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The ╨Ю╤ЦG subclass of antinuclear and antinucleic acid antibodies.

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The rG Subclass of Antinuclear and Antinucleic Acid
Peter H. Schur, MD, Margaret Monroe, MS and Naomi Rothfield, MD
Selected sera from patients with systemic lupus erythematosus (SLE)
and progressive systemic sclerosis (PSS) were studied t o determine the
y G subclass in which the antibody activities were present. These sera
were known t o contain rG antibodies to nuclear antigens, cytoplasmic
antigens or nucleic acids. Antibodies to DNA and those giving a peripheral
pattern in the fluorescent antinuclear antibody test (ANF) primarily were
of the y G 1 and r G 3 types; antibodies giving a speckled pattern primarily
were of the y G 3 type; and antibodies giving a diffuse pattern in the ANA
test primarily were of the y G 3 type, and less so of the r G 1 type. These
findings indicate: that antibodies t o some nuclear antigens and nucleic
acids may be restricted to certain r G subclasses; and that anti-DNA antibodies, which have been most strongly associated with low serum complement levels and active lupus nephritis, are found primarily in those
yG subclasses which fix complement most efficiently-namely, r G 1 and
Antibodies to nuclei and nucleic acids are
found in the sera of patients with connective
tissue disorders, especially those with systemic
lupus erythematosus (SLE) and progressive
systemic sclerosis (PSS). Antibodies to native
deoxyribonucleic acid (DNA) are present only
in patients with SLE (1, 2). These antibodies,
in contrast to other antinuclear antibodies, have
From the Department of Medicine, Robert B. Brigham
Hospital, Harvard Medical School, Boston, Mass., and the
Department of Medicine, University of Connecticut, School
of Medicine, Farmington, Conn.
Supported in part by United States Public Health Service
Grants AM 11414, AM 05577, and AM 12051, and by
grants from the John A. Hartford Foundation, the Massachusetts Kidney Foundation, and the Lupus Erythematoms Foundation, Inc.
Presented in part at the December 5, 1969 meeting of
The American Rheumatism Association.
Submitted for publication June 2, 1971; accepted September 15, 1971.
Reprint requests should be addressed to: Dr. Peter H.
Schur, Robert B. Brigham Hospital, 125 Parker Hill
Avenue, Boston, Massachusetts 02120.
been implicated strongly in the clinical pathogenesis of SLE (3, 4). This would suggest
that there is some variability in the biologic
potential of these antinuclear and antinucleic
acid antibodies (ANA) to mediate an inflammatory reaction. Many ANA in SLE and PSS
patients have been shown to be r G
globulins (5-7). This class of y globulins has
been shown to consist of four subclasses (8, 9)
with different structural (8) and biologic (10)
properties. Because of the possibility that ANA
directed to different nuclear and nucleic acid
antigens belong to different yG subclasses, and
that this variation might explain their variable
correlation with inflammatory responses, we
have examined the y G subclasses of a number
of ANA.
Sera were examined from 88 patients with clinically established SLE and from 18 patients with progressive systemic sclerosis. The patients were selected for the presence
of yG ANA.
Arthritis and Rheumatism, Vol. 15, No. 2 (March-April 1972)
Fluorescent tests for serum antinuclear antibodies (ANF)
were performed using cryostat sections of snap-frozen
mouse liver (1 1). Sera were selected and used at dilutions
that were known to give distinctive nuclear patterns using a
fluorescein isothiocyanate labeled antiserum to the Fc
fragment of gamma G (4,7). In patients with SLE, the
antibody giving a speckled pattern is usually a y M
globulin (6), while in PSS it is generally a $ globulin
(1 1). Therefore, sera from PSS were selected for study of
the speckled pattern. The reaction was graded strong,
moderate or weak. Fluorescent spot tests for antibodies to
DNA were performed according to the method of Friou
et a1 (12). Sera for the florescent spot test were selected
from patients with SLE known by prior testing to contain antibodies to DNA at some time during their illnesscomplement fixation (3, 13) precipitation in agar (14) or
binding assays were used to determine antibodies to DNA.
The fluorescent spot test for ribosomes (RB) was modified from the DNA spot test as follows: microscope slides
were coated with 0.5% silicate of soda, air dried overnight,
and then stored in a 20°C freezer until ready to use;
one drop of rat liver ribosome at a concentration of
100 yRNA/ml in 0.01 M phosphate buffered saline
pH7.4 (PBS) was placed on the slides, air dried, incubated
with serum for 1 hour in a moist chamber, washed with
PBS, stained with the fluoroscein-conjugated antiserum,
washed with PBS; a coverslip was mounted with PBS buffered glycerine and the slides were examined by fluorescent
microscopy. The degree of fluorescence was graded 0-4+.
A similar method was used for the ribonucleic acid (RNA)
spot test. Slides were prepared as for RB, but they were
then coated with a solution of methylated human serum albumin (100 y/ml), and air dried. Onto this was then placed
1 drop of a synthetic polynucleotide of double-stranded
acid (Poly I.Poly C)-at
100 y/ml in PBS.
Antisera to myeloma proteins of @ subclasses $1,
6 2 , yG3 and yG4 were made in rabbits and monkeys
either by direct immunization or by immunizing partially
tolerant animals (16). These antisera were made specific by
absorbing them as necessary with isolated Bence-Jones
proteins and myeloma proteins, with determinations made
by immunoelectrophoresis (17), micro-Ouchterlony immunodiffusion (18) and radial immunodiffusion (19). These
specific antisera were then conjugated with fluoroscein
isothiocyanate and tested for specificity as previously described (1 1). The fluoroscein/protein ratio of the conjugated antisera were all in the range of 2.5-3.9. Antisera to
6subclasses were appropriately diluted so that they had
equivalent titers (of 1:8) when tested against appropriately
isolated myeloma proteins in a concentration of 1 mg/ml
in micro-Ouchterlony diffusion (20). Whole hemolytic
complement was measured by the method of Kent and
Fife (21). Normal individuals have levels of 200 C H 50 u/
ml & 50 u (2 SD) (3).
Fig 1. lmmunofluorescence staining of mouse
liver produced by a serum f r o m a patient with
SLE with anti-DNA antibodies. Reaction using
fluorescein conjugated antigamma G1 producing
a peripheral pattern (upper left); negative reaction
using a fluorescein conjugated antigamma G2
(upper right); peripheral pattern using fluorescein
conjugated antigamma G3 (lower right); and
negative reaction using fluorescein conjugated
antigamma G4 (lower left).
Antinuclear Antibody Patterns
Sera from 44 patients with known strong
ANA nuclear patterns were examined. Sera
with weak to moderate ANA were generally
untypable. Twelve patients whose sera had a
peripheral pattern (Figure 1, Table 1) were
diagnosed as having SLE. Eleven of the 12
ArthrRir and Rheumatism, Vol. 15, No. 2 (March-April 1972)
Table 1. Antinuclear Antibody Patternsand Results of Spot Test
Number positive
Large Speckles
Fine Speckles
Number of
sera tested
peripheral patterns were detected with antiy G l antisera, generally with strong reactions.
Only three reacted with anti-yG2 antisera, all
weakly. Seven reacted with anti-yG3 antisera;
those positive were generally of a strong degree.
T h e r e was no reaction with anti-yG4
antiserum. F o u r of the patients with a
peripheral pattern had active renal disease; sera
from these patients reacted with anti-yG1 and
with anti-yG3 antisera with strong reactions.
Only two sera gave a “large speckled” pattern (Figure 2). Both were obtained from patients with progressive systemic sclerosis. These
reacted with anti-yG2 in one instance and with
anti-yG3 antisera in both instances.
Sera from 9 patients gave a “fine speckled”
pattern (Figure 2)-these from patients with
progressive systemic sclerosis. Only one serum
reacted (weakly) with anti-yG1 antiserum;
three reacted (weakly) with anti-yG2 antiserum; and seven reacted strongly with anti-yG3
Sera from 7 patients with progressive systemic sclerosis gave a “nucleolar” pattern
(Figure 2). Four reacted strongly with anti-yG2
and anti-yG3 antisera. Six sera reacted strongly
with anti-yG4 antiserum.
Sera from fourteen patients with SLE had a
“diffuse” pattern (Figure 2). Five sera reacted
strongly with anti-yGl antiserum; eight
reacted moderately with anti-yG2 antiserum;
a n d ten reacted strongly with a n t i - y G 3
antiserum. Only one serum reacted (weakly)
with anti-yG4 antiserum.
FluorescentSpot Tests
Twenty sera from patients with SLE, known
to contain antibodies to RNA, were examined
(Table 1). A majority of the sera reacted with
most of the yG subclass antisera. T h e strongest
reactions were with the anti-yG1 antisera, and
the reactions with anti-yG4 antisera were
generally weak. Normal sera did not react.
Twenty-one sera with precipitating antibodies to RB were studied from patients with
SLE. Thirteen reacted strongly with a n t i - s l
antisera; 14 moderately with a n t i - y G 2
antisera; 11 moderately with anti-yG3 antisera
and 9 weakly with yG4 antisera.
Sixty-eight sera were studied from 29 pa-
Fig 2. lmmunofluorescence staining of mouse liver. Serum from a patient with PSS using +
fluorescein conjugated antigamma G3 produced a large speckled pattern (upper left); serum
from patient with PSS using fluorescein conjugated antigamma G3 produced a fine speckled
pattern (upper right); serum from a patient with SLE using fluorescein conjugated antigamma
G3 produced a diffuse pattern (lower right); serum from a patient with PSS using fluorescein
conjugated antigamma G4 produced a nucleolar pattern (lower left).
Arthritis and Rheumatism,Vol. 15, No. 2 (March-April 1972)
Arthritis and Rheumatism, Vol. 15, No. 2 (March-April 1972)
tients with SLE known to have anti-DNA
antibodies, all of whom had active nephritis. All
the patients had anti-DNA antibodies of the
yG1 type, 59 of the sera reacted (generally
strongly) with the antisera. Twenty-two patients had detectable anti-DNA antibodies of
the $32 types; 41 of the sera reacted (usually
weakly) with the anti-yG2 antisera. Twentyseven of the patients had anti-DNA antibodies
of the yG3 type; 57 of the sera reacted, generally strongly, with the anti-yG3 antisera.
Twenty-six patients had anti-DNA antibodies
of the yG4 type; 48 of the sera reacted generally
weakly, with the anti-yG4 type.
Serial observations of anti-DNA antibodies
were made in a number of patients, with
and without nephritis, but were of sufficient
intensity to be typed in only 3 patients with
SLE and lupus nephritis-including studies of
1 patient before, during, and after a relapse of
nephritis (Figure 3). It appeared in the three
serially studied patients, that while all four
subclasses were associated with active nephritis, yG1 and yG3 antibodies appeared first and
persisted longer. In the other cases, yG1 and
7G3 antibodies appeared to also be predominant.
There was no apparent correlation between
CH 50 levels and the degree of fluorescence
(graded 0-4+) given by any of the yG subclass
antisera in the DNA spot test.
Selected sera giving different patterns all
fixed complement as determined by reacting
nuclei with test serum, fresh human serum, and
then staining with fluorescent labeled antLC3
Tojo et a1 (22) have noted that the ANA
in patients with active lupus nephritis fixed
complement, while those ANA in patients with
lupus in remission did not fix complement.
They suggested that these differences might be
due to biological differences between the y
globulin found in these two situations. When
I +
m g /BUN
Fig 3. Serial observations on patient RV. normal
and BUN and absent anti-DNA antibodies in
July 1968. Clinical exacerbation with low C
elevated BUN. and anti-DNA antibodies-of
yG2,yG3, 7G4 subclasses in December, 1968-followed by clinical and laboratory remission in February-March, 1969.
they then examined the yG subclasses of isolated anti-nucleoprotein antibodies from these
same two groups they could find no correlation
between the absence or presence of any single
subclass and nephritis, although there was a
trend to yG1 and r G 3 in patients with active
nephritis and a trend to yG2 and yG4 in those
without nephritis (23). Kacaki et a1 (24) found
ANA in patients with SLE, rheumatoid arthritis and the procaine-induced lupus syndrome in
Arthritis and Rheumatism,Vol. 15,No. 2 (March-April1972)
all four subclasses of y G in a distribution similar to that found in normal sera. In the present
study, we have extended these studies to
examine the yG subclasses of a number of yG
antibodies directed to specific nuclear and cytoplasmic structures and nucleic acids.
Previous studies have shown a high correlation between the presence of precipitating or
complement-fixing antibodies to DNA and the
presence of active nephritis in patients with
SLE (3, 4). N o s u c h c o r r e l a t i o n s w e r e
noted (3), however, between nephritis and the
presence of precipitating antibodies to either
nucleoprotein or “CTN” (a group of glycoproteins easily extractable from nuclei with
saline) (25). In addition, a good correlation has
been noted between nephritis and the presence
of precipitating antibodies to a cytoplasmic
constituent, ribosomes (26) and complement
fixing antibodies to nucleoprotein (27). In the
present study, antibodies to these antigens were
examined either by the fluorescent spot test
using specific nuclear antigens or by the ANF
technic, using mouse liver as a source of nuclei.
This latter technic has shown that different
patterns of nuclear fluorescence represent the
presence of antibodies to a number of nuclear
antigens. Using the same technic as in the
present study, it has been shown that the
peripheral pattern represents antibodies directed against native DNA or to the DNA
portion of the soluble DNA-histone complex (4,28). The various “speckled” patterns
have been found by others, using a similar
substrate of another source of nuclei, to be due
to antibodies to a saline-soluble nuclear protein (29, 30). However, the actual antigens
which produce the fine and large speckled patterns have not been identified clearly. The
antigens have been identified in one instance as
the phosphate buffer-extractable antigen (31),
as the SM antigen (28) and as another saline
soluble component of the nucleus.* T h e diffuse
pattern is given by sera containing antibodies to
* Mattioli M, Reichlin M: Personal communication
particulate DNA-histone nucleoprotein (29, 30, 31). The nucleolar pattern is produced by antibodies to a constituent of the nucleoli (30) but the antigen has not been completely identified.
In the present study, antibodies giving a
peripheral pattern, presumably representing
antibodies to DNA, were primarily of the y G l
and yG3 types, while antibodies to DNA detected by the more sensitive spot test were present in all four subclasses, but primarily in the
6 1 and yG3 subclasses. Antibodies giving
speckled patterns were primarily of the $33
type. Antibodies giving a diffuse pattern were
primarily of the yG3 types, and somewhat less
of the y G 1 type. Antibodies to RNA and RB
appeared to reflect the relative serum distribution of the yG subclasses. All sera tested fixed
These results differ from those of Tojo et
a1 (23) and Kacaki et a1 (24). The reason for
these differences are not clear, but may be due
to the fact that different populations of patients
were studied. In addition, Kacaki et a1 (24) did
not describe nuclear patterns and may, therefore, have been looking at a total composite of
antinuclear antibodies which are present in all
subclasses. The present results are similar to
those of Tojo et a1 (23) in that they found antibodies to nucleoprotein primarily in 6 1 , yG2,
and 6 3 classes while we found antibodies giving a diffuse pattern-presumably
antibodies to nucleoprotein (29-31)-p rimar‘
ily in these same classes, with some more
yG3 than yG1.
Human yG was first recognized as having
four subclasses on the basis of antigenic differences among myeloma proteins (8). These
subclasses were also recognized i n the sera of
normal individuals (8). Subsequently, myeloma
proteins of these four subclasses have been
studied in a number of biologically important
systems (Table 2). Of note are the observations
that $33 has a much shorter half-life than do
the other subgroups (33, 34). y G l and yG3 fix
whole complement and bind a portion of the
Althritis and Rheumatism,Vol. 15, No. 2(March-Apill972)
Table 2. Characteristics of the Gamma G Subgroups of Man
Relative concentration in
normal serum (%)
T-1/2 (days)
Complement fixation
PCA in guinea pigs
Cross placenta
Cytophilic antibodies
Incomplete anti-Rh
Antibodies t o
Blood group A
Tetanus toxoid
Diphtheria toxoid
Factor Vlll (AHG)
Staph A
Glomerular basement
rG 1
first component of complement, C l q , avidly;
while yG2 does this only weakly; and yG4
does nothing at all (35, 36). Passive cutaneous
anaphylaxis (PCA) in guinea pigs is mediated
by all the subclasses except yG2 (37). All of the
yG subclasses probably cross the placenta.* A
number of antibodies of the yG class have been
examined for their possible restriction to one or
more yG subclasses. Table 2. lists some of these.
T h e present studies extend some of these observations-ie, that many antigens from cells,
as well as nucleic acids induce a restricted (sub)
class of yG antibodies. T h i s was most apparent
for antibodies to DNA, and the antibodies that
gave a speckled or a nucleolar pattern, especially since yG3 and yG4 comprise only 4-8
and 3% (respectively) of t h e normal yG
globulins (38, 39).
T h e nephritis of SLE is now felt to
result from the deposition in the glomerulus
of circulating complement-fixing immune
* Terry WD: Unpublished observations
complexes (3, 40). An association has been
made between the presence of high titers of
anti-DNA antibodies (3) and high titers of
(complement-fixing) antinucleoprotein antibodies and active nephritis (28), and between
complement fixing IgG anti-DNA or DNAhistone and active nephritis (4).T h e finding of
these antibodies, especially anti-DNA antibodies, primarily in those yC subclasses which
yG1 and yG3-is
fix complement best-ie,
consistent with this hypothesis, as is the finding
of low complement levels in patients with active
lupus nephritis and/or high titers of anti-DNA
antibodies (3). This also supports the observation that D N A can be detected on the glomerular basement membrane of the patients with
lupus nephritis, and that antinuclear (especially
anti-DNA and antinucleoprotein) antibodies
can be eluted from isolated glomeruli (40). By
contrast, those antibodies that were not primarily yC1 and yG3 (antispeckled, antinucleolar) w e r e not associated w i t h clinical
nephritis or SLE. It is interesting to note that
Arthrttis and Rheumatism,Vol. 15. No. 2 (March-April 1972)
both yG1 and yG3 fix complement. Therefore,
one would have expected the antibodies of the
-&3 subclass to be associated with clinical
nephritis, if complement were the main determining factor. The fact that S l and yG3
antibodies seem to be important in association
with one another in nephritis suggests that
another biologic property associated with y
globulins, particularly r G 1 may be important
i n addition to complement fixation for the
induction a n d mediation of clinical nephritis.
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Arthritis and Rheumatism,Vol. 15, No. 2 (March-April 1972)
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