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Severe systemic lupus erythematosus with nephritis in a boy with deficiency of the fourth component of complement.

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A young boy with severe systemic lupus erythematosus was found to be totally deficient in the fourth component of complement. Family studies were consistent
with an autosomal recessive mode of transmission and
with linkage of the gene(s) determining C4 deficiency to
the major histocompatibility complex; no disease states
were associated with heterozygosity. This patient has had
severe multisystem disease and immune complex glomerulonephritis; presumably the alternative pathway of complement was utilized in the pathogenesis of his nephritis.
From the Clinical Research Center Facility of the University
of Washington. Seattle. Washington. and the University of Rochester
School of Medicine, Rochester, New York.
Supported in part by The Arthritis Foundation (Arthritis
Clinical Research Center Grant to the University of Washington). the
National Institutes of Health Grant RR-37 (Clinical Research Center
Facility of the University of Washington), and by United States Public
Health Service Research Grant Al-12568 (University of Rochester).
Jane G. Schaller: Professor of Pediatrics, University of Washington, Seattle. Washington: Bruce G. Gilliland: Associate Professor
of Medicine and Laboratory Medicine, University of Washington.
School of Medicine. Seattle. Washington: Hans D. Ochs: Associate
Professor o f Pediatrics, University of Washington School of Medicine,
Seattle, Washington. Investigator of the Howard Hughes Medical
Institute; John P. Leddy: Professor of Medicine, University of Rochester School of Medicine. Rochester, New York; Lawrence C. Y.
Agodoa. formerly Instructor in Medicine, Nephrology and Pathology.
University of Washington School of Medicine, Seattle, Washington;
Stephen I. Rosenfeld: Assistant Professor of Medicine, University of
Rochester School of Medicine, Rochester. New York.
Address reprint requests to Dr. Jane Schaller, Department of
Pediatrics. RD-20. University of Washington, School of Medicine.
Seattle. Washington 98195
Submitted for publication April 1 I . 1977: accepted April 28.
Arthritis and Rheumatism, Vol. 20, No. 8 (November-December 1977)
Hereditary deficiencies of serum complement
components have been observed in healthy individuals
(1,2) and in patients with various rheumatic disorders
including lupus erythematosus (3-1 I ) , vasculitis
(l2-14), dermatomyositis (15). and Raynaud’s phenomenon (16). This report describes hereditary deficiency of
the fouth component of complement in a young boy
with severe systemic lupus erythematosus (SLE). This
patient is of particular interest because he has had severe
g l o m e r u l o n e p h r i t i s , presumably mediated by immune
complexes, in the presence of apparently total C4 deficiency.
Case Report
A 3-year-old white boy was referred for evaluation of
possible juvenile rheumatoid arthritis. Since age 8 months he
had had a chronic rash on his face, trunk, and extremities,
which was classified by a consultant dermatologist as “granuloma faciale.” At age 3 years several bouts of transient arthritis and fever occurred. When the patient was first seen in
arthritis clinic, he had no abnormal physical findings except a
chronic erythematous dry scaly rash on the cheeks and ears.
Erythrocyte sedimentation rate was elevated and a test for
antinuclear antibodies ( A N A ) was positive.
The patient remained clinically well until age 3 1/2
years when fever and arthritis recurred, along with malaise,
weight loss, and hepatosplenomegaiy. The knees, ankles, hips,
wrists, and finger joints were painful and swollen. The patient
was admitted t o the university hospital for evaluation and
found to have a positive test for A N A (titer of 1 :40), undetectable serum hemolytic complement (CH,,), leukopenia (white
blood count 3,000 cells per mma), and anemia (hematocrit
25%). Direct Coombs test was negative and platelet count was
normal. Serum glutamic oxaloacetic transaminase was 25
units/liter (normal <25), serum glutamic pyruvic transaminase was 78 units/liter (normal < 30 units); serum levels of
creatine phosphokinase and aldolase were normal. Repeated
urinalyses and creatinine clearances were normal. Serum
immunoglobulin levels were IgG 2,110 mg/dl, IgA 209 mg/dl
and IgM 210 mg/dl (normals for age and sex: IgG 539-1506,
IgA 53-336, and IgM 26-106) (17). Tests for Australia antigen
were negative. DNA binding was 23% (normal 20% or less)
and C3 was 159 mg/dl (normal 100-200). Properdin factor B
concentration was 32 mg/dl (normal 12-30) (Table I). Biopsy
of affected facial skin was consistent with lupus erythematosus
by light microscopy, but no immunofluorescent staining was
seen at dermal-epidermal junctions.
The patient was treated with salicylates and topical
steroids were applied to areas of rash. Fever, arthritis, and
hepatomegaly resolved, the rash faded, and weight gain and a
state of well being returned. Over the next 10 months the
patient was followed at monthly intervals; physical examinations, urinalyses, and serum levels of C3 and D N A binding
remained normal.
In July 1975, the patient and several family members
had an acute illness with diarrhea and fever. Within 2 weeks
the patient became pale, lethargic, febrile, and edematous.
Arthritis recurred. The patient was readmitted to the hospital
with a temperature of 39.5"C,extreme irritability, and marked
nuchal rigidity. He has gross leg and periorbital edema and
generalized arthritis and arthralgia. Blood pressure was normal. There were rales in both lung fields. Lumbar puncture
revealed clear cerebrospinal fluid which contained 19 lymphocytes per mms and normal levels of protein and sugar.
Urinalysis showed 4+ protein, numerous red and white cells,
and numerous red and white cell casts. Urinary protein excretion was 3 gm/24 hours. Serum albumin was 1.9 gm/dl, serum
globulins 3.9 gm/dl, creatinine clearance 59 ml/min/mz,
serum cholesterol 176 mg/dl (normal 120-260), white blood
cell count 4,900 per mrn', hematocrit 25%, and platelet count
425,300 per mm'. Serum C3 was 72 mg/dl (normal 100-200),
properdin factor B level was less than 12 mg/dl (normal
12-30), and DNA binding was 76% (normal < 20%) (Table I ) .
A chest radiograph showed bilateral pleural thickening and
infiltrates in both lung fields consistent with interstitial pneumonia. Stool culture grew Salmonella B; antibodies to Salmonella B were detectable in the patient's serum in a titer of 1 :200.
Blood cultures were sterile, throat and sputum cultures grew
no pathogens, and viral studies were unrevealing. Tuberculin
test (intermediate PPD) was negative.
The patient improved on therapy of prednisone. 60
mg/day, and ampicillin (100 mg/kg per day for 2 weeks), but
there was no remission of the nephrotic syndrome. After 4
weeks of prednisone therapy, chlorambucil was added in an
initial dose of 2 mg/day. This was followed by slow clinical
improvement with resolution of edema and return of clinical
well being. Proteinuria has continued over the next 18 months,
however, although serum levels of C3 and D N A binding have
returned to normal (Table I). Serum creatinine and creatinine
clearances have remained normal.
The father, age 3 1, and the mother, age 29, have been
in good health except for a history of atopic eczema in the
mother. One sister, age 2 years, has been in good health. There
has been no family history of rheumatic diseases or increased
susceptibility to infections.
Renal Pathology. Percutaneous renal biopsy was done
in July 1975, and specimens were fixed for light, fluorescence,
and electron microscopy.
Forty-five glomeruli were present for assessment by
light microscopy; none was obsolescent. There was diffuse
intraglomerular cellular proliferation, predominantly of mesangial and endothelial cells (Figure 1). Moderate mesangial
sclerosis was present in all glomeruli. The glomerular capillary
basal lamina was diffusely and irregularly thickened, with
many large subendothelial and mesangial deposits (Figure 2).
Eight glomeruli were present for immunofluorescence
study. All showed granular deposition of IgG (4+), IgA (3+),
IgM (2+), and C3 ( 4 + ) on the glomerular capillary basal
lamina and in mesangial areas.
On electron microscopy the endothelial cell cytoplasm
showed marked hypertrophy, with the lamina rara interna
irregularly expanded and containing many large subendothelial deposits. The lamina densa was likewise thickened
and contained many large intramembranous deposits. The
lamina rara externa also showed irregular expansion but without electron dense deposits. Visceral epithelial cells appeared
normal except for occasional areas of fusion of the foot proc-
Table 1. Clinical Findings of Patient with Systemic Lupus Erythematosus and Nephrotic Syndrome
Nov 1974*
July 19757
Dec 19758
Normal values:
mg/100 ml
* When patient was first seen, before clinically apparent nephritis.
t During episode of active glomerulonephritis and nephrosis.
3 Not done.
8 Following resolution
of nephrotic syndrome.
Binding, % mg/100 ml
< 12
Fig. I . Renal biopsy specimen showing diffuse intraglomerular cell prolijeration. irregularly thickened glomerular capillary basal lamina, with
large subendothelial deposits ( D),and moderately severe mesangial sclerosis. Methacrylate embedding, silver methenamine-Beibrich scarlet
stain. ( X 416.)
Fig. 2. Renal biopsy specimen showing moderately severe mesangial
sclerosis (MS)with mesangial deposits ID,)and irregularly thickened
glomerular capillary basal lamina, with subendothelial deposits ( D,).
Methacrylate embedding, hematoxylin and eosin stain. ( X 1040.)
esses. Moderate mesangial sclerosis was seen, and many electron dense deposits were present in the mesangium (Figure 3).
The mesangial cell cytoplasm appeared moderately increased,
with increased amounts of endoplasmic reticulum.
Complement Studies. Blood specimens for complement
assays were allowed to clot and the sera removed and frozen at
-70” within 2 hours. Total hemolytic complement (CH,,)
titrations were performed as described by Bell el a1 (18). C 3
and C4 were measured immunochemically by radial immunodiffusion using plates obtained from Hyland Laboratories
(Costa Mesa, California). Normal ranges were established
with serum samples from 25 healthy donors. Functional complement component assays were performed by modifications
(9) of previously described methods (19,20). Functionally pure
C4 and other components were obtained from Cordis Corporation (Miami, Florida). Properdin factor B was measured by
radial immunodiffusion using plates supplied by Behring
Diagnostics, Somerville, New Jersey.
Measurements of total hemolytic complement (CH,,)
in the patient’s serum were less than 8 units/mI on repeated
determinations (normals 75- 160). Hemolytic activity of the
patient’s serum was restored with the addition of purified C4.
Functional hemolytic assay for C4 was less than 20 units per
ml (normal controls 94,300 f 32.300). N o C4 was detected by
immunochemical methods. Functional hemolytic activity of
C I , C2. and C3 was present but reduced, although levels of C3
were normal as measured by immunodiffusion. Functional
hemolytic assays for C5, C6. C7, C8, and C 9 were normal.
Mixture of the patient’s serum with serum from normal subjects did not produce inhibition of complement activity. Levels
of properdin factor B were between 20.4 and 32 mg/100 ml on
several determinations in 1974; however, during the patient’s
acute exacerbation of disease with severe nephritis, the level of
properdin factor B fell t o 12 mg/l00 ml (normal 12-30) (Table
Complement studies were performed in family mem-
Fig. 3. Renal biopsy specimen showing thickened glomemlar capillary basal lamina (GBL) with subendothelial deposits ( D). endothelial cell cytoplasmic expansion ( EC). and macrophage ( M) in the capillary
lumen. Electromicrograph. ( X 7,700.)
bers, parents, siblings, and first degree relatives (Figure 4).
Functional hemolytic C4 levels in sera from seven family members were reduced, consistent with heterozygosity. A n eighth
individual (11-4)displayed variable C4 levels over an 18-month
period, ranging from heterozygous to normal ranges: since his
daughter (111-1) had C4 levels clearly in the heterozygous
range, he has been considered a heterozygote. Histocompatibility studies of family members demonstrated linkage of the
gene(s) determining C4 deficiency to the major histocompatibility complex (Figure 4) (21).
This patient had an apparently total deficiency of
the fourth component of complement. Findings in other
family members were consistent with an autosomal recessive mode of transmission. Subsequent family studies
showed that the heterozygous state of C4 deficiency was
linked to HLA haplotypes (21). No other family members were found to have total C4 deficiency or a history
of either rheumatic diseases or increased susceptibility to
infection. The fact that this patient was of an unlikely
age (onset a t age 8 months) a n d sex for SLE makes it
seem likely that his disease was related t o some predisposing factor, possibly the C4 deficiency. His lupus
has been severe, with involvement of multiple systems
including skin, joints, and kidneys, and probably lungs,
liver, and central nervous system as well.
This is the second report of C4 deficiency and
SLE; o n e case has been reported from Strasbourg (7).
Deficiency of C4 secondary to deficiency of CI esterase
inhibitor has also been suggested a s a predisposing factor to lupus ( 6 ) . Additional cases of lupus erythematosus have been associated with deficiency of other complement components, notably C2 (3,5,8,10), also Clr (4)
and C5 (9) and C8 ( I 1 ). Many such cases of SLE have
been mild a n d unassociated with severe nephritis. Since
lupus nephritis and many other manifestations of severe
SLE are thought to result from immune complex deposition utilizing the complement system to mediate inflammation (22.23). the occurrence of severe SLE with
severe nephritis in this C4 deficient patient is of particular interest. Deposition of immunoglobulins and C3 in
the kidney was consistent with a n immune complex
mechanism of nephritis despite the apparently total C4
deficiency. While both the classic a n d alternative pathways of complement may be activated in lupus patients
with intact complement systems (24,25), in this patient
with C4 deficiency only the alternative pathway would
be available for activation, a n d therefore utilization of
the alternative pathway must be postulated in the pathogenesis of the observed nephritis. In support of this,
properdin factor B elevation of anti-DNA antibodies
coincident with nephritis a n d lowering of the patient’s
/ i
See legend
0 0 Normal C4
(> Heterozygous for C4deficiency
Homozygous for C 4 deficiency
HLA haplotypes
- 31
hemolytic U/ml x 1 0 I
mg /dl
C4 levels
L _ _ _ _ _ _ _ _ _ _ _ _ _-J
Fig. 4. Males are represented by squares and females by circles. Thefamily members from three generations are identified by numbers; the
propositus is designated 111-3. The assigned genotypes of HLA-A. B. D and the C4 levels (mean of several determinations) OJ each Jamily
member are shown below each svmbol. The mean f I SD of the hemolytic C4 titer (63 normal individuals)is 94.3 f 32.3 U / m l X
mean f I SD oJthe C4 protein level (49 normal individuals) is 32.7 f 8 mgfdl. 11-4 displayed variable C4 levels over an 18-month
period ranging from the heterozygous to normal ranges; he must be considered a heterozygote since his daughier (111-1 ) has C4 levels
that are clearly in the heterozygous range. The single C4 determination on 111-2 was performed on umbilical cord blood; normal cord
blood has about half the adult level (31). 11-5 may represent a recombination.
serum C3 were consistent with immune complex disease.
These laboratory findings returned to normal with subsequent improvement of disease after therapy with
glucocorticoids and chlorambucil. Onset of the patient’s
clinical renal disease after a documented Salmonella B
infection is also of interest in view of reports of immune
complex nephritis associated with salmonella infections
The occurrences of SLE and other rheumatic
disease syndromes in individuals with complement deficiencies remain unexplained. It seems likely that the
disease states described are indeed associated in some
way with the complement deficiencies, although these
associations are unproved and it must be acknowledged
that complement values are more frequently determined
in rheumatic disease patients than in healthy individuals. The complement system is intimately involved in
both immune and inflammatory mechanisms. It is therefore reasonable to postulate that individuals with defects
of the complement system might have abnormalities
that predispose them to a disease such as SLE which is
associated with chronic inflammation and aberrant immune responses.
Perhaps pertinent to the occurrence of SLE in
complement-deficient patients are the occurrences of
certain rheumatic disease syndromes in patients with
several distinct immune defects: lupus-like illness in carriers of chronic granulomatous disease (27), arthritis in
hypogammaglobulinemia (28), and rheumatoid arthritis-like illness in lipochrome histiocytosis (29). In these
various conditions, the establishment of chronic rheumatic inflammation has occurred in individuals with
deficient immune function. Although the relationships
of these observations remain to be explained, they
would be consistent with a relationship of r h e u m a t i c
disease syndromes t o defects in immune or inflammatory function, or possibly t o latent infections t o
which immunodeficient patients might be predisposed.
Indeed, human sera lacking early c o m p l e m e n t components, including this patient’s C4 deficient s e r u m ,
have demonstrated an impaired rate of neutralization of
enveloped RNA and DNA viruses (30). Such observations and associations may prove valuable in ultimate
unraveling of t h e etiology and pathogenic mechanisms
of rheumatic diseases.
This patient suffered an exacerbation of fever and
clinical nephrosis in May 1977. He was readmitted to the
hospital and found to have septicemia with Moruxellu nonliquefaciens. The sepsis responded satisfactorily to antibiotic
therapy, but the nephrotic syndrome remained unresponsive
to therapy with prednisone and chlorambucil. In July the
patient contracted herpes simplex stomatitis and died suddenly 1 week later of fulminant pneumonia of several hours’
duration. On postmortem examination, both herpes virus and
cytomegalic inclusion virus were found in the lungs and
blood vessels; there was widespread active lupus, particularly in the kidneys, and there had been a recent myocardial
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Primer on the Rheumatic Diseases
Work will soon begin on a new edition (eighth) of the Primer on
the Rheumatic Diseases. The editor of this work welcomes suggestions
from the readers of Arthritis and Rheumatism for new subjects which they
would like to see included in the Primer, and any other advice they may
wish to offer concerning this publication. Please address correspondence
to: Dr. Gerald Rodnan, 985 Scaife Hall, Department of Medicine, University
of Pittsburgh, Pittsburgh, Pennsylvania 15261.
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