期刊论文详细信息
Journal of Neuroinflammation
Low plasma progranulin levels in children with autism
Gehan A Mostafa1  Laila Y AL-Ayadhi2 
[1]Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
[2]Autism Research and Treatment Center, AL-Amodi Autism Research Chair, Department of Physiology, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia
关键词: progranulin.;    neutrophils;    autoimmunity;    Autism;   
Others  :  1213140
DOI  :  10.1186/1742-2094-8-111
 received in 2011-06-16, accepted in 2011-09-05,  发布年份 2011
PDF
【 摘 要 】

Background

Autoimmunity to brain may play a pathogenic role in autism. In autoimmune disorders, the formation of antigen-antibody complexes triggers an inflammatory response by inducing the infiltration of neutrophils. Local administration of recombinant progranulin, which is an anti-inflammatory neurotrophic factor, potently inhibit neutrophilic inflammation in vivo, demonstrating that progranulin represents a crucial inflammation-suppressing mediator. We are the first to measure plasma progranulin levels in autism.

Methods

Plasma levels of progranulin were measured, by ELISA, in 40 autistic patients, aged between 3 and 12 years, and 40 healthy-matched children.

Results

Autistic children had significantly lower plasma progranulin levels, P = 0.001. Reduced plasma progranulin levels were found in 65% (26/40) of autistic children.

On the other hand, there was a non significant difference between plasma progranulin levels of children with mild to moderate autism and patients with severe autism, P = 0.11.

Conclusions

Plasma progranulin levels were reduced in a subgroup of patients with autism. Progranulin insufficiency in some patients with autism may result in many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation that may have a role in autism. However, these data should be treated with caution until further investigations are performed, with a larger subject population, to determine whether the decrease of plasma progranulin levels is a mere consequence of autism or has a pathogenic role in the disease. The role of progranulin therapy should also be studied in autism.

【 授权许可】

   
2011 AL-Ayadhi and Mostafa; licensee BioMed Central Ltd.

【 预 览 】
附件列表
Files Size Format View
20150614115403706.pdf 236KB PDF download
Figure 1. 27KB Image download
【 图 表 】

Figure 1.

【 参考文献 】
  • [1]Cohly HH, Panja A: Immunological findings in autism. Int Rev Neurobiol 2005, 7:317-341.
  • [2]Al-Ayadhi LY, Mostafa GA: Increased serum osteopontin levels in autistic children: Relation to the disease severity. Brain Behav Immun 2011, in press.
  • [3]Singh VK, Warren RP, Odell JD, Warren WL, Cole P: Antibodies to myelin basic protein in children with autistic behavior. Brain Behav Immun 1993, 7(1):97-103.
  • [4]Singh VK, Warren RP, Averett R, Ghaziuddin M: Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr Neurol 1997, 17(1):88-90.
  • [5]Singh VK, Lin SX, Yang VC: Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Clin Immunol Immunopathol 1998, 89(1):105-108.
  • [6]Singh VK, Rivas WH: Prevalence of serum antibodies to caudate nucleus in autistic children. Neurosci Lett 2004, 355(1-2):53-56.
  • [7]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, 23:1413-1418.
  • [8]Mostafa GA, El-Hadidi ES, Hewedi DH, Abdou MM: Oxidative stress in Egyptian children with autism: relation to autoimmunity. J Neuroimmunol 2010, 219:114-118.
  • [9]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. BioMed Central Full Text
  • [10]Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN: Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J Child Neurol 1999, 14:388-394.
  • [11]Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ: Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics 2003, 112(5):420-424.
  • [12]Atladóttir HO, Pedersen MG, Thorsen P, Mortensen PB, Deleuran B, Eaton WW, et al.: Association of Family History of autoimmune diseases and autism spectrum disorders. Pediatrics 1999, 124(2):687-694.
  • [13]Mostafa GA, Kitchener N: Serum anti-nuclear antibodies as a marker of autoimmunity in Egyptian autistic children. Pediatr Neurol 2009, 40:107-112.
  • [14]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, 223:115-119.
  • [15]Mostafa GA, Shehab A Al, Fouad NR: Frequency of CD4+CD25high regulatoryT cells in the peripheral blood of Egyptian children with autism. J Child Neurol 2010, 25:328-335.
  • [16]Mouridsen SE, Rich B, Isager T, Nedergaard NJ: Autoimmune diseases in parents of children with infantile autism: a case-control study. Dev Med Child Neurol 2007, 49(6):429-432.
  • [17]Mostafa GA, EL-Sherif D, Hamza RT, Shehab A: Hyperserotonemia in Egyptian autistic children: relation to allergic manifestations. J Pediatr Neurol 2008, 6(3):227-236.
  • [18]Warren RP, Singh VK, Cole P, Odell JD, Pingree CB, Warren WL, White E: Increased frequency of the null allele at the complement C4b locus in autism. Clin Exp Immunol 1991, 83:438-440.
  • [19]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, 66(2):140-145.
  • [20]Nathan C: Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 2006, 6:173-182.
  • [21]Jancar S, Sanchez CM: Immune complex-mediated tissue injury: a multistep paradigm. Trends Immunol 2005, 26:48-55.
  • [22]Ravetch JV: Fc receptors: rubor redux. Cell 1994, 78:553-560.
  • [23]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, 118:2438-2447.
  • [24]He Z, Bateman A: Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med 2003, 81:600-612.
  • [25]Tolkatchev D, Malik S, Vinogradova A, Wang P, Chen Z, Xu P, et al.: Structure dissection of human progranulin identifies well-folded granulin/epithelin modules with unique functional activities. Protein Sci 2008, 17(4):7117-7124.
  • [26]Daniel R, He Z, Carmichael KP, Halper J, Bateman A: Cellular localization of gene expression for progranulin. J Histochem Cytochem 2000, 48:999-1009.
  • [27]Zhu J, Nathan C, Jin W, Sim D, Ashcroft GS, Wahl SM, et al.: Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell 2002, 111:867-78.
  • [28]He Z, Ong CH, Halper J, Bateman A: Progranulin is a mediator of the wound response. Nat Med 2003, 9:225-229.
  • [29]Van Damme P, Van Hoecke A, Lambrechts D, Vanacker P, Bogaert E, van Swieten J, et al.: Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J Cell Biol 2008, 181:37-41.
  • [30]Meyer-Hoffert U, Wiedow O: Neutrophil serine proteases: mediators of innate immune responses. Curr Opin Hematol 2010, in press.
  • [31]American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington DC: American Psychiatric Association; 1994.
  • [32]Schopler E, Reichler RJ, Renner BR: The Childhood Autism Rating Scale (CARS), for Diagnostic Screening and Classification in Autism. New York, NY: Irvington; 1986.
  • [33]Murch S: Diet, immunity and autistic spectrum disorders. J Pediatr 2005, 146:582-4.
  • [34]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, 120:331-342.
  • [35]Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, et al.: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006, 442:916-919.
  • [36]Cruts M, Gijselinck I, van der ZJ, Engelborghs S, Wils H, Pirici D, et al.: Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006, 442:920-924.
  • [37]Ahmed Z, Mackenzie IR, Hutton ML, Dickson DW: Progranulin in frontotemporal lobar degeneration and neuroinflammation. J Neuroinflammation 2007, 4:7. BioMed Central Full Text
  • [38]Brouwers N, Sleegers K, Engelborghs S, Maurer-Stroh S, Gijselinck I, van der Zee J, et al.: Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Neurology 2008, 71:656-664.
  • [39]Cruts M, Van BC: Loss of progranulin function in frontotemporal lobar degeneration. Trends Genet 2008, 24:186-194.
  • [40]Sleegers K, Brouwers N, Maurer-Stroh S, van Es MA, Van Damme P, van Vught PW, et al.: Progranulin genetic variability contributes to amyotrophic lateral sclerosis. Neurology 2008, 71:253-259.
  • [41]van Swieten JC, Heutink P: Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia. Lancet Neurol 2008, 7:965-974.
  • [42]Irwin D, Lippa CF, Rosso A: Progranulin (PGRN) expression in ALS: An immunohistochemical study. J Neurol Sci 2009, 276:9-13.
  • [43]Yin F, Banerjee R, Thomas B, Zhou B, Qian L, Jia T, et al.: Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med 2010, 207:117-128.
  • [44]Finch N, Baker M, Crook R, Swanson K, Kuntz K, Surtees R, et al.: Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain 2009, 132(Pt 3):583-591.
  • [45]Sleegers K, Brouwers N, Van Damme P, Engelborghs S, Gijselinck I, van der Zee J, et al.: Serum biomarker for progranulin-associated frontotemporal lobar degeneration. Ann Neurol 2009, 65(5):603-609.
  • [46]Ghidoni R, Benussi L, Glionna M, Franzoni M, Binetti G: Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration. Neurology 2008, 71(16):1235-1239.
  • [47]Tang W, Lu Y, Tian QY, Zhang Y, Guo FJ, Liu GY, et al.: The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 2011, 332(6028):478-484.
  • [48]Liu CJ: Progranulin: A promising therapeutic target for rheumatoid arthritis. FEBS Lett 2011, in press.
  • [49]Toh H, Chitramuthu BP, Bennett HP, Bateman A: Structure, function, and mechanism of progranulin; the brain and beyond. Mol Neurosci 2011, in press.
  • [50]Young AM, Campbell E, Lynch S, Suckling J, Powis SJ: a mechanism for neuroinflammation. Front Psychiatry 2011, 2:27. Epub 2011 May 13
  • [51]Vercellino M, Grifoni S, Romagnolo A, Masera S, Mattioda A, Trebini C, et al.: Progranulin expression in brain tissue and cerebrospinal fluid levels in multiple sclerosis. Mult Scler 2011, in press.
  • [52]Schofield EC, Halliday GM, Kwok J, Loy C, Double KL, Hodges JR: Low serum progranulin predicts the presence of mutations: a prospective study. J Alzheimers Dis 2010, 22:981-974.
  • [53]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 form milk, Chlamydia pneumoniae and Streptococcus group A. J Neuroimmunol 2002, 129(1-2):168-177.
  • [54]Suzuki M, Yoshida S, Nishihara M, Takahashi M: Identification of a sex steroid-inducible gene in the neonatal rat hypothalamus. Neurosci Lett 1998, 242:127-130.
  • [55]Eriksen JL, Mackenzie IR: Progranulin: normal function and role in neurodegeneration. J Neurochem 2008, 104:287-297.
  • [56]Ilzecka J, Stelmasiak Z: Increased serum levels of endogenous protectant secretory leukocyte protease inhibitor in acute ischemic stroke patients. Cerebrovasc Dis 2002, 13:38-42.
  文献评价指标  
  下载次数:2次 浏览次数:16次