Manuela

This
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Supplementary
http://www.jimmunol.org/content/188/9/4412
Material
References
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Immunol
March
information
Genetic
10.4049/jimmunol.1103434
2012;
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Moraru,
de
16,
4.DC1.html
Vaquero,
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and
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Type
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Carlos
188:4412-4420;
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HSV-1
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carlos.vilches@yahoo.com
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from http://www.jimmunol.org/ by guest on March 16, 2015

The
FIGURE
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4. CD16A-158(A)andCD32A-131(B)genotypefrequenciesinsymptomaticandasymptom
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4417
symptomatic).
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FIGURE
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cells
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protective
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from http://www.jimmunol.org/ by guest on March 16, 2015

make
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INFECTION
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52),
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defined.
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certain
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context
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incompletely
Regulation
individual.
vary
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expressing
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surface
density
both
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enormously
humans
different
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major
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lectin-like
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Confirmation
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homozygous
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And
associated
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analysis,
escaped
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receptor
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genome
presence
mere
exerted
influence
modulates
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usage
whether
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capacity
inducing
efficacy
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Valine-158
herpes.
8factor
genotypes,
16
allotypes,
(74
symptomatic
factors
risk
potential
markers
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examined
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tested
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immunogenetic
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widest,
knowledge,
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humoral
preferentially
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predominance
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phago
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Lack
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CD32A-131
lack
CD16A-158V
effect
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controversial
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herpesviruses,
infections
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48
aa
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importance
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Also
IgG.
affinity
higher
allotypes
competing
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better
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which,
HSV-1,
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Importance
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3CD16A
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setting
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For
comparisons).
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107
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(0.05
.0.0005
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.5001000
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level
cytotoxic
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shown
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summary,
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between
cooperation
implicated
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molecules
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II
polymorphism
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by
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course
whereas
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ligands,
their
KIR
combinations
I,
class
(HLA
Blymphocytes
with
consistent
are
results
our
Collectively,
cells.
Iphagocytic
type
paracrine
interaction
roles
cells:
dendritic
myeloid
activation
type-1-induced
Katz.
Chain,
Foster,
Coffin,
Kwan,
Rajpopat,
Handley,
G.,
Pollara,
2.
S11S18.
1):
194(Suppl
Dis.
Infect.
control.
transport
infection:
cycle
2006.
Douglas.
Kim,
Bosnjak,
Miranda-Saksena,
Diefenbach,
Cunningham,
1.
References
interest.
conflicts
financial
no
have
authors
The
Disclosures
characterization.
collection
sample
helped
laboratories
virology
HLA
technicians
donors,
voluntary
healthy
patients
interviewed
submitted
colleagues
other
staff,
bank
samples,
blood
donated
generously
who
individuals
all
thank
We
Acknowledgments
disease.
this
contributes
immunity-related
innate
diversity
which
extent
determine
warranted
is
research
Further
HSV-1
susceptibility
variable
part
explain
sabotage,
its
surveillance
responses,
immune
adaptive
controlling
genes
polymorphisms
that
show
they
infection,
herpetic
against
defense
cells
CTLs
role
CD8+
Antigen-specific
Carbone.
F.
Heath,
W.
Wallace,
E.
Jones,
C.,
Cose,
3.
41084119.
173:
secretion.
CD4(+)
Early
2010.
Hendricks.
R.
Cherpes,
T.
Sheridan,
S.
B.
Freeman,
Lepisto,
M.,
Frank,
4.
23102316.
27:
Eur.
infection.
herpes
site
draining
nodes
lymph
distribution
Tsubset
CD8(+)
partial
prevents
1help
Virus
Simplex
of
maintenance
promotes
aexhaustion
recognize
How
1997.
K.
Karre,
7.
225274.
23:
Annu.
recognition.
cell
NK
2005.
L.
Lanier,
6.
670676.
25:
Trends
activation.
NK-cell
human
in
checkpoints
Different
2004.
Moretta.
A.
Mingari,
Vitale,
M.
Pende,
Bottino,
C.
L.,
Moretta,
5.
277286.
184:
Downloaded
411415.
375:
Nature
immunity.
host
evade
to
TAP
the
off
turns
virus
simplex
Herpes
1995.
Johnson.
D.
and
Ploegh,
H.
Yewdell,
Bennink,
J.
Russ,
G.
York,
I.
Jugovic,
P.
A.,
Hill,
8.
59.
155:
Rev.
Immunol.
submarine.
C2
stronger
KIR/ligand
FCGR
pitfall
statistical
confidence
priori,
cells,
lymphocytes,
crucial
IFN
latency.
foreign
from http://www.jimmunol.org/ by guest on March 16, 2015

Friedman.
Frank,
Socolof,
Dubin,
9.
4419
Immunology
3Journal
Toll-like
impaired
leads
molecule
adaptor
TRAF3
Human
Bustamante,
Durandy,
Cardon,
Herman,
Plancoulaine,
Diego,
Perez
13.
14561462.
114:
Clin.
Allergy
dysplasia.
ectodermal
anhidrotic
without
yet
immunodeficiency
child
modulator-deficient
essential
kappaB
factor
Nuclear
Doffinger,
Schroten,
Dirksen,
U.
Lainka,
Horneff,
Gudowius,
Neubert,
Reichenbach,
Niehues,
12.
388391.
STAT1
lethal
interferon-alpha/beta
Impaired
Eid,
Chapgier,
Al-Jumaah,
Al-Mohsen,
Fieschi,
Al-Hajjar,
Dupuis,
11.
308312.
314:
deficiency.
UNC-93B
encephalitis
Nicolas,
Mahfoufi,
Picard,
Alcais,
Yang,
Eidenschenk,
Y.
Casrouge,
10.
70467050.
65:
cytotoxicity.
cellular
antibody-dependent
infected
protects
Identification
Kriesel.
Leppert,
Otterud,
Jones,
Hobbs,
15.
15221527.
317:
Science
deficiency
TLR3
Puel,
Lorenzo,
Sancho-Shimizu,
Segal,
Romero,
Elain,
Smahi,
Ugolini,
Jouanguy,
Y.,
Zhang,
14.
400411.
33:
encephalitis.
Payne.
McNamara,
Mittal,
Dolin,
Blackwelder,
16.
340346.
197:
chromosome
region
labialis
Geraghty.
Lopez-Botet,
Navarro,
Ishitani,
Carretero,
Llano,
N.,
30.
3441.
KIR2DS2.
KIR2DL2
absence
resistance
infection:
HSV-1
course
diversity
Influence
Vilches.
Roustan,
Suarez,
Gonzalez,
Vaquero,
Sepulveda,
Portero,
E.,
Estefana,
29.
217251.
20:
Rev.
Annu.
immunity.
adaptive
innate
evolving
rapidly
diverse,
KIR:
28.
756757.
Vis.
Invest.
Waltman.
Kaufman,
Richman,
McNeill,
Zimmerman,
27.
10871089.
59:
Hautkr.
Z.
multiforme].
exsudativum
postherpetic
recidivans
[HLA
1984.
Schonberger.
Djawari,
Jr.,
Simon,
26.
17211722.
113:
Dermatol.
Arch.
sores.
cold
HLA-A1
Association
1977.
25.
257261.
6:
labialis.
susceptible
subjects
transplantation
HL-A
1975.
Schlaut.
S.,
24.
264267.
21:
simplex.
multiforme
erythema
1983.
Lynd.
Hutchison,
Middleton,
23.
5457.
89:
keratitis.
stromal
1980.
Bernoco.
Terasaki,
ODay,
Pettit,
Maxwell,
Elliott,
Meyers-Elliott,
22.
8589.
19:
infections.
recrudescent
1982.
Jeannet.
Russell,
Legendre,
21.
281287.
9:
infection.
1991.
al-Amar.
al-Samarai,
Jabbar,
20.
191197.
5:
Markers
lesions.
herpetic
circumoral
influencing
(HLA-B35)
factors
MHC1987.
Caruso.
Modica,
Messina,
Cumbo,
G.,
Gallina,
19.
982985.
57:
(Copenh.)
Ophthalmol.
Acta
diseases.
corneal
types
Kissmeyer-Nielsen.
Ehlers,
L.,
Damgaard-Jensen,
18.
263266.
2:
Ophtalmol.
Fr.
transl)].
(authors
results
preliminary
antigens;
ocular
[Recurrent
1979.
Renard.
Morin,
Saleun,
Chastel,
J.,
Colin,
17.
569576.
115:
Epidemiol.
Am.
antigens.
infections
herpesvirus
Bstudy
CD94/NKG2A,
binds
HLA-E
Phillips,
Bell,
Young,
Lazetic,
Ogg,
DAndrea,
Soderstrom,
OCallaghan,
Allan,
Braud,
31.
51995204.
95:
USA
Sci.
Acad.
Natl.
Proc.
CD94/NKG2A.
inhibitory
ligand
by
KIR
Facilitation
2007.
Estefana.
38.
189202.
immunotherapy.
function,
polymorphisms:
FcgammaR
Winkel.
Pol,
der
Sorge,
van
37.
36243631.
107:
fibroblasts.
cytomegalovirus-infected
response
cells
CD94/NKG2C+
Expansion
Hengel,
Brckalo,
Saez,
Budt,
36.
36643671.
104:
repertoire.
NK
Imprint
Botet.
LopezMalats,
Gomez-Lozano,
Angulo,
Guma,
35.
163168.
Int.
deletion.
(KLRC2)
NKG2C
analyses
genetic
Hashimoto,
Kallenberg,
Bijl,
Fukazawa,
Kuroki,
Miyashita,
34.
160167.
4:
Immun.
Genes
population.
general
NKG2-C
occurrence
receptors:
lectin-like
Variations
Tokunaga.
Yabe,
Tsuchiya,
Hikami,
33.
252.
240
168:
genes.
NKG2
CD94
chimpanzee
common
variation
Conservation
Uhrberg,
Cleland,
Khakoo,
Rajalingam,
Muir,
Flodin,
Shum,
32.
795799.
391:
Nature
KIR2DS4
Bushnell,
Hammond,
Gleimer,
Vago,
Norman,
39.
415422.
70:
fragments.
short
amplifies
Gmethod
immunoglobulin
functional
genotyping
Simple
2008.
Penalver.
Munoz,
Castano,
41.
429434.
31:
AIDS.
progression
delays
KIR3DS1
between
Epistatic
Trowsdale,
Vlahov,
Hoots,
Buchbinder,
Goedert,
Detels,
Nelson,
G.
Gao,
Martin,
40.
25572572.
206:
HLA-C.
avidity
diminishing
while
11
HLAA*
specificity
introduced
that
KIR3DL2
conversion
gene
CD32A:
CD16A
panNetCTLpan:
Nielsen.
Lundegaard,
Larsen,
Stranzl,
42.
242246.
71:
panel.
Gypsies:
antigens
Distribution
1992.
Sols,
Rementera,
45.
897905.
138:
virus.
facial-oral
recurrent
history
The
1978.
Freedberg.
Arndt,
Clark,
Ransil,
Schnipper,
Crumpacker,
Bader,
44.
861874.
27:
Lett.
Recognit.
Pattern
analysis.
ROC
introduction
An
2006.
Fawcett,
43.
357368.
62:
predictions.
epitope
populations
two
receptors
genotypes
Variant
1999.
Chanock.
Huppi,
Goldin,
Leitman,
Zhu,
Foster,
B.
Lehrnbecher,
48.
463469.
Opin.
Curr.
latency.
during
Immune
Decman,
V.
Lepisto,
47.
4553.
77:
searching.
donor
unrelated
Implications
patients.
hematopoietic
distribution
frequency
haplotypic
Allelic
2011.
Vicario.
Garca-Sanchez,
Balas,
46.
187196.
40:
astudy.
edge:
Cutting
Simmons.
Scalzo,
Pereira,
51.
4245.
28:
Genet.
Nat.
family.
superlectin
C-type
cell
killer
natural
deletion
cytomegalovirus
mouse
Susceptibility
2001.
Vidal.
Gros,
Belouchi,
Zafer,
Busa`,
Macina,
Girard,
H.,
50.
301306.
29:
Immunogenet.
erythematosus.
lupus
systemic
patients
FcgammaRIIIB
FcgammaRIIIA
FcgammaRIIA,
n.
NunezRolda
Sanchez-Roman,
F.
F.,
Gonzalez-Escribano,
49.
42204232.
94:
Blood
populations.
disease
control
polymorphisms
receptor
Fcgamma
low-affinity
1998.
55.
173:
Dis.
Infect.
interferon-gamma.
treated
keratinocytes
cultured
lymphocyte
CD8
protein
Herpes
Cunningham.
Penfold,
Kesson,
Z.,
Mikloska,
54.
717.
43:
Antigens
Tissue
alleles.
new
several
including
alleles
defined
serologically
nonserological
identification
(PCR-SSP):
primers
sequence-specific
using
HLA-C
typing
DNA
Rapid
1994.
Welsh.
I.
M.,
Bunce,
53.
259263.
37:
Hum.
gypsies.
Spanish
(Cw*1502)
HLA-Cw6.2
allospecificity
novel
encoding
allele
detection
oligonucleotide
reaction-sequence-specific
chain
polymerase
cloning
Molecular
1993.
Kreisler.
Moreno,
Herrero,
Pablo,
de
C.,
Vilches,
52.
58695873.
166:
infection
latent
versus
acute
governs
locus
linked
TcomplexCD8(+)
Hendricks.
Fink,
D.
Chen,
Khanna,
T.,
Liu,
56.
361.
353
79:
Virol.
Gen.
keratinocytes.
epidermal
human
expressing
HLA-DR
cytotoxicity
T-lymphocyte
CD4
for
targets
major
are
gD
gC
1gB,
type
virus
simplex
herpes
block
can
HLA
Natural
2004.
al.
et
Chang,
Bharadwaj,
Mifsud,
Crockford,
Laham,
Ely,
Kjer-Nielsen,
Macdonald,
D.,
Zernich,
58.
703716.
61:
Immunogenetics
HLA-B*3503.
HLA-B*3501
trafficking
intracellular
Assembly
2009.
Raghavan.
Bangia,
N.
Carrington,
Collins,
Filzen,
Schaefer,
V.,
Thammavongsa,
57.
14591466.
191:
neurons.
sensory
latency
reactivation
interaction
differences
specific
Allele1996.
Neefjes.
Melief,
Zang,
X.
Wubbolts,
A.,
Neisig,
59.
1324.
200:
Med.
Exp.
evasion.
viral
to
susceptibility
presentation
pathway
Acontrols
2003.
Ahn.
Kim,
E.
Lee,
S.
B.,
Park,
60.
31963206.
156:
processing.
antigen
associated
transporters
cleft
peptide-binding
within
residue
Ipolymorphic
class
MHC
the
Optimization
2002.
Elliott.
McCluskey,
Purcell,
Peh,
P.,
Williams,
62.
30213028.
30:
Eur.
proteins.
reticulum
endoplasmic
multiple
with
interactions
affects
polymorphism
HLA-B
2000.
Solheim.
Hildebrand,
W.
Lutz,
C.
Prilliman,
R.
K.
Thomas,
R.,
H.
Turnquist,
61.
961968.
170:
Immunol.
J.
dependence.
tapasin
of
spectrum
determines
Downloaded
activating
an
lacking
in
hominids
other
from
differ
Humans
2010.
Parham.
P.
and
Guethlein,
Aguilar,
Older
M.
Abi-Rached,
L.
Graef,
T.
K.,
A.
Moesta,
63.
509520.
16:
Immunity
tapasin.
on
dependent
is
cargo
Fc
population
PCR-SSP
product
reference
comparative
review
glycoproteins
(HSV-1)
single
molecules
peptide
from http://www.jimmunol.org/ by guest on March 16, 2015

KIR2DL2
makes
site
ligand-binding
to
distal
positions
two
at
polymorphism
Synergistic
2008.
Gleimer,
Norman,
K.,
Moesta,
64.
42334237.
185:
I.
class
MHC
C1
recognizes
that
NK
INFECTION
HSV-1
IN
DIVERSITY
GENETIC
HOST
cells
on
(CD16)
IIIa
gamma
unusual
Identification
Tol.
van
Haas,
Haraldsson,
Waaijer,
Borne,
dem
von
Gratama,
W.
Vossen,
Koene,
H.
E.,
Vries,
de
70.
408413.
103:
(CD16-II).
IIIA
type
Fc
epitope-deficient
an
(NK)
Killer
Natural
1996.
Chatila.
T.
Geha,
Finberg,
R.
Chan,
Moody,
S.,
Jawahar,
69.
435442.
26:
Mol.
Int.
polymorphism.
FcgammaRIIIa-48L/R/H
associated
not
is
diseases
immunodeficiency
primary
some
occurring
epitope
B73.1/Leu11c
the
loss
The
2010.
Siedlar.
Zembala,
Szczepanik,
Pituch-Noworolska,
Szaflarska,
Bukowska-Strakova,
Rutkowska,
Trzyna,
E.
Lenart,
68.
633645.
203:
Med.
Exp.
function.
effector
modulation
selection
repertoire
cell
killer
natural
polymorphisms
HLA
Roles
2006.
Parham.
P.
Partheniou,
F.
Little,
A.
Draghi,
N.
Yawata,
67.
4758.
13:
Immun.
Genes
ancestry.
European
individuals
microvariation
by
altered
are
haplotypes
allele-level
KIR
Conserved
2012.
Hurley.
K.
C.
Ng,
Chen,
L.,
Hou,
66.
96113.
16:
Rev.
Microbiol.
research.
vaccine
immunobiology
virus
simplex
herpes
progress
Recent
2003.
Corey.
M.,
D.
Koelle,
65.
39693979.
180:
KIR2DL3.
than
HLA-C
for
receptor
in
discovered
deficiency
CD16
2009.
Orange.
S.
and
Paessler,
M.
R.,
L.
Forbes,
71.
30223027.
88:
Blood
infections.
arecurrent
using
infections
herpesviral
severe
with
patients
of
Downloaded
S67S67.
123:
Immunol.
Clin.
Allergy
J.
test.
diagnostic
stronger from http://www.jimmunol.org/ by guest on March 16, 2015
patient
cohort
new