Abstract
Autism is a multi-factorial neurodevelopmental disorder. We have investigated the molecular mechanism involved in a Chinese family with autism by a proteomic approach. Antibody chips containing 500 spots of human protein antibodies were used to screen for differentially expressed proteins in the peripheral B lymphocytes between autistic and non-autistic siblings in this family. Four proteins relevant to immuno-pathway, including IKKα that was up-regulated and Tyk2, EIF4G1 and PRKCI that were down-regulated, were identified differentially expressed in autistic versus non-autistic siblings. Western blot analysis and reverse transcription quantitative polymerase chain reaction validated the differential expression of these four proteins. Based on the function of these differentially expressed proteins, relevant studies on immunoglobulin E (IgE) level, nuclear factor kappa B signaling activation and cell cycle were conducted in both autistic and non-autistic children of this family. Considering the fact that the family members were in close contact with natural rubber latex (NRL) and that IgE-mediated cross-reactions could be triggered by Hevea brasiliensis (Hev-b) proteins in NRL, we hypothesize that immune reactions triggered by close contact with NRL might influence the functions of B lymphocytes by altering expression of certain proteins identified in our experiments thus contributing to the occurrence of autism.
Similar content being viewed by others
Abbreviations
- IgE:
-
Immunoglobulin E
- RT-qPCR:
-
Reverse transcription quantitative polymerase chain reaction
- NRL:
-
Natural rubber latex
- Hev-b:
-
Hevea brasiliensis
- EBV:
-
Epstein–Barr Virus
References
Allen-Brady K, Miller J, Matsunami N, Stevens J, Block H, Farley M, Krasny L, Pingree C, Lainhart J, Leppert M, McMahon WM, Coon H (2009) A high-density SNP genome-wide linkage scan in a large autism extended pedigree. Mol Psychiatry 14:590–600
Ashwood P, Van de Water J (2004) Is autism an autoimmune disease? Autoimmun Rev 3:557–562
Astrakhan A, Omori M, Nguyen T, Becker-Herman S, Iseki M, Aye T, Hudkins K, Dooley J, Farr A, Alpers CE, Ziegler SF, Rawlings DJ (2007) Local increase in thymic stromal lymphopoietin induces systemic alterations in B cell development. Nat Immunol 8:522–531
Atladóttir HO, Pedersen MG, Thorsen P, Mortensen PB, Deleuran B, Eaton WW, Parner ET (2009) Association of family history of autoimmune diseases and autism spectrum disorders. Pediatrics 124:687–694
Bailey A, Phillips W, Rutter M (1996) Towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives. J Child Psychol Psychiatry 37:89–126
Bakkaloglu B, Anlar B, Anlar FY, Oktem F, Pehlivantürk B, Unal F, Ozbesler C, Gökler B (2008) Atopic features in early childhood autism. Eur J Paediatr Neurol 12(6):476–479
Barré B, Perkins ND (2007) A cell cycle regulatory network controlling NF-kappaB subunit activity and function. EMBO J 26:4841–4855
Boris M, Kaiser CC, Goldblatt A, Elice MW, Edelson SM, Adams JB, Feinstein DL (2007) Effect of pioglitazone treatment on behavioral symptoms in autistic children. J Euroinflammation 4:3
Careaga M, Van de Water J, Ashwood P (2010) Immune dysfunction in autism: a pathway to treatment. Neurotherapeutics 7:283–292
Chih B, Afridi SK, Clark L, Scheiffele P (2004) Disorder-associated mutations lead to functional inactivation of neuroligins. Hum Mol Genet 13:1471–1477
Cohly HH, Panja A (2005) Immunological findings in autism. Int Rev Neurobiol 71:317–341
Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN (1999) Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol 14:388–394
Dochniak MJ (2007) Autism spectrum disorders—exogenous protein insult. Med Hypotheses 69:545–549
Enstrom A, Krakowiak P, Onore C, Pessah IN, Hertz-Picciotto I, Hansen RL, Van de Water JA, Ashwood P (2009) Increased IgG4 levels in children with autism disorder. Brain Behav Immun 23:389–395
Fields AP, Regala RP (2007) Protein kinase C iota: human oncogene, prognostic marker and therapeutic target. Pharmacol Res 55:487–497
Firmbach-Kraft I, Byers M, Shows T, Dalla-Favera R, Krolewski JJ (1990) Tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene 5:1329–1336
Hayden MS, Ghosh S (2004) Signaling to NF-kappaB. Genes Dev 18:2195–2224
Ishikawa H, Carrasco D, Claudio E, Ryseck RP, Bravo R (1997) Gastric hyperplasia and increased proliferative responses of lymphocytes in mice lacking the COOH-terminal ankyrin domain of NF-kappaB2. J Exp Med 186:999–1014
Kaisho T, Takeda K, Tsujimura T, Kawai T, Nomura F, Terada N et al (2001) I kappa B kinase alpha is essential for mature B cell development and function. J Exp Med 193:417–426
Libbey JE, Fujinami RS (2010) Role for antibodies in altering behavior and movement. Autism Res 3:147–152. doi:10.1002/aur.144
Lindelöf B, Granath F, Tengvall-Linder M, Lindelöf H, Ekbom A (2009) Allergy and autoimmune disease: a registry-based study. Clin Exp Allergy 9:110–115
Magalhães ES, Pinto-Mariz F, Bastos-Pinto S, Pontes AT, Prado EA, de Azevedo LC (2009) Immune allergic response in Asperger syndrome. J Neuroimmunol 216:108–112
McAllister AK, van de Water J (2009) Breaking boundaries in neural-immune interactions. Neuron 64:9–12
McCauley JL, Li C, Jiang L, Olson LM, Crockett G, Gainer K, Folstein SE, Haines JL, Sutcliffe JS (2005) Genome-wide and ordered-subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates. BMC Med Genet 6:1
Minegishi Y, Karasuyama H (2007) Hyperimmunoglobulin E syndrome and tyrosine kinase two deficiency. Curr Opin Allergy Clin Immunol 7:506–509
Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, Takada H, Hara T, Kawamura N, Ariga T, Kaneko H, Kondo N, Tsuge I, Yachie A, Sakiyama Y, Iwata T, Bessho F, Ohishi T, Joh K, Imai K, Kogawa K, Shinohara M, Fujieda M, Wakiguchi H, Pasic S, Abinun M, Ochs HD, Renner ED, Jansson A, Belohradsky BH, Metin A, Shimizu N, Mizutani S, Miyawaki T, Nonoyama S, Karasuyama H (2006) Human tyrosine kinase two deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25:745–755
Mobyuddin A, Ayub Q, Sidiqi S, Carvalho-Silva DR, Mazhar K, Rehman S, Firasat S, Dar A, Tyler-Smith C, Mehdi SQ (2004) Genetic instability in EBV transformed lymphoblastoid cell line. Biochem Biophys Acta 1670:2356–2360
Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P, Scherer SW (2007) Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet 81:1289–1297
Molloy CA, Morrow AL, Meinzen-Derr J, Schleifer K, Dienger K, Manning-Courtney P, Altaye M, Wills-Karp M (2006) Elevated cytokine levels in children with autism spectrum disorder. J Neuroimmunol 172:198–205
Mouridsen SE, Rich B, Isager T, Nedergaard NJ (2007) Autoimmune diseases in parents of children with infantile autism: a case-control study. Dev Med Child Neurol 49:429–432
Neitzel H (1986) A routine method for the establishment of permanent growing lymphoblastoid cell lines. Hum Genet 73:320–326
Okazaki Y, Suzuki A, Sawada T, Ohtake-Yamanaka M, Inoue T, Hasebe T, Yamada R, Yamamoto K (2006) Identification of citrullinated eukaryotic translation initiation factor 4 G1 as novel autoantigen in rheumatoid arthritis. Biochem Biophys Res Commun 341:94–100
Parker S, Todd J, Schwartz B, Pickering L (2005) Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data. Pediatrics 115:200
Peng Y, Power MR, Li B, Lin TJ (2005) Inhibition of IKK down-regulates antigen + IgE-induced TNF production by mast cells: a role for the IKK-IkappaB-NF-kappaB pathway in IgE-dependent mast cell activation. J Leukoc Biol 77:975–983
Prévôt D, Darlix JL, Ohlmann T (2003) Conducting the initiation of protein synthesis: the role of eIF4G. Biol Cell 95:141–156
Regala RP, Weems C, Jamieson L, Copland JA, Thompson EA, Fields AP (2005) Atypical protein kinase Ciota plays a critical role in human lung cancer cell growth and tumorigenicity. J Biol Chem 280:31109–31115
Régnier CH, Song HY, Gao X, Goeddel DV, Cao Z, Rothe M (1997) Identification and characterization of an Ikappa B kinase. Cell 90:373–383
Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J et al (1999) A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 65:493–507
Schneider G, Saur D, Siveke JT, Fritsch R, Greten FR, Schmid RM (2006) IKKαlpha controls p52/RelB at the skp2 gene promoter to regulate G1- to S-phase progression. EMBO J 25:3801–3812
Seto Y, Nakajima H, Suto A, Shimoda K, Saito Y, Nakayama KI, Iwamoto I (2003) Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice. J Immunol 170:1077–1083
Singer HS, Morris CM, Williams PN, Yoon DY, Hong JJ, Zimmerman AW (2006) Antibrain antibodies in children with autism and their unaffected siblings. J Neuroimmunol 178:149–155
Stern L, Francoeur MJ, Primeau MN, Sommerville W, Fombonne E, Mazer BD (2005) Immune function in autistic children. Ann Allergy Asthma Immunol 95:558–565
Talebizadeh Z, Butler MG, Theodoro MF (2008) Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism. Autism Res 1:240–250
Tordjman S, Anderson GM, Botbol M, Brailly-Tabard S, Perez-Diaz F, Graignic R, Carlier M, Schmit G, Rolland A-C, Bonnot O, Trabado S, Roubertoux P, Bronsard G (2009) Pain reactivity and plasma β-endorphin in children and adolescents with autistic disorder. PLoS ONE 4:5289. doi:10.1371/journal.pone.0005289
Valenta R, Mittermann I, Werfel T, Garn H, Renz H (2009) Linking allergy to autoimmune disease. Trends Immunol 30:109–116
Vercelli D, Jabara HH, Cunningham-Rundles C, Abrams JS, Lewis DB, Meyer J, Schneider LC, Leung DY, Geha RS (1990) Regulation of immunoglobulin (Ig)E synthesis in the hyper-IgE syndrome. J Clin Invest 85:1666–1671
Win HY, Acevedo-Duncan M (2008) Atypical protein kinase C phosphorylates IKKalphabeta in transformed non-malignant and malignant prostate cell survival. Cancer Lett 270:302–311
Ylisaukko-oja T, Alarcón M, Cantor RM, Auranen M, Vanhala R, Kempas E, von Wendt L, Järvelä I, Geschwind DH, Peltonen L (2006) Search for autism loci by combined analysis of autism genetic resource exchange and finnish families. Ann Neurol 59:145–155
Zhang L, Huang J, Yang N, Liang S, Barchetti A, Giannakakis A, Cadungog MG, O'Brien-Jenkins A, Massobrio M, Roby KF, Katsaros D, Gimotty P, Butzow R, Weber BL, Coukos G (2006) Integrative genomic analysis of protein kinase C (PKC) family identifies PKCiota as a biomarker and potential oncogene in ovarian carcinoma. Cancer Res 66:4627–4635
Ziv Y, Schwartz M (2008) Immune-based regulation of adult neurogenesis: implications for learning and memory. Brain Behav Immun 22:167–176
Acknowledgements
The authors wish to thank the family that participated in this study. This work was supported in part by the “985” program (985-2-035-39) of the Chinese Ministry of Education, the “973” project (2007CB511902) from the Ministry of Science and Technology, the National Nature Science Foundation (30671157), and the New York State Office for People with Developmental Disabilities (NYS OPWDD).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shen, C., Zhao, Xl., Ju, W. et al. A Proteomic Investigation of B Lymphocytes in an Autistic Family: A Pilot Study of Exposure to Natural Rubber Latex (NRL) May Lead to Autism. J Mol Neurosci 43, 443–452 (2011). https://doi.org/10.1007/s12031-010-9463-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-010-9463-5