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IFNG/IFNG-AS1 expression level balance: implications for autism spectrum disorder

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Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with different epidemiological, genetic, epigenetic, and environmental factors. Although its etiology is not fully understood, immune dysfunction is implicated in this disease. Recently, a large number of genes encoding long noncoding RNAs (lncRNAs) were discovered which act as positive or negative regulators of neighboring target genes. The lncRNA, Interferon gamma-antisense RNA (IFNG-AS1), regulates expression levels of the Interferon gamma (IFNG) gene. In the present study, we investigated expression of IFNG and IFNG-AS1 in 50 children with ASD (15 females and 35 males, mean age: 6 ± 1.4 years) and 50 healthy controls (14 females and 36 males, mean age: 6 ± 1.74 years) by real time PCR technique. The results showed significant up-regulation of IFNG and down-regulation of IFNG-AS1 expression in children with ASD compared to controls (Fold change = 1.5, P < 0.0001; Fold change = −0.143, P = 0.013, respectively). The IFNG expression level increase was more pronounced in male ASD children (Fold change = 1.621; p < 0.0001). Our data reveal a functional disruption in the interactive network of IFNG/IFNG-AS1 regulation, which could be a contributing factor in the chronic inflammatory aspect of ASD. Our findings can help understanding the underlying contributors to ASD pathogenesis and find novel treatment options for children with ASD.

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References

  • AbuHashim HM (2013) Association between plasma levels of transforming growth factor-b1, IL-23 and IL-17 and the severity of autism in Egyptian children. Elsevier Ltd. 7

  • Akbar AN, Lord JM, Salmon MJIT (2000) Ifn-Α and Ifn-Β: a link between immune memory and chronic inflammation. Immunol Today 21:337–342

    Article  CAS  PubMed  Google Scholar 

  • American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders 5th edition: DSM 5. American Psychiatric Association, Arlington

    Book  Google Scholar 

  • Ashwood P, Wills S, Van De Water JJJOLB (2006) The immune response in autism: a new frontier for autism research. J Leukoc Biol 80:1–15

    Article  CAS  PubMed  Google Scholar 

  • Ashwood P, Enstrom A, Krakowiak P, Hertz-Picciotto I, Hansen RL, Croen LA, Ozonoff S, Pessah IN, Van De Water JJJON (2008) Decreased transforming growth factor Beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes. J Neuroimmunol 204:149–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van De Water JJJON (2011) Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. J Neuroimmunol 232:196–199

    Article  CAS  PubMed  Google Scholar 

  • Baron-Cohen S, Lombardo MV, Auyeung B, Ashwin E, Chakrabarti B, Knickmeyer RJPB (2011) Why are autism spectrum conditions more prevalent in males? PLoS Biol 9:E1001081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bauman MLJN (2010) Medical comorbidities in autism: challenges to diagnosis and treatment. Neurotherapeutics 7:320–327

    Article  PubMed  PubMed Central  Google Scholar 

  • Corbin JG, Kelly D, Rath EM, Baerwald KD, Suzuki K, Popko BJM, Neuroscience C (1996) Targeted Cns expression of interferon-Γ in transgenic mice leads to hypomyelination, reactive gliosis, and abnormal cerebellar development. Mol Cell Neurosci 7:354–370

    Article  CAS  PubMed  Google Scholar 

  • Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M (2002) Activation of the inflammatory response system in autism. Neuropsychobiology 45:1–6

    Article  CAS  PubMed  Google Scholar 

  • Dorahy MJ (2014) The Diagnostic and Statistical Manual of Mental Disorders–5th edition (DSM-5)

  • Enstrom AM, Lit L, Onore CE, Gregg JP, Hansen RL, Pessah IN, Hertz-Picciotto I, Van De Water JA, Sharp FR, Ashwood P (2009) Altered gene expression and function of peripheral blood natural killer cells in children with autism. Brain Behav Immun 23:124–133

    Article  CAS  PubMed  Google Scholar 

  • Estes ML, Mcallister AKJNRN (2015) Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci 16:469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fombonne EJRDIAR (2005) In: Casanova Mf (ed) The epidemiology of pervasive developmental disorders, pp 1–25

  • Fombonne EJPR (2009) Epidemiology of pervasive developmental disorders. Pediatr Res 65:591

    Article  PubMed  Google Scholar 

  • Fombonne E, Simmons H, Ford T, Meltzer H, Goodman RJJOTAAOC, Psychiatry A (2001) Prevalence of pervasive developmental disorders in the British Nationwide survey of child mental health. J Am Acad Child Adolesc Psychiatry 40:820–827

    Article  CAS  PubMed  Google Scholar 

  • Goines P, Van De Water JJCOIN (2010) The immune system’s role in the biology of autism. Curr Opin Neurol 23:111

    Article  PubMed  PubMed Central  Google Scholar 

  • Gomez JA, Wapinski OL, Yang YW, Bureau J-F, Gopinath S, Monack DM, Chang HY, Brahic M, Kirkegaard KJC (2013) The Nest Long Ncrna controls microbial susceptibility and epigenetic activation of the interferon-Γ locus. Cell 152:743–754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamedani SY, Gharesouran J, Noroozi R, Sayad A, Omrani MD, Mir A, Afjeh SSA, Toghi M, Manoochehrabadi S, Ghafouri-Fard SJMBD (2017) Ras-like without Caax 2 (Rit2): a susceptibility gene for autism Spectrum disorder. Metab Brain Dis 32:751–755

    Article  CAS  PubMed  Google Scholar 

  • Inoue R, Sakaue Y, Sawai C, Sawai T, Ozeki M, Romero-Pérez GA, Tsukahara TJB (2016) A preliminary investigation on the relationship between gut microbiota and gene expressions in peripheral mononuclear cells of infants with autism Spectrum disorders. Biosci Biotechnol Biochem 80:2450–2458

    Article  CAS  PubMed  Google Scholar 

  • Jacquemont S, Coe BP, Hersch M, Duyzend MH, Krumm N, Bergmann S, Beckmann JS, Rosenfeld JA, Eichler EEJTAJOHG (2014) A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am J Hum Genet 94:415–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lai MC, Lombardo MV, Baron-Cohen S (2014) Autism. Lancet 383:896–910

    Article  PubMed  Google Scholar 

  • Lee PY, Li Y, Kumagai Y, Xu Y, Weinstein JS, Kellner ES, Nacionales DC, Butfiloski EJ, Van Rooijen N, Akira SJTAJOP (2009) Type I interferon modulates monocyte recruitment and maturation in chronic inflammation. Am J Pathol 175:2023–2033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Chauhan A, Sheikh AM, Patil S, Chauhan V, Li XM, Ji L, Brown T, Malik M (2009) Elevated immune response in the brain of autistic patients. J Neuroimmunol 207:111–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li H, Hao Y, Zhang D, Fu R, Liu W, Zhang X, Xue F, Yang RJA (2016) Aberrant expression of Long noncoding Rna Tmevpg1 in patients with primary immune thrombocytopenia. Autoimmunity 49:496–502

    Article  CAS  PubMed  Google Scholar 

  • Luo M, Liu X, Meng H, Xu L, Li Y, Li Z, Liu C, Luo Y-B, Hu B, Xue YJCI (2017) Ifna-As1 regulates Cd4+ T cell activation in myasthenia gravis though Hla-Drb1. Clin Immunol 183:121–131

    Article  CAS  PubMed  Google Scholar 

  • Mannion A, Leader GJRIASD (2013) Comorbidity in autism Spectrum disorder: a literature review. Res Autism Spectr Disord 7:1595–1616

    Article  Google Scholar 

  • Masi A, Demayo MM, Glozier N, Guastella AJJNB (2017) An overview of autism Spectrum disorder, heterogeneity and treatment options. Neurosci Bull 33:183–193

    Article  PubMed  PubMed Central  Google Scholar 

  • Noroozi R, Taheri M, Movafagh A, Mirfakhraie R, Solgi G, Sayad A, Mazdeh M, Darvish HJAR (2016) Glutamate receptor, metabotropic 7 (Grm7) gene variations and susceptibility to autism: a case–control study. Autism Res 9:1161–1168

    Article  PubMed  Google Scholar 

  • Noroozi R, Ghafouri-Fard S, Omrani MD, Habibi M, Sayad A, Taheri MJG (2017) Association study of the vesicular monoamine transporter 1 (Vmat1) gene with autism in an Iranian population. Gene 625:10–14

    Article  CAS  PubMed  Google Scholar 

  • Onore C, Enstrom A, Krakowiak P, Hertz-Picciotto I, Hansen R, Van De Water J, Ashwood PJJON (2009) Decreased cellular Il-23 but not Il-17 production in children with autism Spectrum disorders. J Neuroimmunol 216:126–129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paakki J-J, Rahko J, Long X, Moilanen I, Tervonen O, Nikkinen J, Starck T, Remes J, Hurtig T, Haapsamo HJBR (2010) Alterations in regional homogeneity of resting-state brain activity in autism Spectrum disorders. Brain Res 1321:169–179

    Article  CAS  PubMed  Google Scholar 

  • Padua D, Mahurkar-Joshi S, Law IKM, Polytarchou C, Vu JP, Pisegna JR, Shih D, Iliopoulos D, Pothoulakis CJAJOP-G, Physiology, L. (2016) A Long noncoding Rna signature for ulcerative colitis identifies Ifng-As1 as an enhancer of inflammation. Am J Physiol Gastrointest Liver Physiol 311:G446–G457

    Article  PubMed  PubMed Central  Google Scholar 

  • Peng H, Liu Y, Tian J, Ma J, Tang X, Rui K, Tian X, Mao C, Lu L, Xu HJSR (2015) The Long noncoding Rna Ifng-As1 promotes T helper type 1 cells response in patients with Hashimoto’s thyroiditis. Sci Rep 5:17702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Platanias LCJNRI (2005) Mechanisms of type-I-and type-ii-interferon-mediated Signalling. Nat Rev Immunol 5:375

    Article  CAS  PubMed  Google Scholar 

  • Ricci S, Businaro R, Ippoliti F, Vasco VL, Massoni F, Onofri E, Troili G, Pontecorvi V, Morelli M, Ricciardi MRJNR (2013) Altered cytokine and Bdnf levels in autism Spectrum disorder. Neurotox Res 24:491–501

    Article  CAS  PubMed  Google Scholar 

  • Safari MR, Ghafouri-Fard S, Noroozi R, Sayad A, Omrani MD, Komaki A, Eftekharian MM, Taheri MJG (2017) Foxp3 gene variations and susceptibility to autism: a case–control study. Gene 596:119–122

    Article  CAS  PubMed  Google Scholar 

  • Sayad A, Noroozi R, Omrani MD, Taheri M, Ghafouri-Fard SJMBD (2017) Retinoic acid-related orphan receptor alpha (Rora) variants are associated with autism Spectrum disorder. Metab Brain Dis 32:1595–1601

    Article  CAS  PubMed  Google Scholar 

  • Schroder K, Hertzog PJ, Ravasi T, Hume DAJJOLB (2004) Interferon-Γ: an overview of signals, mechanisms and functions. J Leukoc Biol 75:163–189

    Article  CAS  PubMed  Google Scholar 

  • Shatz CJJN (2009) Mhc class I: an unexpected role in neuronal plasticity. Neuron 64:40–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shaw C, Sheth S, Li D, Tomljenovic LJOA (2014) Etiology of autism Spectrum disorders: genes, environment, or both. OA Autism 2:11

    Google Scholar 

  • Spurlock CF, Shaginurova G, Tossberg JT, Hester JD, Chapman N, Guo Y, Crooke PS, Aune TM (2017) Profiles of long noncoding RNAs in human naive and memory T cells. The Journal of Immunology 199(2), pp.547-558

    Article  CAS  PubMed  Google Scholar 

  • Suzuki K, Matsuzaki H, Iwata K, Kameno Y, Shimmura C, Kawai S, Yoshihara Y, Wakuda T, Takebayashi K, Takagai SJPO (2011) Plasma cytokine profiles in subjects with high-functioning autism Spectrum disorders. PLoS One 6:E20470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tager-Flusberg H, Paul R, Lord CJHOA & Disorders, P. D. (2005) Language and communication in autism, vol 1, pp 335–364

  • Tostes M, Teixeira H, Gattaz W, Brandao M, Raposo NJP (2012) Altered Neurotrophin, neuropeptide, cytokines and nitric oxide levels in autism. Pharmacopsychiatry. 45:241

    Article  CAS  PubMed  Google Scholar 

  • Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CAJAONOJOTANA, Society, T. C. N (2005) Neuroglial activation and Neuroinflammation in the brain of patients with autism. Ann Neurol 57:67–81

    Article  CAS  PubMed  Google Scholar 

  • Vigil D, Cherfils J, Rossman KL, Der CJJNRC (2010) Ras superfamily Gefs and gaps: validated and tractable targets for Cancer therapy? Nat Rev Cancer 10:842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J, Peng H, Tian J, Ma J, Tang X, Rui K, Tian X, Wang Y, Chen J, Lu LJIR (2016) Upregulation of Long noncoding Rna Tmevpg1 enhances T helper type 1 cell response in patients with Sjögren syndrome. Immunol Res 64:489–496

    Article  CAS  PubMed  Google Scholar 

  • Werling DM, Geschwind DHJCOIN (2013) Sex differences in autism Spectrum disorders. Curr Opin Neurol 26:146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wing L, Potter DJMR, Reviews DDR (2002) The epidemiology of autistic Spectrum disorders: is the prevalence rising? Ment Retard Dev Disabil Res Rev 8:151–161

    Article  PubMed  Google Scholar 

  • Xu Y, Shao BJJOCLA (2018) Circulating Lncrna Ifng-As1 expression correlates with increased disease risk, higher disease severity and elevated inflammation in patients with coronary artery disease. J Clin Lab Anal 37:E22452

    Article  CAS  Google Scholar 

  • Yaghoobi H, Azizi H, Oskooei VK, Taheri M, Ghafouri-Fard S (2018) Assessment of expression of interferon gamma (Ifn-G) gene and its antisense (Ifng-As1) in breast cancer. World J Surg Oncol 16:211

    Article  PubMed  PubMed Central  Google Scholar 

  • Zerbo O, Leong A, Barcellos L, Bernal P, Fireman B, Croen LAJB, Behavior, & Immunity (2015) Immune mediated conditions in autism Spectrum disorders. Brain Behav Immun 46:232–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The present study was supported by a grant from Shahid Beheshti University of Medical Sciences (grant number: 14254).

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Authors and Affiliations

  1. Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Hamid Fallah, Arezou Sayad, Soudeh Ghafouri-Fard & Mohammad Taheri

  2. Iran University of Medical Sciences, Tehran, Iran

    Fatemeh Ranjbaran

  3. Ohio State University Medical Center, Columbus, OH, USA

    Fatemeh Talebian

  4. Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mohammad Taheri

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  1. Hamid Fallah
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Fallah, H., Sayad, A., Ranjbaran, F. et al. IFNG/IFNG-AS1 expression level balance: implications for autism spectrum disorder. Metab Brain Dis 35, 327–333 (2020). https://doi.org/10.1007/s11011-019-00510-4

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