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Detection of cross-reactive anti-DNA antibody idiotypes in the serum of systemic lupus erythematosus patients and of their relatives.

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Two common cross-reacting anti-DNA antibody
idiotypes designated 1616 and 32/15, previously identified in the serum of patients who have systemic lupus
erythematosus, were found in 24% and 7%, respectively, of 147 first-degree relatives. These findings imply
that high-frequency germ-line genes exist among lupus
relatives, as well as patients. These dominant or public
anti-DNA antibody idiotypes are not likely to be pathogenic factors, but are probably a genetically associated
Evidence of a genetic basis for systemic lupus
erythematosus (SLE) has been accumulated in a variety of studies. Population studies have indicated a
particular predominance of black females (I), while
From the Departments of Rheumatology and Medical Phys.
ics, University College Hospital and the Department of Rheumatology, Hammersmith Hospital, London, UK; and the Department of
Medicine “D,” Division of Rheumatology, Beilinson Hospital, Tel
Aviv, Israel.
Supported in part by the Bat Sheva de Rothchild fund for
the Advancement of Science and Technology and the Meirbaum
Research Fund, The Faculty of Medicine, Tel Aviv University, Tel
Aviv , Israel.
D. A. Isenberg, MRCP: Department of Rheumatology,
University College Hospital; Y. Shoenfeld, MD: Division of Rheumatology, Beilinson Hospital; M. Walport, MRCP: Department of
Rheumatology, Hammersmith Hospital; C. Mackworth-Young,
MRCP: Department of Rheumatology, Hammersmith Hospital; C.
Dudeney, BSc: Department of Rheumatology, University College
Hospital; A. Todd-Pokropek, MPhil: Department of Medical Physics, University College Hospital; S. Brill, MD: Division of Rheumatology, Beilinson Hospital; A. Weinberger, MD: Division of Rheumatology, Beilinson Hospital; J . Pinkas, MD: Division of
Rheumatology, Beilinson Hospital.
Address reprint requests to Dr. D. A. Isenberg, Dept. of
Rheumatology, University College Hospital, Gower Street, London, WCI, UK.
Submitted for publication September 25, 1984; accepted in
revised form March 26, 1985.
Arthritis and Rheumatism, Vol. 28, No. 9 (September 1985)
marked ethnic differences were revealed by a Hawaiian study (2) which found prevalence rates per 100,000
people to vary from 5 . 8 among whites to 24.1 in the
A positive family history of SLE may be found
in approximately 4% of cases (3). In such families,
analyses of monozygotic twins have noted a concordance rate of about 65% for SLE (43).HLA studies
have consistently shown associations with the A l , B8,
DR2, and DR3 antigens (reviewed by Walport et al
[61). Recently, the frequency of the Gm allotype 1,17;
5,6,13 was shown to be significantly increased in
black American SLE patients (7). Inherited complement deficiency states, notably those of the classical
pathway and terminal sequence (C5-C9), have also
been noted (8). In a recent study, more than 80% of
white SLE patients were found to have a silent or null
allele of C4A or C4B (and, in 1 patient, C2), compared
with 40% of a matched normal control group (9).
Finally, many asymptomatic relatives of lupus patients
have hypergammaglobulinemia (lo), serum autoantibodies (1 I), raised circulating immune complex levels
(12), and decreased suppressor T cell function (13).
We now report a study of anti-DNA antibody
idiotypes detectable in the serum of lupus patients and
their first-degree relatives. The sharing of idiotypes by
antibodies obtained from different patients would suggest that they are the products of germ-line genes that
are dispersed throughout the population (14). There is
clear evidence that the germ-line controls and limits
the available and expressed idiotypic repertoire in
newly arising B cells (15). The demonstration of
shared idiotypes among lupus patients and their relatives would further support the concept of the importance of genetic influences in SLE.
Patients. Forty-eight patients with SLE from 44
different families were studied. Forty-six patients were
women and ail patients fulfilled 4 or more of the American
Rheumatism Association's revised criteria for the classification of SLE (16). One hundred forty-seven healthy firstdegree relatives of these patients were also studied. Seventyfour of the relatives were female and 73 were male. The 1 I5
clinically healthy controls studied were mostly drawn from
blood bank donors; none of the controls had a history of
autoimmune rheumatic disease.
Production of anti-DNA antibody idiotypes and their
antiidiotypes. The human monoclonal anti-DNA antibodies
1616 and 32/15 were produced as described elsewhere (17):
16/6 bound (in decreasing order) to poly I, poly(dT), singlestranded DNA (ssDNA), and double-stranded DNA
(dsDNA); 32/15 bound to poly(dT), Z-DNA, ssDNA, and
poly I (18). An antiidiotypic serum (anti-l6/6/R) was prepared by monthly immunization of a rabbit using a multiple
intradermal injection technique. For the first and second
immunizations, 16/6 was mixed with an equal volume of
Freund's complete adjuvant (Difco, Detroit, MI). Thereafter, the immunizations were mixed with Freund's incomplete adjuvant (Difco).
The rabbit was bled after 3 months and 1 week after
each booster. The serum was rendered idiotype-specific by
absorplion on a human IgG-IgM Sepharose column using a
pump to achieve multiple recycling through the column for
18 hours. A monoclonal mouse antiidiotypic antibody (anti32/15/M) was obtained from a hybridoma produced by fusing
the norisecreting myeloma cell line (P3 x 63-Ag 653) with
spleen cells from a Balb/c mouse which had been immunized
with 32/15.
The putative antiidiotype antibodies (both of the IgG
isotype) were tested by enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay in a series of experiments reported elsewhere (14), which showed that the
reactions of the antiidiotypic antibodies with their own
idiotypes were inhibited 50% by 4 ng (16/6) or 15 ng (32115) of
their homologous idiotypes. In contrast, neither in direct
binding nor competition assays did the antiidiotypic antibod:
ies react with 2 pools of affinity-purified IgM obtained from
over 20 normal donors. They also did not react with 5
myeloma or Waldenstrom proteins (both K and A) or with the
IgGK produced by the human fusion cell line GM 4672. In
addition, neither of the antiidiotypes bound to ssDNA,
dsDNA, or other polynucleotides. These 2 antiidiotype
antibodies were inhibited from binding to their homologous
idiotypes by various polynucleotides, indicating that the
antiidiotypes react with structures in or near the antigen
binding site (14).
Detection of anti-DNA antibody idiotypes in sera. The
details of this assay have been previously described (19).
Briefly, 96-well polystyrene plates (Immunulon 11; Dynatech, Alexandria, VA) were incubated with serum diluted in
O.05M borate buffer, pH 8.6, for 18 hours at P C , then
washed 3 times each with 1% phosphate buffered salineTween-20 (PBS-Tween) and PBS. The serum dilution used
for detecting the 1616 idiotype was 1:25,000. For detecting
the 32/15 idiotype it was 1:5,OOO. These dilutions were
considered optimal, since they were close to the midpoint of
the slopes of titration curves which were ascertained on
dilutions of both normal and SLE sera, extending over 3
orders of magnitude. The antiidiotypic serum was diluted in
0.1% PBS-Tween (anti-I6/6/R at 1 : 12,000 and anti-32/15/M
at 1: 1,OOO) and added to the serum-coated wells for 2 hours
incubation at room temperature. Following the same washing procedure as before, 150 pl of goat anti-rabbit or goat
anti-mouse immunoglobulin conjugated to alkaline phosphatase was added. The plates were then incubated overnight at
room temperature. Determination of the bound alkaline
phosphatase was performed as described previously (17).
The results are expressed in optical density (OD) units x
lo3. As positive controls, titration curves of each antiidiotype and its corresponding monoclonal antibody diluted in
normal human serum were ascertained on every plate. The
sera were coded and thus assessed blindly.
Antinuclear antibodies, dsDNA, and ssDNA. The
presence of antinuclear antibodies (ANA) in the SLE patients' and their relatives' sera was tested using serial
dilutions of serum on a human epithelial cell line (HEp-2).
Fluorescence at a titer 2 I :80 was considered positive.
The presence of antibodies to dsDNA was detected
using Crithidia luciliae as a substrate.
We adapted the method described by Morgan and
colleagues (20) to detect the presence of antibodies to
ssDNA. In brief, 96-well flat-bottomed ELISA plates (Dynatech) were incubated at 37°C for 1 hour with 50 pl of poly-Llysine (Sigma, St. Louis, MO) at a concentration of 56pdml.
The wells were washed 3 times in PBS and then overlaid
with 50 p1 ssDNA in PBS at a concentration of 5 pg/ml. The
ssDNA was prepared by boiling dsDNA (Sigma) for 10
minutes, then placing it on ice for 15 minutes. After an 18hour incubation at 4"C, the wells were washed as before,
then blocked with 2% casein (BDH, Poole, UK) in PBS (100
pl per well) for I hour at 37°C. Following 3 washes in 0.1%
PBS-Tween, 50-pl duplicate serum samples diluted 1 :200 in
0.1% PBS-Tween were added to the wells.
A standard curve of a known high-titer serum designated BG, which has been fully described (21), was set up in
duplicate on every plate. The sera were incubated for 2
hours at 4°C after which the wells were washed 3 times with
0.1% PBS-Tween. Fifty microliters of goat anti-human
immunoglobulin conjugated to alkaline phosphatase (Miles,
Stoke Poges, UK) diluted I : 1,500 in 0.1% PBS-Tween with
0.5% casein was added to each well for 2 hours at 4°C. The
wells were then washed 6 times in 0.1% PBS-Tween and
determination of bound alkaline phosphatase was performed
as described previously (17). The values were expressed in
BG units with reference to the standard curve on each plate.
The mean -C standard deviation of 60 normal subjects was 76
2 25 BG units. The upper limit of normal was set at 130 BG
Rheumatoid factor. The 6 highest 1616 and 32/15
idiotype binding sera in the patient and relative groups were
tested for the presence of rheumatoid factor by standard
latex fixation test. In addition, the same sera were examined
for IgG, IgA, and IgM rheumatoid factor using a standard
solid-phase radioimmunoassay. Sera from the SLE patients
and relatives were coded and thus assessed blindly.
Serum levels of 16/6 detected by the rabbit
antiidiotype in 115 normal persons gave a mean k SD
value of 48 ? 32 OD units. The upper limit of normal
was set at 115 OD units. Serum levels of 32/15 detected
by the monoclonal, mouse antiidiotype in the normal
group gave a mean value of 28 t 27 OD units. The
upper limit of normal was set at 85 OD units. Five
healthy individuals (4%) had an elevated 16/6/R level
(up to 138 OD units) and 1 (1%) had an elevated 32/15/
M level (127 OD units).
Figure 1 shows the 16/6 idiotype levels in the
SLE patients, the total group of their first-degree
relatives, the female relatives, the male relatives, and
the normal individuals. Nineteen (40%) of the 48 SLE
patients had idiotype levels above 115 OD units. In
comparison, 35 (24%), of the 147 first-degree relatives
had abnormal values (Table 1). Analysis of the relatives' group showed that of those with high levels of
16/6, 17 (23%) were female and 18 (25%) were male.
The difference between the sexes was not significant.
The differences in the numbers of individuals
with high values in the SLE patient group, the total
first-degree relative group, the female first-degree relative group, and the male first-degree relative group
were all statistically significant compared with the
normal subjects (P < 0.001 in each case). Furthermore, the difference in the number of individuals with
high idiotype levels in the patient group compared with
the relative groups was statistically significant (P <
Figure 2 shows the 32/15 idiotype levels in the
SLE patients, relative groups (total and divided according to gender), and healthy individuals. Eleven
(239%)of the 48 SLE patients had increased idiotype
levels compared with 11 (7%) of 147 first-degree
relatives (P < 0.01) (Table 1). The relatives with
60 0
l n.147)
re a (Ire.
[n. 7 4 )
(n.73 )
. .i
Figure 1. Values of 16/6 detected in the serum of systemic lupus erythematosus (SLE) patients, their relatives, and healthy controls.
Table 1. Raised idiotype levels in systemic lupus erythematosus (SLE) patients and relatives, and
control groups
SLE patients
(n = 48)*
(n = 147)
(n =73)
(n = 74)
(n = 115)
19 (40%)t
1 1 (23%)t
35 (24%)t
I 1 (7%)$
18 (25%)"
5 (7%)$
17 (23%)t
6 (8%H
5 (4%)
* P < 0.05 when SLE patients who had high 1616 levels were compared with their relatives; P < 0.01
when SLE patients who had high 32/15 levels were compared with their relatives.
t P = < 0.001 compared with ndrmal group.
$ P = < 0.05 compared with normal group.
increased values included 6 (8%) of 74 women and 5
(7%) of 73 men. The difference between the male and
female relative groups was not significant. The differences in numbers of individuals with high values in the
SLE patient group, the total first-degree relative
group, the female first-degree relative group, and the
male first-degree relative group were all statistically
significant compared with the normal subjects ( P <
0.001 for the patient group; P < 0.05 for the relative
The distribution of observed values for each of
the 2 idiotypes was clearly not a normal distribution
(see Figures 1 and 2). There were a relatively large
number of readings at and about 0, followed by a
spread of readings extending up to quite high values.
Nonparametric tests were used to analyze the data.
The data were assumed to be ordinal. A Mann-Whitney U test was used to compare each of 2 selected
groups. A Kruskal-Wallis one-way analysis of variance was also used to assess the complete set of data
for all groups for each of the 2 antibodies. Data for the
male and female relatives were considered separately
30 a
.. .. .
SLE R l w n l s
Conmlned SLE
Female SLE
Male SLE
(n 173)
Figure 2. Values of 32/15 detected in the serum of systemic lupus erythematosus (SLE) patients, their relatives, and healthy controls.
2 8 3
2 8 3
p<o .ooo 1
P<O. 000 1
Figure 3. Comparison of the mean rank values between the patient, relative, and normal groups (MannWhitney U test). Group 1 (n = 48) = patients with systemic lupus erythematosus; group 2 (n = 73) = male
relatives; group 3 (n = 74) = female relatives; group 4 (n = 115) = normal subjects. NS = not significant.
Upper diagonal half = 16/6; lower diagonal half = 32/15.
and then pooled. A problem arose with the 0 values.
The frequency of occurrence of 0 values in the data
was not “well behaved” in that runs were observed
associated with the background level for the test on a
given day (this presumably reflects the limits of sensitivity of the assay). Contingency tables were therefore
set up where for each group, the idiotype values were
classified as near 0, defining near 0 as 40 OD x lo3
units, or positive.
The results analyzed by chi-square tests
showed that the difference between the frequency of
occurrence of combined 0 and near 0 values was not
significant for either idiotype, between any of the
groups studied. Figure 3 therefore shows the comparison (by Mann-Whitney U test) of the mean rank
between the patient, male relative, female relative,
and normal groups, excluding the 0 values. This shows
that while there were no significant differences for the
32/15 idiotype, the differences between the patient and
relative groups compared with the normal group were
statistically very significant for 16/6. Further, there
was a significant difference with 16/6 in the patient
versus the relative group.
The correlation between raised or normal 16/6
levels and a positive ANA test result, a positive
dsDNA test result, and raised ssDNA binding was
examined in SLE patients. There was no difference
between those patients with raised or normal idiotype
levels and those patients with positive ANA. However, patients with a raised 16/6 idiotype were statistically more likely to have a positive dsDNA result (P <
0.02) and raised levels of antibody to ssDNA (P <
0.05) (Table 2).
No statistically significant associations were
found when the same correlations were examined in
the lupus relative group.
The relationship was analyzed between patients
whose sera had high or normal 32/15 idiotype levels
and a positive result on ANA and dsDNA tests and
raised ssDNA binding. In neither the patient group
nor the relative group were significant associations
found (Table 3).
Only 2 of the highest 16/6 idiotype-containing
sera in the SLE patient group had a positive rheumatoid factor (at titers of 1:40 and 1:80). All the remaining patient sera and sera of relatives who had high
levels of 16/6 were negative. Using the solid-phase
radioimmunoassay for IgG, IgA, and IgM rheumatoid
factor, all the sera tested were within normal limits.
Autoantibodies in the sera of lupus patients can
bind to a wide variety of antigens including nucleic
acids, nucleoproteins, cell membranes, and phospholipids (21,22). However, analyses using hybridomaderived monoclonal antibodies have shown that the
diversity of lupus autoantibodies is restricted (18,23).
For example, monoclonal autoantibodies that were
selected for their ability to bind to ssDNA may also
bind to the phospholipid cardiolipin and demonstrate
features of a lupus anticoagulant (24). Further, monoclonal anti-DNA antibodies have been shown to bind
to vimentin, a cytoskeletal protein (25). These studies
indicate that the apparent diversity of serologic abnormalities may in fact be restricted by a limited number
of epitopes (antigenic determinants).
An alternative approach to studying the serologic diversity among lupus autoantibodies has been to
analyze antibody idiotypes. These are serologically
defined regions of the antigen binding (or hypervariable) regions of immunoglobulins. Originally viewed as
unique markers of individual antibodies, it is now clear
Table 2. Comparison of systemic lupus erythematosus (SLE)
patients and relatives with high or normal 16/6 idiotype levels, with
respect to positive antinuclear antibody (ANA), single-stranded
DNA (ssDNA) binding, and positive double-stranded DNA
ssDNA binding
SLE patients
with t values
(n = 19)
SLE patients
with normal values
(n = 29)
SLE relatives
with t values
(n = 35)
SLE relatives
with normal values
(n = 112)
* P < 0.05 compared with SLE patients with normal values.
t P < 0.02 compared with SLE patients with normal values.
Table 3. Comparison of systemic lupus erythematosus (SLE)
patients and relatives with high or normal 32/15 idiotype levels, with
respect to positive antinuclear antibody (ANA), single-stranded
DNA (ssDNA) binding, and positive double-stranded DNA
SLE patients
with t values
(n = 11)
SLE patients
with normal values
(n = 37)
SLE relatives
(n = 11)
SLE relatives
with normal values
(n = 136)
ssDNA binding
that different antibody molecules can possess closely
related idiotypes. These cross-reactive or shared idiotypes are very probably the product of germ-line genes
In this study, we have extended our original
observations (19) that in the sera from a large group of
SLE patients, at least 2 cross-reactive idiotypes could
frequently be demonstrated. Thus, in the original
study the 16/6 idiotype was present in the sera of 54%
of the patients with active lupus and the 32/15 idiotype
was present in 28%. A similar finding was reported by
Solomon et a1 (26), who found a cross-reactive idiotype of anti-DNA autoantibodies in the serum of 8 of 9
patients who had SLE. Our results show a slightly
lower frequency of detection of the 16/6 (40%) and 321
15 (23%) idiotypes. This is perhaps due to our patients’
having less clinically active disease at the time they
were studied. However, the observation that 24% of
147 healthy first-degree relatives had raised 1616 levels
and 7% of them had raised 32/15 levels indicates that
these hypervariable region structures are determined
by high-frequency germ-line genes present within lupus patients and their clinically normal family members. It would be of interest to follow those family
members with high idiotype levels to see if the presence of these serologic markers has any predictive
value in terms of the development of overt SLE.
Since anti-l6/6/R is a polyclonal reagent, it is
probably recognizing a set of idiotopes, in contrast to
anti-l6/6/M which, being monoclonal, is presumably
identifying an individual idiotope. This may be why
the 16/6 idiotype is more frequently identified than the
32/15 idiotype.
The antiidiotypic antibodies and serum have
both been used in relatively high dilutions. The princi-
ple of the assay we have used, with serum on the solid
phase, was first described by Solomon et a1 (26). These
authors used test serum dilutions of 1 : 10 and 1 : 100,
though they give no information as to whether higher
dilutions were tried. The assay we describe is very
sensitive (the high dilutions also help to reduce the
background) and in experiments in which we have
added measured amounts of 16/6 to normal serum, this
assay can detect the idiotype in picogram to nanogram
quantities (data not shown). Allowing for the dilution
factor, the strongly positive sera probably have no
more than a few micrograms of the idiotypes. As the
results indicate, we very rarely found normal subjects
with idiotype levels above the normal range as determined in 115 individuals. Interestingly, Datta et a1 (27)
recently found that some normal mice could produce
immunoglobulins that share idiotypes with a monoclonal anti-DNA antibody derived from lupus-prone
MRL-lprllpr mice.
In this study we have been unable to determine
any difference between male and female relatives with
respect to the presence of either of the 2 idiotypes.
This contrasts with the observation by Miller and
Schwartz (13) that it was the female relatives who
primarily had the abnormalities of suppressor cell
function. Similarly, Lehman et a1 (11) observed that
39% of female lupus relatives were ANA-positive
compared with 22% of males (P> 0.05). The lack of
distinction between the sexes in our study implies that
the genes coding for the idiotypes we have detected
must be widely dispersed. Further, the development of
SLE in any given individual is clearly dependent on
several inherited anomalies and environmental stimuli
The question must be asked, on which immunoglobulin molecules are these anti-DNA antibody
idiotypes present? It would seem obvious that they
are not confined to anti-DNA molecules. This is not
surprising since it has already been shown that in
the MRL-lprllpr lupus mouse model, a major fraction
(probably more than 80%) of H130 idiotype-positive
immunoglobulins do not bind DNA although this common cross-reactive idiotype was originally identified
on anti-DNA antibodies (29). Further, it has been
observed in 3 lupus sera with high 16/6/R levels that at
least 30% of the 16/6 idiotype, although originally
detected on an anti-DNA antibody, was in fact present
on other unidentified immunoglobulins (Isenberg DA,
Shoenfeld Y, Madaio M: unpublished observations).
The results in this study suggest that among the
patient population, the sera with high 16/6 idiotype
levels were statistically significantly more likely to
have dsDNA antibodies and high ssDNA binding.
While this does not prove that the idiotypes were
present on ssDNA and/or dsDNA antibody molecules,
it perhaps makes it more probable. In contrast, the
other studies of ANA and rheumatoid factor binding
give no clue as to which immunoglobulin molecules
bear the idiotypes 16/6 or 32/15. Precedents have been
described for idiotypes being shared by antibody molecules with different antigen-binding properties (30,3 1).
In addition, Oudin and Cazenave (32) demonstrated
that rabbits immunized with ovalbumin produce
immunoglobulin with shared idiotypes, some of which
bind to ovalbumin. Recently, using a computerized
method, Madaio et a1 found no relationship between
the antigen-binding and idiotypic patterns of a panel of
monoclonal autoantibodies derived from MRL-lpr/lpr
mice (personal communication). They suggested that
this implies that idiotypes and antigen-binding sites
(paratopes) of autoantibodies are encoded for by different subregions of V genes.
In our original study (19) it was indicated that
the 16/6 idiotype might be a useful marker of disease
activity in some SLE patients. Another study has
shown that in the renal tissue of lupus patients, but not
in a wide variety of disease controls, 16/6 and/or 32/15
idiotypes may be found (33). However, high idiotype
levels of both 16/6 and 32/15 have now been found in
some asymptomatic lupus relatives. An explanation
might be that the idiotypes detected in the lupus
relatives’ sera are on immunoglobulin molecules
which are nonpathogenic, either because they do not
form immune complexes or because the immune complexes they are part of do not get deposited in the
It will be important to try to determine which of
these possibilities is correct, since one of the great
attractions of being able to show cross-reactive idiotypes on pathogenic molecules is the potential for
modulation of the immune response by antiidiotypic
therapy. That this may be feasible is suggested by the
inhibition of autoimmune tubulointerstitial nephritis in
guinea pigs by antiidiotypic antibodies (34). Similarly,
Hahn and Ebling (35) have shown that suitably timed
injections of an antiidiotype to a cross-reacting antiDNA antibody idiotype in lupus-prone New Zealand
blacWNew Zealand white mice significantly decreased
the nephritis in these animals and prolonged their
survival, though for a limited period. In contrast, when
Teitelbaum et a1 (36) attempted the same sort of
therapy in the MRL-lpr/lpr mice no such benefits
accrued; indeed the undesired effect of augmenting
autoantibody production was noted.
In summary, this study has shown that 2 common cross-reacting anti-DNA antibody idiotypes previously found in the serum of SLE patients may also
be found in their first-degree relatives. These findings
suggest that high-frequency germ-line genes must exist
among lupus patients and their relatives. In the relatives (and possibly in the patients, too), most of the
detectable idiotypes are present on unidentified
immunoglobulin molecules.
The authors gratefully acknowledge the help of Dr.
Ian Addison and Dr. Robert Bernstein in measuring the
antinuclear antibodies and rheumatoid factors. We thank
Sarah Harding for typing the manuscript. Dr. Michael Snaith
and Dr. Graham Hughes kindly gave permission for us to
study some of their patients. We also thank Dr. M. Jones
(Immunology Department, the Middlesex Hospital) for kindly measuring the IgG, IgA, and IgM rheumatoid factors.
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patients, idiotype, detection, systemic, dna, serum, erythematosus, anti, cross, antibody, reactive, lupus, relative
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