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Analyikal
Review
Human
Gamma
By
Globulin
T. B. Tosi,
JR.
I
N localized
1939,
Tiselius
by electrophoresis
and
Kabat’
primarily
demonstrated in the that
slowest antibodymoving, activity
y-globulin was
fraction
cf the serum
proteins.
Subsequent
studies
have
shown
that
antibody
activity
and
is associated
molecular
more
or
certain
with
size.
less
specifically
structural
reactions.
a group
These
have
the
material
which
are
with
similarities
The
group
of
proteins
described
protein
a naturally
occurring
posed
at the conference
held
in Prague
lined
in table
An
1964,
along
The
L
contribution
has
been
the
molecule
7S
or
( heavy)
or
types
of chains
relucing
B
with
can
association
include
cf
the
forces
by
agents
in
reducing
which
reform
The
for
the
the
of
of
be
In
the
or
as
cross-
they
are
fre-
the low-molecuthere
is the re-
which
y
also
antigenic
may
represent
usage
pro-
are
out-
of
anti-
V-GLOBULIN
of
that
are
of
molecular
treatment
of the
by
alkylation
and
groups
by
the
fact
result
appropriate
have
7S molecule
The
been
in
that
blocked
treatment
two
disulfide
of chromatogwhich
prevent
participation
of
of
or
isolated
by
H
These
with
conditions
dissociation
conditions,
and
chromatography
urea,5
not
chains:
60,000.
subsequent
columns.
bridges.
20,000
acid,#{176}or detergents7
noncovalent
bonds.
The
as
through
under
disulfide
polypeptide
approximately
by
does
of
is a multi-
approximately
isolated
cellulose
structure
V-globulin
by
types
weight
weight
such
the
7S
cross-linked
two
followed
alone
L
alkylaticn
7S
loss
V-globulin
of
and
will
antibody
H
chains
interact
to
75 molecules.8’#{176}
amino
acid
7S v-globulin.
in the ease
with
which
to reduce
are probably
analysis,10’1’
there
are approximately
It is known
that
different
disulfide
they
can
intrachain
be reduced;
disulfides
those
which
some
of which
the interior
of the molecule.
Several
of the more
includes
those
linking
the L and H chains
to each
Oct.
#{176}Rowo
& Sahey
munoglobulin
their
in current
understanding
chains
is evidenced
SH
According
to
bonds
in human
Submitted
interact
and
terminology
recently
Human
Immunoglobulins”
terms
Edelman4
molecular
chains
addition,
7S
consists
agents
noncovalent
the
by
or ion-exchange
must
activity.
that
chains
agents
on Sephadex
to
molecule
A chains
bond
raphy
of 7S
to
formation
v-globulins
H chain
OF
discovery
and
y-globulin
(light)
their
for
the
mobility
ability
1.
important
chained
eliciting
subunit
of v-globulin.2
on the “Nomenclature
in May
of varying
the
7S y, 19S y, ViA, and
in urine.
In addition
to the
Smuc’ruiu
bodies
common
responsible
include
primarily
related
proteins
in
composing
quently
called,
immunoglobulins,
lar weight
v-globulins
found
cently
of multichained
proteins
class,
20,
labile
other
are
may
interchain
and the
14
disulfide
bonds
vary
most
difficult
be buried
in
disulfides
critical
bond
1964; accepted
for publication
Nov. 19, 1964.
Exper.
Med. 121:171,
1965)
have
recently
described
a new
imIgD, which
has a median
level of .03 mg. per ml. in normal
serum.
(J.
382
BLOOD,
VOL.
25,
No.
3
(MARCH),
1965
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HUMAN
383
(;LOBULIN
(;AMMA
_______-
Table
1.-Nomenclature
Present
for
the
Human
Immunoglobulins
Terms
New
Terms
7S,
v
v
y,,B2A
l9Sy, y11,B2I
Type I or B proteins
Type
II or A proteins
Type
I or B L chains
Type
II or A L chains
V G
V
linking
A (lambda)
v ( gamma)
Heavy
chains
75
Heavy
Heavy
chains
chains
Vi.
a
ViM
/L
V
Fragment
A, C, 5, I, II
Fragiiient
B, F, III
the
al.12
two
by
acidification
The
half
chains
et al.13
Fc-fragment
results
are
a single
disulfide
by
the disulfide
localized.
The
bonds
remaining
the
of
Franklin
H chains.
abnormal
ment
the
of
protein
75
H chain
of
chains.2
it has
al.’4
y.
molecule
to
into
from
3.5
of
Fraction
III
the
specificity.
other
( slow )
( Franklin’s
to he
characteristic
of
which
residual
portion
105,000
fragment
(5S)
of
Cm
and
reaction
7S
v-globulin
and the
responsible
the
7S
F
can
three
with
to
report
The
the
F frag-
7S molecule,
then
of six polypeptide
treatment
dissociation
II, and III
C of Franklin)
been
shown
determinants
at least
and
of v-globulin
of the 7S
of Porter15
possess
to
both
be
such
as:
complement
and
uni-
derived
univalent
frag-
fraction.2’
activity
but
responsible
in large
part
molecule
for
for
class
certain
skin
fixation,21
fixation,2527
fixation
factor.2”#{176}
destroys
resembles
the
F fragment
of
molecule
has
a molecular
and
retains
bivalent
antibody
cysteine
reduces
a single
labile
four
partially
subunits
recent
disease.
same
chromatographic
is devoid
of antibody
pepsin
or
even
link
H
be separated
by electroand by chromatography
( fast )
closely
the
that
in
has
rheumatoid
their
available
for this thesis
of isolated
H chains.
molecules;’#{176}
specificity,2’4
with
related
unit of the
7S v-globulin
each
fraction
75 v-globulin
moiety
is also
only
have
been
or possibly
closely
Nisonoff
followed
molecules.
through
1. Thus
digest
and
appearing
in the
B ) or F fragment
permeability,22
with
figure
other
molecule
intrachain
three
fractions-I,
I and II (A and
aiid
of
carbohydrate
The F fragment
Treatment
each
by
v-globulin
of half
has been
suggested
by the
the so-called
“heavy-chain”
papain
The
into
Fractions
antibody
to microsomes,25
molecule
in
appears
fractions--S
activity
populations
properties
placental
disease
S fragments.
a given
contains
to
made
the important
observation
the presence
of cysteine
results
two
antibody
different
ments
depicted
latter
possibility
a patient
with
on carboxymethylcellulose
A, B, C of Franklin.15
valent
as
linked
described
of rabbit
amounts
no direct
evidence
is presently
possible
to obtain
further
reduction
Porter15’1#{176} first
with
papain
in
phoresis
formation
presumably
in this
been
Fd-fragment
fragments
reduction
of large
If this is indeed
a true structural
may consist
of two subunits
and
However,
not
the
that
present
in the native
bonds
are either
The
et
S antibody
shown
in
molecules
of
of
3.5
have
( alpha)
( mu)
Fab-fragment
---
univalent
Palmer
orlgA
yMorlgM
K
L
k (kappa)
A I)ieCe_______
et
IgG
or
A
a
of
activity.
disulfide
large
the
weight
portion
papain
of
of
digest.
the
The
approximately
Treatment
of
bond
resulting
the
5S
in two
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384
T.
B.
TOMASI,
U)
Id
IJo
T
N
IZ....
lijo
Q
z
-
a
IL
a
z.Id’-.
cO.
‘I,
+
8z
r)T1 8
z
Id
O_
0
N
0
j
)QU)
L
U)
N
o
L
lo
L/A’
o
a
-v
-a
00
2
z
I
01
..a
IL
Cla
‘I)
V
I-
z
N+N
40
I
IL
N
‘.:
I’,,
a
JR.
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
(;AMMA
HUMAN
univalent
to
fragments
3.5S
those
by
produced
rived
from
has
possible
using
different
tions42’43
These
with
that
the
workers
75
that
with
From
mixed,
75
molecular
weights
that
have
the native
molecule
must
been obtained
by Marler
contain
et al.44
for rabbit
are
pair
most
of
cooperate
antibody
semblance
chain
consistent
an
L
to produce
interaction
in
have
labeling.
of each
type
Several
the
the
been
However
of chain
a
by
pair,
work
is
the
site.
to
of the
of Kratky
of elliptical
cross
et al.5’
section
in which
details
likely,
the
chains
the
with
75 v-globulin
dimensions
arranged
are
molecule
240
with
respect
sites are located
studies
of human
fail
v-globulins,54
helical
content.
derived
from
absence
of
All
to
papain55
significant
evidence
various
have
helical
types
shown
content
may
similar
be
Similar
of
affinity
contribution
site.
to be
a cylinder
manner
another
related
as well
been
elucidated.
et al.5#{176}
that
the
molecule.
as well
optical
the
as the
the
rotatory
animal
amounts
as well
to
as
It seems
antibody
Optical
as several
significant
of v-globulins
strikingly
reof
a length
of approxito the x-ray
scattering
to one
of
close
thesis
electronmicro-
appears
at the two ends
of the
7S,52 19S,525
and
Vi,4
demonstrate
of the
a
x 19 A x 57 A. The
A
of the folding
of the individual
chains
has not
however,
from
the recent
studies
of Almeida
combining
dispersion
exact
combining
angle
x-ray scattering
studies
indicate
the 7S antibody
molecule.
According
studies
the
the
site.
hydrodynamic,49
of
of
of specific
method
the
sc’opic,5#{176}and low
mately
240 A for
half
chains
recovery
the
clarify
antibody
including
two
combining
using
ratio
results
of these
each
the
chains,
calculated
Similar
results
chains9’45’40
and
75 v47 support
al.48
H
a molar
it was
The
antibody
et
in
chains
which
suggesH chains.
L and
molecule,
in
separate
to native
needed
activity
measurements
formed
two
two H chains.
v-globulin.
The
combining
of
S-S
from
previous
from
symmetrical
Metzger
critical
are
and
L
isotope
of the
L and
chain
formation
reached
to the
of
H
mixing
of
molecules
further
types
an
an antibody
activity
from
of reconstituted
conclusions
with
and
the
of two
the
the
consists
of
derived
molecules
reconstituted
unity.
which
not
theory.40’41
contained
two
the
fragments
confirmed
near
experiments
and
lattice
molecules
do
treatment
of the fragments.4#{176} These
a mixture
of the two
antigens
consists
isotopes,
cell
uni-
they
prior
reoxidize
hybrid
recombination
only
with
molecule
different
this
to
conclusively
v-globulin
truly
enzymes.
If univalent
of the
have
if
by
reaction,
other
red
are
after
finger-
very
similar,
is provided
antibodies,
or
de-
and
antibodies
7S
antibody
are
prediction
found
labeled
cell
medium,
activity.111
of random
agglutinate
the
Edelman5
red
proteolytic
specificity
as a result
precipitate
or
and
protein
purified
identical)
evidence
homologous
precipitin
from
anti-Rh
and
from
or other
precipitating
of
in accordance
each
trypsin
not
available
fragments
are
the fragments
unfragmented
in a high
with
antibodies
of the
derived
derived
perhaps
chromatography,3
the two univalent
the univalency
of
“incomplete”
restore
Olins
Presently
inhibition
of fragments
even
been
and
apparently
hybrids
( although
fragments
cells
erythrocytes
It
similar
of papain.’2
that
for
studies,:.;
to cells
The
unlike
agglutinate
bond
are
action
electrophoresis,2
suggests
Evidence
binding
binding
antibodies.7M
‘alt,
since
the
which
the
sedimentation,15
printing
data,4
not identical.
haptene
and the
385
GLOBULIN
of
alpha-
fragments
properties.
The
relatively
high
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
386
T. B. TOMASI,
content
of
line)
which
large
acids
( valine,
to Blout51
are
those
amino
according
number
of
formation.57
A
disulfide
bonds
conformation
in
by Imahori58
is the cross
is derived
both
from
the
and
from
studies
The
that
apparent
of human
will
reassociate
of oriented
one
with
in figure
less
to form
which
terminants
immunoglobulin
and
OF
reduction
geneous
The
195
agents
The
logic
specificity
precipitating
of
and
loss
of
antibody
is of
activity
the
has
agglutinins,5
7S subunits
inately
90
The
2 and
ViA
of
mole
ViA
per
cent
serum
structure
of
myeloma
proteins,
following
quite
75
similar
to those
proteins
characteristic
and
units
been
molecule.5
has
in the
polymers
rates
in
common
dethe various
patterns
on
Yi
and
of the
7S
pathologic
of homo-
proteins
.
been
original
differ
In
6-12
with
that
reducing
approximately
six
The 75 subunits
generally
contain
all of the immuno-
most
reports,
disappears
completely
commonly
used
activity,
of “mixed
treatment
estimated
of 19S protein.6
component’14
and
activity
the
of the
Vi.
macroglobulins
to
It has
with
the studies
suggests
that the
probably
75
of 7S v-globulins.6#{176}
parent
activity
of normal
amounts
of
of sedimentation
of the
details
myeloma
banding
Vi.
activity7072
and with
the
from
19S anti-A
and anti-B
10-20
the
gel
rheumatoid
agent
along
subunits
for
studies
discussed
is represented
starch
and
reducing
cent
A model
isolated
isohemagglutinins,#{176}9
by removal
of the
produced
than
in general
of the
discrete
dissociate
the
Yi,
urea
in several
75 subunits
derived
molecules”
globulin
urea.62
the
However,
in the
factor
light.
MOLECULES
195 type.67
been
found
per
rheumatoid
subunits
of
antibody
tion,66
ments,
that
are present
per
one electrophoretic
and
tion
H chains
absence
7S subunits
possess
only
of
v-globulins
to
various
species
L chains
carrying
the
cross
reactions
between
show
are
from
globulins
ViM
in the
recently
this type
measurements
infrared
animal
from
and physical
GaIly59
and
Yi.
and
Vin
all
which
in mobility
for
polarized
molecules.5
regarding
The L chain
areas
show
the
typical
proteins.
somewhat
Normal
alkylation
v-globulins.60’61
macroglobulins
AND
contain
for the
macroglobulins
and
Yii
is available
classes.
pathologic
alpha-helix
data
1.
molecules.
Both
are responsible
ViA
restrict
Evidence
dispersion
with
75
The
dispersion
of certain
chains
with the chemical
by Edelman
and
information
and
Vilt
also
the
of v-globulin
another
consistent
proposed
form
Much
may
with
and prorelatively
threonine,
formers.
beta
structure.
optical
rotatory
films
STRUCTURE
the
v-globulin
similarity
of the configurations
may explain
why
the polypeptide
molecule
has been
schematic
serine,
alpha-helix
consistent
proposed
structure
antibody
above
isoleucine,
poor
JR.
as
195
one
reduc-
criteria
recently
including
results
agglutinating
following
that
reported
those
an
experifrom:
Rh
factor.T#{176} Reaggregation
of
in a return
of approxi-
both
of
macroglobulins
isohemagglutinins.73
antibodies
followed
molecules.”Ta
The
showing
various
intact
19S molecule
having
Mixtures
by reassocia-
formation
activities
has
of
of “mixed
in the
a valence
macrogreater
range.
is primarily
(90+
are also present.75
The
(9-19S)
and are commonly
per
cent)
ViA
7S,4
polymers
found
although
have
in
the
small
a variety
sera
of pa-
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
HUMAN
GAMMA
myelomas.7”
reducing
agents
tients
with
ment
with
found
to be associated
One
of the
with
most
carbohydrate,
and
and
single
type
to an
aspartyl
hydrate
side
75
linking
molecule
most
likely
the
acid
the
residue.5
The
cept
a glucosamine
a terminal
position.
is responsible,
at
one
unit
group
Using
the
molecule
to
enzyme
charge
the faster
Various
types
of
zone
heterogeneity
in
especially
well
well
into
the
purified
on
the
beta
human
in
region.
of
individual
ing
against
number
many
localized
(by
haptenes
yield
and mobility
of
by
suggests
acid
starch
Kunkel
can
cxoccupies
be
block,54
which
of the
removed
the
individual
suggested
by
and
starch
gel
fast bands
the
long
work
slower
of the two areas
on the starch
gel
The H chain
bands
of different
7S antibodies
other
than
electrophoresis
(antigen
analysis)
show
arc
that
highly
a localized
of 75
arc
v may
be
a
Homogeneity
of Edelman
et al.55
) guinea
patterns
which
corresponding
gel,55
heterogeneity
is
which
extends
give
antibodies.
alkylation
starch
electrophoretic
et al.87
antigens
that
of
reduction
urea
the
acid
sialic
acid
mobility
considerable
well-defined
arcs
is also
dissociated
glycosylasparagine
established
sialic
immunoelectrophoresis,
long arc of 7S v-globulin
studies
against
This
antibodies
that
In
Recent
antibodies
irnmunoelectrophoresis.
composite
including
typical
the
acyl
of
in mobility.74
demonstrate
v-globulins.
likely
group
I-IETERO(;ENEITY
all
shown
an
been
to
type
but
of an
the
sialic
slowing
electrophioresis
immunoelectrophoresisTM”
The
carboxyl
not
and
the
in significant
of carbo-
H chain.
and
a
linked
appears
on the terminal
electrophoretic
neuraminidase
resulting
ELECTROPHORETIC
and
protein
molecule
there
nitrogen
has
the
cent
The
number
beta
amide
monosaccharides
is attached
the
the
their
fucose,
7S
is uncertain
the
of glucosamine,52
and
It is the negative
least
in part,
for
proteins.
exact
protein
ifl
per
cent.
5
is covalently
to each
between
glucosamine
of the
the
the
determined
attached
treatbeen
mannose,
in
the
ViM
2.5
10 per
which
been
to
bond
2-amino
sequence
not
two,
amide
between
that
is present
has
carbohydrate
an
and
linkage
chain
and
galactose,
likely
protein,50”#{176} although
per
include
seems
on
has
polymers.74
Vi.
approximately
approximately
include
It
195
75 and
globulins
v-globulin
side
of the
number,
that
contains
acid.TM5t
residue
and
v-globulin
VIM
dissociate
activity
Isoagglutinin
between
and
of
sialic
chains
possil)ilities
Y1.
intermediate77
they
proteins,
differences
of carbohydrate
a small
of bond
vi.
units
glucosamine,
from
both
75
the
monosaccharide
amine
the 19S Viat
7S subunits.
striking
content;
aspartic
Like
to
Yi
carbohydrate
be
387
GLOBULIN
pig
of
show-
antibodies
have
a characteristic
to the L chains.
The
patterns
represents
are quite
similar
are required
to
the H chains.
and technique
show
H chain
heterogeneity.
Studies
on
isolated
trans,
levans,
blood
banding
patterns
appears
simpler
nent
that,
the
L chain
in
L chain
band.
human
group
which
general,
pattern.
This
antibodies
A substance,
differ
for
the
more
In
is the
one
type
against
tetanus
antibodies
restricted
well-defined
toxoid)
of
the
antigens
also show
characteristic
different
specificity.59
antigenic
determinant,
(dcxIt
the
presented89
there
was a single
promiof pattern
which
would
be expected
for
case
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388
T. B.
a homogenous
body
antibody
contains
Although
relatively
Of
two
both
simple
the several
many
cases
in
slight
from
guinea
possible
explanations
it is related
to the
of
L
with
consistent
a single
to
chain
varieties
for multiple
heterogeneity
in specificity.
the
Although
This
patterns
high
has
been
weight
ago,
of
types
appreciated
Waldenstr#{246}m
presence
IN
It seems
likely
single
clone
of
antigens
not
are
complement-fixing
of less
cold
bodies.m
Although
antigens
such
proteins.93
immunization
immunization
little,
for
if any,
continued
7S
the
markedly
antibody.
19S
different
cells.90
Similarly
sera.#{176}7
properties
classified
as antibodies
heterophile,
and
of 19S
also
neonatal
i.e.,
elicited
by
has
7S
been
response
This
suppressed
suggested
are
is consistent
due
period
simple
that
with
passively
the
the
the
differences
work
in
of
of
response
the
Chiappino
has
of antigen
is primarily
or higher
antibody
titers
does
is also
sug-
with
small
doses
the
serum
titers
administered
synthesis
globular
of primary
Secondary
75 type occurs.#{176}8
antibody
re-
in rabbits
treated
were
formed
and
by
to
19S
antibody
7S
leukagcomplex
persistence
in equal
involving
studies#{176}#{176}
showing
that
only
19S antibodies
rapidly
the
the
195
anti-
against
change
to the
the subsequent
antibody
control
of
such
as
well
as a
Wasserman
directed
Apparently
a rapid
inhibits
autoimmune
of classical
antibodies
and isoagglutinins,
as
are
in the
third
month
when
of 75 antibody
activity
and
immunologic
commonly
they
of feedback
and
It
versus
are
cells,
administration
possibility
gested
by recent
of 6-mercaptopurine
were
usually
of a
whose
antibody-like
factor,
the
sera.
the products
antibodies
in these
and
by
in their
7S antibodies.
whereas
not.9#{176}The
proteins
however,
memory#{176}5’#{176}#{176}
and requires
synthesis.
is
molecular
characterized
195
demonstrated
high
elicits
19S#{176}7
until about
the
Passive
administration
sponse,
on
are formed
mainly
in the early
stages
by antibodies
of the 7S variety.93’94
primarily
with
specificities
19S antibodies
and are followed
immunologic
case
increasing
macroglobulins.
rheumatoid
antibodies
and
the
The
were
described
by Pederson#{176}’
significance
as a distinct
class
patients
cases,
conglutinins,
as bacteria
The
a few
proteins
195
show
bands.
proceeds
myeloma
proteins,
are
high
molecular
weight
chemical
agglutinins,
the
anti-
SIZE
of Kunkel67
These
include
a number
human
antityphoid,
well-defined
glutinins,
to be
different
pathologic
of
agglutinins,
the
proteins
multiple
immunization
homogeneous
) has been
reviewed
antibodies
in detail.67
horse
antipneumococcal,
group
In
cell
work
group
like the
represent
activity
has
the
a
known.
sheep
as
MOLECULAR
on the
of highly
these,
and
yet
( cold-agglutinins,
Kunkel
described
that
cells
shown
of slightly
v-globulins
that their
through
amounts
myeloma
show
haptene).9#{176}
results
Waldenstr#{246}m92
first
of large
the
recruited.
are
largely
and
been
antibodies
molecular
weight
it is only recently
antibodies
has
which
appearance
of cell
years
20
in which
banding,
it seems
likely
that
of antibodies
which
results
( dinitrophenyl
DNP
HETEROGENEITY
some
determinant
antibodies
and
purified
patterns,
they
most
frequently
antibodies
complexity
against
JR.
L chains.
isolated
L chain
differences
pig
as larger
made
identical
TOMASI,
homologous
the
two
character
antibodies
and
Pemis101
of
by
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HUMAN
GAMMA
showing
synthesis
spleen.
of
However,
is capable
In
195
Nossal
of forming
addition
weight
This
389
GLOBULIN
to
and
both
195
75
19S and
proteins
there
are
are
complexes
and the
logically
proteins
High
intermediate
to 7S rather
( approximately
sedimenting
than
19S.
) have
19S
immunologically
also
related
to
been
Three
resemble
so
) studies
types
have
logically
related
antinuclear
A third
type
such
protein,
sera
in classiweight
in these
molecular
as
saliva,
although
of multiple
like
the
not
dissociate
higher
polymers
on
that
of
treatment
antibody
Recent
saliva
of cows
ViA
found
with
in
to
Both
of
studies
and
studies74
suggest
indicate
that
and
perhaps
other
species
assistance
in the
considerable
parotid
tissue
local
the
colostrum.107#{176}9
antigenic
It is composed
However,
unsera,
of
culture
in
salivary
excreted
a study
serum
urea.
u#{176}
production
that
of
it does
absence
selectively
as well and
identification
have
and saliva.74
body
secre-
myeloma
in
also
is
these
unique
reagents
its
Vi
immuno-
Intermediate
possesses
and
propis
activity.
fluids,
normal
of
loss
These
additional
antibody
in some
LE sera106
been
found
in certain
sulfhydryl
the
) sedimentation
isoagglutinin
been
described
antibody
has
with
agents.
proteins
intermediate
another
with
radioautography
fluorescent
tissue.
of
cf
are
are
them.
tears,
nasal
and
bronchial
closely
related
to serum
Immunoelectrophoresis
he
VIM
which
Vi mobilities,
dissociate
reducing
( 9-uS
intermediate
saliva
fast
and
bond
the 19S
distinguish
type
and
have
which
clearly
distinguish
it from the vi of serum.
polypeptide
chains
cross-linked
by disulfide
bonds.
determinants
and
cases
are related
immunoweight
isohemagglutinins
in colostrum
column,
disulfide
of
association
weight
macro-
are not found
high
molecular
v-globulin1#{176}5 and
in
factors
have
of intermediate
.‘
This
to 75
in
molecular
latter
features
sera.
Both
the
to
One
high
into 7S units
in acid.103
in several
patients
with
to the high molecular
peak
found
in classical
antibodies
those
with
described.
cell
rates
found
necessary
of v-globulins
been
found
tions
closely
are
human
sedimentation
eluted
in the late fractions
of a DEAE
of biological
activity
on treatment
with
properties
( immunologic
the
a single
intermediate
These
ViA.
of
that
polymers,
dissociate
found
with
These
Yi
disulfide
reported
which
has
also
been
also
cells
75 antibodies.
and elevation
of the 7S globulins.
cal Waldenstr#{246}ms
macroglobulinemia
been
different
demonstrated
syndrome.’#{176}4 In these
cases,
in addition
( 15-19S ) which
may resemble
the
globulinemia,
erties
in
clearly
which
v-globulins
have been
type
of macroglobulin
SjOgrens
components
globulins
et al.1#{176}2
have
in
the
of saliva
may
Vi . in various
species.
ANTIGENIC
Important
of their
by
19S
differences
antigenic
immunologic
which
have
properties.
based
on
F fragments.2’’3
(2)
H chain
heterogeneity.47
L chains.8’#{176}
(4)
been
found
The
analysis:
are
HETEROGENEITY
(1)
The
major
antigenic
v-globulins
subdivisions
based
have
immunoglobulin
determinants
Subgroups
(3)
Subgroups
in the
following
present
on
within
a major
H chain
Group
I and II determinants
within
a given
major
L chain
on
been
a study
identified
classes
7S,
the
H chains
and
ViA,
and
group
based
present
on
group
due
to
on
the
L
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390
T.
chain
( 5)
heterogeneity.120’12’
individual
specificity
of
Determinants
which
are
and
Jones
proteins,
myeloma
Bence
and of isolated
antibodies.87’12212#{176}
These
are also
in certain
instances
on the H chains.
(6)
Genetic
on both
the
H and
Within
the
75
subgroups
by
the
proteins.
These
the
H chain.
Ofl
well
may
use
subgroups
loma
B, on the basis
proteins
have
and
Fahey
normal
and
7S
J ones
J ones
In
be
can
and
antisera
either
the
of
II,
either
finding
of
center
cells
cules
each
two
groups
Pernis
II
in
that
shown
antibody
preparations
present
workers11511T’13’
and
Kunkel,
I and
to
although
into
three
A
groups:
well
as
proteins
that
group
and
Bence
protein
and
Bence
same
group.
Each
Bence
on the
P-laheled
basis
which
were
Jones
of
specific
60
30 per
pro-
antigenic
v-globulin
75
approximately
for
per
cent
cent
are
group
on separate
molecules.
That
molecules
is further
suggested
and
by
of
on
as the
I and
reside
different
determinants
present
of the
macroglobuliits
both,
II
those
always
Jones
are
four
myeloma
determinants
myeloma
nearly
VIM)
serum
never
myeloma
fluorescent
proteins
antibody
are
studies
of
group
I and
II L chains
are synthesized
in view
of the recent
immunofluorescent
Chiappin&36
which
both
both
group
cells
group
that
may
suggest
I and
II
I and
II ) the
remains
unsettled.
against
in
least
showing
that
cells.
However,
antibodies
proteins
group
identical
(7S,
pathologic
different
myeloma
Grey
a serum
determinants
present
on
synthesize
carrying
at
Subsequently
group
three
myeStudies
by Mannik
and KunkeP1M
demonstrated’4
II
but
and
can
are
are
Bernier
and Cebra135
in different
lymphoid
studies
both
in normal
I or
by
that
are
with
was
the
shown
Bence
I and
that
group
L chains
and
which
reside
isolated
by other
group
I and II molecules
on their
L chains.
Using
it
7S molecules
the
the
in all cases.
differences.
as VIA.
proteins
against
I or
in
described
proteins
into
reside
II, and that
group
the group
determinants
by
for
1956
divided
myeloma
proteins’32
and Bence
Jones
proteins1#{176} into two
classes
made
group
the
against
differences
excluded
have
two
divided
which
determinants
JR.
macroglobulins,
distinguished
made
described
been
a patient
the
on
those
of antigenic
been
identified
immunoglobulin
teins
based
not
myeloma
proteinuria,
of the
with
Solomon119
v and
proteins.
responsible
present
on
determinants
have
heterogeneity
Lipari
in
and three,
two,
KunkeP14
of antisera
are
have
and
one,
and
H chain
identical
Korngold
and
Grey
of a variety
subgroups
groups:
TOMASI,
L chains.127”10
v class,
The
be
additional
B.
restricted
the
ratio
differ
of
that
question
Mannik
antigenic
group
node
II
germinal
( or “mixed”
mole-
of the origin
and
KunkeP7
determinants
I and
significantly
lymph
molecules
behave
molecules
from
that
group
I and
II proteins
have
revealed
of the
have
in
present
in
like
isolated
the
whole
serum.
Structural
tryptic
tween
peptide
the
studies
digests
group
was
same
showed
known
by
Putnam,
of Bence
Jones
I and
identical
antigenic
some
to occur
II
molecules.138
in the two
group
differences,
in these
of the
proteins
shared
probably
proteins.
In fact,
rather
groups.
However,
many
common
representing
marked
by
surprisingly,
Bence
Jones
peptides
the
analysis
differences
although
individual
not
of
be-
a single
proteins
they
specificity
of
also
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HUMAN
Studies
391
GLOBULIN
GAMMA
of
the
amino
acid
composition,
thermal,
and
spectrofluorometric
properties,u
peptide
maps
of tryptic
hydrolsates,14’
and immunologic
analysis,141
all indicate
that Bence
Jones
proteins
are identical
with the L chains
of
the
myeloma
protein
from
the same
patient.
Berggard
and
Edelma&42
have
shown
that
chains
(v )
The
normal
Bence
mers
both
are
Jones
L chains
are
linked
Both
v
been
of normal
of
of v-globulin
specificity
L chains
l)ut
7S
possess
in certain
isolated
individual
specificity.57
rabl)it
human
human
anti-Rh
antibody
human
system,
the
the
coated
and
the
cells
inhibiting
containing
factor
inhibitor
Cm(
). Subsequently
specificity
derived
more
inhibitory
globulin,
factors
of
have
The
alleles
inherited
present
recently
factors
at each
reviewed
are
controlled
Gm(a)
immunoglobulins.
of the
v-globulin
H
As
the
chains
mv
of
Gm
activities
molecule.
and
is
The
unique
Gm
to
pro-
two
been
differ-
shown
to
as
were
reported
in humans.
technics,
with
an
rheumatoid
inhibit
in the
coats
and
more
v-globulin
loci
of
fraction.
those
lacking
been
of the
Sera
inhibitor
sera,
have
aspects
the
determined
and agglutinators
certain
normal
other
In
agglutination
genetically
) and
+
in
The
whereas
the
incomplete
factor.
the
to be
of varying
eight
or
described.
genetics
of v-
in detail.’27129’14
two
nonlinked
Gm(h)
enzyme
splitting
have
been
determinant
7S
loci
and
linked
alleles.
Ins’ determinants
result
Recently
by
to
or
two
by
a
myeloma
The
individual
primarily
on the
v-globulins
Gruhh125
in
found
Rh
and
and
the
cells.
have
precipitin
cells
coated
Gm(
by
locus
)
and
to reside
as well
as codominant
nonsex
only in 7S v whereas
the
experiments
and
factors,
a
from
GLOBULINS
was
different
rheumatoid
being
resulting
in the
serum
senim
found
latter
as well.
containing
designated
controlled
these
been
genetic
major
from
serum
normal
represent
former
plasma
human
classical
red
factor
using
both
-
A description
a
was
the
H chains
GAMMA
using
positive
of
were
to monomers
consist
of two
isolated
antibodies.57
been
shown
to reside
a single
rheumatoid
dimers
dissoci-
concepts
demonstrated
( allotyes
ill rabbits
and
capacity
by
in
OF
was
system
and
has
from
investigated
employed
Rh
system
been
differences
Oudi&45
by
mono-
dissociable
in the
to present
and
has
on the
GENETICS
Intraspecies
genetic
1956 simultaneously
L
proteins.
forms:
molecule-the
by “neoplastic”
instances
antibodies
in several
and are converted
the stable
dimers
metabolism
specificity
of free
Jones
stable
and
The
subunits
according
macroglobulins,125’126
of the myeloma
proteins
teins,122’124
bonds
whereas
amounts
Bence
to occur
v-globulin
v-globulin
synthesis
the
bond.
the
antigenic
asynchronous
small
to
found
proteins
chains
contain
22,000,
45,000.’”
disulfide
Jones
L
Individual
have
by noncovalent
such
as urea,
Bence
urine
counterparts
weight
approximately
weights
about
linked
agents
unincOrjOrate(l
and
normal
by a single
and
by-product
serum
the
proteins
of molecular
with
molecular
able dimers
by dissociating
CIlt
human
which
v-globulins,
in which
Inv(a)
The
are
and
the
Gm
determinants
common
to all
and
localized
is present
both
disulfide
on
on
normal
two
Inv(h)
are
types
are
of
reduction
different
the
parts
F fragment
and
patho-
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392
T. B.
logic.23’147’148
L chains149
genes
The mv factor
is localized
and Bence
Jones
proteins.147
regulate
globulin
the
synthesis
molecule.
analogous
Factors
to the
they probably
However
the
cation
Gm
of the
the
different
controlling
factors
exist and
“classical”
in view
of
on the S fragment23’145
It appears,
therefore.,
for
the
have been
description
recent
not
of
chains
and
ViA
as yet
been
of
19S
designated
above
may
as Gm
require
of Kunkel
et al.’5#{176}
suggesting
the
v-
v-globulins
reported,
tentatively
outlined
work
JR.
and on isolated
that
different
polypeptide
H chains
7S y have
TOMASI,
although
3 and Gm 4127
some
modifithe
existence
of at least three
and possibly
more
loci which
determine
characteristics
on the
H chains
of 7S v-globulin.
Moreover,
it appears
from
this work
that the newly
described
Gm (f)’51
and not Gm (b) may be the true allele
of Gm (a).
Evidence
has
Gm types
of tryptic
been
peptide
differences
between
proven,
Gm
(h+
that these
to
the
the
presented
differ
from
hydrolysates
genetic
by
Meltzer
each
other
in
of F fragments
between
) and
(breside
differences
variations
( a+ ) and
) fragments.
Gm
Gm
in
the
et al.152
that
proteins
primary
structure.
of 75 v-globulins
It
amino
in single
primary
( a-
Gm
of different
Fingerprint
analysis
showed
specific
single
) fragnients
and
also
is possible,
although
not
acid substitutions
similar
structure
of
other
proteins
such
as
hemoglobins.
Factors
determinants
other
suggested
ing
the
certain
react
instances
directly
the
from
primary
structure
may,
in genetic
specificity.
the possible
antigenicity
Rather
antibodies
with
the
The
be
with
allotypes
and
altered
v-globulins
and
Kunkel155
have
production
of anti-Gm
typ e absent
factors
from
found
a foreign
measles,
found
after
veloping
fusion
patient’s
normal
as a result
reactions.
serum.
sera
allotypes,
have
found
tion
fetus
by their
that
is
mother’s
most
by
of a foreign
the
author’s
7S v-globulin
Snagg
v-globulin.
allotype
from
those
would
not
always
sera
apparently
of
agglutinator)
with
exposure
to
similar
to those
their
specificity
sensitization
may
lead
its
the
reactions
mother,
the
mother.
develop
case.
allotypes
Although
in the
result
deto trans-
transfusion
the
a Gm
immunization
that
knowledge
the
against
being
exists
elicit
may
following
very
sriking
possibility
apparently
many
antibodies
normal
arisen
influ-
implications.
directed
( serum
have
distance
molecule.
anti-v-globulin
Snagg
child
are
primarily
immune
tolerance
this
of
The
also
some
latter
of the
a specificity
of the
The
have not been reported.
human
fetus
acquires
mother’s
structure
with
may
one
to
at
in
may
not
mutants.
structure-the
v-globulin
administration
Snagg
factors
have
properties
However,
proteins
different
located
primary
formation
of administration
Wilson156
groups
in
the
potentially
important
clinical
that
multiple
transfusions
allotype.
in the newborn
be expected
that
of the
spatial
the
transfusions,
v-globulin
on this basis
Since
the
present
might
e.g.,
etc. The
multiple
a single
the
agglutinators
the
allotype,
hepatitis,
of
have
shown
in some
acid
area
antigenic
have
structure
in determinand
suggest
that
genetic
variations
substituted
in
amino
controlled
by controlling
v-globulin
against
Allen
detecting
amino
acids
may
genetically
antigenicity
however,
influence
the
Recent
experiments149’153’154
importance
of three
dimensional
of a genetically
controlled
site
reaction
the
encing
for
than
involved
fetus
it
to
Steinberg
from
immuniza-
the
and
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
HUMAN
GAMMA
Fudenberg
globulin
by
globulins
in
fetal
v-globulin.
may
be
et
the
the
al.157 have
reported
the
synthesis
human
fetus
and
have
described
mother’s
serum
apparently
resulted
They
of
interact
the
with
7S
the
allotype)
and
be,
at least
in part,
allotypic
further
that
on
antibodies
offspring
The
factors
transient
basis.
genetic
produce
the
toid
directed
globulin
are
molecule
antigen-antibody
Investigations
genetic
myeloma
proteins.
two genetic
allele)
even
et
human
Gm
( a ) and
(a)
and
only
By virtue
1rodllct
the
ferent
10 per
of
only
the
are
not
clarify
evidence
studies
in
variable
that
the
contrary
important
A question
numbers
of
genetically
of
ratios.
true
to the
the
the
than
those
carry
Dray164
to
myeloma
view
Gm
data.
dif-
cell
syn-
reticulocyte
from
a
S.163 Moreover,
the
and
in
two
) is quite
heterozygous
is able
the
synthesizing
data
rabbit
in
allelic
products,
formation
of the
of
a single
A and Hb
However,
a heterozygous
both
apparent
Colberg
alleles
suggest
produce
of
the
that
both
questions
system,15#{176} these
More
work
the
allelic
re-
results
is necessary
point.
of paramount
importance
individual
antibodies
can
antibodies
cer-
that
molecules
from
capable
example,
both
Hb
a heterozygous
work
in
and
the
cell
the
concerning
necessarily
this
plasma
which
of
the
character.147
a given
For
the
at the
factors
common
of
in
cell
although
cent
hemoglohins
of hemoglobin.
cell trait produces
of
) individual,
more
per
abnormal
forms
sickle
raised
(b)
a cell
all
by
genetic
molecules
myeloma
immunofluorescent
cently
separate
the
recent
products
in
v-
in different
determined
(a+b+
by
both
with
plasma
on
Gm
capability
of synthesizing
(b+ ) molecules.
The
allele
that
extended
( as evidenced
thesizes
patient
normal
the
Gm
the
in vivo
present
factors
system
v-globulin
from
Gm
also
of
the
60
endowment
have
one
the
shown
are
( a ) are considerably
cent
) and
have
is further
in
approximately
of its genetic
should
Gm (a+
that
reside
Gm
( b ) since
rheumain
accompanying
distribution
appears
“nongenetic”
is that
determinants
contains
antibodies
characters
producing
Gm
individual
i.e., both
(b )
Gm
of cells
It
against
represent
of more
than one allele
( or presumed
the whole
v-globulin.
The
similarities
a restricted
antibodies.
producing
Gm
isolated
showing
they
observations
v-globulin
gen-
are
anti-v-globulin
sera,
alterations
protein
allotype
sera
although
directed
proteins’47
human
rheumatoid
antigenic
spatial
myeloma
and
al.162
tam
clones
A single
proteins
of Allen
the
may
of maternal
of a specific
that
these
several
may
appropri-
of infancy
passage
in
being
they
( if it is of the
in rheumatoid
with
against
in normal
Snagg
that
by Dray.16#{176}
found
specificity
by
rabbit
present
loci, but never
the products
when
both
are present
in
myeloma
of
in
found
factors
since
placenta
infant
suggests
interactions.30’161
of isolated
myeloma
factors
that
the
suppression
)
consistent
unmasked
of vanti-vby
transplacental
in the
are
major
hypothesis
factors
the
evidence
specificities
component,
the
prolonged
present
sites.3#{176}A current
pass
of small
amounts
a case
in which
from
immunization
hypogammaglobulinemia
That
agglutinators
and
possibility
by
demonstrated
( rheumatoid
with
a minor
the
this
been
polyvalent,
the
therefore
synthesized
can
has
Ragg
erally
suggest
typ&58’15#{176} and
v-globulin
ate
in the
393
GLOBULIN
of different
be
specificity
is the mechanism
synthesized.
There
differ
from
each
by which
large
is considerable
other
in amino
to
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
394
T.
Table
2.-Diseases
of v-Globulin
Metabolism
and
Their
Protein
__________
Diseases
7S or
Bence
Excess
L chains
proteinuria
disease
Y1
Vi
Excess
H chains
of 7S
Excess
7S,
ViM
Hypergammaglobulinemias
y
in varying
proportions
see table
1)eficiency
Agaiiimaglobulinemia
and
I)ysgammaglobulinemia
3.
of 7S,
Deficiency
of 7S and
with
t 19S
ficiency
Vi
2A aglobulinemia
Hereditary
chain
in normals
Hvl
involving
\Vitll
ii
HvIM
and
proh:ihly
or (le-
of Vi
I)eficiency
telangectasia
diseases
y
Vii
Yi.
Beta
JR.
Abnormality
Excess
Excess
Jones
TOMASI,
Abnormalities
Protein
Multiple
myeloma
Niacroglohulinemia
#{176}H
chain
*H
B.
of
7S.
nornial
Y1
I)eficiency
of Vi
exist
have
l)Ut
afl(l
‘
not
yet
been
reported.
acid
sequence.
discussed
tion
of two
reported
of
sulting
in
necessary
highly
Koshland
loci
would
to the
still
it would
differing
of antibodies.
numbers
be
the
which
divisions
system.
This
type
products
in
little definitive
occur
of crossing
which
rearrangement
of
different
evidence
the
would
The
clinical
course
of the
would
presumably
the
excellent
recent
abnormalities
normalities
synthesized
of clones
the
serum
reviews.2’#{176}2”676”
are
are
associated
in
cells;
this
to
which
a single
each
small
large
of
synthesized.
occurs,
either
the somatic
of the
result
both
correct,
numbers
he
over
during
in
immune
chromosomal
different
however,
attractive
reto the
in pri-
and
to be
can
polypeptide
at present
hypothesis.
there
is
DISORDERS
with
v-globulin
proteins
Some
have
of
these
metabolism
been
the
disorders
and
subject
and
outlined
in table
2. Two
general
types
found:
those
in which
a homogeneous
presumably
by
of cells
proliferate
vary
proves
of
recently
mutations
development
production
antibody-producing
available
to support
disorders
abnormalities
by
over
to
animal
give
rise
varying
able
thesis
studies
composi-
a relatively
point
acid
sequence
in which
crossing
sister
chromatids
CLINICAL
served
were
if this
in the
lead
same
are
that
mechanism
in amino
a mechanism
or between
the
acids
would
of polypeptides
chains
Even
immunologic
amino
acid
there
unlikely
if both
problem
from
single
amino
The number
site.59’6
L and
H chains
differing
SmithiesifiB
has suggested
within
a single
chromatid
mitotic
in
and
in the
Since
appear
reduced
combining
remains
antibodies
Englberger.UiS
involved,
structure
the chemical
differences
purified
and
v-globulins
contributed
there
is suggested
by
by the significant
different
by
number
mary
This
and
above
the
of
their
protein
of proliferative
protein
product
clone
of cells, and those
in which
producing
an electrophoreticall
ob-
several
abis
a variety
different
v-globulin.
The
factor(s)
leading
to
the
marked
proliferation
of
lymphocytes
and
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HUMAN
(;AMMA
395
GLOBULIN
TabIe3.-Serum
ImmunoglobulinConcentrations
cases
SLE
Pul. fibrosis
22
1.3
10.3
2.4
1.5
9.0
6
11
12.4
39.9
1.8
4.6
0.85
6.9
8.9
17
33.2
3.0
1.8
14.4
11
14.4
2.1
1.2
8.1
Rheum.
15
11.3
4.0
2.1
hepatitis
6
18.3
1.5
1.9
13.2
10
8
24
49.4
18.3
10.0
1.9
6.6
1.6
1.3
1.7
1.1
26.3
2.8
6.4
Rheum.
titer
Infectious
Lupoid
hepatitis
Laennec’s
cirrhosis
Normals
plasma
cells
in the
considered
etiology
has
myeloma
be
may
cells.170
complete
represent
one
Jones
myeloma
of the
production
The
The
diffuse
with
one of
are
of
globulinemias
on
patients
the
genes
loci
would
the
in
not
elevated
the
in
the
shows
relative
abnormal
sera
have
which
with
controlling
and
hemoglobins
have
of 7S alone.
specifically
excessive
of
the
the
syn-
production
been
or associated
the immuno-
of
may
the
in a variety
differences
mean
vary
values
in
dif-
for
the
of clinical
syndromes.’7’
in the proportion
of
elucidated.
Marked
v-
increases
advanced
cirrhosis
and
also in
factor,
particularly
those
sera with
been
Franklin’72
have
to
the
explain
observed.
postulated
various
They
hypogammaglohulinemia
the
which
complexes.
Heremans,
the
in
capable
he
idiopathic
Generally,
all
form
with
Bence
multiple
described.14
Both
of the proliferation
committeed
to
concentrations
not
in sera
from
patients
high
titers
of rheumatoid
may
described.
summary
immunoglobulins
lead
to the striking
The
with
disorder,
the
by
been
may
3
disorders
molecule.
it is normally
diseases.
although
Table
yet
viral
within
or
association
a proliferative
characterized
have
Vill
A
monoclonal
v-globulin
chains
It is general-
diseases.
viral
particles
macroglobulinemia
found
of
diseases
agammaglobulinemia.
controls
the synthesis
of synthesis
types
of intermediate
to
of the
usually
hypergammaglobuhinemias
many
well-recognized
found
with
amounts
analogous
chains
chains
two
and
Vi.
in certain
Fudenberg,
in
and
Recently,
of the
of
which
in Vi. are
rheumatoids
L
postulated
diseases.
concentrations
The
factors
large
free
of one
globulins
produced
myeloma
3.3
is unknown.
neoplastic
showing
to Fl chains
of 75 v-globulin,
has been
diseases
presumably
represent
the products
cells
which
for unknown
reasons
becomes
H chains
ferent
proteins
multiple
macroglobulinemias.
l)roteins
related
L and H chain
of a clone
of
globulins
in
-
of abnormalities
represent
studies
polypeptide
are
OI
thesizing.
type
conditions
by recent
The
as
protems
of free
monoclonal
that
these
been
suggested
ly
some
A
2.6
Sarcoid
High
2”1
19.7
colitis
titer
‘
17.6
Sj#{246}grens
Low
Disorders
7
Ulcerative
Boecks
Clinical
Average
mg./cc
-_______________________________________
‘2
#{149}‘
I.
No.of
Disease
in Various
cite
as
which
subunits
of
v-globulin
results
Similarly,
defects
the
synthesis
in the
of
of
evidence
suggest
Defects
produced
by mutations
of H chains
of 7S v-gloublin,
suppress
a genetic
forms
family
that
in
the
postulated
or
various
Gm
ViM.
studies
mutations
at the Gm
would
result
VIA
system
hypogammaof
types
of
locus,
which
in inhibition
3 and
Decreases
Gm
in
two
4
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396
T. B.
of
the
three
volving
two
immunoglobulins
of
disorder
than
mutation
at
these
chains
emia
are
common
three
whereas
would
each
the
the
described
in bacteria.
pothesis,
although
major
one being
and
are
structural
of regulator
As
out
pointed
type
not,
by
would
result
seen
in
agammaglobulinthe
defect
in agamma-
for
the
being
located
and
structural
the
A
since
of defect
gene
gene
separations
result.
and
there
is the
a regulator
clinical
L chains
congenital
Ins’ loci
in-
serious
presumably
of
immunoglobulins
involve
the
analogous
would
This
JR.
heterozygosity
a more
synthesis
Since
Gm
presumably
case
defect
impaired
of
double
this
of v-globulins.
X chromosome,
Somewhat
been
to
from
in
agammaglobulinemia.
is sex linked,
some.
to
and
a single
leads
types
result
loci
by
locus
in all
the
gene
produced
Inv
congenital
globulinemia
located
on
would
three
that
the
deficiencies
classical
the
TOMASI,
authors,
Ins’
on
factor
an
auto-
genes
have
however,
attractive,
remains
highly
speculative
for several
that a regulator
gene has not been
demonstrated
the
hy-
reasons-a
in a human
system.
Evidence
linemia
that
the
is a result
been
presented
in vitro
cultures
were
able
that
ings
do
cell
the
differentiate
the
that
into
antigenic
cells
the
are
defect
synthesis
which
in
accompanies
v-globulin
Hirschhorn.173
derived
from
normally
transformed
suggest
defect
and
appropriate
of protein
deficiency
genetic
Fudenberg
of lymphocytes
under
tion
failure
tion.
by
to
,‘-globulin
plasma
of
in
rather
plasma
cells
but
cells
to
further
produce
these
may
a failure
that
patients
confirma-
is necessary,
production
from
recently
showed
failed
Although
plasma
antibody
than
has
These
workers
agammaglobulinemic
stimulus.
truly
agammaglobu-
synthesis
result
of plasma
findfrom
cell
a
matiira-
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bivalent
by
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antibody
reduction
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of
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molecule
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disulfide
bonds.
& Biophys.
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1965 25: 382-403
Analytical Review: Human Gamma Globulin
T. B. Tomasi, Jr.
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