Table Of ContentMajor histocompatibility complex peptide
ligands as olfactory cues in human body
odour assessment
Manfred Milinski1, Ilona Croy2,3, Thomas Hummel2 and Thomas Boehm4
rspb.royalsocietypublishing.org
1DepartmentofEvolutionaryEcology,Max Planck Institute ofEvolutionary Biology,August-Thienemann-
Strasse2,24306Ploen, Germany
2DepartmentofOtorhinolaryngology, UniversityofDresdenMedical School,Fetscherstrasse74,
01307Dresden, Germany
Research 3DepartmentofOccupational and Environmental Medicine, UniversityofGothenburg,Medicinaragatan 16,
40530Gothenburg, Sweden
4DepartmentofDevelopmental Immunology, MaxPlanck Institute ofImmunobiologyandEpigenetics,
Cite this article: Milinski M, Croy I, Hummel
Stuebeweg 51, 79108Freiburg, Germany
T, Boehm T. 2013 Major histocompatibility
complex peptide ligands as olfactory cues in Inmanyanimalspecies,socialcommunicationandmatechoiceareinfluenced
human body odour assessment. Proc R Soc B bycuesencodedbythemajorhistocompatibilitycomplex(MHC).Themech-
280: 20122889. anism by which the MHC influences sexual selection is a matter of intense
debate.Inmice,peptideligandsofMHCmoleculesactivatesubsetsofvomer-
http://dx.doi.org/10.1098/rspb.2012.2889
onasalandolfactorysensoryneuronsandinfluencesocialmemoryformation;
insticklebacks,suchpeptidespredictablymodifytheoutcomeofmatechoice.
Here,weexaminewhetherthisevolutionarilyconservedmechanismofinterin-
dividualcommunicationextendstohumans.Inpsychometrictests,volunteers
Received: 4 December 2012
recognized the supplementation of their body odour by MHC peptides and
Accepted: 7 January 2013
preferred‘self’to‘non-self’ligandswhen askedtodecidewhetherthemodi-
fied odour smelled ‘like themselves’ or ‘like their favourite perfume’.
Functional magnetic resonance imaging indicated that ‘self’-peptides specifi-
callyactivatedaregionintherightmiddlefrontalcortex.Ourresultssuggest
Subject Areas: that despite the absence of avomeronasal organ, humans have the ability to
detect andevaluate MHC peptides in bodyodour. This may provide a basis
behaviour, immunology, physiology
forthesensoryevaluationofpotentialpartnersduringhumanmatechoice.
Keywords:
matechoice,majorhistocompatibilitycomplex,
fMRI 1. Introduction
Majorhistocompatibilitycomplex(MHC)moleculesareinvolvedinantigenpresen-
tationandtheirstructuredeterminestheprobabilitywithwhichagivenpathogen
Author for correspondence: willberecognizedbytheindividual’simmunesystem[1].BecauseMHCmolecules
Thomas Boehm criticallyinfluencethesusceptibilitytoinfection,maintenanceofasufficientdegree
ofMHCdiversityinnaturalpopulationsisakeysurvivalparameterinthefaceof
e-mail: [email protected]
constantlychangingpathogenspectra[2–5].Behaviouralmechanismsthatguide
non-randommatingbasedonMHCgenotypesareconsideredtobeameansby
which an optimum degree of individual MHC diversity is maintained in the
offspring.WhilethereisstrongexperimentalsupportforMHC-associatedbehav-
iour in animals [5–9], including non-human primates [10,11], the situation in
humansis more complex. Evidence in favourof MHC-associated behaviour has
emergedfromstudiesonthesexualinterestoffemales[12]andtheirpreferences
forcertainmalebodyodour[13,14];studiesonthedegreeofgeneticrelatedness
ofmatedandunmatedcouplesoftheoppositesexhaveproducedmixedresults,
suggestingaroleforMHCgenotypeinsome[15,16]butnotallpopulations[17].
Inadouble-blindstudy,Wedekindetal.[14]foundthatwomenpreferredthe
odour of shirts worn by men with different MHC allelesto those of men with
Electronic supplementary material is available more closely matching MHC alleles; a similar observation was made with
at http://dx.doi.org/10.1098/rspb.2012.2889 or maleparticipants[18].Thesefindings(reviewedin[12])suggestedarelationship
betweenMHC-dependentodoursignallingandpreferenceforaspecificpersonal
via http://rspb.royalsocietypublishing.org.
&
2013TheAuthors.PublishedbytheRoyalSocietyunderthetermsoftheCreativeCommonsAttribution
License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original
authorandsourcearecredited.
perfume.InasubsequentstudywiththeMHC-typedstudent GmbH (Ulm, Germany). The peptides and their cognate HLA 2
cohort originally tested by Wedekind et al. [14], Milinski & allelesarelistedintheelectronicsupplementarymaterial,tableS2.
Wedekind [19] tested this prediction directly; participants rs
p
b
who shared MHC alleles expressed a strong preference for (c) Psychometric test procedure .ro
the same natural perfume ingredient for use on themselves, ya
Participants were provided with a perfume-free body soap, an ls
butnotonapotentialpartner.Thus,becauseMHCgenotypes untreated cotton T-shirt and two pairs of two bottles per test ocie
determineindividualperfumepreferences,itappearsthatper- day containing synthesized HLA ligand peptides, specific for ty
p
fumesfunctionasamplifiersofMHC-relatedindividualbody either HLA A*0201 or HLA A*2402 (0.005mM in phosphate- ub
odours[20].Indeed,arecentstudyshowedthatself-preferred buffered saline (PBS)), or solvent (PBS). After a shower using lish
in
perfumesaddedtobodyodourarepreferredtoperfumesallo- thebodysoapandwearingtheT-shirtovernight,theparticipant g
.o
cated bythe investigatorand added to the samebodyodour put four drops from bottle 1 in her left hand and rubbed them rg
[21]. Collectively, these findings may provide an explanation under her right armpit, then put four drops from bottle 2 in
P
for the fact that humans of all cultures have used fragrances her righthand andrubbed themunderher left armpit.In mice ro
c
forat least 5000 years and for the observation that persistent [22] and sticklebacks [28], MHC peptide ligands elicit a R
behaviouralresponseonlywhenaccompaniedbyanaturalvali- So
interindividual differences exist for the preference of certain c
dating factor. We assumed that validation is also necessary in B
perfumes[19]. humans and that it is likely to be produced by certain glands 28
Recentworkonthemolecularnatureofthechemosensory inthearmpit[29–31].Theparticipantwasthenaskedtoevaluate 0:
2
stimuli underlying MHC-associated behaviour in animals the smell of each of her armpits by sniffing repeatedly from a 01
2
indicatesthatpeptideantigenspresentedbyMHCmolecules closedistanceandtodecidewhetherone side,andifso, which 28
8
act as olfactory cues in different species in addition to their side, smells like herself or a perfume she would like to smell 9
well-known function in eliciting immune responses [22–25]. on herself (‘would you like to smell like this?’). She marked on
Here, we have examined the ability of humans to recognize a questionnaire ‘I prefer for myself the smell of my left
and evaluate the modification of their bodyodour byallele- armpit/my right armpit; Ido not smell a difference;if I havea
preference, it is weak, medium or strong.’ The following night,
specific MHC peptide ligands. The present psychophysical
wearingthesameT-shirt,theprotocolwasrepeatedwithbottles
and neurophysiological studies suggest that MHC peptide
3 and 4; this time sides allocated to peptide and solvent were
ligands convey information about the MHC genotype and
swappedinordertocontrolforpossiblesideeffects[32].Inthe
may thus represent at least part of natural MHC-dependent
questionnaire, the participants were asked about their smoking
human bodyodour signals.
habits, their use of contraceptive medication, and whether they
had a cold during the test. Participants took part in two to six
ofsuchtestsessions dependingonavailabilityatintervals ofat
2. Material and methods leastthreemonths.
(a) Study participants (d) Data analysis for psychometric test
Female students were recruited from the Universities of Ham- The psychometric tests were carried out in a double-blind
burg and Kiel. They were genotyped for human leucocyte fashion and the results of the genotype were revealed only
antigen(HLA)HLA-AandHLA-B[26]attheUniversityHospi- after completion of the tests. The scores assigned to ‘non-self‘
tal Hamburg using the reverse SSO line blot assay (Dynal Reli stimuliweresubtractedfromscoresgivento‘self’stimuli(result-
SSO, Invitrogen); note that for historical reasons, the products inginpositivevalueswhenselfispreferredtonon-self(seetext
ofthehumanMHClocusaredesignatedasHLA.Thisanalysis fordetails));thefollowingscorescouldbegiven:nopreference,0;
revealed that 19 were positive for HLA-A*02, six were positive weak preference, 1; medium preference, 2, strong preference, 3.
for HLA-A*24 (of which twowere also positive for HLA-A*02) Datafromeachparticipantwereaveragedandonlytheaverage
and nine carried neither HLA-A*02 nor HLA-A*24. In one enteredintotheanalysistoavoidpseudo-replication.
participant (no. 6), the presence of the A*3002 allele was con-
sidered to be functionally equivalent to A*2402, because their
(e) Functional magnetic resonance imaging study:
peptide specificity is identical [27]. Sixteen participants carried
one or more alleles (in addition to HLA-A*02 or HLA-A*24) participants
withunknownpeptidespecificity,whichwereconsideredtobe
Twenty-tworight-handedwomenparticipatedinthefunctional
‘non-self’;however,giventhediversityofresiduesatanchorpos-
magnetic resonance imaging (fMRI) study; medical histories
itions, the probability that such a ‘non-self’-peptide has the
indicated that all participants were in good health. Olfactory
qualityof ‘self’ is much lessthan 0.5; in this case, the effect on
function, assessed by means of ‘Sniffin Sticks’, (Burghart,
our results would be conservative, that is, it would weaken
Wedel, Germany) [33] was compatible with a normal sense of
anyobservedeffect.Fourparticipantscarriedalleleswhosepep-
smellforallbutonepersonwhowasexcludedfromtheanalysis;
tidespecificitiesarenotpreciselyknown,butareunlikelytobe
two further participants had to be excluded from the analysis,
identical tothose used as astimulus peptide; ifnot, their influ-
one because of pronounced brain abnormalities, the other
ence would diminish rather than increase the observed effects,
because of technical problems with the dataset. Data from par-
because scores would then be given the wrong sign. At the
ticipants 15–33 (see the electronic supplementary material,
timeofperformingthepsychometrictests,theageofparticipants
tableS1fordetailsofthestudypopulation)wereprocessed. At
was 25.9+0.9 years (mean+s.e.; n¼25; range 21–36 years).
the time of the fMRI studies, the age of participants was
Detailsofthestudypopulationaresummarizedintheelectronic
27+1.1years(mean+s.e.;n¼19;range18–35years).
supplementarymaterial,tableS1.
(f) Functional magnetic resonance imaging procedure
(b) Design of peptide ligands
The study was performed with a 1.5T MR-scanner (Sonata;
Onthebasisofknownligandspecificities[27],nonamerpeptides Siemens, Erlangen, Germany). Peptide solutions were prepared
were synthesized and purified by Thermo Fisher Scientific from lyophilized stocks at a final concentration of 25mM in
PBS. Peptide and mock control solutions were prepared using with the two conditions ‘side’ (two: left, right) and ‘substance’ 3
the same type of plastic ware (50ml polypropylene Falcon (four: two peptides in solvent, solvent, additional odour
tubes; BectonDickinson). Two peptide solutions, the solvent (peach)). Whole brain analysis and small volume region of rs
p
control, and an additional odour (peach) were presented to interest (ROI) analysis were performed for seven cortical b
both nostrils in a total of eight sessions. Peach is an odour areas previously reported to be related to self-processing: .roy
a
known to cause reliable activation in olfactory-relevant areas right middle frontal cortex, superior and inferior parietal lso
c
and was therefore used as a control to ascertain the validity cortex and fusiform cortex [34], right inferior frontal and ie
ty
of the experiment; the solvent without peptides also generated anterior cingulated cortex and left insular cortex [35]. Masks p
u
activation of olfactorily relevant areas, presumably owing to were created using the aal atlas [36] embedded in the WFU blis
contaminants in the plastic containers used. The order of the PICKATLAS v. 2.4 software [37]. Four t-contrasts were calculated hin
sessions using peptides or solvent was counterbalanced (‘self’-peptide minus solvent, ‘self’-peptide minus ‘non-self’- g.o
between participants. Peach was always presented in sessions peptide, ‘non-self’-peptide minus solvent, ‘non-self’-peptide rg
7 and 8. To focus their attention on self-assessment, partici- minus ‘self’-peptide). A comparative analysis of activated
P
pants were instructed that, after each session, they would be brain areas resulting from exposure to two different olfactory ro
c
asked to rate the quality of odours on a scale of 0–10 (0, I stimuli tends to cancel out olfactory areas and instead high- R
S
would not like to smell like this at all; 10, I would very lights differentially activated regions only, such as those o
c
much like to smell like this). Each experimental session com- activated by either self or non-self-peptides. Note that the sol- B
2
prised six on/off blocks lasting 20s each. Participants were vent control also activated olfactory regions, presumably 8
0
:
blind to compound identity. The odours were applied to the owing to the presence of trace contaminants in the disposable 2
0
participants using a computer-controlled olfactometer plasticcontainersusedthroughoutthestudy;therefore,subtrac- 12
2
(Sommer, Mannheim; Germany). Stimuli were embedded in tive analysis was considered the most reliable approach to 8
8
a constant flow of odourless air (total flow 2lmin21). The revealpeptide-inducedactivation.Moreover,activationofacer- 9
stimuli were directed through a small tube from the olfact- tain brain areawas considered to be present only when signals
ometer to the participants’ noses. During the ‘on’-blocks weredetectedinaparticularregionforbothself-peptideversus
odourized air was intermittently (1s air, followed by 2s solvent and self-peptide versus non-self-peptide, or non-self-
pause) delivered to the nasal cavity, at a rate of 2lmin21. peptideversussolventandnon-self-peptideversusself-peptide,
During the ‘off’-block, participants received pulses of odour- respectively. Analysis was based on t-tests with global height
less air. With respect to the intensity of the odours, threshold p,0.001, Bonferroni-corrected for the seven search
participants reported no significant differences between solvent areas and extent threshold of k¼3. Additionally, the family-
(8.4+3.6 (mean+s.d.)), self-peptide (9.4+4.7) and non-self- wise error (FWE) rates for activations found within the search
peptide (8.5+4.1) (scores, from undetectable odour (0) to areasarepresented.
very strong odour (20) (the scores from applications to both
nostrils were totalled for the analysis); control peach odour
intensity rating, 16.4+3.6). These results indicate that self-
3. Results
peptide and non-self-peptide stimuli were presented supralim-
inally. With respect to the preference as self-odours, no
(a) Psychometric assessment of body odour
significant differences were observed when the participants
gave their scores after the short exposure to each odour In a first set of experiments with human volunteers, we
during the individual sessions of the fMRI experiment (sol- examined self-assessment of natural body odour emanating
vent, 9.1+3.7; self-peptide, 7.3+3.5; non-self-peptide,
from the armpits after supplementation with prototypic
8.8+2.7). Note the different experimental design of the psy-
MHCpeptideligands.Hence,incontrasttopreviousstudies,
chometric test that involves a comparative rather than an
our experimental paradigm specifically focused on self-
independent assessment of odours without time restrictions.
preference. As expected from HLA allele frequencies in the
Forfunctional brain activationdata, 96volumesper session
catchmentareaforourstudypopulation,18outof22partici-
were acquired by means of a 26 axial-slice matrix 2D spin-
echo/echo-planar sequence (repetition time(TR): 2500ms/echo pantswerepositiveforeitherHLA-A2orHLA-A24alleles(or
time (TE): 40ms, matrix¼64(cid:2)64, voxel size 3(cid:2)3(cid:2)3mm3). both; electronic supplementary material, table S1), justifying
FollowingthefMRIsessions,aT1-weightedimagewasacquired the use of two prototypic peptide ligands (SLLPAIVEL for
by using a T1-MPR sequence (TR: 2180ms/TE: 3.9ms; TI HLA-A2 and KYPENFFLL for HLA-A24; electronic sup-
1100ms,matrix352(cid:2)384). plementary material, table S2) as self and non-self stimuli
inthedouble-blindstudydesign(see§2fordetails).Inindi-
vidual test sessions, comparisons were made for peptide
(g) Functional magnetic resonance imaging data analysis versus solvent, or A2 versus A24 peptides. The participants
Data analysis was performed with SPM 8 software (Statistical were asked to apply two different solutionsto their left and
Parametric Mapping; Wellcome Department of ImagingNeuro- right armpits on two consecutive days and then to compare
science, Institute of Neurology at University College London, thesmellofbotharmpits(see§2fordetails).Inthesolutions
UK), implemented in MATLAB R2007b (Math Works Inc., providedtotheparticipantsforthesecondday,thecontents
Natick, MA, USA), following spatial pre-processing with the wereexchangedrelativetotheprevioussessiontocontrolfor
same software (spatial filtering: high-pass filter 128Hz, regis- potential side bias. Participants had to decide which armpit
tering, realignment, co-registration between functional and
smelled ‘like themselves’ (or ‘like their favourite perfume’).
structural images, normalization using segmentation pro-
They were also asked if their preferencewas weak, medium
cedure, smoothing by means of 6(cid:2)6(cid:2)6mm3 FWHM
or strong, or whether they detected no difference between
Gaussian kernel). Motion parameters were included as co-
thetwo armpits.
variates. Activation coordinates are presented in MNI space.
IntheparticipantspositiveforHLA-A2,butnegativefor
SPM-matrices reflecting the ON–OFF differences were calcu-
lated for each session and participant. Analysis was based HLA-A24,thescoresforthearmpitexposedtoHLA-A2pep-
on the general linear modelling approach. Individual SPM- tide (‘self’) were given positive values, the scores for the
contrasts were subjected to a full-factorial second level analysis armpit exposed to HLA-A24 peptide or solvent (both
‘non-self’ relative to the HLA-A2 peptide) were given nega- 1.5 4
tive values. For the participants negative for HLA-A2, but
positive for HLA-A24, only the scores for the armpits us 1.0 rs
ul pb
evthxaepluosecssoe.dreFsotrofoHrHLeLiAtAh-eA-Ar2p2/4eHpLptiAedpe-At(id‘2se4elfd(’‘o)suewlbfel’re)e-pwgoievsrieetnivgpeiovpseaintritvipceio,ptsahitnoivtssee, elf’ stim 0.5 .royalsoc
for solvent (‘non-self’) negative values; for HLA-A2/HLA- or ‘s 0 ietyp
A24 double-negative participants, the scores for solvent e f ub
wsaclseoorreersegcfioovrredneedipthowesrihteipvtheepert(i‘dspeealfr’t(,i‘cniropenala-nsttievslfew’)teonreepgsaemtpiotvikedeervss)alouarneshd.adWthaee preferenc ––01..50 lishing.org
cold when they carried out the test. Individual scores were
–1.5 P
averaged across all test sessions. When the data for all ro
c
sessions of non-smokers without a cold were analysed sessions of sessions of sessions of R
S
non-smokers non-smokers smokers o
(two-tailed Wilcoxon one-sample test; average preference c
without cold with cold without cold B
compared with 0), a significant preference for the ‘self’ side 2
8
was found (n¼17 participants (total number of trials¼37; Figure 1. Preference for body odour supplemented with ‘self’ stimuli. Par- 0:
2
average number of trials per participant¼2.2+0.3s.e.m), ticipants indicated preference on a scale from þ3 to 23. Although 0
1
2
z¼ 22.394, p¼0.0167, two-tailed; figure 1). When the participants took part in several trials, only the mean values were used to 2
8
8
sessions of the same cohort with a cold were examined, avoidpseudo-replication.Preferenceisshownforallsessionsofnon-smokers 9
no significant difference was found (n¼12, z¼ 20462, withoutacold(left),non-smokerswithacold(middle),andsmokerswithout
p¼0.647,two-tailed);similarly,sessionsofsmokerswithout a cold (right). Mean+s.e.m.; *p¼0.0167, two-tailed.
a cold failed to show a difference (n¼4, z¼ 20.365, p¼
0.715, two-tailed; figure 1). Thus, the preference for ‘self’
(either self-peptide or solvent) to ‘non-self’ (either non-self-
t-values were lower and the overlap of activated regions
peptideorsolvent)wasclearlyevidentwhenallparticipants
resulting from comparisons of non-self-peptide versus sol-
with potential impairment of their sense of smell (smoking
vent and of non-self-peptide versus self-peptide was less
and/orcold) [38,39] wereomitted.
obvious (see the electronic supplementary material, figure
S1). The peach odour elicited robust activation of olfactory
(b) Functional magnetic resonance imaging brain areas (see the electronic supplementary material, table
S3). Collectively, these results indicate that ‘self’-peptides
The results of the above psychometric tests indicate that
elicit aresponsein adistinct brain region.
humanparticipantsarecapableofrecognizingmodifications
oftheirbodyodourbyMHCpeptides.Ouraimwastocon-
firm this distinct perceptual capacity using fMRI. For this,
peptides were delivered to the nostrils of study participants 4. Discussion
in aerosolized form, and the activation of particular brain
areas was determined. To focusthe attention of participants Thenon-classicalfunctionofMHCpeptidesasactivatingcues
onself-assessment,theywereaskedtoratewhethertheypre- for sensory neurons of the olfactory system provides a
ferred to smell like the presented odour and to repeat this mechanisticexplanationfortheroleofMHCallelesinguiding
aftereachsession(see§2fordetails).Elevenof19participants behavioural decisions in a variety of contexts and animal
(all right-handed) included in this analysis had also species. Our study suggests that MHC peptide ligands may
participated in the psychometric tests (see the electronic play a similar role in humans. In a behavioural paradigm of
supplementary material, table S1). Four different stimuli self-preference, participants considered the modification of
(solvent; ‘self’-peptide; ‘non-self’-peptide; peach odour as their body odour by ‘self’-peptides more desirable than the
control) were delivered to both nostrils in eight consecutive modificationby‘non-self’-peptides,indicatingthatMHCpep-
sessions(see§2fordetails).Peptidestimuli(seetheelectronic tide ligands comprise a functionally relevant component of
supplementary material, table S2) were selected according human body odour. These findings are in keeping with pre-
to the HLA genotype of the test participants (see the elec- vious observationsthat humans sharing specific MHC alleles
tronic supplementary material, table S1). ROI analysis was alsoshareapreferenceforparticularnaturalperfumeingredi-
performed for sevencortical areas previously reported to be ents [19] and posit that perfumes may contain structurally
related to self-processing: right middle frontal cortex, diverse peptide mimics. Interestingly, customers usually buy
superior and inferior parietal cortex and fusiform cortex, perfumes for their own use [42] and have always done so
right inferior frontal and anterior cingulated cortex, and left [43].Ifperfumesareindeedchosentorevealand/orenhance
insularcortex[34,35,40].‘Self’-peptidesinducedspecificacti- one’sownbodyodour[20,21],itisnotsurprisingthatonedis-
vation in the right middle frontal region, when compared likes on others what one likes foroneself [19]. This switch of
with both solvent (Montreal Neurological Institute, MNI, choice preference with respect to perfume usage might be
coordinates (x,y,z)¼26,32,32; P ,0.001) and ‘non-self’- explained by ‘phenotype-matching’ [44], a process that is
corr
peptides (MNI (x,y,z)¼28,32,34; P ,0.001; figure 2). alsoimplicatedinkin-recognition.
corr
Middlefrontalstructuresareknowntobeinvolvedincogni- Remarkably,exposuretoMHCpeptideligandsactivated
tive self-representation [41]. By contrast, activation induced specificbrainregions,indicatingthathumans,despitelacking
by ‘non-self’-peptides was much weaker, as expected from a functional vomeronasal organ [45], possess the sensory
the ‘self’-centric paradigm of the study; in this case, facilitytorecognizethepresenceofMHC-associatedolfactory
5
(a) (b)
right middle frontal right superior parietal
rs
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b
right inferior parietal .ro
y
a
right middle frontal lso
c
right inferior frontal ie
inferior typ
u
frontal b
lis
h
in
right fusiform g.o
sagittal rg
4.5 4.5 (d) Pro
c
transverse 4.0 4.0 R
S
o
c
(c) 3.5 3.5 B
x=16–36; y=22–42; z=32 2
8
3.0 3.0 ‘self’-peptide minus 0:2
right middle 0
solvent 1
frontal 2.5 2.5 22
8
8
2.0 2.0 (e) 9
left insula anterior
cingulate 1.5 1.5
right inferior
x=18–38; y=22–42; z=34
frontal 1.0 1.0
‘self’-peptide minus
coronal t values
‘non-self’-peptide
(f)
‘self’ minus solvent ‘self’ minus ‘non-self’
NI (26,32,32) 000...543 * NI (28,32,34) 000...543 *
M 0.2 M 0.2
mate at 0.10 mate at 0.10
contrast esti––00..12 contrast esti––00..12
self non-self solvent self non-self solvent
Figure2.Activationoftherightmiddlefrontalcortexby‘self’-peptides.ActivatedareasarevisualizedinaT1-weightedstructuraltemplate.(a)Transversesection;
this section encompasses parts of the right middle and inferior frontal cortex as ROI (outlined). The t-values foractivations induced by ‘self’-peptides relative to
solvent are indicated on a blue-to-green scale, those for ‘self’-peptides relative to ‘non-self’-peptides on a red-to-yellow scale. Note the co-localization of the
activatedregions.(b)SagittalsectionwithROIsindicated.(c)CoronalsectionwithROIsindicated.(d)Spatialactivationprofilefor‘self’-peptiderelativetosolvent.
TheMNIcoordinatesareindicatedasarethecolour-codedt-values(P(FWE)corr¼0.074;heightthresholdwassettop,0.001(Bonferroni-corrected)andextend
thresholdtok¼3(see(f )forcontrastestimates).(e)Spatialactivationprofilefor‘self’-peptiderelativeto‘non-self’-peptide.TheMNIcoordinatesareindicatedas
are the colour-coded t-values (P(FWE)corr¼0.111); height threshold was set to p,0.001 (Bonferroni-corrected) and extend threshold to k¼3 (see (f ) for
contrast estimates). (f ) Contrast estimates for selected regions after stimulation with ‘self’-peptides. *,p,0.001, Bonferroni-corrected. Activated areas are
visualized in a T1-weighted structural template.
cues. It is possible therefore that peptides activate sensory and is reminiscent of an equivalent facility in MHC-associ-
neurons located in the main olfactory epithelium, as was ated behavioural decisions in mice [22,25] and sticklebacks
observed in mice [25]. Our results are compatible with the [24]. Hence, our study suggests that, as in mice and fish,
notion that the right middle frontal region is a multimodal sensoryevaluationofMHCdiversitythroughtherecognition
convergence zone [40] that might provide the anatomical of structurally diverse MHC ligands may be involved in
basis for self-referentiality by integrating various extero- human MHC-associatedbehaviour.
andinteroceptiveinputs,includingpeptidestimuli.Notably,
the activation of particular brain regions by exposure to ThepsychometrictestswereconductedbetweenDecember2005and
December2007andapprovedbytheEthicsCommitteeoftheUniver-
peptides does not reflect the precise chemical structure of
sity of Freiburg Medical School (260/02). fMRI studies were
MHC peptides but rather their ‘self’ or ‘non-self’ qualities
conducted between September 2010 and June 2011 and approved
relative to the individual’s MHC genotype. This suggests by the ethics committee of the University of Dresden Medical
the presence of an internal reference for MHC genotype School(EK#156052010).
We thank T. Eiermann for HLA-typing and B. Baron, Dr N. Sobel, Dr A. Bartels and Dr C. Frith for constructive com- 6
R. Derner and A. Haas-Assenbaum for assistance and J. Gerber ments on the manuscript. This work was funded by the Max
for help with data acquisition and analysis. We are indebted to Planck Society. rs
p
b
.ro
y
a
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