REVIEWS

MOLECULAR DEFECTS IN
T AND B CELL PRIMARY
IMMUNODEFICIENCY DISEASES
Charlotte Cunningham-Rundles and Prashant P. Ponda
Abstract | More than 120 inherited primary immunodeficiency diseases have been discovered
in the past five decades, and the precise genetic defect in many of these diseases has now
been identified. Increasing understanding of these molecular defects has considerably
influenced both basic and translational research, and this has extended to many branches of
medicine. Recent advances in both diagnosis and therapeutic modalities have allowed these
defects to be identified earlier and to be more precisely defined, and they have also resulted
in more promising long-term outcomes. The prospect of gene therapy continues to be
included in the armamentarium of treatment considerations, because these conditions could
be among the first to benefit from gene-therapy trials in humans.

Division of Clinical Immunology, Mount Sinai School of Medicine,

1425 Madison Avenue, Box 1089, New York, New York 10029, USA.
Correspondence to C.C.R. e-mail: charlotte. cunninghamrundles@mssm.edu doi:10.1038/nri1713

The
human
immune
system is
confronte
d with the
chal-lenge
of
host
defence.
This
is
accomplis
hed
through
vari-ous
innate
immune
responses
(which are
nonspecific)
and
adaptive
immune
responses
(which are
specific)
that work
synergisti
cally
to

achieve this goal. Cells of

the adaptive immune
system include T and B
cells, which are derived
from
a
common
multipotent
haematopoietic stem cell. Defects
involving T and B cells
have been described with
respect
to
their
development,
effec-tor
function and roles in
immunoregulation1.
Although defined primary
natural killer (NK)-cell
deficiencies
are
rare
among
primary
immunodeficiency
diseases, other cells of
the
innate
immune
system,
which
were
previously thought to
function independently of
adap-tive
immune
responses, are now seen
as important partners in
the
development
of
adaptive immunity. The

clinical
presentation of
patients with a primary
immunodeficiency reflects
the complex underpinnings
of the immune system and
depends on the underlying
genetic defect. Patients
with
severe
combined
immuno-deficiency (SCID)
generally
present
with
opportunistic infections and
fail to thrive within a few
months of life. Recurrent
bacterial infections are the
hallmark of disease in
patients with defects in B
cells, phagocytic

cells or complement, whereas opportunistic infections with viruses or inherited

fungi are particularly common in patients with T-cell deficiencies. A in
an
subset of primary immunodeficiencies is associated with inflammatory autosom
or autoimmune manifestations, and certain subgroups of patients areal
susceptible to developing malignancies. This Review focuses on the recessive
recent advances in the field, with an emphasis on newly identified or an Xgenetic deficiencies and therapeutic options for patients.
linked
2
SCID an immunodeficiency that is character-ized by severely manner
10
.
Four
reduced numbers or an absence of functional T cells, which in turn
results in the absence of an adaptive immune response is a lymphocy
consequence of a mutation in any one of ten distinct genes that are te
880 | NOVEMBER 2005 | VOLUME 5

www.

phenotypes
are
possible on the basis of
the influence of the
defective gene on B-cell
and
NK-cell
development TABLE 1 . A
diag-nosis is possible at
birth, with most affected
infants
having
lymphopaenia
(less
than 2,000 lymphocytes

nature.com/revi
ews/immunol

per mm3 of blood) and

their
lymphocytes
showing
decreased
proliferation in vitro after
stimulation with mitogen,
antigen or allogeneic
cells11. Although these
infants have a severely
reduced amount of thymic

REVIEWS
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REVIEWS
or
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of
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o This
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whic
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as
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has
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8
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REVIEWS
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no
acce
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iNATURE
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kIMMUNO
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VOLUME
a
s5 |
eNOVEMB
ER 2005
o| 883
f
7
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2005 Natur

REVIEWS
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bef
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ma
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nt
org
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da
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the
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me
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ldy
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om
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(A
PE
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o
kn
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n
as
AP
S1
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res
ult
s
fro
m
a
def
ect
in
the
aut
oi
m
mu
ne
reg
ula
tor
(AI
RE
)
ge
ne3
4

.
Pat
ien
ts
wit
h
AP
EC
ED
us
ual
ly
ha
ve
chr
oni
c
mu
co
cut
an
eo
us
ca
ndi

- o
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aa
sid
sr
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al
sa
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al
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dn

d
s
k
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3
5

.
A
I
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i
s
e
x
p
r
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s
e
d
a
t
h
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g
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l
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l
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y
p
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d
h
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m
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h
y
m
i
c
s
t
r
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m
a
l
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ll
s
,
e
s
p
e

cial
ly
me
dul
lar
y
thy
mi
c
epi
the
lial
cell
s,
an
d it
is
tho
ug
ht
to
reg
ula
te
the
ect
opi
c
cell
sur
fac
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ex
pre
ssi
on
of
tiss
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eci
fic
pro
tei
ns,
su
ch
as
ins
uli
n
an
d
thy
rog
lob
uli
n36
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Ex
pre
ssi
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of
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se
sel
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wo
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m
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an
inte
rle
uki
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wn
to
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uce
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ma
n
per
iph
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CD
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de
ndr
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cell
s
(D
Cs)
to
upr
eg
ulat
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AI
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mR
NA
exp
res
sio
n
str
on
gly,
in
con
jun
ctio
n
wit
h
cell
sur
fac
e
MH
C

cl w
ae
sr
se
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ma
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ce
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T
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h
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pre
sen
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self
pe
ptid
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bec
aus
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the
CD
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Tcell
pro
lifer
atio
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occ
urr
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in
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abs
enc
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of
exo
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us
anti
ge
n
an
d
wa
s
the
ref
ore
attr
ibut
ed
to
the
pre
sen
tati
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of
self
pe
ptid
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MH
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co
mpl
exe
s
by
DC
s.

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ni
vg
it a
r s
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dii
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t
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sm
ae
n
Ep
3a
ut
bih
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ti y
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F
u
rt
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r
m
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,
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s
liga
se
acti
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8
.
Th
e
pre
cis
e
ubi
quit
in
pro
tea
so
me
pat
hw
ay
an
d
ubi
quit
ylat
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sub
str
ate
s of
the
AI
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pro
tein
hav
e
yet
to
be
ide
ntifi
ed,
an
d
the
ove
rall
sig
nifi
can
ce
of
this
pat
hw
ay
in
the
est
abli
sh
me
nt
an
d
mai

nk
t n
eo
nw
an
n
cg
ee
on
f e
Tt
- i
cc
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l d
se
elf
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t c
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h
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t
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w
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el
l
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t
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pf
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Ap
La
Pt
Si
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(
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s
s
o
c

iat
ed
wit
h
dy
sre
gul
ati
on
of
ap
opt
osi
s
me
dia
ted
by
CD
95
(al
so
kn
ow
n
as
FA
S).
CD
95
is
a
cell
sur
fac
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rec
ept
or
tha
t is
a
me
mb
er
of
the
tu
mo
urne
cro
sis
fac
tor
(T
NF
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or
su
per
fa
mil
y,
an

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de
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lex
in
as
so
cia
tio
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wit
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ca
sp
as
e-8
an
d
ca
sp
as
e10.
All
pat
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ha
ve
at
lea
st
thr
ee
of
the
fou
r
ma
in
fea
tur
es
of
AL
PS
:
aut
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mu
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,
hy
per
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m

e
tha
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bas
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on
the
un
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lyin
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ge
neti
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def
ect
40
.
Def
ecti
ve
CD
95ind
uce
d
ap
opt
osi
s is
obs
erv
ed
in
ho
mo
zyg
ous
CD
95
defi
cie
ncy
41

(cla
ssif
ied
as
AL
PS
0),
het
ero
zyg
ous
do
min
ant
CD
95
mu
tati
ons
42

(cla
ssif
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as
AL

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Sc
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aa
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as
ni
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si i
ge
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pA
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d
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e9
ct5
st i
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sp
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8
Ri
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F.

i
n
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r a
cc
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Ra
Ed
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4 i
4 t
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3

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o
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l
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m
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t
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4
5

(
c
l
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if
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A
L
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1
b
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n

d
tho
se
wit
h a
clin
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AL
PS
ph
en
oty
pe
but
in
wh
om
a
mol
ecu
lar
def
ect
has
yet
to
be
ide
ntifi
ed4
6

(cla
ssif
ied
as
AL
PS
3).
A
sub
set
of
pati
ent
s
wh
o
wer
e
pre
vio
usl
y
cat
eg
oriz
ed
as
hav
ing
AL
PS
3
has
no
w
be
en

ide
el
nl
tifs
ie4
d7
t .
o
hI
an
vt
ee
sr
oe
ms
at
ti i
cn
hg
el
t y
e,
r
oa
zl
yl
g
op
ua
st
Ci
De
9n
5t
ms
u
t i
an
ti
ot
nh
si
ins
u
ns
stu
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ms
ule
at
t
eh
da
dd
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ui
bld
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nt
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gc
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v
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c9

5
m
u
t
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s
o
r
m
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t
h
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t
l
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tr
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s
i
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C
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9
5
t
o
t
h
o
s
e
o
b

ser
ved
in
pati
ent
s
wit
h
AL
PS
1a.
Ho
we
ver,
mu
tan
t
CD
95
pro
duct
s
cou
ld
not
be
det
ect
ed
in
Tcell
bla
sts
foll
owi
ng
in
vitr
o
acti
vati
on.
It is
unc
lea
r
wh
y
the
mu
tati
ons
in
the
se
ne
wly
ide
ntifi
ed
pati
ent
s
do
not
lea

de
t d
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f o
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iv o
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Ci
Ds
9.
5
e
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p
p
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M
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mp
air
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mu
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in
CLA
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REC
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BIN
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ON

(C
SR
)
an
d
SO
MAT
IC
HYP
ERM
UTA
TIO
N

(S
H
M)
or
by
imp
air
ed
SH
M
alo
ne.
Pat
ient
s
wit
h
the
se
syn
dro
me
s
typi
call
y
hav
e
rec
urr
ent
bac
teri
al
infe
ctio
ns
an
d
oft
en
hav
e

ly o
mf
p
hm
oie
dm
ho
yr
py
e
r B
pl
ac
si e
al
. l
Ts
h
e(
yw
hh
ai
vc
eh
n
oa
r r
me
al
nC
uD
m2
b7
e+
r )
s
oa
f n
pd
e
ri n
po
hr
em
r a
all
B
co
elr
ls
, i
aln
bc
eir
t e
wa
it s
he
ad
lo
wl
pe
r v
oe
pl
os
rt
ioo
nf

HM
s
e
r
u
m
I
g
M
a
s
s
o
c
ia
t
e
d
w
it
h
l
o
w
l
e
v
e
l
s
o
r
a
b
s
e
n
t
s
e
r
u
m
I
g
G
,
I
g
A
a
n
d
I
g
E
.
C
S
R
4
8

a
n
d
S

49

occ
ur
onl
y
aft
er
anti
ge
n
bin
ds
B
cell
s
dis
pla
yin
g
cell
sur
fac
e
Ig
M
(th
at
is,
the
Bcell
rec
eptor,
BC
R),
an
d
the
se
are
two
me
cha
nis
ms
by
whi
ch
the
pri
ma
ry
anti
bo
dy
rep
ert
oir
e is
fine
tun
ed
to
ge
ner

af
t a
ec
ai
hil
gi
hlt
ya
at
ne
ti d
g
et
nh
- r
so
pu
eg
ci h
fi
ct
i h
me
m
ui
nn
et
r e
er
sa
pc
ot
ni
so
en
.
To
hf
e
sC
eD
e4
v0
eL
n
tsa
at
r
et
Th
- e
c
els
l u
dr
ef
pa
ec
ne
d
eo
nf
t
aa
nc
dt
ai
r v
ea

t
e
d
T
c
e
ll
s
w
it
h
it
s
r
e
c
e
p
t
o
r
C
D
4
0
,
w
h
i
c
h
i
s
c
o
n
s
ti
t
u
ti
v
e
l
y
e
x
p
r
e
s
s
e
d
b
y
B
c
e
ll
s
.
B
c
e
ll
s

tha
t
pro
duc
e
hig
haffi
nity
spe
cifi
c
anti
bo
dy
as
a
res
ult
of
SH
M
hav
e a
sur
viv
al
adv
ant
ag
e.
Tw
o
enz
ym
es

acti
vati
onind
uce
d
cyti
din
e
de
ami
nas
e
(AI
D)
an
d
ura
cilDN
A
gly
cos
yla
se
(U
NG
)
are
cru
cial

f e
or
r t
t o
hii
sr
ee
di
ti h
na
gs
p
r a
o
ch
ei
sg
s.h
C
Sa
Rf
af
ni
dn
Si
Ht
My
.
w
oM
r u
kt
t a
ot
gi
eo
t n
hs
e
r i
sn
o
t t
hh
ae
t
t
h
e
s
e
c
o
n
d
a
r
y
a
n
ti
b
o
d
y
r
e
p

8
4

2005 Nature Publishing Group

REVIEWS
o far,
seve
n
defe
c cts
o that
m are
p kno
o wn
n to be
e invol
nt ved
s in
th HIG
at M
ar have
e been
in char
v acter
ol ized:
v defe
e cts
d in
in CD4
th 0L,
e clas
s sifie
e d as
pr HIG
o M
c type
e 1
s (HIG
s M1;
e also
s kno
re wn
s as
ul Xt linke
in d
th HIG
e M,
in XHI
h GM);
er defe
e cts
nt in
d AID,
ef clas
e sifie
ct d as
s HIG
in M2;
p defe
at cts
ie in
nt CD4
s 0,
wi clas
th sifie
H d as
I HIG
G M3;
M defe
. ctive
S CSR

with
pres
erve
d
SHM
,
clas
sifie
d as
HIG
M4;
defe
cts
in
UN
G;
defe
cts
in
IKK
G
(IB
(inhi
bitor
of
nucl
ear
facto
r-B,
NFB)
kina
se-;
also
kno
wn
as
NE
MO);
and
defe
cts
in
NFK
BIA
(whi
ch
enco
des
IB
)5059
TABL
ES
2,3 .

P
atien
ts
with
defe
cts
in
CD4
0L,
who
com
prise
the
HIG

Ma
1 defe
s ct in,
u bindi
b ng of
gr CD4
o 0L to
u CD4
p, 0 is
a caus
c ed
c by a
o muta
u tion
nt that
fo affec
r ts
a the
p extra
pr cellu
o lar
xi dom
m ain
at of
el CD4
y 0L50.
t Ther
w e is
o- no
th intrin
ir sic
d Bs cell
of defe
al ct
l obse
p rved
at in
ie thes
nt e
s patie
wi nts:
th their
HB
I cells
G gene
M rate
. nor
In mal
th imm
e unos glob
e ulin
p clas
at sie switc
nt hing
s, resp
a onse
n s in
a an
b appr
s opria
e te
n micr
c oenv
e iron
of ment
, 50.
or Furt

her
mor
e, in
contr
ast
to
most
patie
nts
with
hypo
gam
magl
obuli
nae
mia,
indiv
idual
s
with
HIG
M1
are
susc
eptib
le to
oppo
rtuni
stic
infec
tions
,
espe
cially
to
pneu
moni
a
caus
ed
by
Pne
umo
cysti
s
carin
ii,

and
is
th
char
er
acte
e
rize
b
d by
y
the
u
abs
n
enc
d
e of
er
CD4
s
0
c
expr
or
essi
in
on
g
at
a
the
n
cell
in
surf
h
ace
er
of B
e
cells
nt
,
Tmac
c
roph
el
age
l
s
d
and
ef
DCs
e 53,54
.
ct
The
.
se
H
pati
I
ents
G
are
M
also
3
susc
h
epti
a
ble
s
to
b
dev
e
elopi
e
ng
n
opp
d
ore
tunis
s
tic
cr
infec
ib
tions
e
. It is
d
imp
in
orta
fo
nt to
ur
note
p
that
at
ther
ie
e
nt
mig
s
ht
fr
be
o
defe
m
cts
th
in
re
com
e
pon
fa
ents
m
of
ili
the
e
sign
s
allin

g
path
-way
that
are
dow
nstr
eam
of
CD4
0
CD4
0L
inter
actio
ns
to
acco
unt
for
othe
r
pati
ents
in
the
clini
cal
spec
trum
of
HIG
M.
In
addi
tion,
othe
r
repa
ir
mec
hani
sms
that
work
in
conj
uncti
on
with,
or
inde
pen
dent
of,
AID
and
UN
G
hav
e
yet
to
be
clarif
ied.
P
atie
nts
with

de
ef level
e of
ct seru
s m
in IgM
A is
I nor
D mal
oror
U incr
N eas
G ed,
h and
a this
v occu
e rs
a toge
si ther
m with
il low
arlevel
cl s or
in an
ic abs
al enc
p e of
h IgG
e and
n IgA.
ot How
y ever
p,
e owin
51,g to
52 intac
. t TSicell
m func
il tion,
arthes
to e
p pati
at ents
ie do
nt not
s see
w m to
it be
h susc
a epti
C ble
D to
4 opp
0 ortu
L nisti
dc
ef infec
ic tions
ie and
n mig
c ht
y, not
th be
reco

gniz
ed
as
havi
ng
an
imm
une
defe
ct
until
the
seco
nd
or
third
dec
ade
of
life60
.
The
exac
t
proc
ess
by
whic
h
AID
and
UN
G
med
iate
CSR
and
SH
M is
not
kno
wn;
how
ever
,
swit
chregi
on
dou
blestra
nde
dDNA
brea
ks
are
requ
ired
for
both
to
occu
r,

Table 3 |
involve B cells

immunodeficiency;
immunodeficien
HIGM,
syndrome;
stimulator;
IgAD, selective IgA deficie
NATURE
IGAD1
REVIEW
1;
immunoglobulin
heavy cha
S|
gene
encoding
IMMUNO
nuclear-factorLOGY
*M. C. leucine-rich-repeat-contain
van
Zelm, personal
VOLUME
communication;
not
determined;
J. L. Franco,
pre-B cell
precursor-B
cell; pro-B ce
5 |communication.
personal
cell;
NOVEMB
Salzer,progenitor-B
personal communicatio
transmembrane
activator
ER 2005
AID
calcium-modulating
cyclop
deaminase;
| 885
interactor;receptor;
activating-factor
glycosylase; XL-EDA-ID, X
cell linker;
kinase;ectodermal dysplasia with

2005 Natur

REVIEWS
t
h
H
Y
T
h
T
O
(
T

ds

are

con

serv

ed

mol
ecul

ar

patt

erns

kno

wn

as

path

oge

n-

ass

ocia

ted

mol

ecul

ar

patt

erns

it

that

are

foun

d in

bact

ll

eria,

viru

ses

and
fung

c
e
ll
s
a
n
d
i
n
t
e
s
ti
n
a
l
H
Y
P
O
M
O
R
P
H
I
C
M
U
T
A
TI
O
N

A
t
y
p
e
o
f
m
u
t
a
ti
o
n

e
p
it
h
e
li
a
l
c
e
ll
s
.
T
h
e
i
r
n
a
t
u
r
a
l
li
g
a
n

i.

n
t

a
T
n
h
d
CA
Sp
RD
-e
i
n
d
u
c
e
d
b
r
e
a
k
s
h
a
v
e
b
e
e
n
s
h
o
w
n
t
o
o
c
c
u
r
m
u
c
h
l
e
s
s
fr
e
q
u
e
n
tl
y
i
n
A
I
D
d
e
fi
c
i
e

g
e
n
e
s
o
f
N
F

B
m
e
d
i
a
t
e
d
t
r
a
n
s
c
r
i
p
t
i
o
n
a
r
e
A
I
D
a
n
d
U
N
G
,
s
o
i
n
s
o
m
e
p
a
t

ien
ts
wit
h
IK
K
def
icie
ncy
,
the
pro
ce
ss
es
of
CS
R
an
d
SH
M
are
hin
der
ed,
lea
din
g
to
the
inc
rea
se
d
Ig
M
lev
els
tha
t
ha
ve
be
en
ob
ser
ve
d65
.
An
HI
G
M
ph
en
oty
pe
si
mil
ar
to
IK
KG
def
icie
nc

yb
hi
aI
sn
bD
ee
e
D
n
e
d
F
e
o
s
c
ri
b
e
d
f
o
r
p
a
ti
e
n
t
s
w
it
h
a
m
u
t
a
ti
o
n
i
n
N
F
K
B
I
A
,
w
h
ic
h
e
n
c
o
d
e
s
I

,
a
n
i
n
h
i

m
m
a
g
l
o
b
u
l
i
n
a
e
m
i
a
.
S
e
v
e
r
a
l
g
e
n
e
t
i
c
d
e
f
e
c
t
s
h
a
v
e
b
e
e
n
i
d
e
n
t
i
f
i
e
d
t
h
a
t
a
c
c
o
u
n
t

for
the
ph
en
oty
pe
of
ag
am
ma
glo
bul
ina
em
ia,
whi
ch
is
ch
aract
eri
ze
d
by
a
Bcell
def
ect
an
d
int
act
Tcell
fun
ctio
n.
Of
all
of
the
for
ms
of
ag
am
ma
glo
bul
ina
em
ia,
Xlink
ed
ag
am
ma
glo
bul
ina
em
ia
(X
LA
)
pro
vid
es
the

pr
8
8
6

|
N
O
V
E
M
B
E
R
2
0
0
5

|
V
O
L
U
M
E
5
w
w
w
.
n
a
t
u
r
e
.
c
o
m
/
r
e
v
i
e
w
s
/
i
m
m
u
n
o
l

REVIEWS

RAG1, P
RAG2 e
Ig
B Ig
o 5 B
T
n BLNK
eI
K
m
ag I
m IgM
rr
m
o a
w
t
u P
IL-7Rr l

P
JAK3 B cell
r

IgM

e
L
yB
m
pC
h
oR
i
dPro-B cell
l
i
n
e
a
g
e
s

CD10
CD19

H
CD34
S
C
C
D
3
4
+

M
y
e
l
o
i
d
li
n
e
a
g
e
s

 Class-switch
recombination
Somatic
hypermutation

IgD

a
Ft
i
gB
u
r
e
2
|
P
r
o
t
e
i
n
a
n
d
g
e
n
e
d
e
f
e
c
t
s
i
n
B
c
e
l
l
d
e
v
e
l
o
p
m
e
n
t
a
n
d
f
u
n
c
t
i
o
n
.
H
a
e
m

ion
of
prolif
erati
on
and
differ
entia
tion
of
the B
cell.
In
the
perip
hery,
after
stimu
lation
with
antig
en,
matu
re B
cells
furth
er
devel
op
follo
wing
class
switc
h
reco
mbin
ation
and
som
atic
hype
rmut
ation
and,
ultim
ately,
differ
entia
te
into
mem
ory B
cells
or
plas
ma
cells.
Deve
lopm
ental
block
s
throu
ghou
t Bcell
matu
ratio
n
and
differ
entia
tion
occu
r as

ac
r
e
s
u
l
t
o
f
d
e
f
e
c
t
s
i
n
g
e
n
e
s
e
n
c
o
d
i
n
g
t
h
e
m
o
l
e
c
u
l
e
s
l
i
s
t
e
d
i
n
t
h
e
y
e
l
l
o
w
b
o
x
e
s
.
B
l
o

of
defe
cts in
gene
s
enco
ding
the
mole
cules
listed
in
the
yello
w
boxe
s.
Bloc
ks in
the
functi
on of
matu
re B
cells
can
also
occur
.
Prim
ary
imm
unod
eficie
ncy
synd
rome
s
that
caus
e
thes
e
block
s are
also
listed
.
AID,
activ
ation
induc
ed
cytidi
ne
dea
mina
se;
BAF
FR,
Bcellactiv
ating
facto
r
rece
ptor;
BCR,
Bcell
rece
ptor;
BLN
K, Bcell
linker
;

BT
r
o
T
E
N

B
R
O
N
C
H
I
E
C
T
A
S
I
S

A
p
e
r
m
a
n
e
n
t
d
i
l
a
t
i
o
n
o
f
t
h
e
b
r
o
n
c
h
i
,
o
w
i
n
g
t
o
c
h

m
u

os a
om s
al D
rec e
es T
siv E
e
s
mu
tati
on
s
an
d
on
e
tra
nsl
oc
ati
on
ha
ve
als
o
be
en
de
scr
ibe
d
in
pat
ien
ts
wit
h
ag
am
ma
glo
bul
ina
em
ia.
De
fec
ts
in
the
ind
ivid
ual
pre
BC
R
co
mp
on
ent
s
5
(al
so
kn
ow
n

e
.

N
A

REVIEWS
T
O
R
(
I
C
O
S
)
.
A
h
o
m
o
d
i
m
e
r
i
c
t
r
a
n
s
m
e
m
b
r
a
n
e
p
r
o
t
e
i
n
t
h
a
t
i
s
s
e
l
e
c
t
i
v
e
l
y

I e
N
x
D
Up
Cr
IB e
L
Es
Ts
Ce
E
L d
L
Ca
Ot
S
TI
Mt
Uh
L
e
A

7-

2)
,

hi
c

is

pr

e
d

b
y

el
l

ty

p
e

s,

in

cl

di

prof

essi

onal

l
y
i

anti
genpres

enti

ng

cells

fibro

blas

t
s
w

ts,
epit
heli

al

cells

and
end

othe

lial

O
S
l
i
g
a
n
d
(
a
l
s
o
k
n
o
w

cells
.

e
n
in
e
fl
u
s
e
e
n
g
c
m
e
e
o
n
f
t
I
s
g

e
o
n
n
c
B
o
C
d
R
i
d
n
e
g
v
el
t
o
h
p
e
m
e
i
n
m
7
t m
9
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I n
go
g
el
xo
pb
r u
el
si
si n
o
nh
die
da
nv
oy
t
hc
ah
va
ei
an
n
e
ff
et
cth
oe
n
uv
sa
ar
gi
ea
ob
f l
t e
her
ge

g
i
o
n
s
e
g
m
e
n
t
(
V
H

)
,
t
h
e
d
i
v
e
r
s
it
y
s
e
g
m
e
n
t

(
D
)
a
n
d
t
h
e
j
o
i
n
i
n
g
s
e
g
m
e
n
t
(
J
H

r
on
im
mu
noglo
bul
in
lig
htch
ain
ge
ne
rec
om
bin
ati
on
or
ex
pre
ssi
on.
Ho
we
ver
,
per
sist
ent
se
co
nd
ary
VJ
rea
rra
ng
em
ent
s
of
the
ge
ne
en
co
din
g
Ig
we
re
not
ed
in
Ig
def
icie
nt
pro
-B
cell
s
co
mp
are
d

wm
it p
hl
ce
ox
n,
tr
ow
l h
pi
r c
oh
Bi
cs
e
ll r
se
. q
Tu
hi
isr
ise
pd
r
od
bu
ar
bi
lyn
cg
a
un
so
er
dm
ba
yl
t
hd
ei
l f
af
ce
kr
oe
f n
sit
gi
na
at
lli i
no
gn
t
ho
r f
o
ut
gh
he
t s
he
e
Bc
Ce
Rl
cl
os

i
n
t
o
p
r
e
B
c
e
ll
s
.
A
l
t
h
o
u
g
h
t
h
e
s
u
b
s
t
r
a
t
e
s
f
o
r
B
T
K
h
a
v
e
n
o
t
b
e
e
n
e
l
u
c
i
d
a
t

ed,
Ig
M
at
the
sur
fac
e
of
B
cell
s is
tho
ug
ht
to
be
on
e
of
its
ke
y
act
iva
tor
s80,
81
.
Col
lec
tiv
ely,
the
se
dat
a
un
der
sc
ore
the
im
por
tan
t
rol
e
of
tra
ns
me
mb
ran
e
Ig
M
in
Bcell
sig
nal
lin
g
an
d
in
nor
ma
l B-

cs
e8
ll 2
d.
e
vI
en
l
ot
ph
me
es
ne
t.

C
D
1
9

e
Tx
Kp
he
ar
si
alm
se
on
bt
es
e,

n
i a
mn
plt
ic i
at b
eo
dd
ini
t e
hs
e
r w
ee
gr
ule
a
ti c
ol
no
on
f e
Bd
cf
elr
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t m
ol
ei
r s
ao
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et
t e
hd
r
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ol0
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C
D
2
7

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g
M
+

c
e
ll
s
(
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c
h
a
r
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n
e
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l
y
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g
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t
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d
f
r
o
m
t
h
e
b
o
n
e
m
a
r
r
o
w
)
f
r
o

m
fou
r
pati
ent
s
wit
h
XL
A.
Th
ese
anti
bo
die
s
wer
e
fou
nd
to
hav
e a
rep
ert
oir
e
con
sist
ing
of
spe
cifi
c
VH
an
dD
ge
ne
seg
me
nts
an
d
to
un
der
go
ext
ens
ive
sec
on
dar
y
rec
om
bin
atio
n
on
bot
h
im
mu
noglo
buli
n
ligh
t-

cX
hL
aiA
n
low
ci e
cr
oe
m
pf
ao
r u
en
dd
w
it t
ho
a
np
ti r
bo
od
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ec
se
fr
oa
m
c
no
on
r s
mi
ald
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cr
ona
tr b
oll
By
c
elh
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ne
ar
d
dif
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oe
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Be
cn
elc
ls y
fr
oo
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ps
ae
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ef
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we
it a
hc

ti
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e
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n
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o
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h
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n
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o
r
m
a
l,
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o
n
t
r
o
l
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c
e
ll
s
.
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a
k
e
n
t
o
g
e
t
h
e
r
,
t
h

ese
dat
a
indi
cat
e
an
ess
enti
al
rol
e
for
BT
K
in
BC
R
sig
nall
ing
tha
t
inv
olv
es
sub
seq
ue
nt
del
etio
n
of
cell
s
tha
t
pro
duc
e
aut
ore
acti
ve
anti
bo
die
s.

L
ast
,
kar
yot
ypi
c
an
aly
sis
of
the
leu
ko
cyt
es
of
on
e
pat

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ea
nt
t i
wo
it n
h
a
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o6
v,
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l X
f ,
ot
r (
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li q
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l
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o
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t
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r
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p
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t
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o
n
t
a
i
n
i
n

g 8
(L
RR
C8
)83.
In
a
mo
us
e
mo
del
,
retr
ovi
ral
tra
nsf
ect
ion
of
bo
nema
rro
w
cell
s
wit
h
thi
s
mu
tan
t
ge
ne
foll
ow
ed
by
bo
nema
rro
w
tra
ns
pla
nta
tio
n
led
to
de
vel
op
me
nta
l
arr
est
of
B
cell
s
at
the
pro

- t
Be
cd
e
ll a
sl
t l
ae
gl
ee
,
t i
on
g
et
t h
hi
es
r
wp
it a
ht
ai
me
an
r t
k
ec
do
du
el
fi d
ci
ep
nr
co
yd
i u
nc
pe
r
en
- o
Br
cm
ea
ll l
s
. L
I R
nR
tr C
i 8
g
up
i r
no
gt
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, i
t n
h,
e
ui
nn
ad
ff i
ec
ca

t
i
n
g
t
h
a
t
t
h
e
m
u
t
a
n
t
p
r
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e
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n
h
a
s
a
d
o
m
i
n
a
n
t
s
u
p
p
r
e
s
s
o
r
e
f
f
e
c
t
o
n
B
c
e
ll
d
e

vel
op
me
nt.
CV
ID.
Co
m
mo
n
vari
abl
e
im
mu
no
defi
cie
ncy
(C
VI
D)
is
cha
rac
teri
zed
by
a
def
ect
in
anti
bo
dy
pro
duc
tion
.
Mal
es
an
d
fe
mal
es
are
eq
uall
y
aff
ect
ed,
wit
h
an
inci
de
nce
bet
we
en
1 in
10,
00
0
an

dn
1t
in
5p
0y
, o
0g
0e
0n
. i
It c
is
us
si
un
alo
ly p
diu
al
gm
no
on
sa
er
dy
in
t i
hn
ef
se
ec
cot
ni
do
on
r s
t 8
hi4
r .
d
dS
ee
cr
au
dm
e
ol
f e
lif v
ee
al
ft s
e
r o
af
hi
stI
og
r G
y
oa
f n
r d
e
cI
ug
rr A
e

a
r
e
l
o
w
e
r
t
h
a
n
i
n
u
n
a
f
f
e
c
t
e
d
i
n
d
i
v
i
d
u
a
l
s
;
h
o
w
e
v
e
r
,
a
p
p
r
o
x
i
m
a
t
e
l
y
o
n
e
h
a
lf
o
f
p

atie
nts
hav
e a
nor
mal
ser
um
lev
el
of
Ig
M.
Th
e
nu
mb
er
of
circ
ulat
ing
B
cell
s is
red
uce
d
or
nor
mal
,
an
d
the
se
cell
s
can
res
po
nd
an
d
pro
lifer
ate
ap
pro
pri
atel
y to
sti
mul
atio
n
wit
h
anti
ge
n;
ho
we
ver,
the
y
fail
to
ter-

m
in
a
al
n
ly
t
di
i
ff
b
e
o
r
d
e
y
n7
ti 3
a
.
t
e
O
in
n
t
e
o
pl
a
a
p
s
p
m
r
a
o
c
a
elc
ls h
,
wt
hio
c
hc
sl
ea
cs
r s
ei
t f
ey
i
n
g
t
h
e
B
c
e
l
l
p
h
e
n
o
t
y
p
e
i
n
p
a
t

i
e
n
t
s
w
it
h
C
V
I
D
i
n
v
o
l
v
e
s
c
h
a
r
a
c
t
e
r
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z
i
n
g
t
h
e
p
o
p
u
l
a
ti
o
n
o
f
c
l
a
s
s
s
w
it
c
h
e
d
m
e
m
o

ry
B
cell
s
(wh
ich
hav
e
the
ph
en
oty
pe
CD
27+
Ig
M
IgD

)
in
the
se
pati
ent
s.
Tw
o
gro
ups
can
be
ide
ntifi
ed
on
this
bas
is,
usi
ng
a
cla
ssifica
tion
sys
te
m
tha
t
wa
s
pro
pos
ed
by
Wa
rna
tz
et
al.8
5

Pat
ient
s in
gro
up
1
hav

ev
ae
lo
wa
p
en
r o
cr
em
na
t l
a
gp
ee
(l r
ec
se
sn
t t
ha
ag
ne
0
. (
4g
%r
) e
oa
f t
cl e
ar
s
st
- h
sa
wn
it
c0
h.
e4
d%
m)
e.
m
oT
r h
ye
B
cf
elo
ls r
, m
ae
nr
d
pc
aa
ti n
e
nb
tse
in
gs
r u
ob
ud
pi
2v
hi
ad

e
d
i
n
t
o
t
h
o
s
e
p
a
ti
e
n
t
s
w
it
h
a
n
i
n
c
r
e
a
s
e
d
p
r
o
p
o
r
ti
o
n
o
f
C
D
1
9
+

C
D
2
1

cell
s
(gr
ou
p
1a)
an
d
tho
se
wit
h a
nor
mal
pro
por
tion
(gr
ou
p
1b)
.
Ma
ny
pati
ent
s
wit
h
spl
en
om
eg
aly
an
d
aut
oim
mu
ne
cyt
op
ae
nia
s
wer
e
fou
nd
to
seg
reg
ate
into
gro
up
1a.

p
e
r
i
p
h
e
r
a
l
B

U
nlik
e
pat
ien
ts
wit
h
XL
A,
Tcell

ph
r
ot
lif h
ee
r
as
ti e
or
nu
t m
o
ml
it e
ov
ge
el
n
iso
i f
m
pI
ag
ir G
e8
d6
i .
n
4P
0a
%t
i
oe
f n
pt
as
ti
ew
ni
t t
sh
w
it C
hV
CI
VD
I
Da
, r
ae
n
da
it t
is
da
ir n
e
ci
tl n
yc
ar
se
sa
os
cie
ad
t
er
di
ws
it k

o
f
d
e
v
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l
o
p
i
n
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n
u
m
e
r
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s
a
s
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o
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i
a
t
e
d
d
i
s
e
a
s
e
s
o
r
c
o
n
d
i
t
i
o
n
s
,
i
n
c
l
u
d
i
n
g
i
n
f
e

cti
on
s,
aut
oi
m
mu
ne
dis
ea
se
s,
he
pat
itis,
gra
nul
om
ato
us
infil
trat
ion
s,
ga
str
oin
tes
tin
al
an
d
pul
mo
nar
y
dis
ea
se
s,
an
d
ma
lig
na
nci
es7
3,86

.
Th
e
de
vel
op
me
nt
of
str
uct
ura
l
da
ma
ge
to
the
lun
gs
tha
t
lea

ds
s
t w
oi
bt
r h
o
nX
cL
hA
i ,
e
ca
t l
at
sih
so
isu
ag
lsh
o
oa
f t
c
oa
n
cl
ea
r t
ne
ar
n
da
og
ce
c
uo
r f
s
wo
it n
hs
ae
sit
m7
il 4
a.
r T
dh
ise
tr
i m
bu
ut
ti a
ot
ne
t d
o
t g
he
an
t e
os
f
pt
ah
ti a
et
n
t p

r
o
d
u
c
e
t
h
e
C
V
I
D
p
h
e
n
o
t
y
p
e
a
r
e

ey
are
div
ers
e
in
the
ir
infl
ue
nc
e
on
im
mu
ne

fun
cti
on.
Th
ey
inc
lud
e
IND
UCI
BLE
T
CEL
L
CO

k
n
o
w
n
o
n
l
y
f
o
r
a
m
i
n
o
r
i
t
y
o
f
p
a
t
i
e
n
t
s
,
a
n
d
t
h

STI
MUL
ATO
R

(IC
OS
),
SH
2D
1A
26,8
7

(w
hic
h
is
inv
olv
ed
in
XL
P),
an
d
thr
ee
ge
ne
s
tha
t
ha
ve
rec
ent
ly
be
en
de
scr
ibe

ds
t m
oe
bm
eb
i r
na
vn
oe
lv
ea
dc
: t
Ci
Dv
1a
9t
, o
Br
ca
en
ll d
ac
ca
ti l
vc
ai
ti u
nm
gf m
ao
cd
t u
ol
r a
( t
Bi
An
Fg
F
) c
r y
ec
cl
eo
pp
- h
t i
ol
r i
( n
BAl
Fi
Fg
Ra
) n
ad
n
di
Tn
At
Ce
I r
(t a
r c
at
no

r
)
.
H
o
m
o
z
y
g
o
u
s
l
o
s
s
o
f
I
C
O
S
a
s
a
r
e
s
u
l
t
o
f
a
l
a
r
g
e
g
e
n
o
m
i
c
d
e
l
e
t
i
o
n
h
a
s
b
e

en
ch
ara
cte
riz
ed
in
nin
e
pat
ien
ts
fro
m
fou
r
fa
mili
es
tha
t
are
not
kn
ow
n
to
be
rel
ate
d88,
89

.
Bin
din
g
of
IC
OS
to
its
lig
an
d
ind
uc
es
a
ma
rke
d
inc
rea
se
in
Tcell
pro
life
rati
on
an
d
cyt
okin
e
pro
du
cti
on,

ec
se
pl
el
cis
a9
ll 0
y.
o
f F
I u
Lr
- t
1h
0e
, r
w
hg
ice
hn
he
at
si
bc
e
et
ne
i s
mt
pi
li n
cg
a
t o
ef
d
i t
nh
t e
hs
ee
d
if n
f i
en
r e
e
ni
ti n
ad
ti i
ov
ni
od
f u
Bca
el
ll s
s
i s
nh
t o
ow
pe
l d
a
st
mh
aa

t
t
h
e
y
a
ll
h
a
d
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d
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t
i
c
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l
h
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m
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s
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p
l
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y
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e
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n
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h
e
I
C
O
S
l
o
c
u
s
,
i
n
d
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c
a
t
i
n

g
tha
t
the
mu
tati
on
wa
s
mo
st
pro
ba
bly
inh
erit
ed
fro
m
the
sa
me
an
ce
sto
r.
IC
OS
def
icie
nc
y
ha
s
als
o
be
en
inv
est
iga
ted
as
a
pot
ent
ial
aet
iol
og
y
in
pat
ien
ts
wit
h
HI
G
M
tha
t is
ca
us
ed
by
an
un
kn
ow

nh
go
ew
ne
ed
ti
ca
d
ed
f e
ef
ce
t9 c
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.
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ae
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t
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e
x
o
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o
u
n
d
a
r
i
e
s
o
f
I
C
O
S
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T
h
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r

efo
re,
alt
ho
ug
h it
is
pro
ba
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olv
ed
in
Bcell
act
iva
tio
n
an
d
cla
ss
swi
tch
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,
IC
OS
co
uld
not
be
ide
ntif
ied
as
the
ge
net
ic
def
ect
tha
t is
res
po
nsi
ble
for
the
clin
ical
pre
se
nta
tio
n
of
thi
s
su
bs
et
of
pat
ien
ts.
P

ao

in

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inte

rm

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edi

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fi

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co

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mp

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nb

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8
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REVIEWS
erso
nal
com
muni
p catio
at n),
h BAF
w FR
a (U.
y Salz
s. er,
S pers
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al and
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ef 116,117
e have
ct rece
s ntly
in been
C ident
D ified
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L. have
Fra Ba celln defe
c ct
o, phen
p otyp
er e.
s BAF
o F is
n a
al ligan
c d for
o BAF
m FR,
m TACI
u and
ni Bc cell
at matu
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n, n
a antig
n en
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M MA)9
. 2,93.
C Anot
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v TNF
a n famil
Zy
el mem
m ber,
, a
p prolif

erati
onindu
cing
ligan
d
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RIL),
also
bind
s
BCM
A
and,
with
lowe
r
affini
ty,
TACI
;
how
ever,
it
does
not
bind
BAF
FR94
. The
expr
essi
on of
BAF
F
and
APR
IL
has
been
sho
wn
to be
upre
gulat
ed
by
hum
an
DCs
and
mon
ocyt
es
after
expo
sure
to
interf
eron
-,
interf
eron
- or
CD4
0L95.
In
the

pr C
e and/
s or
e C
n gene
c seg
e ment
of s in
IL B
- cells
1 .
0 Ther
or efor
tr e,
a patie
n nts
sf with
or muta
m tions
in in
g BAF
gr FR
o or
w TAC
th I
fa prob
ct ably
or do
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, have
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n g
d that
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R ded
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v actio
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b with
e BAF
e F
n and
s APR
h IL
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w is
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d pro
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C n of
SB
R cells
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o gene
m ratio
C n of
a
to diver

se
antib
ody
repe
rtoir
e.

IgA
D.
Sele
ctive
IgA
defic
ienc
y
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D) is
the
mos
t
com
mon
prim
ary
imm
uno
defic
ienc
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with
a
prev
alenc
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betw
een
1 in
400
and
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0 in
heal
thy
bloo
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don
ors96
.
Ethn
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renc
es
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mor
e
disp
arat
e,
rang
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in
prev
alen

c curr
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fr pyo
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n are
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s) are
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97
ple
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Aln
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od
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p IgA
at D96.
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nt mol
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y acco
m unts
pt for
o the
m abs
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res

swit
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n in
mos
t
case
s,
alth
oug
h
mut
atio
ns in
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I
can
lead
to
an
abs
enc
e of
clas
s
swit
chin
g116,1
17
.
Fam
ilial
studi
es
hav
e
impli
cate
d
the
exist
enc
e of
an
alleli
c
relat
ions
hip
betw
een
IgA
D
and
CVI
D,
indic
ating
that
thes
e
diso
rder
s

reIgA
fl D
e and
ct CVI
di D,
ff incr
ereas
e ed
nt allel
ia e
l shar
e ing
x at
prchro
e mos
s ome
si 6p2
o 1,
n whic
of h is
th in
e the
s prox
a imal
m regi
e on
m of
ol the
e MH
c C,
ul was
arobs
a erve
et d,
io and
lo this
g susc
y9 epti
8
. bility
In locu
os
n was
e desi
st gnat
u ed
d IGA
y D1
of REF.
8 99 .
3 Mor
me
ul sens
ti itive
pl gen
y- etic
af anal
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ct was
e later
d carri
fa ed
m out
ili in
e 101
s multi
w pleit case
h famil

ies
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whic
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mor
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than
one
famil
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me
mbe
r is
affe
cted
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110
singl
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famil
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and
this
furth
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local
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the
defe
ct to
the
HLA
-DQ
and
HLA
-DR
loci1
00
.
The
rape
utic
opti
ons
Repl
ace
ment
ther
apy,
hae
mato
poiet
ic
stem
-cell
trans
plant
ation
(usin
g
bone
marr
ow,
cord
bloo
d or
perip

h nogl
er obuli
al nbl repla
o cem
o ent
d) ther
a apy
n is
d the
g main
e treat
n ment
e for
th antib
er odya defic
p ienc
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ar disor
e ders
th and
e is
a usua
v lly
ai give
l- n
a ever
bl y 3
e 4
tr wee
e ks. It
at can
m be
e give
nt n by
s eithe
fo r an
r intra
p veno
at us or
ie a
nt subc
s utan
wi eous
th rout
pr e,
i and
m the
ar dose
y and
i freq
m uenc
m y of
u admi
n nistr
o- ation
d can
ef be
ici adju
e sted
n on
cythe
. basi
I s of
m the
m clinic
u al

resp
onse
of
the
patie
nt
and
on
the
adeq
uacy
of
the
conc
entr
ation
of
seru
m
IgG

y
poly
th
ethyl
at
ene
is
glyc
m
ol
ai
can
nt
be
ai
use
n
d to
e
treat
d
pati
in
ents
th
with
e
ADA
s
er
defic
u
ient
m
SCI
.
D
E
who
n
are
z
not
y
can
m
dida
e
tes
re
for
pl
hae
a
mat
c
opoi
e
etic
m
ste
e
mnt
cell
w
or
it
bon
h
eb
marr
o
ow
vi
tran
n
spla
e
na
tatio
d 101
n .
e
Both
n
mod
o
alitie
si
s of
n
repl
e
ace
d
men
e
t
a
ther
m
apy
in
are
a
gen
s
erall
e
y
(
well
A
toler
D
ated
A
and
)
prov
m
ide
o
thes
di
e
fi
pati
e
ents
d
with
b
a

muc
h
impr
ove
d
quali
ty of
life.
H
aem
atop
oieti
c
stem
-cell
trans
plant
ation
has
been
atte
mpte
d for
patie
nts
with
multi
ple
type
s of
prim
ary
imm
unod
efici
ency
,
most
succ
essf
ully
to
treat
patie
nts
with
SCI
D102.
The
large
st
stud
y of
patie
nts
with
SCI
D
who
had
recei
ved
a
hae
mato
poiet
ic
stem
-cell
trans

pl opea
a n
nt Soci
w ety
a for
s Imm
re unod
p efici
or enci
te es103
d .
b Ther
y e
a were
m 475
ul patie
ti nts
n who
at were
io studi
n ed,
al and
re each
gi had
st recei
ry ved
, a
th trans
e plant
E in
ur the
o previ
p ous
e thre
a e
n deca
G des,
ro inclu
u ding
p 205
fo (43
r %)
Bl who
o did
o not
d recei
a ve a
n che
d moM ablat
ar ive
ro prec
w ondit
Tr ionin
a g
n regi
s men.
pl Fact
a ors
nt that
at were
io asso
n ciate
a d
n with
d poor
th er
e outc
E ome
ur s

amo
ng
patie
nts
recei
ving
nonHLA
ident
ical
trans
plant
s
inclu
ded
a B
SCI
D
phen
otyp
e,
abse
nce
of a
prot
ectiv
e
envir
onment
and/
or
pres
ence
of a
pulm
onar
y
infec
tion
befo
re
trans
plant
ation
.
Alth
ough
the
use
of a
prec
ondit
ionin
g
regi
men
was
sho
wn
to
pro
mote
funct
ional
engr
aftment
in

th oups
e of
gr patie
o nts.
u Amo
p ng
of patie
p nts
at recei
ie ving
nt HLA
s wi ident
th ical
B trans
plant
S s,
C survi
I val
D rates
, were
th impr
is oved
w whe
a n
s trans
n plant
ot ation
st occu
at rred
is at
ti less
c than
al 6
ly mont
si hs of
g age
ni and
fi whe
c n
a prop
nt hyla
c xis
o with
m the
p antib
ar iotic
e s
d trime
wi thop
th rim
th and
e sulp
re ham
s etho
ul xazo
ts le
a was
c used
hi .
e
v
O
e
d ne
fo stud
r y of
ot 132
h pati
er ents
gr with

SCI
D
who
had
rece
ived
a
hae
mat
opoi
etic
ste
mcell
tran
spla
nt(s)
withi
n
the
prev
ious
two
dec
ade
s
has
also
bee
n
repo
rted1
1

.
Mos
t of
thes
e
pati
ents
rece
ived
neit
her
pretran
spla
ntati
on
che
mot
hera
peut
ic
con
ditio
ning
(to
aid
engr
aftm
ent)
nor
post
tran
spla
ntati
on

grnfra
af ction
t- ated
v HLA
ers iden
u tical
s- bon
he
o marr
st ow
- but
di was
s dela
e yed
a by
s up
e to 4
prmon
o ths
p in
h pati
yl ents
a who
xi rece
s. ived
N Torcellm depl
al eted
T-bon
c e
el marr
l ow,
fu owin
n g to
ct the
io fact
n that
w mat
a ure
s T
s cells
e are
e not
n tran
w sferr
it ed
hi to
n thes
2e
w pati
e ents
e 104.
k The
s survi
of val
tr rate
a for
n thes
s e
pl 132
a pati
nt ents
a-was
ti posit
o ively
n corr
of elat
u ed

with
Cau
casi
an
race
,
fem
ale
gen
der
and
you
nger
age
at
the
time
of
tran
spla
ntation.
It is
imp
orta
nt to
note
that,
alth
oug
h
pati
ents
in
this
stud
y
who
had
not
rece
ived
myel
oabl
ative
pretran
spla
ntati
on
che
mot
hera
py
had
high
er
rate
s of
survi
val,
long
term
studi
es
that
wer
e
carri

e ed
d rate
o of
ut decli
m ne
orin
e the
th TRE
a Cs
n in T
a cells
d from
e such
c pati
a ents
d and
e in
af the
te dev
r elop
tr men
a t of
n oligo
s pl clon
a al
nt pop
at ulati
io ons
n of T
h cells
a 12,105
v .
e Simi
s lar
h longi
o tudi
w nal
n studi
a es
n of Ta cell
c func
c tion
el and
erthy
at mic
E
V
NI
AE
TW
US
R
E|
I
RM

outp
ut
hav
e
not
bee
n
carri
ed
out
in
pati
ents
with
SCI
D
who
rece
ived
pretran
spla
ntati
on
con
ditio
ning
.
Furt
her
long
term
follo
wup
studi
es
are
nee
ded
to
asse
ss
the
effic
acy

MVOLUME
U5 |
NNOVEMB
OER 2005
L| 889
O
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Y
2005 Natur

REVIEWS
y
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e
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c
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l
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c
l
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r
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l
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c
i
l
i
t
a
t
e

atio
n110.
The
exac
t
mec
hani
sm
by
s whic
i h
g the
n LM
a O2
l locu
l s
i was
n sele
g ctiv
ely
t targ
o eted
for
i pron viru
ds
u inte
c grati
e on
in
t thes
he
e pati
i ents
r is
unc
d ertai
i n.
v Be
i fore
s this
i trial,
o the
n risk
, of

retr
r ovir
e al
s inse
u rtion
l al
t mut
i age
n nesi
gs

was

i thou
n ght

to

c be
l mai
o
nly
n
theo
a
retic
l

al,
bec
p
aus
r
ea
o
sing
l
le
i
roun
f
d of
e
tran
r
sdu

c
ti
o
n
w
o
u
l
d
n
o
t
a
c
c
o
u
n
t
f
o
r
t
h
e
m
u
lt
i
p
le
m
u
t
a
ti
o
n
s
t
h
a
t
a
r
e
g
e
n
e
r
al
ly
r
e
q
u
ir
e
d
f
o
r
cl
o
n
al
p
r
o
li
f
e

r in
a prec
t linic
i al
o and
n clini
. cal
trial
Ts
h usin
i g
s repli
cati
i ond inco
e mpe
a tent
retr
wovir
a al
s vect
ors1
f 12
.
u
Nev
r
erth
t
eles
h
s,
e
inse
r
rtion
al
s
mut
u
age
p
nesi
p
s
o
prov
r
ed
t
to
e
be a
d
seri
ous
b
adv
y
erse
eve
t
nt in
h
thes
e
e
pati
a
ents
b
,
s
and
e
furt
n
her
c
insi
e
ght
is
o
nee
f
ded
for
t
the
h
desi
i
gn
s
and
deli
p
very
h
of
e
retr
n
ovir
o
al
m
vect
e
ors
n
befo
o
re
n
this

li
f
e
s
a
vi
n
g
t
h
e
r
a
p
y
c
a
n
b
e
p
r
o
vi
d
e
d
i
n
t
h
e
f
u
t
u
r
e.

of various approaches
to
haematopoietic
stem-cell
transplantation and to
assist
in
the
identification of patient
subgroups that are
likely to benefit from
one form of therapy
over another.
Clinical trials have been
carried out using gene
therapy for the treatment of
patients with X-linked,
recessive SCID (which is
caused by a deficiency in
the common cytokinereceptor -chain, c) and
for patients with ADA
deficiency106108.
For
patients with X-linked,
recessive SCID, those
without an HLA-identical
sibling were infused with
autologous
CD34+
haematopoietic stem cells
(enriched
from
bone
marrow) that had been
incubated with cytokines
and exposed to a cencoding retroviral vector.

Initial resultscau
were promising,
with nine
sed
of ten
by
treate
retr
d
ovir
patient
als
vec
develo
tor
ping
ins
norma
erti
l T-cell
on
functio
in a
n and
loc
not
us
requiri
tha
ng
t
gamm
con
aglobu
tain
lins
replac
the
ement
LI
therap
M
y.
do
Howe
mai
ver,
n
3
onl
years
y 2
after
(L
gene
M
therap
O2)
y, the
onc
2
og
young
en
est
e,
patient
an
s
d
develo
the
ped
exp
clonal
res
prolife
sio
ration
n
of
of
matur
LM
e
TO2
cell
in
popula
ma
tions10
tur
9
.
A
e T
third
cell
child
s
also
led
develo
to
ped
thei
an
r
abnor
unc
mal
ont
clonal
roll
pheno
ed
type.
pro
In the
lifer
first
atio
two
n110
cases,
.
leukae
Thi
mias
like
ph
prolife
en
ration
om
was
en

o r the
n use of
is gene
k therap
ny
to
o treat
w patient
n s with
a SCID
s or
r other
e selecti
tr ve
o immun
vi e
r defect
als, and
inadvan
s ces in
e the
rt selecti
ioon of
n additio
alnal
mvector
u s and
t the
a elucid
- ation
g of the
e mecha
n nisms
e of
si gene
s transd
B uction
O might
X allow
1 its re. imple
C menta
letion
a for the
rl treatm
y, ent of
t these
h patient
e s.
r
e Looki
is ng
forwa
tr
rd
e
As we
m
look
e
to the
n
future
d
of the
o
field
u
that
s
enco
p
mpas
o
ses
t
primar
e
y
n
immu
ti
nodefi
al
ciency
f
disea
o

ses
,
em
ph
asi
s
ne
ed
s
to
be
pla
ce
d
on
the
ear
ly
det
ecti
on
of
life
thr
eat
eni
ng
SC
ID,
the
elu
cid
ati
on
of
the
un
kn
ow
n
mo
lec
ula
r
def
ect
s
tha
t
un
der
lie
im
mu
ne
dys
fun
ctio
n
an
d
the
im
ple
me
nta
tio
n

o into
f newb
n orne scree
wning
mprogr
o amme
d s will
a aid in
litthe
i diagn
e osis,
s treatm
o ent
f and
t longh term
e mana
r geme
a nt of
p these
y patien
t ts.
h Advan
a ces in
t haem
a atopoi
i etic
mstemtcell
o isolati
c on
o protoc
rr ols
e allow
c transp
t lantati
t on of
h far
e greate
sr
e numb
g ers of
e highly
n purifie
ed
ti haem
c atopoi
d etic
e stem
f cells,
e and in
c conju
t nction
s with
. more
A efficie
d nt
o negati
p ve
ti selecti
o on of
nT
o cells,
f this
S will
Cundou
I btedly
Dimpro

ve
the
out
co
me
s
of
ha
em
ato
poi
etic
ste
mcell
tra
ns
pla
ntati
on1
11

.
Ge
ne
the
rap
y,
alt
ho
ug
h
in
its
inf
an
cy,
ha
s
sh
ow
n
re
ma
rka
ble
suc
ces
s in
so
me
pat
ien
ts,
an
d a
gre
ate
r
un
der
sta
ndi
ng
of
the
me
ch
ani
sm

s and
t devel
h opme
a nt of
t safer
a metho
r ds of
e gene
i correc
n tion
v might
o allow
lv this
e promi
d sing
r
g
y

1.

that
&
is
L
base
de on
o
the
n
most
a
rece
r
nt
d
cons
,
ensu

3.

C
N
l
oi
tn
a.
r
aI
nm
gm
eu
ln
oo
,l
.
L
.1
1
e4
t,
a6
l7
.7

P6
r8
i7
m
a(
r2
y0
0
i4
m)
m.
u
n
o
d
e
f
i
c
i
e
n
c
y
d
i
s
e
a
s
e
s
:
a
n
u
p
d
a
t
e
.
J
.
A
l
l
e

the
rap
y
to
be
us
ed
in
clin
ical
pra
ctic
e.

n
c
D
a

f
i
c
i
e
in n
sevc
erey

co
mbi
inen
d
im h
muu
no m
defa
icien
ncys
. .
N.
En C
gl. e
J. l
Mel
d.
34 7
9 3
18 ,
21
1
18 4
28 7
(20
03)1
. 5

s of
W
the
.
Prim
ary
J
Imm
.
uno
defic
D
ienc
e
yf
Dise
e
ase
c
Clas
t
sific
i
ation
v
Com
e
mitte
eI of
the
L
Inter
7
R
natio
nal
e
Unio
nx of
p
Imm
r
unol
e
ogic
7
s
al
s
Soci d (
i
eties
1
.o
or 9
n
the9
P
3
i
u
su )
n
e
bu .
l
nit
T
,
of

4.

Th
is
is
an
up
da
te
d
su
m
m
ar
y
an
d
cla
ssi
fic
ati
on
sc
he
m
e
of
pri
m
ar
y
im
m
un
od
efi
cie
nc
y
di
se
as
es

2.

AB
+
.
,N
K

6.CDK

Z
i
es
ge
lv
ee
rr
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Sc
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m
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e
Bd

5.

u
ci
km
lm
eu
yn
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d
Re
.f
i
Hc
.i
e

3. u
J. n
Cli g
n. ,
Inv
estC
. .
11
4 e
15 t
12
a
15 l
17 .
(20
04)M
. u
t
a
N
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s
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y

r4
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p(
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7.

v
e
l
Ro
up
sm
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en
lt
l.

p
a

S
Sc
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e

9.
10
e
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7
a0
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7
M9
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14
.

o
n(
1
o9
f9
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J)
a.
k

w
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h

8. 3M

s
e
v
e
r
e

ao

io
ns
h

c
o
m
b
i
n
e
d
i
m
m
u
n
o
d
e
f
i
c
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e
n
c
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d
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e
a
s
e
.
N
a
t
u
r
e
M
e
d
.
6
,
3

ps
a,
t
iD
e.
n
te

11

w
ia
tl
h.
SA
Cr
It
De
:m
i

es
s,
s
ea
n
tn
io
av
le
l

r
oD
lN
eA
od
fo
u

Jb
al
ke
3s

it
nr

ln
yd
m
pb
hr
oe
ia
dk
dr
ee

lead
Ce s to
ll sup
10 erior
5 thy
17 mic
7
outp
18
ut
6
(20 and
01) impr
. ove
d
surv
ival.
S Blo
od
in 99,
tw 872
o
pat 878
ien (200
ts 2).
wit
h
se
verL
elyi
im n
paid
rede
cellg
ular
r e
im n
mu,
nity
. M
La .
nc
et L
2 .
10
67 e
t
10
69 a
(19l
72).
.
A
p
Thip
s l
pa y
pe i
r n
revg
ie
wsp
SCu
ID b
an l
d i
thec
ou
tcoh
mee
s a
of l
bo t
ne-h
ma
rros
w t
trar
ns a
plat
ntae
tio g
n i
of e
13 s
2
patt
ieno
ts
ov p
er r
tw i
o m
de a
ca r
de y
s.

12
13

i
m
m
u
n
o
d

e&
f Pu
i ck,
c J.
i M.
eDe
nvel
c op
y me

s
Arnai
17bloo
d
z
spot
sSto
V
scre
t
A i
en
l
o
infan
l
l
e
ts
l
n
for
e
a
SCID
r
,
.,

18
.

nt

dof
i po
s pul
eati
aons ba
ese
sd
: ne

16 J
. Y.

wb

aorn
scr

pee
onin
tg
efor
nse
t ver
ie
aco
l mb
ine

ad
pim
pmu
r no
odef
aici
c en
hcy.
J.
t All
o er
gy
g Cli
e n.
n Im
m
e
un
t
ol.
i 11
c 5,
39
d 1
i 39
s 8
o (2
r 00
d 5).
e Th
r is
s pa
. pe

r
de
sc
rib
es
th
R e
e no
c vel
o ap
m pr
m oa
. ch
of
R m
e ea
p su
. rin
g
5 th
3 e
, nu
m
1 be
r
2 of
9 TR
EC
( s
2 in
0 D
0 N
4 A
) is
. ol
at
ed
fro
m
Chan,
K dri
ed
.

M
M
W
R

15.

aZ
g.
i
,&
HE
.p
s
et
te
i
an
l,
.
J
R.
o
lA
e.
oI
fd
e
Tn
Bt
Xi
1f
i
ic
na
t
hi
uo
mn
a
no
f
d
ea
l
2n
2o
qv
1e
1l
.
2n
u
sc
yl
ne
da
rr
o
ml
eo
.c
a
Ll
ai
nz
ca
et
ti
o
3n
6
2s
,i
g
1n
3a
6l
6
i
1n
3
7T
3b
x
(1
2
0t
0h
3a
)t
.
i

A
.
e
t
a
l
.
P
r
i
m
a
r
y
i
m
m
u
n
o
d
e
f
i
c
i
e
n
c
y
c
a
u
s
e
d
b
y
m
u
t
a
t
i
o
n
s
i
n
t
h
e
g
e
n
e
e
n
c
o
d
i
n
g
t
h
e
C
D
3

s
u
b
u
n
i
t
o
f
t

h,
e
F
T.
-,
l
yF
mi
ps
hc
oh
ce
yr
t,
e
A
r.
e
c&
e
pL
ti
os
ro
.w
Ns
.k
a
EnG
gr
lo
.s
p
Ji
.e
r
Mr
ee
d,
.
B
3.
2
7I
,n
5d
2e
9p
e
5n
3d
3e
n
(t
1
9m
9u
2t
)a
.t

19 i
. So
on
us
d
ao
if
s
,t
h
Ce
.
,h

u
dm
ea
n
V
iC
lD
l3
ar
t
ag
ye
,n
e
J
.r
-e
Ps
.u
,l
t
Li
en
g
D
ei
in
s
ta

T
c
e
l
l
r
e
c
e
p
t
o
r
/
C
D
3
c
o
m
p
l
e
x
i
m
m
u
n
o
d
e
f
i
c
i
e
n
c
y
.
N
a
t
u
r
e
G
e
n
e
t
.
3
,
7
7

8
1
(
1
9
9
3
)
.

REVIEWS

20
.

t
r
a
n
s
p
o
r
d t
e e
r
l
a T
A
S P
a 1
l .
l
e
,
H
.

a
l
.
H
L
A
c
l
a
s
s
I
d
e
f
i
c
i
e
n
c
i
e
s

21
D
o
n
a
t
o
,

d
L
u
.
e
e
t
t
o
a
m
l
u
.
t
a
A
t
s
i
s
o
o
n
c
s
i
a
i
t
n
i
o
s
n
u
b
o
u
f
n
i
H
t
L
A
1
c
o
l
f
a
s
t
s
h
e
I
p
e
p
t
i
d
e

22.

1
0.
Cli
n
.
I
n
v
e
s
t.
1
0
3
,
R
9

R
1
3
(
1
9
9
9
).

e
t

a
n
t
i
g
e
n

9
d
9
e
5
f
)
i
.
c
i
e
n Masterna
c
k,
y
K.,
Mu
r
hlet
e
hale
l
ra
Mot
t
tet,
e
A.,
d
Villa
rd,
t
J.,
o
Per
etti,
a
M.
&
T
Reit
A
h,
P
W.
2
Mol
ecul
g
ar
e
gen
n
etic
e
s of
the
m
bar
u
e
t
lym
a
pho
t
cyte
i
syn
o
dro
n
me.
Rev
w
.
i
Im
t
mu
h
nog
ene
f
t. 2,
a
267
m

i
282
l
(20
i
00).
a
l

23
G
b.
r
o
n
c
h
i
e
c
t
a
s
i
s
.
J
.
P
e
d
i
a
t
r
.
1
2
7
,
8
9
5

9
0
0
(
1

o
l
d
m
a
n
,
F
.
D
.
e
t
a
l
.
D
e
f
e
c
t
i
v
e
e
x
p
r
e
s
s
i
o
n
o
f

H.,

,
117

12
3
(20
01)
.

p Coh
5 en,
6 A. &
l

Rolf
ma
n,
C.
i M.
n Def
ecti
a ve
n T
cell
i rec
n ept
f or
a sign
n alin
t g
and
w CD
i 8+
t thy
h mic
sele
s ctio
e n in
v hu
e ma
r ns
e lack
ing
c Zap
o -70
m
kina
b
se.
i
Cell
n
76,
e
947
d

958
i
(19
m
94).
c
k

26
. E

u
25.
n

de

o
d
e
f
i
c
i
e
n
c
y
.

la
Call
eMar
tin,
O.
et
al.
Fa
mili
al
CD
8
defi
cien
cy
d
u
Cli e
t
o
a
m
u
t
a
ti
o
n
i
n
t
h
e
C
D
8

1
0.

24.
Arpaia,
E.
,
S
h
a
h
ar
,
M
.,
D
a
di
,

g
e
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80.

Aoki, Y.,
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se
lb
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a
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e

ard,
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9
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i mo
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. S

atio
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A)
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rec
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or
(BC
R).
Clin
.
Exp
.
Im
mu
nol.
110,
386

391
(19
97).

p
r
e
Ng,- Y.-

82.

S.,
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de
ma
lym
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ph
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Bdles
, C.
cell
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Pr
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ovs
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I.,
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A.
D.
Vorech B.,
o Ple
v ban
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k &
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I. mm
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Im
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340
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s in

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/fac
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Ac
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| 55
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9
2

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Lmmunol
U
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