1438

BRIEF REPORT

A LUPUS-LIKE SYNDROME IN A PATIENT WITH DEFICIENCY OF THE SIXTH COMPONENT OF COMPLEMENT

FRANCESCO TEDESCO, CARLA M. SILVANI, MARIA AGELLI, ANNA M. GIOVANETTI, and STEFAN0 BOMBARDIER1

The hereditary deficiencies of the complement components have been found to be associated with different clinical manifestations. Systemic lupus ery- thematosus (SLE), lupus-like syndrome, and chronic glomerulonephritis occur frequently in patients who lack the early components (C1, C4, and C2), while subjects with deficiencies of C3, C3b-inactivator, and the late-acting components undergo frequent bacte- rial infections (1,2). In a recent survey of published and unpublished cases of C6, C7, and C8 deficiencies, Peterson et a1 (3) have emphasized the high incidence of infections by Neisseria meningitidis and N gonorr- hoeae in these patients. We wish to report an unusual case of C6 deficiency in a patient who is suffering from a lupus-like syndrome and has no history of bacterial infections.

Case Report. A 46-year-old woman (CL) was admitted in October 1977 to the Rheumatic Disease

From the Transplantation Immunology and Blood Transfu- sion Service, Ospedale Policlinico, Milan, Italy and the 1st Institute of Medical Pathology, University of Pisa, Italy.

Francesco Tedesco: Associate Professor of Immunology, University Hospital, Milan, Italy; Carla M. Silvani: Fellow in Immunohematology, University Hospital, Milan, Italy; Maria Agelli: Fellow in Rheumatology, University of Pisa, Italy; Anna M. Giovanetti: Fellow in Immunohematology, University Hospital, Milan, Italy; Stefan0 Bombardieri: Associate Professor of Rheuma- tology, University of Pisa, Italy.

Address reprint requests to Dr. F. Tedesco, Centro Trasfu- sionale e di Immunologia dei Trapianti, Ospedale Policlinico, via Frances0 Sforza, 35, Milano Italy.

Submitted for publication February 19, 1981; accepted in revised form May 21, 1981.

Arthritis and Rheumatism, Vol. 24, No. 11 (November 1981)

Unit of the University of Pisa for evaluation of an intermittent polyarthritis and Raynaud’s phenomenon of 3 months’ duration. In 1953, she suffered from a right fibrinous pleurisy that resolved in 1 month and recurred 8 years later. Between 1969 and 1971, she complained of several episodes of inflammatory arthri- tis of her left knee, which was treated with intraarticu- lar steroids. In 1974, the patient underwent a hysterec- tomy with ovariectomy for an ovarian cyst and vaginal leukoplasia. From 1971 until 3 months before admis- sion, she was free of joint symptoms. On July 1977, she noticed the onset of polyarthritis in both hands and feet, elbows, ankles, and shoulders and a Ray- naud’s phenomenon on both upper extremities. At the time she was admitted, results of physical examination were unremarkable, except for small digital vasculitic ulcers. The blood pressure was 130/85, and results of urinalysis were repeatedly normal with a creatinine clearance of 96 ml/minute. White blood count was 5.8 X 109/liter with normal differential; platelet count 206 x 10g/liter; and the hemoglobin level 12.2 gm/dl. Serum proteins were 6.3 gm/dl, and the electrophoret- ic pattern was in the normal range. The measurement of the immunoglobulins revealed IgG 1.1 gm/dl, IgA 198 mg/dl, and IgM 149 mg/dl. Coagulation screening tests did not show any abnormality.

The search for rheumatoid factor was positive at a titer of 1 : 80. A test for LE cell phenomenon was negative, but a test for antinuclear antibodies was positive at 1:lO dilution, and DNA binding was 5% with native (normal value < 10%) and 29% with heat- denatured DNA (normal value < 10%). A search for

BRIEF REPORTS 1439

extractable nuclear antigen (ENA) antibodies by pas- sive hemagglutination, counterimmunoelectrophore- sis, and immunodiffusion yielded negative results. Circulating immune complexes could not be found, although they were measured on repeated occasions both by a competitive enzyme immunoassay with solid phase bovine conglutinin (4) and by the C Iq binding test (5 ) . Tests of muscle enzymes, screening tests for coagulation, chest roentgenograms, and an esophago- gram all resulted in normal findings.

The most striking observation was the extreme- ly low CH50 hemolytic activity of the patient serum, which was confirmed over a followup period of 3 years and contrasted with the normal antigenic levels of C4, C3, and factor B. The results of the hemolytic tests for the individual components and the alternative pathway carried out as previously described (6) are shown in Table 1. The markedly reduced hemolytic activity of the patient serum is certainly dependent on C6, which was found to be less than 1%, compared to the control sera.

The activity of the alternative pathway was similarly reduced, but the function levels of all the other components were either within or at the lowest limit of the normal range, except for C5 and C7, which had a significantly reduced hemolytic activity. Split products of C3 searched for by cross-immunoelectro- phoresis as an indication of in vivo complement activa- tion were not found. The patient serum was also analyzed by immunodiffusion for the presence of anti-

Table 1. Hemolytic evaluation of the complement system in the patient’s serum

Patient’s serum, Normal range.

genic C6, using a specific antiserum raised in C6- deficient rabbits against rabbit C6 and cross-reacting with human C6. Precipitin lines were not seen at two different concentrations of the serum.

According to the dose-response curve estab- lished with increasing amounts of partially purified C6 (Cordis Laboratories, Miami, FL), as little as 20 units of C6 were able to fully restore the hemolytic activity of CL’s serum. Experiments carried out by mixing the patient serum with partially purified C6 did not show evidence for the presence of a C6 inhibitor in CL’s serum.

Complement-dependent biologic activities of the C6-deficient serum were investigated in regard to the ability of the serum to opsonize baker yeast cells for phagocytosis and Cundidu ulhicuns for killing by polymorphonuclear leukocytes (7); to promote chemo- taxis after activation of the alternative pathway (8-10); and to kill a strain of Eschericlziu coli 01 1 1 :B4 ( I I ) . All of these functions were found to be within the range of the controls, except for the bactericidal activity of the serum, which was undetectable. Family studies could not be performed because CL is an only child and both parents are dead.

Discussion. Complement studies carried out on the serum of a patient (CL), who had almost undetect- able hemolytic activity, enabled us to discover an additional case of selective C6 deficiency. This defi- ciency was established by the finding that the C6 hemolytic activity was less than 1% compared to that of the controls and by the ability of partially purified C6 to restore the lytic activity of the serum. C6 could not be found in the serum by immunochemical analy- sis. so the presence of a dysfunctional protein as a possible explanation of the markedly reduced hemo-

I

Component d m l d m l lytic activity of the serum is therefore unlikely. In addition, the results of mixing the patient serum with

CH50 71 890 ? 161 purified C6 did not provide evidence for a C6 inhibitor. Although the conclusion that the C6 deficiency CI 8.4 x 105 7.7 * 2 . 2 x 10’

c 4 1.4 x l o5 1.5 -c 0.6 x 10’ c2 5.9 x 104 7.3 1.4 x 104 of our patient has a genetic basis cannot be established

Classical pathway

~~

c3 Total Rabbit E GPEAC43 b - B Rabbit E GPEAC43b

c5 C6 C l C8 c9

Alternative pathway

Late-acting components

1 . 6 x 103

36 I37

92 350

1.9 X 10‘ 15

6.6 x 10‘ 4.0 x 104

12.2 x 104

2.6 2 0.5 x 10’

78 t 21 404 ? 34

129 t 20 436 2 130

6.3 5 0.9 x lo4 8.2 c 0.2 x 10’ 6.9 t 0.9 x lo4 8 .2 t 2.3 x 10‘ 6.7 * 2.2 x 104

because complement studies could not be performed on family members of CL, the possibility that the defect was acquired is very low because the deficiency is selective for C6, which was confirmed over a follow- up period of 3 years.

The function levels of C3 and factor B at the lowest limits of the normal range and the more pro- nounced reduction of C5 and C7 raise the question of the possible consumption of these components, which can only be definitely ascertained by in vivo metabolic studies. However, the results of the tests for immune

1440 BRIEF REPORTS

complexes and for split products of C3, which gave repeatedly negative results on many occasions, do not support the hypothesis of an in vivo process of com- plement activation. Moreover, complement activation does not explain the finding of a reduced hemolytic activity of C7, which occurs in spite of the absence of C6 and in the presence of either normal or elevated levels of C8 and C9. i t may well be that the deficiency of C6 is accompanied by hyposynthesis of C7 because of the close linkage of the loci for C6 and C7 (12), and this possibility is further supported by the discovery of a combined deficiency of C6 and C7 (13).

The association of the C6 deficiency with a lupus-like syndrome in our patient represents a rare observation (14), because SLE and lupus-like syn- drome are more frequently seen in patients who have deficiencies of the early components. It is surprising that our patient did not experience episodes of neisser- ial infections, which appear to be the hallmark of all the reported cases of C6 deficiency. Whether this is due to the lack of exposure of our patient to the bacteria of the genus Neisseria or due to other protec- tive mechanisms not involving the late-acting comple- ment components is not known.

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Escherichia coli p-galactosidase in the probe and of bovine conglutinin as the complex-binding reagent. Clin Immunol Immunopathol 16:131-141, 1980

5. Zubler RH, Lange G, Lambert PH, Miescher PA: De- tection of immune complexes in unheated sera by a modified '251-Clq binding test: effect of heating on the binding of Clq by immune complexes and application of the test to systemic lupus erythematosus. J Immunol

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7. Lehrer RI, Cline MJ: Interaction of Candida albicans with human leukocytes and serum. J Bacteriol 98:996- 1004, 1969

8. Wilkinson PC: Neutrophil leukocyte function tests, Techniques in Clinical Immunology. Edited by RA Thompson. Oxford, Blackwell, 1977, pp 201-218

9. Beebe DP, Ward PA, Spitznagel JR: Isolation and characterization of an acidic chemotactic factor from complement-activated human serum. Clin Immunol Irn- munopathol 15:88-105, 1980

10. Zigmond SH, Hirsch JG: Leukocyte locomotion and chemotaxis: new methods for evaluation, and demon- stration of a cell-derived chemotactic factor. J Exp Med 137:387-410, 1973

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12. Hobart MJ, Joysey V, Lachmann PJ: Inherited structur- al variation and linkage relationship of C7. J Immuno- genet 5:157-163, 1978

13. Lachmann PJ, Hobart MJ, Woo P: Combined genetic deficiency of C6 and C7 in man. Clin Exp Immunol

14. Trapp RG, Mooney H, Husain I , Coleman TH, Forristal J , Herman JH: Hereditary complement (C6) deficiency with discoid lupus/Sjogren's syndrome. Arthritis Rheum 23:757, 1980

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