Advertisement

Levels of Soluble Platelet Endothelial Cell Adhesion Molecule-1 and P-Selectin Are Decreased in Children with Autism Spectrum Disorder

      Background

      Although the etiopathology of autism spectrum disorder (ASD) is not clear, there is increasing evidence that dysfunction in the immune system affects many children with ASD. Findings of immune dysfunction in ASD include increases in inflammatory cytokines, chemokines, and microglial activity in brain tissue and cerebrospinal fluid, as well as abnormal peripheral immune cell function.

      Methods

      Adhesion molecules, such as platelet endothelial adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), P-selectin, and L-selectin, function to facilitate leukocyte transendothelial migration. We assessed concentrations of soluble adhesion molecules, sPECAM-1, sICAM-1, sVCAM-1, sP-selectin, and sL-selectin in the plasma of 49 participants with ASD and 31 typically developing controls of the same age, all of whom were enrolled as part of the Autism Phenome Project. Behavioral assessment, the levels of soluble adhesion molecules, and head circumference were compared in the same subjects.

      Results

      Levels of sPECAM-1 and sP-selectin were significantly reduced in the ASD group compared to typically developing controls (p < .02). Soluble PECAM-1 levels were negatively associated with repetitive behavior and abnormal brain growth in children with ASD (p = .03).

      Conclusions

      Because adhesion molecules modulate the permeability and signaling at the blood–brain barrier as well as leukocyte infiltration into the central nervous system, the current data suggest a role for these molecules in the complex pathophysiology of ASD.

      Key Words

      To read this article in full you will need to make a payment
      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        4th edition, text revision. American Psychiatric Publishing, Arlington, VA2000
        • Morbidity and Mortality Weekly Report
        Prevalence of autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, United States, 2006.
        MMWR Surveill Summ. 2009; 58: 1-20
        • Ashwood P.
        • Wills S.
        • Van de Water J.
        The immune response in autism: A new frontier for autism research.
        J Leukoc Biol. 2006; 80: 1-15
        • Enstrom A.M.
        • Van de Water J.A.
        • Ashwood P.
        Autoimmunity in autism.
        Curr Opin Investig Drugs. 2009; 10: 463-473
        • Patterson P.H.
        Immune involvement in schizophrenia and autism: Etiology, pathology and animal models.
        Behav Brain Res. 2009; 204: 313-321
        • Careaga M.
        • Van de Water J.
        • Ashwood P.
        Immune dysfunction in autism: A pathway to treatment.
        Neurotherapeutics. 2010; 7: 283-292
        • Vargas D.L.
        • Nascimbene C.
        • Krishnan C.
        • Zimmerman A.W.
        • Pardo C.A.
        Neuroglial activation and neuroinflammation in the brain of patients with autism.
        Ann Neurol. 2005; 57: 67-81
        • Ashwood P.
        • Enstrom A.
        • Krakowiak P.
        • Hertz-Picciotto I.
        • Hansen R.L.
        • Croen L.A.
        • et al.
        Decreased transforming growth factor beta1 in autism: A potential link between immune dysregulation and impairment in clinical behavioral outcomes.
        J Neuroimmunol. 2008; 204: 149-153
        • Ashwood P.
        • Krakowiak P.
        • Hertz-Picciotto I.
        • Hansen R.
        • Pessah I.
        • Van de Water J.
        Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome.
        Brain Behav Immun. 2011; 25: 40-45
        • Ashwood P.
        • Krakowiak P.
        • Hertz-Picciotto I.
        • Hansen R.
        • Pessah I.N.
        • Van de Water J.
        Associations of impaired behaviors with elevated plasma chemokines in autism spectrum disorders.
        J Neuroimmunol. 2011; 232: 196-199
        • Croonenberghs J.
        • Wauters A.
        • Devreese K.
        • Verkerk R.
        • Scharpe S.
        • Bosmans E.
        • et al.
        Increased serum albumin, gamma globulin, immunoglobulin IgG, and IgG2 and IgG4 in autism.
        Psychol Med. 2002; 32: 1457-1463
        • Heuer L.
        • Ashwood P.
        • Schauer J.
        • Goines P.
        • Krakowiak P.
        • Hertz-Picciotto I.
        • et al.
        Reduced levels of immunoglobulin in children with autism correlates with behavioral symptoms.
        Autism Res. 2008; 1: 275-283
        • Enstrom A.
        • Krakowiak P.
        • Onore C.
        • Pessah I.N.
        • Hertz-Picciotto I.
        • Hansen R.L.
        • et al.
        Increased IgG4 levels in children with autism disorder.
        Brain Behav Immun. 2009; 23: 389-395
        • Warren R.P.
        • Yonk L.J.
        • Burger R.A.
        • Cole P.
        • Odell J.D.
        • Warren W.L.
        • et al.
        Deficiency of suppressor-inducer (CD4+CD45RA+) T cells in autism.
        Immunol Invest. 1990; 19: 245-251
        • Yonk L.J.
        • Warren R.P.
        • Burger R.A.
        • Cole P.
        • Odell J.D.
        • Warren W.L.
        • et al.
        CD4+ helper T cell depression in autism.
        Immunol Lett. 1990; 25: 341-345
        • Denney D.R.
        • Frei B.W.
        • Gaffney G.R.
        Lymphocyte subsets and interleukin-2 receptors in autistic children.
        J Autism Dev Disord. 1996; 26: 87-97
        • Gupta S.
        • Aggarwal S.
        • Rashanravan B.
        • Lee T.
        Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism.
        J Neuroimmunol. 1998; 85: 106-109
        • Ashwood P.
        • Anthony A.
        • Pellicer A.A.
        • Torrente F.
        • Walker-Smith J.A.
        • Wakefield A.J.
        Intestinal lymphocyte populations in children with regressive autism: Evidence for extensive mucosal immunopathology.
        J Clin Immunol. 2003; 23: 504-517
        • Ashwood P.
        • Krakowiak P.
        • Hertz-Picciotto I.
        • Hansen R.
        • Pessah I.N.
        • Van de Water J.
        Altered T cell responses in children with autism.
        Brain Behav Immun. 2011; 25: 840-849
        • Warren R.P.
        • Foster A.
        • Margaretten N.C.
        Reduced natural killer cell activity in autism.
        J Am Acad Child Adolesc Psychiatry. 1987; 26: 333-335
        • Vojdani A.
        • Mumper E.
        • Granpeesheh D.
        • Mielke L.
        • Traver D.
        • Bock K.
        • et al.
        Low natural killer cell cytotoxic activity in autism: The role of glutathione, IL-2 and IL-15.
        J Neuroimmunol. 2008; 205: 148-154
        • Enstrom A.M.
        • Lit L.
        • Onore C.E.
        • Gregg J.P.
        • Hansen R.L.
        • Pessah I.N.
        • et al.
        Altered gene expression and function of peripheral blood natural killer cells in children with autism.
        Brain Behav Immun. 2009; 23: 124-133
        • Jyonouchi H.
        • Sun S.
        • Le H.
        Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression.
        J Neuroimmunol. 2001; 120: 170-179
        • Sweeten T.L.
        • Posey D.J.
        • McDougle C.J.
        High blood monocyte counts and neopterin levels in children with autistic disorder.
        Am J Psychiatry. 2003; 160: 1691-1693
        • Enstrom A.M.
        • Onore C.E.
        • Van de Water J.A.
        • Ashwood P.
        Differential monocyte responses to TLR ligands in children with autism spectrum disorders.
        Brain Behav Immun. 2010; 24: 64-71
        • Braunschweig D.
        • Ashwood P.
        • Krakowiak P.
        • Hertz-Picciotto I.
        • Hansen R.
        • Croen L.A.
        • et al.
        Autism: Maternally derived antibodies specific for fetal brain proteins.
        Neurotoxicology. 2008; 29: 226-231
        • Martin L.A.
        • Ashwood P.
        • Braunschweig D.
        • Cabanlit M.
        • Van de Water J.
        • Amaral D.G.
        Stereotypies and hyperactivity in rhesus monkeys exposed to IgG from mothers of children with autism.
        Brain Behav Immun. 2008; 22: 806-816
        • Singer H.S.
        • Morris C.
        • Gause C.
        • Pollard M.
        • Zimmerman A.W.
        • Pletnikov M.
        Prenatal exposure to antibodies from mothers of children with autism produces neurobehavioral alterations: A pregnant dam mouse model.
        J Neuroimmunol. 2009; 211: 39-48
        • Wills S.
        • Cabanlit M.
        • Bennett J.
        • Ashwood P.
        • Amaral D.G.
        • Van de Water J.
        Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders.
        Brain Behav Immun. 2009; 23: 64-74
        • Singh V.K.
        Plasma increase of interleukin-12 and interferon-gamma.
        J Neuroimmunol. 1996; 66: 143-145
        • Okada K.
        • Hashimoto K.
        • Iwata Y.
        • Nakamura K.
        • Tsujii M.
        • Tsuchiya K.J.
        • et al.
        Decreased serum levels of transforming growth factor-beta1 in patients with autism.
        Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31: 187-190
        • Croen L.A.
        • Goines P.
        • Braunschweig D.
        • Yolken R.
        • Yoshida C.K.
        • Grether J.K.
        • et al.
        Brain-derived neurotrophic factor and autism: Maternal and infant peripheral blood levels in the Early Markers for Autism (EMA) Study.
        Autism Res. 2008; 1: 130-137
        • Grigorenko E.L.
        • Han S.S.
        • Yrigollen C.M.
        • Leng L.
        • Mizue Y.
        • Anderson G.M.
        • et al.
        Macrophage migration inhibitory factor and autism spectrum disorders.
        Pediatrics. 2008; 122: e438-e445
        • Croonenberghs J.
        • Bosmans E.
        • Deboutte D.
        • Kenis G.
        • Maes M.
        Activation of the inflammatory response system in autism.
        Neuropsychobiology. 2002; 45: 1-6
        • Jyonouchi H.
        • Geng L.
        • Ruby A.
        • Reddy C.
        • Zimmerman-Bier B.
        Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders.
        J Pediatr. 2005; 146: 605-610
        • Molloy C.A.
        • Morrow A.L.
        • Meinzen-Derr J.
        • Schleifer K.
        • Dienger K.
        • Manning-Courtney P.
        • et al.
        Elevated cytokine levels in children with autism spectrum disorder.
        J Neuroimmunol. 2006; 172: 198-205
        • Onore C.
        • Enstrom A.
        • Krakowiak P.
        • Hertz-Picciotto I.
        • Hansen R.
        • Van de Water J.
        • et al.
        Decreased cellular IL-23 but not IL-17 production in children with autism spectrum disorders.
        J Neuroimmunol. 2009; 216: 126-129
        • Li X.
        • Chauhan A.
        • Sheikh A.M.
        • Patil S.
        • Chauhan V.
        • Li X.M.
        • et al.
        Elevated immune response in the brain of autistic patients.
        J Neuroimmunol. 2009; 207: 111-116
        • Zimmerman A.W.
        • Jyonouchi H.
        • Comi A.M.
        • Connors S.L.
        • Milstien S.
        • Varsou A.
        • et al.
        Cerebrospinal fluid and serum markers of inflammation in autism.
        Pediatr Neurol. 2005; 33: 195-201
        • Baron J.L.
        • Madri J.A.
        • Ruddle N.H.
        • Hashim G.
        • Janeway Jr, C.A.
        Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma.
        J Exp Med. 1993; 177: 57-68
        • Ley K.
        • Laudanna C.
        • Cybulsky M.I.
        • Nourshargh S.
        Getting to the site of inflammation: The leukocyte adhesion cascade updated.
        Nat Rev Immunol. 2007; 7: 678-689
        • Sharief M.K.
        • Noori M.A.
        • Ciardi M.
        • Cirelli A.
        • Thompson E.J.
        Increased levels of circulating ICAM-1 in serum and cerebrospinal fluid of patients with active multiple sclerosis.
        J Neuroimmunol. 1993; 43: 15-21
        • Losy J.
        • Niezgoda A.
        • Wender M.
        Increased serum levels of soluble PECAM-1 in multiple sclerosis patients with brain gadolinium-enhancing lesions.
        J Neuroimmunol. 1999; 99: 169-172
        • Tsuchiya K.J.
        • Hashimoto K.
        • Iwata Y.
        • Tsujii M.
        • Sekine Y.
        • Sugihara G.
        • et al.
        Decreased serum levels of platelet-endothelial adhesion molecule (PECAM-1) in subjects with high-functioning autism: A negative correlation with head circumference at birth.
        Biol Psychiatry. 2007; 62: 1056-1058
        • Iwata Y.
        • Tsuchiya K.J.
        • Mikawa S.
        • Nakamura K.
        • Takai Y.
        • Suda S.
        • et al.
        Serum levels of P-selectin in men with high-functioning autism.
        Br J Psychiatry. 2008; 193: 338-339
        • Lord C.
        • Risi S.
        • Lambrecht L.
        • Cook Jr, E.H.
        • Leventhal B.L.
        • DiLavore P.C.
        • et al.
        The autism diagnostic observation schedule-generic: A standard measure of social and communication deficits associated with the spectrum of autism.
        J Autism Dev Disord. 2000; 30: 205-223
        • Lord C.
        • Rutter M.
        • Le Couteur A.
        Autism Diagnostic Interview—Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders.
        J Autism Dev Disord. 1994; 24: 659-685
        • Berument S.K.
        • Rutter M.
        • Lord C.
        • Pickles A.
        • Bailey A.
        Autism screening questionnaire: Diagnostic validity.
        Br J Psychiatry. 1999; 175: 444-451
        • Rothman K.J.
        No adjustments are needed for multiple comparisons.
        Epidemiology. 1990; 1: 43-46
        • Schwartz M.
        • Kipnis J.
        A conceptual revolution in the relationships between the brain and immunity.
        Brain Behav Immun. 2011; 25: 817-819
        • Kipnis J.
        • Cohen H.
        • Cardon M.
        • Ziv Y.
        • Schwartz M.
        T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions.
        Proc Natl Acad Sci U S A. 2004; 101: 8180-8185
        • Ziv Y.
        • Ron N.
        • Butovsky O.
        • Landa G.
        • Sudai E.
        • Greenberg N.
        • et al.
        Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood.
        Nat Neurosci. 2006; 9: 268-275
        • Derecki N.C.
        • Quinnies K.M.
        • Kipnis J.
        Alternatively activated myeloid (M2) cells enhance cognitive function in immune compromised mice.
        Brain Behav Immun. 2011; 25: 379-385
        • Derecki N.C.
        • Cardani A.N.
        • Yang C.H.
        • Quinnies K.M.
        • Crihfield A.
        • Lynch K.R.
        • et al.
        Regulation of learning and memory by meningeal immunity: A key role for IL-4.
        J Exp Med. 2010; 207: 1067-1080
        • Ziv Y.
        • Finkelstein A.
        • Geffen Y.
        • Kipnis J.
        • Smirnov I.
        • Shpilman S.
        • et al.
        A novel immune-based therapy for stroke induces neuroprotection and supports neurogenesis.
        Stroke. 2007; 38: 774-782
        • Schwartz M.
        • Moalem G.
        • Leibowitz-Amit R.
        • Cohen I.R.
        Innate and adaptive immune responses can be beneficial for CNS repair.
        Trends Neurosci. 1999; 22: 295-299
        • Beers D.R.
        • Henkel J.S.
        • Zhao W.
        • Wang J.
        • Appel S.H.
        CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS.
        Proc Natl Acad Sci U S A. 2008; 105: 15558-15563
        • Chiu I.M.
        • Chen A.
        • Zheng Y.
        • Kosaras B.
        • Tsiftsoglou S.A.
        • Vartanian T.K.
        • et al.
        T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS.
        Proc Natl Acad Sci U S A. 2008; 105: 17913-17918
        • Curran L.K.
        • Newschaffer C.J.
        • Lee L.C.
        • Crawford S.O.
        • Johnston M.V.
        • Zimmerman A.W.
        Behaviors associated with fever in children with autism spectrum disorders.
        Pediatrics. 2007; 120: e1386-e1392
        • Torres A.R.
        Is fever suppression involved in the etiology of autism and neurodevelopmental disorders?.
        BMC Pediatr. 2003; 3: 9
        • Han Y.M.Y.
        • Leung W.W.M.
        • Wong C.K.
        • Lam J.M.K.
        • Cheung M.C.
        • Chan A.S.
        Lymphocyte subset alterations related to executive function deficits and repetitive stereotyped behavior in autism.
        Res Autism Spect Dis. 2011; 5: 486-494
        • Stenberg P.E.
        • McEver R.P.
        • Shuman M.A.
        • Jacques Y.V.
        • Bainton D.F.
        A platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation.
        J Cell Biol. 1985; 101: 880-886
        • Bonfanti R.
        • Furie B.C.
        • Furie B.
        • Wagner D.D.
        PADGEM (GMP140) is a component of Weibel-Palade bodies of human endothelial cells.
        Blood. 1989; 73: 1109-1112
        • McEver R.P.
        • Cummings R.D.
        Perspectives series: Cell adhesion in vascular biology.
        J Clin Invest. 1997; 100: 485-491
        • Burger P.C.
        • Wagner D.D.
        Platelet P-selectin facilitates atherosclerotic lesion development.
        Blood. 2003; 101: 2661-2666
        • Michelson A.D.
        • Barnard M.R.
        • Hechtman H.B.
        • MacGregor H.
        • Connolly R.J.
        • Loscalzo J.
        • et al.
        In vivo tracking of platelets: Circulating degranulated platelets rapidly lose surface P-selectin but continue to circulate and function.
        Proc Natl Acad Sci U S A. 1996; 93: 11877-11882
        • Newman P.J.
        • Newman D.K.
        Signal transduction pathways mediated by PECAM-1: New roles for an old molecule in platelet and vascular cell biology.
        Arterioscler Thromb Vasc Biol. 2003; 23: 953-964
        • Muller W.A.
        • Weigl S.A.
        • Deng X.
        • Phillips D.M.
        PECAM-1 is required for transendothelial migration of leukocytes.
        J Exp Med. 1993; 178: 449-460
        • Goldberger A.
        • Middleton K.A.
        • Oliver J.A.
        • Paddock C.
        • Yan H.C.
        • DeLisser H.M.
        • et al.
        Biosynthesis and processing of the cell adhesion molecule PECAM-1 includes production of a soluble form.
        J Biol Chem. 1994; 269: 17183-17191
        • Ilan N.
        • Mohsenin A.
        • Cheung L.
        • Madri J.A.
        PECAM-1 shedding during apoptosis generates a membrane-anchored truncated molecule with unique signaling characteristics.
        FASEB J. 2001; 15: 362-372
        • Liao F.
        • Ali J.
        • Greene T.
        • Muller W.A.
        Soluble domain 1 of platelet-endothelial cell adhesion molecule (PECAM) is sufficient to block transendothelial migration in vitro and in vivo.
        J Exp Med. 1997; 185: 1349-1357
        • Qing Z.
        • Sandor M.
        • Radvany Z.
        • Sewell D.
        • Falus A.
        • Potthoff D.
        • et al.
        Inhibition of antigen-specific T cell trafficking into the central nervous system via blocking PECAM1/CD31 molecule.
        J Neuropathol Exp Neurol. 2001; 60: 798-807
        • Piccio L.
        • Rossi B.
        • Scarpini E.
        • Laudanna C.
        • Giagulli C.
        • Issekutz A.C.
        • et al.
        Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: Critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric G(i)-linked receptors.
        J Immunol. 2002; 168: 1940-1949
        • Kisucka J.
        • Chauhan A.K.
        • Zhao B.Q.
        • Patten I.S.
        • Yesilaltay A.
        • Krieger M.
        • et al.
        Elevated levels of soluble P-selectin in mice alter blood-brain barrier function, exacerbate stroke, and promote atherosclerosis.
        Blood. 2009; 113: 6015-6022
        • DeLisser H.M.
        • Newman P.J.
        • Albelda S.M.
        Molecular and functional aspects of PECAM-1/CD31.
        Immunol Today. 1994; 15: 490-495
        • Schimmenti L.A.
        • Yan H.C.
        • Madri J.A.
        • Albelda S.M.
        Platelet endothelial cell adhesion molecule, PECAM-1, modulates cell migration.
        J Cell Physiol. 1992; 153: 417-428
        • Reinke E.K.
        • Lee J.
        • Zozulya A.
        • Karman J.
        • Muller W.A.
        • Sandor M.
        • et al.
        Short-term sPECAM-Fc treatment ameliorates EAE while chronic use hastens onset of symptoms.
        J Neuroimmunol. 2007; 186: 86-93
        • Graesser D.
        • Solowiej A.
        • Bruckner M.
        • Osterweil E.
        • Juedes A.
        • Davis S.
        • et al.
        Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1-deficient mice.
        J Clin Invest. 2002; 109: 383-392
        • Persidsky Y.
        • Stins M.
        • Way D.
        • Witte M.H.
        • Weinand M.
        • Kim K.S.
        • et al.
        A model for monocyte migration through the blood-brain barrier during HIV-1 encephalitis.
        J Immunol. 1997; 158: 3499-3510
        • Wispelwey B.
        • Lesse A.J.
        • Hansen E.J.
        • Scheld W.M.
        Haemophilus influenzae lipopolysaccharide-induced blood brain barrier permeability during experimental meningitis in the rat.
        J Clin Invest. 1988; 82: 1339-1346
        • Wilkinson R.
        • Lyons A.B.
        • Roberts D.
        • Wong M.X.
        • Bartley P.A.
        • Jackson D.E.
        Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) acts as a regulator of B-cell development, B-cell antigen receptor (BCR)-mediated activation, and autoimmune disease.
        Blood. 2002; 100: 184-193
        • Duncan G.S.
        • Andrew D.P.
        • Takimoto H.
        • Kaufman S.A.
        • Yoshida H.
        • Spellberg J.
        • et al.
        Genetic evidence for functional redundancy of platelet/endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions.
        J Immunol. 1999; 162: 3022-3030
        • Mahooti S.
        • Graesser D.
        • Patil S.
        • Newman P.
        • Duncan G.
        • Mak T.
        • et al.
        PECAM-1 (CD31) expression modulates bleeding time in vivo.
        Am J Pathol. 2000; 157: 75-81