Severe systemic lupus erythematosus with nephritis in a boy with deficiency of the fourth component of complement.код для вставкиСкачать
1519 SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS WITH NEPHRITIS IN A BOY WITH DEFICIENCY OF THE FOURTH COMPONENT OF COMPLEMENT J A N E G. SCHALLER, BRUCE G. GILLILAND, HANS D. O C H S , JOHN P. LEDDY, LAWRENCE C. Y. AGODOA, and STEPHEN I. ROSENFELD 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. 1977. 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. MATERIALS AND METHODS 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 SCHALLER ET AL I520 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 U/ml CI U/ml c4 U/ml <8 <8 <8 22,850 NDS ND <20 <20 CHm Date ~~~~ Nov 1974* July 19757 Dec 19758 Normal values: 75-160 75.486f 12,547 c3 mg/100 ml ~~ ND 159 72 178 23 76 12 94.300f 32.300 100200 <20 * 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. Properdin DNA FactorB Binding, % mg/100 ml 32 < 12 25 12-30 SLE WITH NEPHRITIS 1521 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 1). Complement studies were performed in family mem- SCHALLER ET AL 1522 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). DISCUSSION 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 1523 SLE WITH NEPHRITIS 1 20.8 6.4 I / i I I 32.0 8.8 i I III * See legend 0 0 Normal C4 (> Heterozygous for C4deficiency H Homozygous for C 4 deficiency HLA haplotypes HLA-A HLAB - 31 hemolytic U/ml x 1 0 I mg /dl I I---------- C4 levels I I 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 The 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 (26). 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 SCHALLER ET AL 1524 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. Addendum 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 infarction. REFERENCES I . Klemperer MR, Woodworth HC, Rosen FS, Austen, KF: Hereditary deficiency of the second component of complement (C2) in man. J Clin Invest 45:880-890. 1966 2. Cooper N R , ten Bensel R, Kohler PF: Studies of an additional kindred with hereditary deficiency of the second component of human complement (C2) and description of a new method for the quantitation of C2‘a2. J lmmunol 101:1176-1182, 1968 3. Agello V, DeBracco MME, Kunkel H C : Hereditary C2 deficiency with some manifestations of systemic lupus erythematosus. J Immunol 108:837-840, 1972 4. Moncada B, Noorbibi KBD, Good RA. Windhorst, DB: Lupus-erythematosus-like syndrome with a familial defect of complement. N Engl J Med 296:689-693, 1972 5 . Day NK, Geiger H. McLean R, et al: C2 Deficiency, development of lupus erythematosus. J Clin Invest 52: I601 - I 607, 1973 6. Kohler PF, Percy J, Campion WM, Smith CJ: Hereditary angioedema and “familial” lupus erythematosus in identical twin boys. Am J Med 56:406-411, 1974 7. Hauptmann G ,Grosshans E, Heid E: Lupus krythkmateux aigus et dkficits hkrkditaires en complement. Annales de Dermatologie et de Syphiligraphie 101:479-496, 1974 8. Osterland CK, Espinoza L, Parker LP, Schur PH: Inherited C2 deficiency and systemic lupus erythematosus: studies on a family. Ann Int Med 82:323-328, 1975 9. Rosenfeld SI, Kelly ME, Leddy J P Hereditary deficiency of the fifth component of complement in man. J Clin Invest 57: 1626- 1634. I976 10. Glass D, Raum D, Gibson D. et al: Inherited deficiency of the second component of complement. J Clin Invest 58:853-861, 1976 1 1 . Jasin HE: Absence of the eighth component of complement (C8) and SLE-like disease. Arthritis Rheum 19:803-804, 1976 12. Sussman M, Jones JH, Almeida JD, Lochman PJ: Deficiency of the second component of complement associated with anaphylactoid purpura and presence of mycoplasma in the serum. Clin Exp lmmunol 14531-539. 1973 13. Gelfand EW, Clarkson JE, Minta JO: Selective deficiency of the second component of complement in a patient with anaphylactoid purpura. Clin Immunol Immunopath 4: 269-276, 1975 14. Friend P. Repine JE. Kim Y, et al: Deficiency of the second component of complement (C2) with chronic vasculitis. Ann Int Med 83:813-816, 1975 15. Leddy JP, Griggs RC, Klemperer MR. Frank MM: Hereditary complement (C2) deficiency with dermatomyositis. Am J Med 58:83-91, 1975 16. Boyer JT, Gall EP, Normal ME, et al: Hereditary deficiency of the seventh component of complement. J Clin Invest 56:905-913, 1975 17. Buckley RH. Dees SC, O’Fallon WM: Serum immunoglobulins. I . Levels in normal children and in uncomplicated childhood allergy. Pediatrics 41:600-61 I. 1968 18. Bell DA, Lebland PF. Leddy JP, et al: Immune hemolysis. J lmmunol 108:467-474, 1972 19. Nelson RA Jr, Jensen J, Gigli I, Tamura N: Methods for the separation, purification and measurement of nine components of hemolytic complement in guinea-pig serum. lmmunochemistrv 3:1I1-135. 1966 20. Rapp HJ, Borsos T: Molecular basis of’complement action. New York, Appleton-Century-Crofts, 1970 21. Ochs HD, Rosenfeld SI, Thomas ED, et al: Linkage between the gene (or genes) controlling synthesis of the fourth component of complement and the major histocompatibility complex. N Engl J Med 296:470-476. 1977 22. Koffler D, Kunkel HG: Mechanisms of renal injury in systemic lupus erythematosus. Am J Med 45:165-169. 1968 23. Christian CL: Immune complex disease. N Engl J Med 280~878-884, 1969 24. Rothfield N , Ross HA, Minta J, Lepow IH: Glomerular and dermal deposition of properdin in systemic lupus erythematosus. N Engl J Med 287:681-685, 1972 25. Ziegler SB. Rosen FS, Alper CA, et al: Metabolism of properdin in normal subjects and patients with renal disease. J Clin Invest 56:761-767, 1975 26. Sitprija V, Pipatanagul V, Boonpucknavig V , Boonpucknavig s: Glomerulitis in typhoid fever. Ann Int Med 81:210-213. 1974 I525 SLE WITH NEPHRITIS 27. Schaller JG: Illness resembling lupus erythematosus in mothers of boys with chronic granulomatous disease. Ann Int Med 76:741-750, 1972 28. McLaughlin JF, Schaller JG, Wedgwood RJ: Arthritis and immunodeficiency. J Pediatr 81:801-803, 1972 29. Rodey GE, Park BH, Ford DK: Defective bactericidal activity of peripheral blood leukocytes in lipochrome his- tiocytosis. Am J Med 49:322-327, 1970 30. Leddy JP, Simons RL, Douglas RG: Effect of selective complement deficiency on the rate of neutralization of enveloped viruses by human sera. J lmmunol I18:28-34, 1977 31. Kohler PF: Quantitative comparison of complement in mother and newborn. Fed Proc 27:491, 1968 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.