From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
Absence
of Both
the
9lkD
in Two
By
Chronic
ited
Charles
in
X-Iinked
terms
or autosomal
phils
display
the
cytochrome
burst
The
the
finding
lated
and
a 22kD
question
the
various
studied
types
the
three
expression
genetically
chrome
b-negative
b-negative
two
(Al.
and
we
HRONIC
disorder
other phagocytic
hydrogen
peroxide
tive
oxygen
amide
oxidase,
are
CGD
inactive
activated
killing
reac-
to
of
due
that
studies.
either
upon
a 1989
to
two
Grune
opsonized
part
and
Experimental
Jolla.
CA
School.
of
respon-
but
Medicine,
Research
and
the
is
December
Supported
in
RR00833,
and
Institute
part
of General
as
to
the
(type
I),
Molecular
of Scripps
Pediatrics,
and
Clinic,
Harvard
reprint
Institute
La
Medical
A117354,
a recipient
funds
A124838,
of
National
a National
Research
of the
active
of
oxidase
is absent
to John
T. Curnutte,
Medicine
in part
been
supported
some
forms
10666
North
Torrey
PhD,
(BCR7),
Pines
charge
payment.
“advertisement”
indicate
©
costs
ofthis
article
This
article
must
in accordance
this fact.
1 989 by Grune
Rd.
therefore
18 U.S.C.
in part
be hereby
section
This
and
to
Inc.
expresappears
in a manner
stable
Based
on
of expression
subunits
is dependent
for
patients
heterogeneity
hand,
the
both
the
major
comphementation
chrome-negative
(X
negative
(A ),
(Ak).’
The
importance
and
neutrophil
in CGD’3:
by
purification
b
the
the
X-hinked/cyto-
of the
b
has
in
CGD
has
application
of
cytochrome
of the X-hinked
cytochrome
and
recessive/cytochrome-
cytochrome
genetics
inheritance
suggests
that at least
result in the phenotype
recessive/cytochrome-positive
established
the
the
neutro-
of the autosomal
b.’o’5’6’8
of
autosomal
autosomal
of
form,
in
by genetic
complementation
hybrids
that
revealed
three
groups
),
in
of the
ofcytochrome
mode
of CGD.
This
is supported
studies
using
CGD
monocyte
form
detected
majority
levels
has
absent
recessive
be
of the cytochrome
b spectrum
distinct
genetic
mutations
can
been
and
been
research
studies
form
of CGD.
purified
and
on
Human
shown
to
consist
of two subunits:
a heavily
glycosyhated
polypeptide
with an M, of 9lkD,
and a smaller,
nonglycosylated
22kD
DepartResearch
polypeptide.9””9
La Jolla,
CGD,
by page
marked
1 734 solely
in
neutrophils.
function
X-hinked
autosomal
normal
for the
NADPH
it is spectrally
cannot
it
is also
in CGD
the classic
of the
have
components,8
b in oxidase
that
of
cytosohic
that it is responsible
The activity
of this
finding
In both
a variety
four
cytochrome9’2
diminished
subset
least
membrane
.
spectrum
and
of at
cytochrome
the
a rare
the molecular
of
peptides,
and
O2
or greatly
b
presence
several
to
has
The
been
cytochrome
and
CGD.9”9
Thus,
the
gene,
cloned20
subunit.2’
cloned22
chrome
& Stratton,
0006-4971/89/7306-0046$3.00/0
1416
with
were defrayed
eventual
patients.
b-type
enzyme
by
cytochrome
involving
92037.
The publication
the
there-
the
mutation
the
additional
of CGD.
of
is an Investigator
MD,
the
of patients
CGD
a group
oxygen
role
by
investigators
contributed
S.H.O.
22kD
a low-potential
unequivocally
Award
institute.
Experimental
Clinic.
20. 1989.
are Established
with
of the A.H.A.
and
ofScripps
A.J.J.
Medical
requests
of Molecular
is
Sciences
and
January
AI22735,
CAP.
Association
affiliate
Hughes
Address
grants
Medicine
Heart
California
the Howard
by
J. T.C.
the American
CA
of
30, 1 988; accepted
HD18661.
PHFGMO7I98.
ment
Institute
Department
gene.
CGD,
and
group
chemotactic
putative
that
disease
stimuli
Boston.
Submitted
the
and
latter
Inc.
Besides
and
A central
becomes
to such
Immunology
This
91 kD
from
in A
gene
cytochrome
microbes,
reduction
is nicotin-
The CGD designations
used in this report are related
Scripps Classification
Scheme for CGD (17) as follows:
X
AF (type II), and A- (type Ill).
Departments
male).
distinct
that
& Stratton,
agents.”4
recessive
the
one
X
X
four
other.
phils.’#{176}”3’7On the other
From
the
in the
could
in
Furthermore.
hypothesize
the
additional
a normal
22kD
in this
seen
we
of
the
is believed
of many
enzyme
cells,
the
subunit
subunit
three
mutation
subunit.
previously
undetectable
bears
The
involves
prevented
also
subunits
the
neither
genetically
group.
91 kD
with
females.
are
sion
be
cytochrome
from
likely
22kD
proteins5’7
(02)
reduced
(NADPH)
complex
that
of neutrophils
patients
of the
Curnutte
patients,
(three
most
X
T.
both
were
of the
other
recurrent
The
unstimuhated
exposure
is an
neutrophils
neutrophils
phosphate,
flavoprotein
in
following
(CGD)
from
in human
of
CGD
probably
b
controls
superoxide
Since
these
for the
suffer
the
lysates
in which
required
adenine
dinucheotide
a membrane-bound
of
In the
disease
defense
bof
X
expression
these
each
blots
patients.
infections.2’3
production
catalytically
to
A
kD-defective
to
CGD.
neutrophils
patients
converse
recessive/cytochrome
patients
life-threatening
O2
in
X-Iinked/cyto-
cells fail to generate
upon stimulation.’
CGD
have
recessive/cytochrome
of host
compounds
microorganisms,
we
the
John
Consistent
subunits
with
since
A
in five
in
Both
fore.
in
b subunits
CGD:
Western
ten
raised
defective)
with
finding
of
and
detected.
identified
group
91
glycosy-
question
reported
patients
cyto-
has
(or
patients
Cytochrome
Disease
H. Orkin,
easily
patients.
respiratory
a 91 kD
antibodies
prepared
and
and
for
of
autosomal
from
b-type
Stuart
three
be
of a unique
cytochrome
GRANULOMATOUS
inherited
sible
the
forms
polyclonal
neutrophils
sometimes
this
autosomal
Using
subunits.
intact
To address
of
(Xi.
(Al.
positive
absent
be
neutro-
neutrophil
are
distinct
were
(either
polypeptide
subunits
and
the
of
J. Jesaitis,
of inhercan
Neutrophil
Granulomatous
generate
CGD
of the
consisting
of CGD.
of
purified
nonglycosylated
of which
to
whether
function
that
Algirdas
inheritance
spectrum
for
b is a heterodimer
the
forms
of
and
absorbance
oxidase.
C
mode
recessive),
important
chrome
various
the
fail
of Human
of Chronic
is a group
cells
The
Subunits
C. Dinauer,
(CGD)
phagocytic
of
22kD
Forms
Mary
disease
oxidants.
classified
Parkos,
in which
antimicrobial
Genetic
A.
granulomatous
disorders
and
been
b appears
which
and
The
shown
the
to
be
9lkD
subunit.22
Two
major
questions
to encode
22kD
subunit
to be
expression
somehow
are
is defective
shown
absent
of the
Blood, Vol 73. No 6 (May
has
in the
22kD
linked
raised
in X-linked
for the
by
9lkD
also
X
subunit
been
form
of
of cyto-
to the
expression
these
studies
of
with
1). 1989: pp 14 16-1420
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
CVTOCHROME
regard
subunit
B
DEFICIENCY
to CGD.
of the
affect
the
IN CGD
First,
does
cytochrome
expression
1417
the genetic
in X-hinked
of the
other
absence
CGD
subunit?
of the one
consistently
Second,
Three
of the cytochrome
the other in both
antibodies
indicate
directed
against
each
that the genetic
absence
subunits
is accompanied
the X and A forms
and
year-old
in the
using
the
cell-free
described
MATERIALS
by Western
All
blot
three
had
spectroscopy.
AND
patients
analysis
with
for
CGD,
not previously
analyzed
chain
protein
and
heavy
chain
levels
E.H.
and
former
has
against
have
been
previously
reported.23
The mother
and sister
CGD based on a dimorphic
staining
hum
slide
whom
females
test.’4
have
and
been
one
Three
patients
of patient
M.P. are carriers
of
pattern in the nitroblue
tetrazowith A COD were studied,
all of
previously
reported’8:
male
A
with
CGD
N.S.,
were
R.G.,
examined
and
iC.
in this
studied
as well
activation
previously
the
charac-
fourth,
and
as membrane
of
a 37-
found
NADPH
to be
activity
oxidase
as
to cytochrome
22,000
To
obtain
chin
synthetic
antibodies
peptides
by
rabbit
Rabbit
antiserum
b has been
reactive
with
the
M
both a fl-galactosidase-9lkD
derived
from
Royer-Pokora
The
previously
two
b.
of cytochrome
of the cytochrome,
as antigens.
been
light
antiserum
described.2’
the
raised
Antisera
cysteine-conjugated
sequence
Ct al?#{176}
and
et
against
to the
peptides,
of
Teahan
the
latter
were
ARKRIKN-
PEGGC
(Residues
154 through
164) and KQSISNSESGPRGC
(Residues
546 through
558), which were kindly prepared
by Dr
Michael
Buchmeier
(Research
Institute
of Scripps Clinic, La Jolla,
CA) as described
previously.
The peptides were coupled to keyhole
b subunits,
were studied.
of cytochrome
b by difference
J.C.
been
subsequently
for
described
used
raised
cytochrome
undetectable
Patients
METHODS
X
Mr
elsewhere.9
al25 were
Three
the
heavy
91,000
the
system
have
while
b spectrum
of antibodies
with
fusion
was
A.V.)
laboratory24
ehsewhere’4’8
reactive
by the absence
of
of CGD,
but not the
and
by this
cytochrome
Preparation
of the
of one
G.S.,
(E.C.I.),
of the
described
A type.
Patients.
(L.N.,
reported
female
devoid
other autosomal
forms of CGD,
how are the two cytochrome
subunits
affected?
In this report,
we have studied
the cytochrome
b subunit
composition
in the three
major
genetic
forms of CGD using
subunits.
Our results
of them
terized
limpet
hemocyanin
described,
(KLH)
substituting
Three
Rabbits
study.
peptide-KLH
were
with
KLH
initially
immunized
conjugate
glutaraldehyde
as
previously
for albumin.27
emulsified
intradermally
with
with
1 mg of the
complete
Freund’s
adju-
AND
ANTISERA
C-
TO NTERMINI
PEPTIDES
ThE
91
KD SUBUNIT
91 kD-
I
Fig 1 .
Western
blots of X and A CGD neutrophils
with antibodies
to both subunits
of cytochrome
b. Antibodies
to the M,
91 .000 heavy
chain (upper panel) and M, - 22.000
(lower
panel)
of cytochrome
b were
used to probe neutrophils
from patients
with X
and A CGD. The corresponding
lanes
in both panels
contain
the same
samples
as follows:
lane
1 #{149}1 g
purified
cytochrome
b; lanes 2 through
4. normal
human
neutrophils;
lane 5. neutrophils
from
an X
CGD
carrier
(female)
which
had a diminished
ability to
produce
superoxide
anion (26% of normal);
lanes 6
through
8. neutrophils
from three
male X
CGD
patients;
lanes
9 through
1 1 , neutrophils
from
three female
A CGD patients.
Lanes 2 through
11
each contained
40 Lg of protein
from
a Triton
x-100 lysate of intact neutrophils
(equivalent
to
1 .5 to 2.5 x bc
cells)
that
was
prepared
as
described
in Materials
and
Methods.
2
3
4
5
6
7
8
9
1011
ANTISERUM
22
22
kD-e-
I
Cyt
2
3
4
5
6
Normal
78
XCGD
b
x_
Carrier
FROM
91011
A+CGD
cD
TO
SUBUNIT
THE
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1418
vant. Intradermal
booster
injections
with the same amount
of
KLH-peptide
emulsified
in incomplete
Freund’s adjuvant
were given
at 2, 4, and 6 weeks, respectively.
Antiserum
obtained
1 week after
the last booster injection was assayed for reactivity
with cytochrome
b by Western
blot
Sample
preparation
prepared
excess
as previously
Western
blotting.
described,’4
treated
Neutrophils
with
phosphate,’4
and frozen at -70#{176}Cin aliquots
PMN. Neutrophils
and cytochrome
b samples
Western
blotting as described
previously.9
diisopropyl
fluoro-
were
5 x
106
prepared
for
RESULTS
Because
we
of the dual
investigated
subunit
the
chrome-negative
structure
of the cytochrome
that
of CGD
each
might
of
the
be to due
two
b,
of several
cytochrome
neutrophils.
regions
heavy
neutrophil
9lkD
subunit
chain
of both
extracts
panel
of
other
bands
cific
antibody
91
antibodies
b and extracts
from
The pooled
antisera
of the
91000
anticytochrome
Fig
to a defect
1, lanes
reacted
1 and
neutrophil
labeling,
since
with
normal
prepared
purified
on Western
in the
males
with
band
characteristic
X
the
directed
against
in
and
blots
lanes
are
competition
These
is abnormal.’8
patient
peptide
duced
the
ing
M,
result
The
oxidized)
9lkD
analyzed
amount
of
subunit
9lkD
this
all
gene
three
are
in the
X
CGD
obviously
had
also
25%
panel.
of
As
The
deficient
from
CGD
for oxidase
levels
difference
show
whose
normal
normal
and
the
an
extract
1 1 are
panel
panel.
patients
5 shows
only
contain
parallels
upper
antisera
Lane
normal
Fig
of cytochrome
upper
antithree
observation
using
cytochrome-positive
activity
required
lower
subunit
the
of the broad
This
by absorbance
The
subunit
observed
in that
with
in
absence
9 through
spectroscopy
subunit.
of the 22kD
extracts
of nonspe-
experiments
minus
of the
who
cells
b as determined
the content
b and normal
in the upper
4, respectively.
the
activation
CGD
against
as shown
2 through
recessive
factor
cytochrome
with
CGD
shown).
in a neutrophil
Lanes
patients
with autosomal
(Ak) in whom the cytosol
purified
strongly
of X
not
pooled
from
protein.9’2’
subunit
activity.
while
(data
not
anti-9lkD
(data
finding
fusion
labeling
of the
extracts
subunit.
reported
ET AL
blocked
using the
complete
9lkD
of 9lkD
carrier
their
antiserum
show
the 9lkD
burst
both
cytochrome
and
previously
a female
respiratory
inhibit
completely
obtained
the reactivity
to neutrophil
of the
level
not
protein
CGD
confirms
from
cyto-
one or the other subunits
of the cytochrome
in a complementary fashion.
To test our hypothesis,
we examined
the reactivity
fusion
6 through
8 show
peptide
antibodies
intermediate
possibility
forms
did
was
were
Lanes
9lkD
were
containing
synthetic
/3-galactosidase
analysis.
and
peptides
that of the 9lkD
band
shown).
Similar
results
PARKOS
of
(relabel-
1 examines
b in the same
can
levels
be
of
seen,
the
the
9lkD
result
is noteworthy
defect
resides
in the 22kD
in the
subunit.
kD
ANTISERA
TERMINI
THE
N-
TO
PEPTIDES
91
KD
C-
AND
FROM
SUBUNIT
1234567
ANTISERUM
SUBUNIT
22
kD-
234567
-
cyt
b
Norm
ACGD
TO
THE
22
KD
Fig 2.
Western
blots of A CGD neutrophils
antibodies
to both subunits
of cytochrome
b.
Antibodies
to the M, = 91 .000 heavy chain (upper
panel) and Mr
22.000
light chain (lower
panel) of
cytochrome
b were used to probe neutrophils
from
patients
with A CGD. The corresponding
lanes in
both panels
contain
the same samples
as follows:
lane 1 #{149}1 ;ig purified
cytochrome
b; lanes 2 and 3.
normal
human
neutrophils;
lanes
4 through
7.
neutrophils
from four patients
(one male. three
females)
with A
CGD.
Lanes 2 through
7 contamed
40 ig of protein
from a Triton
X-1 00 lysate
of intact neutrophils
(1 .5 to 2.5 x 10 cell equivalents)
prepared
as described
in Materials
and
Methods.
with
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
CYTOCHROME
Autosomal
absorbance
been
DEFICIENCY
B
recessive
CGD
with
spectrum
(A-)
is a rare
reported
in only
responsible
must
for
this
somehow
Figure
Fig
eight
type
with
CGD
A
1 . In the
are seen
upper
both
patients.’3”4”6’7
with
Western
absent
cytochrome
form of CGD
and
of CGD,
interfere
2 shows
patients
1419
IN CGD
while
the expression
blots
of
in the purified
mutation
yet
identified,
is similar
levels
of the
cytochrome
b.
from
b (lane
four
to that
9lkD
in
subunit
1) and
in the
two controls
(lanes
2 and 3). Lanes
4 through
7 are from one
male and three female
A CGD patients.
The 9lkD
subunit
is undetectable
in all of these patients.
The lower panel shows
that
a similar
pattern
Again,
neutrophils
through
7 are devoid
is observed
from
the
for
four
of the 22kD
the
A
22kD
that
b heterodimer
the
genetic
in lanes
4
9lkD
clearly
subunit
of human
the X
form
characterized
present
X
CGD,
of
we have
patients.
both
levels-a
b spectral
the
that
neutrophil
extended
cytochrome
absence
our
condition
subunit.9”9
finding
are
show
that
present
at
disease
involves
the
cytosohic,
distinct
ized
by the
forms
b
possible
molecular
defect:
component
of
basis
by the purification
it is a heterodimeric
22kD.9”9
human
endothehial
able levels of the
spectral
respiratory
of the
A,
two
dual
absence
their
cell
hack
type
of a normal
of the cytochrome
the other.
of CGD
might
in A-
CGD
22kD
subunit.
(and
be
there-
of the 22kD
observed
in
the
A-
CGD
22kD
even
gene
in the
Alternatively,
a more
con-
The simplest
interpretation,
A CGD,
the stable expression
however,
of each
proteins
on these
will
measurof the
or transcriptional
b subunit
Based
in
cultured
message
neutrophils.
pertain
to
mRNA.
the
do not have
the presence
the expression
to what we have
of translational
trol could be involved.
is that in both X and
cyto-
findings,
found
to
requires
the
we predict
involve
the
presence
that
gene
of
the defect
coding
for
the
ACKNOWLEDGMENT
oxidase.
was
A
suggested
structure
each
9 1 kD
that
including
9lkD
CGD
may
of
is present
patients.
Failure
to transcribe
or translate
the
would
result
in the absence
of the 9lkD
protein
mechanism
geneti-
cells
presence
finding
subunit
cells
despite
of the
genetically
defective
X
The
converse
situation
the
is the
not the 9lkD,
cells.22 These
22kD
protein
presence
of the
burst
subunit
that
the
requires
from the X
missing.
One
expression
of
are character-
heterogeneity
hypothesized
forms
Thus,
distinct
are also
the stable
interpretation
but
of nonmyeloid
complex
membrane,
is that
and
the
the
More-
of this
addi-
of cytochrome
b which demonstrated
that
protein
consisting
of subunits
of 9IkD
we
chrome-negative
X
the
for this
Because
protein,
of CGD
of the disease,
same
chrome
not
the fact
subunit.
b subunits
for the 22kD,
in A
normal
despite
9lkD
In support
in
is also
In the
to three
results
b subunits
of the
b results
result consistent
with the fact that the cytochrome
content
is normal
and that the defect
in this form
cally
heme
this
22kD
this
Furthermore,
components
of the oxidase.5’7”8
A remaining
puzzling
feature
and
genetic
cytochrome
of CGD2’
and
that
by the absence
of the
study,
tional
established
CGD
the
cytochrome
fore protein)
may have precluded
protein
in a manner
analogous
DISCUSSION
been
in X
only
each of the
the other.
message.
It has
affects
CGD,
which
is genetically
cytochrome
b subunits
of these results
is that
a number
subunit.
are absent
lesion
over, in A
form,
both
interpretation
mRNA
subunit.
patients
one or the other subunits
of the cytochrome
in a complementary
fashion.
The data
presented
in this report
do not,
however,
support
this hypothesis.
Both subunits
of the cytochrome
ofcytochrome
that
normal
The
neutrophihs
in a format
panel,
not
b
has
of
the
be due
of this
two
cyto-
to a defect
in
The
authors
kindly
allowed
would
like to thank
us to obtain
blood
the following
samples
from
physicians
their
patients:
who
Robert
L. Roberts, E. Richard Stiehm, R. Alan B. Ezekowitz,
Paul G. Quie,
Stephen
E. Malawista,
Lee Hoffman,
Richard
Axtell,
William
lisdale,
Stanley
Schwartz,
and A.P. Gilhio. We also thank Carol
Fedoryszyn
and Nancy McCarthy
for their help in preparing
this
manuscript.
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1989 73: 1416-1420
Absence of both the 91kD and 22kD subunits of human neutrophil
cytochrome b in two genetic forms of chronic granulomatous disease
CA Parkos, MC Dinauer, AJ Jesaitis, SH Orkin and JT Curnutte
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