10(3):209.

52. Receptor for AGE (RAGE) and its ligands-cast into leading roles in diabetes and the inflammatory response.
Yan SF, Ramasamy R, Schmidt AM.
J Mol Med. 2009 Mar;87(3):235-47

53. HMGB1, an innate alarmin, in the pathogenesis of type 1 diabetes.
Zhang S, Zhong J, Yang P, Gong F, Wang CY.
Int J Clin Exp Pathol. 2009 Sep 8;3(1):24-38.

This document prepared by
Teresa Binstock
Researcher in Developmental & Behavioral Neuroanatomy
April 2010