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Neurotensin and Extracellular Mitochondrial DNA: Potential Biomarkers and Novel Treatment Targets. Theoharides TC, Asadi S.

Neurotensin and Extracellular Mitochondrial DNA: Potential Biomarkers and Novel Treatment Targets. Theoharides TC, Asadi S.

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Published by: autismone on Dec 22, 2011
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AUTISMSCIENCEDIGEST:THEJOURNALOFAUTISMONE
ISSUE01
APRIL2011REPRINTEDWITHPERMISSIONwww.autsmone.org
 
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thEOhARIS C. thEOhARIDES,PhD, MD
is the director o theMolecular Immunopharmacologyand Drug Discovery Laboratory aswell as a proessor o pharmacology,biochemistry, and internal medicineat Tuts University. He received hisdegrees rom Yale University. He haspublished over 300 research papersand three textbooks. Dr. Theoharideswas the frst to show that mast cells canbe stimulated by non-allergic triggers,such as stress hormones, to secreteinammatory mediators selectivelyleading to disruption o the gut-blood-brain barriers. Based on his discoveries,Dr. Theoharides proposed the novelconcept that mast cells play a criticalrole in brain inammation and autism.
AUTISMSCIENCEDIGEST:THEJOURNALOFAUTISMONE
ISSUE01
APRIL2011REPRINTEDWITHPERMISSIONwww.autsmone.org
ShAhRzAD ASADI,PhARMD
perormsinvestigations inthe MolecularImmunopharmacologyand Drug DiscoveryLaboratory,Department oPharmacologyand ExperimentalTherapeutics, at Tuts University. She is currentlyworking on the role o mast cells in stress-induced neuroinammatory diseases. She hasbeen investigating the eect o corticotropin-releasing hormone (CRH) and o mercury onhuman mast cell release o molecules that coulddisrupt the blood-brain barrier and contribute tothe pathogenesis o autism. O particular interestis the interaction o environmental, immune andstress triggers o mast cell activation.
 
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INTRODUCTION
Autism spectrum disorders (ASD) are pervasive developmental disorderscharacterized by defcits in social interactions, communication, andlearning, as well as repetitive stereotypic behaviors.
42
At least 30%o ASD children present with sudden clinical regression at around 3years o age.
55,79
There has been an impressive rise in ASD, especiallyater 1986,
56
with current prevalence estimates being about 1/68boys.
27,47,10
 Some possible autism susceptibility genes have been identifed.
77 
 However, no single gene or group o genes can explain the meteoricrise in autism incidence. Gene interactions with environmental actors(epigenetic actors) have been suspected as related to the increasein autism prevalence.
35
For instance, a recent paper reported thatmothers with one autistic child had a much higher chance o havinganother i born within one year o the frst pregnancy.
16
This fndingsuggests that actors other than genetics must have been inuencingthe outcome o the pregnancy during that frst year. Such actors couldnot be genetic because they would then have inuenced the outcomeregardless o the time rom the frst pregnancy. More likely contributorsinclude nutrition, stress due to a second child being born within a yearo the frst, or environmental actors (or example, parents might moveto a larger house as their amily grows). Unortunately, in most casesthe cause o ASD is said to be unknown.
50
 Interestingly, epigenetic mechanisms may also explain the“epidemic” o immune diseases and allergies.
54
An inappropriateimmune response by autistic subjects to antigenic stimuli has been
neuRoTensin andexTRacellulaR miTochondRial dna:
poTenTial BiomaRkeRs andnovel TReaTmenT TaRGeTs
By HEOHAriS C. HEOHAriDES, PHD, MD AND SHAHrZAD ASADi, PHArMD
 Abbreviations:
ASD: autsm spectum dsodesBDNF: ban-deved neuotophc actoBBB: blood-ban baeCgrP: calctonn-ene elated peptdeCrH: cotcotopn-eleasn homoneCSF: ceebospnal udFcεri: hh afnt iE eceptogi: astontestnaliFN: nteeonLPS: lpopolsacchadeM-CHA: Moded Checklst o Autsmn oddlesMCP-1: chemoattactant poten-1MiF: macophae nhbto actoNgF: neve owth actoNK cells: natual klle cellsN: neuotensnPCB: polchlonated bphenlPDD-NOS: pevasve developmentaldsode – not othewse specedSP: substance PgF-β1: tansomn owth acto-beta1Lr: toll-lke eceptoNF: tumo necoss actoUP: utcaa pmentosa  VEgF: vascula endothelal owth acto ViP: vasoactve ntestnal peptde
Autsm spectum dsodes (ASD) ae neuodevelopmental dsodes chaactezed b dects n socal nteactons,communcaton, and leann, as well as steeotpc behavos. Tee ae stll ew nshts o ts eal detecton oteatment. Te pesence o ban expesson o po-nammato ctoknes and cculatn autoantbodes aanstban potens ndcate mmune dsuncton. Man ASD chlden sue om “allec-lke” poblems n esponse toenvonmental tes that could contbute to ban nammaton n at least a suboup o ASD patents. We ecentl dented hh seum levels o neuotensn, a neuopeptde pesent both n the ban and ut, and mtochondal DNAn oun chlden wth autsm. Tese molecules could seve as unque bomakes as well as taets o novel teatments.
 
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generally, allerc reactons are assocated wth elevated plasma iE antbodes. in theabsence o elevated serum iE, “allerc-lke” reactons are not always consdered “true”alleres. Many ASD chldren sufer rom just such “allerc-lke” symptoms.
observed in unaected siblings, suggesting a particular geneticbackground inuenced by environmental triggers.
64
A number opapers have reviewed amily or personal history o children with ASDand reported an association with immune disorders, especially duringthe third trimester o pregnancy or in the child with ASD.
8,30
Usinghealth records, a nested case-control study o inants with ASD bornin Caliornia between 1995-1999 reported that the prevalence omaternal psoriasis, asthma, hay ever, and atopic dermatitis during thesecond trimester o pregnancy correlated with a greater than 2-oldelevated risk o ASD in the children.
20
In a National Survey o Children’sHealth, similarly, parents o autistic children (n=483) reported moresymptoms o allergies, especially ood allergies or intolerance, thanthose o healthy control children (n=84,789).
33
These results, andthe presence o autoantibodies against brain proteins in the serum omany autistic children and their mothers, prompt the suggestion thatthere may be a neuroimmune component
8,30,71
in at least some ASDendophenotypes within the autism spectrum.
59
“AlleRGIC” sympTOms IN AUTIsm:A lITeRATURe sURvey 
Generally, allergic reactions are associated with elevated plasmaIgE antibodies. In the absence o elevated serum IgE, “allergic-like”reactions are not always considered “true” allergies. Many ASDchildren suer rom just such “allergic-like” symptoms.
43,68,4
As shownin Table 1, a number o conditions can present with allergic-likesymptoms such as chronic idiopathic or chronic autoimmune urticaria,without any o the typical test results or allergies (e.g., elevated serumIgE or positive skin tests).
46
A recent preliminary study o children with ASD (n=245) indicatedthat the strongest association o autism was with a history o allergies.
63
 Another paper reported that increased atopic dermatitis, asthma,rhinitis, high serum IgE, and positive skin tests were present in 70%o Asperger’s syndrome patients (n=15) compared to 7% o age-matched healthy controls (n=15).
53
As mentioned earlier, however,not all reports o allergic symptoms in children with ASD implicateallergic IgE antibodies. In a hospital-based case-control study usingquestionnaires completed by the parents and scored blindly by anallergist, 30% o autistic children (n=30) had a amily history oallergic eatures compared to 2.5% o age-matched “neurologiccontrols” (n=39) (p<0.005); there was no dierence, however, inserum IgE or skin prick tests to 12 common antigens between autisticsubjects and controls, suggesting non-immune triggers.
9
Another studyreported that the prevalence o atopic disorders in subjects with ASD(n=133) was similar to that o the controls, but non-IgE-mediatedood intolerance was observed at a signifcantly higher rate in ASDcompared to controls (n=13), again highlighting the likely role o othernon-allergic actors.
44
Some colleagues speculate that elevated IgG1antibodies may be indicative o non-allergic reactions, but even thisis controversial. For instance, the signifcance o increased plasmaIgG4 levels in children with autism (n=114) compared to normally-developing children (n=96) in one study is unclear,
25
because highlevels o IgG4 antibodies to oods during inancy are associated withtolerance later in lie
73
while many ASD children are intolerant to oods.Unortunately, one can only test or ood allergies against suspectedavailable ood “allergens.” When anecdotal reports suraced thatsome children with ASD present with hives ater eating meat, theywere greeted with skepticism by some investigators. Nevertheless, asrecently reported, this phenomenon turns out to be true due to IgEantibodies specifc or the meat carbohydrate epitope galactose-
α 
-1,3-galactose, which result in delayed angioedema and urticaria atereating bee, lamb, or pork.
18
mAsT Cells
Mast cells are immune cells oten attributed with causing allergicreactions. In addition to being necessary or the development oallergic reactions,
70
mast cells are also critical or both innate andacquired immunity
28
as well as inammation.
69
Functional mast cell-neuron interactions occur in the GI tract
5
and the brain.
62
Given thatGI-related symptoms are quite common in ASD patients,
51
especiallyabnormal intestinal permeability,
11
it is important to note that mast cellsare involved in GI inammation and increased gut permeability.
26
gven that gi-elated smptoms ae qute common n ASD patents,especall abnomal ntestnal pemeablt, t s mpotant to note that mast cells aenvolved n gi nammaton and nceased ut pemeablt.
1.
primary
a. mastoytosisb. mooloal ast ell ativatio isorer (mmAd)
2.
scondary
a. Allergiesb. mast ell ativatio i ifaatio or aer. Physial urtiarias. chroi autoiue urtiaria
3.
Idioatic
a. Aaphylaxisb. Agioeea. Urtiaria. mast ell ativatio syroe (mcAS)*Aapte ro
2
Tabl 1:
diseases ivolvig ast ell ativatio*

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