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Deficiency of c7 with systemic lupus erythematosus. solubilization of immune complexes in complement-deficient sera

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87
DEFICIENCY OF C7 WITH
SYSTEMIC LUPUS ERYTHEMATOSUS
Solubilization of Immune Complexes in Complement-Deficient Sera
HOWARD J. ZEITZ, GARY W. MILLER, THOMAS F. LINT, MIR A. ALI, and HENRY GEWURZ
A woman with systemic lupus erythematosus
(SLE) was found to have undetectable serum total complement (C) activity with marked reductions in levels of
several C components. Recognition of rising C4, C3, and
C5 levels coupled with sustained absence of hemolytic
activity led to studies of individual C components that
identified a persisting selective and complete absence of
C7 hemolytic activity. Review of the literature indicated
that the frequency of SLE is increased in patients with
complete deficiency of a late-acting C component (7% as
compared to 0.05% in the general population); however,
the disease frequency is less than that observed in patients with complete deficiency of an early-acting C
component (41% incidence in patients lacking C1, C4, or
C2). In order to explore one possible basis for this association, the capacity of serum from the patient described
herein and from patients with other C component deficiencies to mediate in vitro solubilization of immune
complexes was studied by using a recently developed asFrom the Institute of Allergy and Clinical Immunology,
Grant Hospital of Chicago; La Rabida-University of Chicago Institute; and the Department of Immunology, Rush Medical Center, Chicago, Illinois.
This work was supported in part by a grant (#I R 0 1
CA26143) from the NCI, DHEW.
Howard J. Zeitz, MD: Institute of Allergy and Clinical Immunology; Gary W. Miller, PhD: La Rabida (present address, Loyola
University School of Dentistry, Maywood, Illinois); Thomas F. Lint,
PhD: recipient of NCI Research Career Development Award 0 1 R 0 4
CA00558, Rush Medical Center; Mir A. Ali, MD: Institute of Allergy
and Clinical Immunology (present address, Ravenswood Hospital
Medical Center, Chicago, Illinois); Henry Gewurz, MD: holder of
Thomas J. Coogan, Sr., Chair in Immunology established by Marjorie
Lindheimer Everett, Rush Medical Center.
Address reprint requests to Howard J. Zeitz, MD, Institute of
Allergy and Clinical Immunology, Grant Hospital of Chicago, 550 W.
Webster, Chicago, IL 60614.
Submitted for publication January 22, 1980; accepted in revised form August 1 1, 1980.
Arthritis and Rheumatism, Vol. 24, No. 1 (January 1981)
say. The patient’s serum had a markedly decreased capacity to induce solubilization of immune complexes, as
did sera of other patients with active SLE and sera of
individuals with inborn deficiencies of C1, C2, or C3
without SLE. By contrast, the sera of patients with a selective terminal C component deficiency (C5, C6, C7, or
C8) but without SLE readily supported immune complex
solubilization. These results suggest that patients lacking a terminal C component are predisposed to the development of SLE by a process which is independent of
C-mediated immune complex solubilization. Whether
the compromised capacity for C-mediated immune complex solubilization contributes to the even greater frequency of SLE in patients lacking an early-acting C
component remains to be established.
In recent years, hereditary abnormalities of the
complement (C) system have been recognized with increasing frequency (1,2). Selective C component deficiencies have been noted in individuals who are apparently healthy at the time of study (3-9, but most reports
have suggested that patients with inborn complement
errors are predisposed both to repeated and/or unusual
infection (6,7) and to a variety of inflammatory diseases,
especially systemic lupus erythematosus (SLE) (1,8). Although the association of SLE or SLE-like syndromes
with hereditary deficiency of an early-acting (Cl, C4, or
C2) component of the classical complement pathway
(9-14) (Table 1) is well known, the relationship between
SLE and complete deficiency of a late-acting (C5, C6,
C7, C8, or C9) component has been less well characterized. Patients with selective deficiency of a late-acting C
component have a very high frequency of Neisseria infection (15); in addition, two previously reported patients have developed SLE (16,17).
ZEITZ ET AL
88
The nature of the association between SLE and
complete deficiency of a C component is not established. One possibility is that C-deficient patients might
also be deficient in the ability to dispose of circulating
immune complexes, with subsequent development of
the lupus process. Previous studies have demonstrated
that C-mediated solubilization of immune complexes
proceeds via the alternative activation pathway alone,
but this is substantially enhanced by concomitant participation of the classical activation pathway (18,19).
The late-acting C components are thought to be nonessential for immune complex solubilization (18,20); however, studies of solubilization in sera of patients with
late-acting C component deficiencies have not yet been
reported.
We present here a patient with SLE who has selective absence of C7, and we report the results of studies of the capacity of serum from this patient and individuals with other C component deficiencies to mediate
solubilization of immune complexes in vitro.
CASE REPORT
GS, a 27-year-old Mexican woman, was hospitalized in April 1977 after 10 days of fever and cough
which had failed to respond to acetylsalicylic acid and
ampicillin. She had been well until December 1974
when she developed premature labor in the 18th week
of her second pregnancy and gave birth to a female infant who died shortly after delivery; the placenta exhibited hydatid mole formation without evidence of choriocarcinoma. During the next 4 months, she noted
symmetrical joint pain and swelling in her knees, feet,
and hands, with subsequent loss of weight (10 kg) and
hair. There was no history of Raynaud's phenomenon,
dysphagia, or diarrhea; a urinalysis 4 months prior to
admission had revealed mild (1+) proteinuria. She had
received treatment with prednisone (5 mg twice daily)
for 5 months until abruptly electing to halt this therapy
1 month prior to admission.
On admission, the patient was febrile (38.9"C)
and tachypneic. She had diminished breath sounds at
the right posterior lung base, mild bifrontal alopecia,
and severe oral ulceration, but the joints appeared normal. No other abnormalities were noted.
The initial hematocrit was 31%, and the white
blood cell count was 3,800/mm3 (70% neutrophils and
8% band forms). There were 8-10 fine granular casts/
high power field, with quantitative urinary protein excretion ranging between 1.2 and 4.0 gm/24 hours. The
blood urea nitrogen, serum creatinine, and creatinine
clearance levels were within normal limits. Definitive
renal biopsy study was precluded by the patient's religion (Jehovah's Witness). No chorionic gonadotropins
were detected in the urine.
The Westergren erythrocyte sedimentation rate
was 6 mm/hour, and serum C-reactive protein (CRP)
was undetectable by immunoprecipitation assay. LE
cell preparations were positive on several occasions. Indirect immunofluorescence demonstrated antinuclear
antibodies in a relatively high titer (1 :500) with a homogeneous and peripheral staining pattern. Hemagglutinating antibodies to double-stranded DNA
(dsDNA) were also detected in a high titer (1 :640),
while rheumatoid factor and antibodies to smooth
muscle, mitochondria, and parietal cells were undetectable. Histocompatibility typing revealed only single
specificities at the A and B loci-Aw24 and B12. Most
strikingly, serum hemolytic C activity was absent; detailed studies of the complement system are described
below. Admission chest x-ray revealed bilateral pulmonary infiltrates. Pure cultures of Escherichia coli were
isolated from the blood, and treatment with intravenous
antibiotics (first cephalothin and gentamycin, and later
tobramycin) was initiated. Icteric hepatitis and
thrombocytopenia were noted shortly after admission,
but hepatitis-associated antigen was not detected. Corticosteroid therapy resulted in slow but steady clinical
improvement accompanied by a marked reduction of
the anti-dsDNA antibody level. She became totally afebrile on the thirty-seventh hospital day and was discharged 10 days later.
MATERIALS AND METHODS
Total serum C hemolytic activity via both the primary
and alternative pathways was assayed semiquantitatively in
gels containing sensitized sheep or unsensitized rabbit
erythrocytes, respectively, as previously described (2 1). Determination of the hemolytic levels of components C1-C9 and
protein levels of Clq, C4, C3, C5, properdin, and factor B
were performed by previously described methods (7).
Complement-mediated solubilization of immune precipitates or complex release activity (CRA) was quantitated
by a new, standardized procedure (22). Briefly, IZ5I-labeled
bovine serum albumin (BSA) and guinea pig anti-BSA antiserum were precipitated at equivalence to form appropriate
immune complexes. The complexes were washed four times in
isotonic phosphate-buffered saline (PBS) and adjusted to 25
pg BSA/ml. For the assay of solubilization, precipitates containing 0.15 pg '251-BSAwere added to 75 pl of test serum in a
total volume of 0.6 ml PBS containing 0.15 mM CaCl, and I .O
mM MgC12. Tubes were incubated at 37"C, and 50 p1 aliquots
were removed at various times up to 30 minutes, diluted in 2.0
ml ice-cold saline, and centrifuged 20 minutes at 1200g. Radioactivity was counted in both the supernatants and the pel-
C7 DEFICIENCY WITH SLE
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Hemolytic Activity
C
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10
20
30
40
50
60
DAY OF OBSERVATION
Figure 1. Persisting inability of patient’s serum to lyse sensitized sheep
erythrocytes (classical complement pathway = 0-0)and unsensitized rabbit erythrocytes (alternative pathway = UU),even while
C3 and CS protein, anti-dsDNA antibody, and maximum daily temperature were returning to normal in response to steroid therapy.
lets to calculate the amount of immune precipitate solubilized
after each interval. For each serum, a plot of “% soluble versus time” was constructed. The areas under the curves were
measured and were divided by the area for the standard control serum (area = 100%by definition) run at the same time.
Solubilization by patient GS serum was compared to
solubilization by a series of C-deficient sera and sera from patients with active SLE. Sera with selective deficiency of C2,
C3, C6, or C7 were obtained from patients previously studied
in our laboratory. In addition, sera from patients with deficiency of Clr (9,23), C5 (16), or C8 (24) were generously supplied by Drs. R.P. Young, F. Schmid, J.P. Leddy, and B. Petersen, respectively.
RESULTS
Analysis of complement activity in patient GS
serum. The patient’s serum was unable to lyse either
sensitized sheep or unsensitized rabbit erythrocytes suspended in agarose gels, reflecting deficiencies in function of the primary and alternative complement pathways, respectively. While prolonged incubation of gels
containing patient and normal serum in adjacent wells
resulted in no lysis around the well containing the pa-
tient’s serum, distinct lines of lysis developed between
the wells containing patient and normal serum. These
lines are indicative of the presence of an activated complex of C5 and C6 (CS), known to be formed when
serum which contains C5 and C6 in excess of C7 is
added to gels such as those used in the present study
(25,26).
Analysis of the C component hemolytic activities
and protein levels on day 84 (Table 2) revealed selective
total deficiency of C7. Hemolytic activities of several
other individual components (C 1, C4, C3, and C6) were
present but reduced to 23-54% of normal. C4, C3, C5,
properdin, and factor B protein levels were markedly
reduced during the first 3 weeks of hospitalization (levels on day 14 are shown in Table 2), with the depletion
pattern indicating substantial activation via the alternative complement pathway. With administration of corticosteroid therapy and in association with the reduction
of anti-dsDNA antibodies and the disappearance of fever, complement components (with the exception of C7)
returned to normal or near-normal levels, but without
restoration of hemolytic activity via either the classical
or alternative pathway (Figure 1).
Solubilization of immune complexes by sera of
patient G S and other C-deficient individuals. C-mediated solubilization was measured in sera from several
patients with a selective C component deficiency. As
seen in Figure 2, sera from patients deficient in Clr, C2,
or C3 had <5%, <15%, and <5%, respectively, of the
immune complex release activity (CRA) of a standard
normal serum. CRA activities of 96 f 15% were obtained for a group of 10 normal sera under identical
conditions. These results are consistent with the hypothesis that in this assay C3 activation by the classical path-
-2
E 100
0
0
-8a
IX
V
50
ClrD
C2D
C3D
C5D
C6D
C7D
C8D
(C A )(G.S.)
SLE
SERA
Figure 2. Solubilization of immune precipitate by sera from patients
with defined C component deficiencies or active SLE. Solubilization
(CRA) activity is expressed as a percentage of a standard normal control serum. The shaded area defines the mean f standard deviation
for a group of 10 normal sera run under identical conditions. Each
circle represents an individual patient.
ZEITZ ET AL
90
Table 1. Lupus erythematosus and Neisseriu infection in individuals with isolated complement
component deficiencies*
Deficient
component
Reported
individuals
c1
'i ) -
Lupus
erythematosust
55
8 (62)
3(1m)
18 (33)
)
c3
5
0 (0)
c5
c7
C6
9
C8
c9
8
2
]
c4
c2
71
44
1 (11)
01 (0)
(9)
1 (12)
0 (0)
Neisseriu infection?
29 (41)
1(20)
3)
5 (56)
83 (27)]
(57)
19(43)
3 (38)
0 (0)
* Individuals reported in the literature through January 1, 1980.
t % indicated in parentheses.
f Including C7-deficient patient reported herein.
way is required for efficient immune complex solubilization (20). By contrast, sera from patients deficient in C5,
C6, or C8 possessed CRA activities within the normal
range. Serum taken from patient GS on four separate
occasions over an 8-week period (day 7 to day 60), even
when C3 levels had returned to 70% of normal, showed
no CRA activity, while serum from another C7deficient individual (CA) without evidence of SLE
showed normal releasing activity. Two sera from patients with active SLE but without an inborn C defect,
shown for comparison, had 4%
CRA activity.
DISCUSSION
The patient reported here was found to have
Gram negative septicemia on hospital admission, along
with subsequently diagnosed SLE. The diagnosis of
SLE was supported by a group of clinical features including arthralgias, fever, thrombocytopenia, leukopenia, abnormal urinary sediment, and proteinuria;
when occurring together, these features clearly meet the
proposed criteria for the diagnosis of SLE (27). Circu-
lating antibodies to dsDNA were detected in high titer
and provided the single laboratory finding most indicative of SLE (28).
Complement component analysis of our patient
strongly suggested that the C cascade was being activated via both the primary and the alternative pathways
in association with the active SLE process. Levels of
properdin, factor B, and C4, as well as of C3 and C5,
were markedly depressed during the initial investigations, but the values returned to normal or near-normal
after several weeks of therapy. Recognition of rising C
component protein levels coupled with persistent absence of hemolytic activity led directly to tests to determine whether a selective C component deficiency was
present, and isolated deficiency of C7 was subsequently
observed in 8 separate samples taken over a 15-week interval. C7 deficiency was also suggested by the reaction
of lysis in gels. Previous studies have demonstrated that
C7-deficient serum has a marked capacity to generate
persisting C% in agarose and thus form a distinctive
pattern of reactive lysis in the absence of primary lysis,
which seems to be diagnostic of C7 deficiency (26).
Table 2. Complement component profile of patient GS
Hemolytic C
% normal
Day 84,
C protein
Day 14,
Pdml
Day 84,
Pg/ml
c1
c4
c2
c3
c5
C6
c7
C8
c9
54
24
72
40
90
23
C h
c4
c3
c5
Factor B
Properdin
181
48
330
37
58
<2
173
134
450
91
140
5
<o. I
67
346
Normal values,
Pg/ml
110-210
200-800
800-1,800
70- 170
175-275
10-20
C7 DEFICIENCY WITH SLE
Identical studies in the patient reported here confirmed
the previous findings and emphasized the ease of demonstration of this deficiency.
The inability to obtain serum samples from family members in Mexico precluded definitive identification of the hereditary nature of this deficiency; however,
an autosomal codominant pattern of inheritance has
been demonstrated in 9 other individuals with C7 deficiency (26,29-32). Studies of HLA antigens in those patients and their families demonstrated the Aw24 and
B12 alleles in only 1 other patient (26); linkage between
the HLA-A and B loci and the C7 deficiency locus was
not observed in 4 unrelated families (26, 30-32).
None of the previously reported individuals with
C7 deficiency (26,29-34) were known to have developed
SLE. However, 2 patients having SLE in association
with the isolated absence of another late-acting complement component have been reported previously
(Table 1): a 20-year-old woman with C5 deficiency (16)
and a 56-year-old woman with C8 deficiency (17). The
occurrence of SLE in 3 (including the patient reported
herein) of the 44 reported individuals (7%) with a terminal C component deficiency suggests an increased prevalence of this disease in these patients, since the prevalence of SLE in the general population is only 0.05%
(35). SLE has been noted even more frequently (41%)
(Table 1) in patients wi&%ereditary deficiency of C1,
C4, or C2 (9-14, 21, 23). While patients with rheumatic
complaints undergo coniplement analysis more frequently than the general population, it is unlikely that
selection bias alone can explain the markedly increased
frequency of SLE in C-deficient patients. Since in the
general population the approximate frequency of C
deficiency is 0.03% (36) and that of SLE is 0.05% (35),
the probability that both SLE and C deficiency will be
found in the same individual is of the order of one in six
million. Thus, there appears to be a unique susceptibility to the development of SLE in all patients with an inborn C component deficiency, which is particularly
marked in individuals lacking an early-acting classical
pathway component. This is reflected in the difference
in frequency of SLE in patients with early-acting (41%)
versus late-acting (7%) component deficiency.
The mechanism whereby an inborn deficiency of
a C component might contribute to the development of
SLE is uncertain. As suggested elsewhere (1,8,12), the
development of immune complex disease in C-deficient
patients might be due to an unusual host propensity to
infection, attributable to the lack of complement per se
or to genetic linkage with another factor predisposing to
91
SLE. Alternatively, C-deficient patients might lack the
ability to dispose of circulating immune complexes in a
normal manner, with consequent tissue damage.
To examine this latter possibility, we measured
C-mediated solubilization in the sera of 13 patients with
various selective C component deficiencies, including 2
with C7 deficiency, and 2 patients with SLE in the absence of inborn C deficiency. In this assay, which requires participation of the classical complement pathway for optimal activity, sera from patients with
deficiency of C 1r, C2, or C3 lacked normal CRA activity, as predicted by the finding (20) that C3b fixation is
required for immune complex solubilization. (It is of interest that in preliminary experiments performed by
GWM, the sera deficient in C l r and C2 demonstrated
normal or near-normal CRA activity in an assay involving activation via the alternative pathway alone.)
Sera from our patient GS and 2 other patients with SLE
but with no inborn C defect also lacked solubilization
activity. By contrast, sera from patients deficient in C5,
C6, C7, or C8 but without SLE demonstrated normal
CRA activity.
Thus, our results support the concept that immune complex solubilization does not require participation of the late-acting C components, and suggest that
the defective solubilization in the C7-deficient serum
described herein is due to an as yet undefined defect associated with SLE rather than to deficiency of C7 per se.
The findings of a more detailed study of immune complex solubilization in patients with SLE, which will be
the subject of a separate report (37), indicate that CRA
depression correlates directly with the severity of clinical disease in patients with active SLE, while SLE patients in complete remission display completely normal
CRA.
In conclusion, studies prompted by the identification of our C7-deficient patient with SLE revealed
that patients with a selective homozygous terminal C
component deficiency have an increased frequency (7%)
of SLE despite a normal ability to solubilize immune
complexes. Patients with selective homozygous deficiency of an early-acting C component have an even
higher frequency (41%) of SLE, as well as a markedly
reduced capacity to solubilize immune complexes. The
data pesented here suggest that patients with inborn terminal C component deficiencies are predisposed to the
development of SLE by a process which is independent
of the C-mediated ability to solubilize immune complexes. Whether the compromised capacity for C-mediated immune complex solubilization in patients lacking
ZEITZ ET AL
an early-acting C component contributes to the greater
incidence of SLE in these patients remains to be established.
ACKNOWLEDGMENTS
The authors wish to thank Lisbeth Suyehira for
thoughtful assistance and Dr. Zakira Khan for referring this
patient for study.
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93
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