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Behavioral and Brain Functions
Published in: Behavioral and Brain Functions 1/2015

Open Access 01-12-2015 | Research

The possible link between elevated serum levels of epithelial cell-derived neutrophil- activating peptide-78 (ENA-78/CXCL5) and autoimmunity in autistic children

Authors: Gehan Ahmed Mostafa, Laila Yousef AL-Ayadhi

Published in: Behavioral and Brain Functions | Issue 1/2015

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Abstract

Background

In autoimmune disorders, the underlying pathogenic mechanism is the formation of antigen-antibody complexes which trigger an inflammatory response by inducing the infiltration of neutrophils. Epithelial cell-derived neutrophil-activating peptide-78 (ENA-78) is a chemokine that recruits and activates neutrophils, thus it could play a pathogenic role in inflammation and autoimmune disorders. Some autistic children have elevated levels of brain specific auto-antibodies. We are the first to evaluate serum expression of ENA-78 and its relation to antineuronal auto-antibodies in autistic children.

Methods

Serum ENA-78 and antineuronal auto-antibodies were measured by ELISA test in 62 autistic children aged between 4–11 years and 62 health-matched controls.

Results

Serum levels of ENA-78 were significantly higher in autistic children than healthy controls (P < 0.001). Increased serum levels of ENA-78 have been found in 69.35% of autistic patients. In addition, autistic children had significantly higher percent positivity of serum antineuronal auto-antibodies (64.5%) than healthy controls (6.45%), P < 0.001. There was a significant positive association between the positivity of serum antineuronal auto-antibodies and the elevated levels of serum ENA-78 (P < 0.001) in autistic children.

Conclusions

Serum levels of ENA-78 were elevated in autistic children and they were significantly associated with the increased levels of serum antineuronal auto-antibodies. However, these data should be treated with caution until further research is conducted to determine the pathogenic role of ENA-78 in autism and its relation to brain specific auto-antibodies that have been found in some autistic children. The possible therapeutic role of ENA-78 antagonist in autistic children should be also studied.
Literature
1.
Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12(2):121–7.CrossRefPubMed
2.
Smit JJ, Lukacs NW. A closer look at chemokines and their role in asthmatic responses. Eur J Pharmacol. 2006;533(1–3):277–88.CrossRefPubMed
3.
Ono SJ, Nakamura T, Miyazaki D, Ohbayashi M, Dawson M, Toda M. Chemokines: roles in leukocyte development, trafficking and effect or function. J Allergy Clin Immunol. 2003;111:1185–99.CrossRefPubMed
4.
Sanz MJ, Kubes P. Neutrophil-active chemokines in in vivo imaging of neutrophil trafficking. Eur J Immunol. 2012;42:278–83.CrossRefPubMed
5.
6.
Smith JJ, Lukacs NW. A closer look at chemokines and their role in asthmatic responses. Eur J Pharmacol. 2006;3:277–88.CrossRef
7.
Bisset LR, Schmid-Grendelmeier P. Chemokines and their receptors in the pathogenesis of allergic asthma: progress and perspective. Curr Opin Pulm Med. 2005;11(1):35–42.CrossRefPubMed
8.
Minshall EM, Cameron L, Lavigne F, Leung DY, Hamilos D, Garcia-Zepada EA, et al. Eotaxin mRNA and protein expression in chronic sinusitis and allergen-induced nasal responses in seasonal allergic rhinitis. Am J Respir Cell Mol Biol. 1997;17(6):683–90.CrossRefPubMed
9.
Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol. 2006;6:173–82.CrossRefPubMed
10.
Jancar S, Sanchez CM. Immune complex-mediated tissue injury: a multistep paradigm. Trends Immunol. 2005;26:48–55.CrossRefPubMed
11.
12.
Singh VK, Warren RP, Averett R, Ghaziuddin M. Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr Neurol. 1997;17:88–90.CrossRefPubMed
13.
Mostafa GA, El-Sayed ZA, Abd El Aziz MM, El-Sayed MF. Serum anti-myelin-associated glycoprotein antibodies in Egyptian autistic children. J Child Neurol. 2008;23:1413–8.CrossRefPubMed
14.
Mostafa GA, Al-Ayadhi LY. Increased serum levels of anti-ganglioside M1 auto-antibodies in autistic children: relation to the disease severity. J Neuroinflammation. 2011;8:39.CrossRefPubMedCentralPubMed
15.
Mostafa GA, Al-Ayadhi LY. A lack of association between hyperserotonemia and the increased frequency of serum anti-myelin basic protein auto-antibodies in autistic children. J Neuroinflammation. 2011;8:71.CrossRefPubMedCentralPubMed
16.
Mostafa GA, Al-Ayadhi LY. The possible link between the elevated serum levels of neurokinin A and anti-ribosomal P protein antibodies in children with autism. J Neuroinflammation. 2011;8:180.CrossRefPubMedCentralPubMed
17.
Mostafa GA, Al-Ayadhi LY. The relationship between the increased frequency of serum antineuronal antibodies and the severity of autism in children. Eur J Paediatr Neurol. 2012;16:464–8.CrossRefPubMed
18.
Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ. Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics. 2003;112:420–4.CrossRef
19.
Mostafa GA, Kitchener N. Serum anti-nuclear antibodies as a marker of autoimmunity in Egyptian autistic children. Pediatr Neurol. 2009;40:107–12.CrossRefPubMed
20.
Mostafa GA, Shehab A. The link of C4B null allele to autism and to a family history of autoimmunity in Egyptian autistic children. J Neuroimmunol. 2010;223:115–9.CrossRefPubMed
21.
Mostafa GA, El-Hadidi ES, Hewedi DH, Abdou MM. Oxidative stress in Egyptian children with autism: relation to autoimmunity. J Neuroimmunol. 2010;219:114–8.CrossRefPubMed
22.
Karpus WJ, Fife BT, Kennedy KJ. Immunoneutralization of chemokines for the prevention and treatment of central nervous system autoimmune disease. Methods. 2003;29:362–8.CrossRefPubMed
23.
Karpus WJ, Ransohoff RM. Chemokine regulation of experimental autoimmune encephalomyelitis: temporal and spatial expression patterns govern disease pathogenesis. J Immunol. 1998;161:2667–71.PubMed
24.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington DC: American Psychiatric Association; 1994.
25.
Schopler E, Reichler RJ, Renner BR. The Childhood Autism Rating Scale (CARS), for diagnostic screening and classification in autism. New York NY: Irvington; 1986.
26.
Meleka LK, Ismail ME. Arabic translation of Wechsler Intelligence Scale for children. 6th ed. Egyptian Anglo library: Cairo; 1999.
27.
Wechsler D. Wechsler intelligence scale for children. 3rd ed. New York: Psychological Corporation. Harcourt Brace and Company Publishers; 1991.
28.
Amoli MM, Larijani B, Thomson W, Ollier WE, Gonzalez-Gay MA. Two polymorphisms the epithelial cell-derived neutrophil-activating peptide (ENA-78) gene. Dis Markers. 2005;21(2):75–7.CrossRefPubMedCentralPubMed
29.
Nakayama S, Mukae H, Ishii H, Kakugawa T, Sugiyama K, Sakamoto N, et al. Comparison of BALF concentrations of ENA-78 and IP10 in patients with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Respir Med. 2005;99(9):1145–51.CrossRefPubMed
30.
Okabe H1, Beppu T, Ueda M, Hayashi H, Ishiko T, Masuda T, et al. Identification of CXCL5/ENA-78 as a factor involved in the interaction between cholangiocarcinoma cells and cancer-associated fibroblasts. Int J Cancer. 2012;15(131(10)):2234–41.CrossRef
31.
Song J, Wu C, Zhang X, Sorokin LM. In vivo processing of CXCL5 (LIX) by matrix metalloproteinase (MMP)-2 and MMP-9 promotes early neutrophil recruitment in IL-1β-induced peritonitis. J Immunol. 2013;190(1):401–10.CrossRefPubMed
32.
Keglowich L, Tamm M, Zhong J, Miglino N, Borger P. Proteolytic activity present in house-dust-mite extracts degrades ENA-78/CXCL5 and reduces neutrophil migration. J Allergy (Cairo). 2014;2014:673673.
33.
Zineh I, Aquilante CL, Langaee TY, Beitelshees AL, Arant CB, Wessel TR, et al. CXCL5 gene polymorphisms are related to systemic concentrations and leukocyte production of epithelial neutrophil-activating peptide (ENA-78). Cytokine. 2006;33(5):258–63.CrossRefPubMed
34.
Zineh I, Luo X, Welder GJ, DeBella AE, Wessel TR, Arant CB, et al. Modulatory effects of atorvastatin on endothelial cell derived chemokines, cytokines, and angiogenic factors. Pharmacotherapy. 2006;26(3):333–40.CrossRefPubMed
35.
Persson T, Monsef N, Andersson P, Bjartell A, Malm J, Calafat J, et al. Expression of the neutrophil activating CXC chemokine ENA-78/CXCL5 by human eosinophils. Clin Exp Allergy. 2003;33(4):531–7.CrossRefPubMed
36.
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67–81.CrossRefPubMed
37.
Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water JJ. Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders. Neuroimmunol. 2011;232(1–2):196–9.CrossRef
38.
Al-Ayadhi LY, Mostafa GA. Elevated serum levels of macrophage-derived chemokine and thymus and activation-regulated chemokine in autistic children. J Neuroinflammation. 2013;10:72.CrossRefPubMedCentralPubMed
39.
Al-ayadhi LY, Mostafa GA. Increased serum osteopontin levels in autistic children: relation to the disease severity. Brain Behav Immun. 2011;25(7):1393–8.CrossRefPubMed
40.
41.
Greenwood DL, Gitlits VM, Alderuccio F, Sentry JW, Toh BH. Auto-antibodies in neuropsychiatric lupus. Autoimmunity. 2002;35:79e86.CrossRef
42.
Mostafa GA, Nazif HK, El-Shahawi HH, Abd El-Aziz MM, Hassan MA. Antineuronal antibodies and electroneurophysiological studies in pediatric patients withneuropsychiatric systemic lupus erythematosus. Pediatr Allergy Immunol. 2009;20:192–9.CrossRefPubMed
43.
Cojocaru IM, Cojocaru M, Botnaru L, Miu G, Sapira V, Tănăsescu R. Detection of serum of IgG anti-neuronal antibodies in systemic lupus erythematosus patients with central nervous system manifestations. Rom J Intern Med. 2010;48:267–9.PubMed
44.
Huizinga R, Linington C, Amor S. Resistance is futile.antineuronal autoimmunity in multiple sclerosis. Trends Immunol. 2008;29:54–60.CrossRefPubMed
45.
Gentile I, Zappulo E, Militerni R, Pascotto A, Borgia G, Bravaccio C. Etiopathogenesis of autism spectrum disorders: fitting the pieces of the puzzle together. Med Hypotheses. 2013;81(1):26–35.CrossRefPubMed
46.
Mazur-Kolecka B, Cohen IL, Gonzalez M2, Jenkins EC, Kaczmarski W, Brown WT, et al. Autoantibodies against neuronal progenitors in sera from children with autism. Brain Dev. 2014;36(4):322–9.CrossRefPubMed
47.
Piras IS, Haapanen L, Napolioni V, Sacco R, Van de Water J, Persico AM. Anti-brain antibodies are associated with more severe cognitive and behavioral profiles in Italian children with Autism Spectrum Disorder. Brain Behav Immun. 2014;38:91–109.CrossRefPubMedCentralPubMed
48.
Anderson G, Maes M. Redox regulation and the autistic spectrum: role of tryptophan catabolites, immuno-inflammation, autoimmunity and the amygdala. Curr Neuropharmacol. 2014;12(2):148–67.CrossRefPubMedCentralPubMed
49.
Theoharides TC, Asadi S, Panagiotidou S, Weng Z. The “missing link” in autoimmunity and autism: extracellular mitochondrial components secreted from activated live mast cells. Autoimmun Rev. 2013;12(12):1136–42.CrossRefPubMed
50.
Odell D, Maciulis A, Cutler A, Warren L, McMahon WM, Coon H, et al. Confirmation of the association of C4B null allele in autism. Human Immunol. 2005;6:140–5.CrossRef
51.
Vojdani A, Pangborn JB, Vojdani E, Cooper EL. Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major investigators of autoimmunity in autism. Int J Immunopathol Pharmacol. 2003;16:189–99.PubMed
52.
Li L, Huang L, Vergis AL, Ye H, Bajwa A, Narayan V, et al. IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. J Clin Invest. 2010;120:331–42.CrossRefPubMedCentralPubMed
53.
54.
Kessenbrock K, Fröhlich L, Sixt M, Lämmermann T, Pfister H, Bateman A. Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin. J Clin Invest. 2008;118:2438–47.PubMedCentralPubMed
55.
Metadata
Title
The possible link between elevated serum levels of epithelial cell-derived neutrophil- activating peptide-78 (ENA-78/CXCL5) and autoimmunity in autistic children
Authors
Gehan Ahmed Mostafa
Laila Yousef AL-Ayadhi
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Behavioral and Brain Functions / Issue 1/2015
Electronic ISSN: 1744-9081
DOI
https://doi.org/10.1186/s12993-015-0056-x

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