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The expression of C3b receptors in the differentiation of discoid lupus erythematosus and systemic lupus erythematosus.

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BRIEF REPORT
THE EXPRESSION OF C3b RECEPTORS IN THE DIFFERENTIATION
OF DISCOID LUPUS ERYTHEMATOSUS AND SYSTEMIC LUPUS
ERYTHEMATOSUS
FRANCISCO TAUSK, ELAINE HARPSTER, and IRMA GIGLI
We studied the expression of the C3b receptor,
CR1, on erythrocytes (E-CR1) of patients who, in spite
of having mild systemic symptoms, were diagnosed as
having discoid lupus erythematosus and followed accordingly. We found that E C R l was markedly reduced
in these patients, similar to that Seen in patients with
systemic disease. In contrast, those patients with completely asymptomatic discoid lupus erythematosus had
the same expression of E-CRl as the normal population.
The receptor for the C3b/C4b fragments of the
human complement system, CR 1, is a polymorphic
glycoprotein that is present on a variety of blood and
tissue cells (1). This receptor functions as a cofactor of
Factor I-mediated degradation of C3b and C4b. It
accelerates the decay of the alternative and classical
pathway C3/C5 convertases (2,3), participates in the
phagocytic process. and provides erythrocytes with
the ability to bind and clear circulating immune complexes (CIC) (4).
In the presence of complement, soluble immune
complexes bind to the CR1 on erythrocytes (E-CRI)
and are removed from the circulation when these cells
traverse the liver and spleen (4). The notion that this
mechanism is important in the clearance of CIC has
prompted the study of CR1 in various diseases.
Patients with systemic lupus erythematosus (SLE),
From the Division of Dermatology, University of California, San Diego School of Medicine.
Supported by NIH grant A1-20476.
Francisco Tausk. MD; Elaine Harpster. MD; Irma Gigli, MD.
Address reprint requests to Francisco Tausk. MD, Division
of Dermatology/H-811J. UCSD Medical Center, 225 Dickinson
Street, San Diego, CA 92103.
Submitted for publication August 4. 1989; accepted in
revised form January 17, 1990.
Arthritis and Rheumatism, Vol. 33, No. 6 (June 1990)
lepromatous leprosy, acquired immunodeficiency syndrome, and hemolytic anemia have a decreased number of CRl on the membrane of their erythrocytes,
suggesting a causal relationship between this phenomenon and some of the clinical manifestations of these
disorders (5-7).
The nature of E-CR1 deficiency in patients with
SLE has been a subject of controversy. While some
reports have shown that this alteration is inherited in a
codominant manner (6). others have reported that the
acquired decrease in E-CRI is related to disease
activity (8). It is now apparent that both mechanisms
are present, resulting in lower numbers of CRI on the
surface of erythrocytes, as well as leukocytes.
Patients with chronic cutaneous forms of discoid lupus erythematosus (DLE) lack the clinical and
serologic abnormalities found in SLE. Patients present
with a history of a benign course of disease, although
it is recognized that between 2% and 12% of these
patients will eventually develop systemic manifestations (9). Because patients with SLE have a marked
abnormality in the expression of CR1 on their erythrocytes, we compared this with E-CRl expression in
patients with DLE, in order to establish whether this is
an effective parameter to differentiate and/or detect a
subgroup of patients with DLE who are at risk of
developing systemic disease.
PATIENTS AND METHODS
Patients. The study population was selected
from the Division of Dermatology of the Medical
Center of the University of California, San Diego.
Eleven patients had been diagnosed in the past as
having SLE, according to the American Rheumatism
889
BRIEF REPORTS
Table 1. Symptoms and/or laboratory abnormalities in patients
with DLE and mild signs and symptoms of SLE'
~
ARA criteria (ref. 10)
Patient
Clinical
~
1
2
ANA 1:W
(speckled)
ANA 1:160
(speckled)
Arthritis
Leukopenia
Arthritis
Anti-Sm, ANA
1:640 (speckled)
ANA l:W
(homogeneous)
7
-
8
Arthritis
9
Arthritis
-
Other abnormalities?
~~
-
Arthritis
10
Laboratory
~
Anti-Sm. ANA
1:W (speckled)
ANA 1:160
(homogeneous)
ANA 1:lfX
(speckled)
Increased ESR.
arthralgias,
Raynaud's
phenomenon
Fever of unknown
origin
-
Increased ESR
Malaise, arthralgias.
fever of unknown
origin
-
Malaise
Increased ESR,
decreased CH5O.
microcytic anemia
All patients had discoid skin lesions. Since photosensitivity very
frequently correlates with chronic discoid lupus erythematosus
(DLE), we have not included it herein. SLE = systemic lupus
erythematosus; ARA = American Rheumatism Association; ANA
= antinuclear antibodies; ESR = erythrocyte sedimentation rate.
t Abnormalities not included in the ARA criteria for SLE.
Association revised criteria (10). Nineteen patients
presented with clinical and histopathologic characteristics of DLE. Eight of these patients had widespread
skin lesions localized above and below the neck, and
the remaining 11 had 1 or more lesions involving the
head exclusively. Ten of the patients presented with
mild clinical or laboratory abnormalities such as those
seen in SLE, but their disease did not conform to the
criteria for this diagnosis (Table 1). They were therefore diagnosed as having DLE and were followed
accordingly. The evaluation of these patients consisted of a medical history and physical examination,
complete blood cell count, SMAC 12, determination of
the erythrocyte sedimentation rate, urinalysis, and
testing for antinuclear antibodies, anti-Ro/La, antidouble-stranded DNA, and anti-smooth muscle antibodies. For the purpose of this study, we chose to
exclude patients who had anti-Ro or anti-La antibodies
and were thought to meet criteria consistent with the
diagnosis of subacute cutaneous lupus erythematosus (1 1).
The control population consisted of 7 healthy
volunteers. Although this is a limited sample, the mean
number of receptors per cell did not differ from that in
the 132 normal individuals previously analyzed in our
laboratory (5.6).
Quantitation of CR1 on erythrocyte membranes.
To measure the number of CR1 molecules on the
erythrocyte surface, a radiobinding assay was performed as previously described (6), using '"1-Fab'
fragments of a monoclonal antibody directed against
the receptor. Ten milliliters of venous blood was
drawn into vacutainer tubes containing 0.02M EDTA
(Fisher Scientific, Fairlawn, NJ). The cells were separated, washed in veronal buffered saline, and the
b d y coat was removed after each wash. The erythrocytes were then resuspended at a concentration of
2.5 x 108/ml in veronal buffered saline (0.075M NaCI)
containing 2.5% dextrose (Mallinckrodt, St. Louis,
MO) and 0.5% gelatin (JT Baker Chemicals, Phillipsburg, NJ). Fifty microliters of erythrocytes was incubated on ice with 50 pl of increasing dilutions of
l2'I-Fab' anti-CR1 in dextrose/gelatin/veronal buffer,
ranging from 6.5 &ml to 0.4 pg/ml.
After 60 minutes, the mixtures were layered on
200 pl of dibutylphthalate (Eastman-Kodak, Rochester, NY), and after centrifugation for 1 minute in a
microfuge (Beckman Instruments, Palo Alto, CA), the
pellets and supernatants were measured for bound and
free "'I-Fab'. Nonspecific binding was determined by
incubating the samples for 60 minutes with a 200-fold
excess of unlabeled anti-CR1 before adding the "'IFab'. The number of' CRl molecules per cell was
calculated by binding isotherms and Scatchard analysis of the binding data.
RESULTS
The number of CRl molecules per erythrocyte
for each of the groups studied is shown in Figure 1.
Patients with SLE had a mean t SD of 210
122
CR Verythrocyte, which differed significantly from the
values for healthy controls (laboratory personnel and
individuals who were blood donors) (512 t 174 CRl/
erythrocyte; P < 0.0005). Those patients who presented with cutaneous lesions of DLE and no clinical
or laboratory abnormalities typical of SLE (designated
DLE 1 in the figure) had 480 2 107 CRl/erythrocyte,
which did not differ from the value in the normal
population ( P = 0.66). The only patient in the DLE 1
group who had <400 CRVerythrocyte had widely
*
890
BRIEF REPORTS
900
600
300
0
Controls
DLE 1
DLE 2
SLE
N=9
N=10
N=ll
X=512+174 x=480+107 x=2362113 x=2102122
- N=7
Figure 1. Expression of CRI on erythrocytes of patients with lupus erythematosus. Results are expressed as the mean % SD.
Discoid lupus erythematosus patients were classified as to those who were asymptomatic (DLE 1) and those who had mild
systemic symptoms (DLE 2). Open circles indicate paticnts with widespread skin lesions above and below the neck. SLE =
systemic lupus erythematosus.
disseminated lesions measuring >2 cm in diameter. In
contrast, patients who were diagnosed as having DLE
and who presented with 1 or more clinical or laboratory symptoms of SLE during the course of their
disease (designated DLE 2 in the figure) had 236 ? 113
CR Verythrocyte. Thus, these patients differed from
those with no symptoms or abnormal laboratory examination results and from normal controls, but did
not differ from patients with SLE. It is interesting to
note that 6 of 10 of these patients (DLE 2) had
widespread skin lesions, compared with only 2 of 9
patients with DLE and no clinical symptoms or laboratory abnormalities typical of SLE.
DISCUSSION
In the present study, we examined patients with
lupus erythematosus, whose manifestations are characterized by a spectrum that spans between patients
whose abnormalities are confined to the skin (DLE)
and those who present severe systemic disease (SLE)
with organ involvement. Although it is known that
-20% of patients with SLE develop discoid skin
lesions (12) and that in 2-12% of patients who present
with DLE, the disease will eventually progress to
SLE, the relationship between these 2 forms of the
disease remains controversial.
Considerable interest has been focused on defining clinical and serologic manifestations that could
identify those patients with DLE who will eventually
develop SLE. It has recently been shown that patients
with DLE have polyclonal B cell activation (13)and an
increase in the number of circulating Ig-secreting cells
similar to that observed in SLE (14). It is of interest
that these DLE patients do not have circulating immune complexes, which are frequently present in SLE
patients. One possible explanation for this difference
could be that mechanisms responsible for the clearance of immune complexes in patients with DLE are
intact, whereas in patients with SLE, there are alterations that result in defective removal, and subsequent
89 1
BRIEF REPORTS
deposition in organs prone to immune complexmediated damage.
Because the erythrocyte membrane glycoprotein CRI has been shown to play a role in the clearance
of CIC (4), we analyzed the expression of E-CRI in
DLE and SLE patients. SLE patients have been
shown to have a marked decrease in E-CRl expression, and, consistent with these findings, we observed
that these patients had a mean 2 SD of 210 2 122
CRl/erythrocyte, a significant decrease compared
with normal controls ( P C 0.0005). Patients with DLE
and no systemic or serologic abnormalities had 480 2
107 CRl/erythrocyte, which did not differ from the
control population ( P = 0.66),whereas the subset of
patients with DLE who had mild signs and symptoms
of SLE had 236 +- 113 CRl/erythrocyte, which represents a significant difference between these 2 groups ( P
< 0.0002). These results show that patients diagnosed
with DLE who have mild signs of SLE share the
abnormal E-CRI expression seen in patients with
SLE. This observation raises the question of whether
these patients may have a mitigated form of SLE, and
thus require closer followup.
When analyzing the previously reported data on
the number of IgG-synthesizing and -secreting cells in
the blood of DLE patients (14), it was noted that
approximately 50% of these patients had levels that
were within the normal range, whereas in the rest of
the patients, these levels were markedly elevated. The
patients in the latter group may very well correspond
to those we have identified with low levels of E-CRI.
The decrease in the level of CRI may occur as a result
of CIC clearance; recent reports supporting this notion
indicate that normal erythrocytes infused in SLE
patients undergo a rapid loss of E-CR1. probably
during their transit through the liver, where local
macrophages remove CIC bound to the erythrocyte
membrane (4,15).
Alternatively, the low levels of E-CRI found in
the symptomatic group of DLE patients could be the
result of a genetic deficiency, which may render erythrocytes less effective in the clearance of CIC, predisposing these patients to eventual immune complex
damage. Genetic studies such as those reported in
SLE (7) will be required to support this hypothesis.
The DLE patient group with clinical or laboratory
abnormalities typical of SLE would be free of severe
systemic manifestations as long as the levels of CIC
are low enough to enable their clearing mechanism to
function competently. A marked increase in CIC may
overload a deficient system and lead to the development of systemic disease.
In the past, considerable effort has been concentrated on identifying parameters that would distinguish those patients with DLE who are at potential
risk of developing SLE. We have observed that a
subset of patients with DLE who presented with mild
systemic signs and symptoms, but did not meet criteria
for the diagnosis of SLE, had a marked reduction of
E-CKI. It is of interest that within this group, most
patients had widespread skin lesions, supporting the
notion that this feature may be an indicator of more
severe disease.
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