THE JOURNAL OF INFECTIOUS DISEASES. VOL. 140, ]\0. 1 • JULY 1979 © 197!} by The University of Chicago. 0022-1899179/4001-0001$01.02

MAJOR ARTICLES Assessment of Serum Factor B, Serum Opsonins, Granulocyte Chemotaxis, and Infection in Nephrotic Syndrome of Children Donald C. Anderson, Thomas L. York, Gilbert Rose, and C. Wayne Smith

From the Departments of Human Development and Anatomy, Michigan State University, East Lansing, Michigan; the Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri; and the Department of Pediatrics, Baylor College of Medicine, Houston, Texas

Pediatric patients with nephrotic syndrome are at high risk for the development of severe systemic infections, which in turn constitute the leading cause of death during the initial years of disturbed renal function in these patients [1-9]. Received for publication July 31, 1978, and in revised form November 13,1978. This study was supported in part by the National Institutes of Health biomedical research support grants to Michigan State University (no. 71·9040 and no. 71·9004) and in part by Eli Lilly Laboratories support grant no. 7145D. The authors thank Jennifer Huntzberger, Eileen Bostwick, and James Hollers for technical assistance. The authors appreciated the inspiration, cooperation, and valuable suggestions provided by Drs. Donald Kaufman (Pediatric Nephrology Section, Department of Human Development, Michigan State University, East Lansing) and Allen Robson (Pediatric Nephrology Section, St. Louis Children's Hospital). We also thank Drs. William B. Weil, M. E. Norman, M. D. Yow, and Ralph D. Feigin for their helpful suggestions and review of the manuscript.

Although the pathogenesis of infectious complications is not fully understood, the high proportion of cases of nephrotic syndrome following infections with enteric gram-negative rods and organisms containing capsular polysaccharides suggests an abnormality of serum complement function in these children at the time of infection. In support of this possibility, Mcl.ean et al. [10] have recently documented impaired serum opsonic activity for Escherichia coli associated with significantly decreased values for properdin factor B during exacerbations of disease in nephrotic patients. To explore further the potential importance of serum complement activity in the pathogenesis of infections in nephrotic syn-

Please address requests for reprints to Dr. Donald C. Anderson, Infectious Disease Section, Texas Children's Hospital, 6621 Fannin, Houston, Texas 77030.

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Chemotactic and opsonic functions and concentrations of factor B were investigated in serum from 18 steroid-sensitive and four steroid-resistant pediatric patients with nephrotic syndrome during various clinical states. Placement of sera from nephrotic children in relapse in the stimulant compartment of Boyden chambers resulted in chemotaxis scores that were significantly lower (P < 0.001) than scores for remission or control sera. Scores observed for zymosan-activated sera of relapsing nephrotic patients were also diminished compared with scores for sera from the same patients during remission or scores for sera from adult controls. In a modified chemiluminescence assay, opsonic activity for zymosan in relapse sera was diminished significantly (P < 0.05, P < 0.01) compared with that in remission and control sera respectively. Chemiluminescent values increased in all cases in remission sera compared with those in the respective relapse sera. As demonstrated by indirect immunofluorescence, C3 zymosan deposition in relapse sera was generally decreased compared with that in the respective remission sera or in control sera. Concentrations of factor B (mean ±SE, in mgjdl) in relapse sera (9.13 ± 1.0) were significantly lower (P < 0.001) than concentrations in remission sera (22.1 ± 1.3) or in adult (control) sera (23.1 ± 1.4). Systemic bacterial infection of nephrotic patients in relapse states was related to decreased values for serum chemotaxis, chemiluminescence, and immunofluorescence and diminished concentrations of factor B in serum.

2

drome, we investigated serum opsonic activity and chemotactic functions in nephrotic populations. Our results are presented in this report. Materials and Methods

pensions obtained from the cell button generally contained >97% granulocytes. Granulocyte suspensions isolated for use in phagocytosis experiments were hypotonically lysed to eliminate erythrocyte contamination, washed twice, and resuspended in PBS with 0.2% dextrose. Immunodiffusion assays of factor B C3, and albumin in serum. Immunodiffusion assays of serum for factor B, C3, and albumin were performed as previously described [11]. All determinations were performed on sera that had been stored at -70 C. Serial dilutions of reference sera were placed on each immunodiffusion plate used for test sera and assayed as a check for control values. Chemotaxis assays. The humoral and cellular contributions to granulocyte chemotaxis were evaluated using a modified Boyden technique [12] with Boyden chambers (no. 100-187; Neuroprobe, Bethesda, Md.) and filters with a pore size of 3 fLm (Mi'llipore Corp., Bedford, Mass.), In most experiments, fresh sera were used, but in some assays, serum samples stored at -70 C (thawed only once) were used. Directed migration of patient cells or healthy adult control cells was assessed by placing granulocyte suspensions in fresh control plasma (10% in PBS) in the cell compartment (4 X 104/mm2 of filter surface area) together with patient or control sera or zymosan-activated sera (1070 in PBS) in the stimulant compartment. Activation was carried out by incubation of zymosan A (Sigma) in sera (I mg/ml) at 37 C for 60 min prior to centrifugation at 800 g for )0 min and removal of zymosan particles. To evaluate the possibility of cell-directed chemotactic inhibitors, suspensions of control granulocytes in patient plasma or sera (10% in PBS) in the cell compartment were subjected to control sera or zymosan-activated control sera in the stimulant compartment. All assays in the chemotaxis chambers were performed in duplicate, and sera of healthy adult controls were assayed simultaneously with each patient sera. After incubation for 3 hr in an atmosphere of 10% CO:!, the number of cells migrating through and attached to the bottom surface of a Millipore filter with 3-fLm pores was counted in 10 high-power (magnification, x40) fields. For purposes of comparisons between paJ

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Patients. The study population consisted of 22 individuals, 17 male and five female, between six months and 18 years of age, with nephrotic syndrome. All patients enrolled were followed in the pediatric nephrology clinics of Michigan State University or by the pediatric nephrology division, St. Louis Children's Hospital. Informed consent for the reported studies was obtained from all patients or parents of patients included in the study. A diagnosis of nephrotic syndrome was made on the basis of proteinuria, hypoalbuminemia, and clinical edema. Eighteen patients in the study population were responsive to steroid therapy; of these, five were steroid-dependent. Results of renal biopsies performed in 12 of these 18 patients were interpreted as normal ("nil lesion"). In four patients clinically resistant to corticosteroid therapy, renal biopsies revealed membranous glomerulonephritis in two, focal glomerulosclerosis in one, and normal histology in one. Patients were assigned to categories of "severe relapse," "partial remission," or "remission" on the basis of severity of clinical edema, proteinuria, and hypoalbuminemia. "Severe relapse" patients included only those individuals who demonstrated clinical edema and serum albumin values of 3.0 g/dl at the time of investigation. Isolation of granulocytes. Leukocyte suspensions were obtained by dextran sedimentation of heparinized (10 units /rnl) samples of whole blood. Leukocytes were separated from plasma by centrifugation (300 g for 10 min) and resuspended in sterile phosphate-buffered saline (PBS) prior to density gradient centrifugation (800 g for 20 min) with Ficoll-Hypaque (Winthrop, New York, N.Y.; Sigma, St. Louis, Mo.). Sus-

Anderson et al,

Infections in Nephrotic Children

15]. CL was quantitated in a liquid scintillation spectrometer (model LS-I00; Beckman Instruments, Irvine, Calif.) in the out-of-coincidence mode and a setting of 0.2% SE in the tritium region. Experiments were performed at 31 C in a partially darkened room. Reaction mixtures containing 10 /Lg of bovine serum albumin and IO-T M of luminol (5-amino-2,3-dihydro-l,4-phthalazinedione; Sigma) in 0.1 ml of PBS with 0.2% dextrose were prepared in 1.5ml conical polyethylene microvials. Under red il-

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Figure 4. Chemiluminescent activity of phagocytosis reaction mixtures containing zymosan particles opsonized in sera from nephrotic patients in relapse and remission, control pooled human sera, or heat-inactivated (56 C, 60 min) sera. Left, tracings of time vs. activity for 11 pooled human sera ( _), 17 sera from nephrotic patients in remission (~I~ ), 16 sera from nephrotic patients in relapse (WI~), and 12 heat-inactivated sera ( • -), compared with base-line (no zymosan; . . ) experiments. Solid bars indicate ± SD of mean group values. Right, individual peak values for chemiluminescence. Numbers in parentheses indicate number of sera studied. Solid diagonal lines connect values for individual patients assessed during both relapse and remission. Dotted bars indicate ± SD of mean (0) group values.

strated between corticosteroid regimen and Boyden assay scores, CL, or C3 values. Clinical findings and laboratory determinations in selected nephrotic patients. Table 4 summarizes the clinical findings and laboratory investigations of six "nil lesion" nephrotic patients who were studied serially at different stages of their disease. Patients no. 3 and no. 4 acquired pneumococcal sepsis and peritonitis during exacerbations of their disease. With few exceptions, factor B, Boyden chamber chemotaxis scores, CL activity, and C3 zymosan binding were higher in these patients during remission than during partial remission or severe relapse. The apparent discrepancies with respect to patient no. 3 are difficult to explain. Except for a decreased concentration of serum albumin (0.4 g/ 100 ml),

other determinations performed on day I reflected normal values or values comparable to corresponding remission values on day 60. By day 6, when clinical infection presented, factor B levels, Boyden chemotaxis scores, and CL activity were substantially diminished compared with values on day 1 and day 60. Discussion

Previous investigators have implicated excessive urinary loss and accompanying decreased concentrations of serum immune globulins as a partial explanation for infectious complications during the active stages of disease [3, 16-20J. Additional reports have provided indirect evidence that minimal-change nephrotic syndrome

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1.0- I 0.5 ..-...----...... Figure 5. Deposition of C3 on zymosan particles incubated in sera from nephrotic patients in severe relapse, partial remission, and remission. A range of scores from 0.5 (trace) to 3 + (strong) fluorescence was determined as described in Materials and Methods.

may represent a primary immunologic disorder [21-26]. Inflammatory functions dependent on serum complement, including leukocyte chemotaxis and opsonic activity, have not been evaluated sufficiently in nephrotic populations. Further assessment is of critical importance, because these nonspecific immune functions provide a fundamental first-line defense against microbial invasion, especially in nonimmune hosts [27]. Clinical disorders characterized by infections resulting from specific aberrations of serum complement activity have been well documented [29-35]. Enhanced susceptibility to infection in these pathologic states is thought to result from impaired generation in serum of activated complement components with opsonic and/or chemotactic properties. Infections in these disorders are generally secondary to encapsulated bacterial pathogens whose virulence is primarily de-

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pendent upon antiphagocytic properties that are effectively neutralized by serum opsonins in normal individuals [27]. The well-recognized predominance of infections due to encapsulated (especially S. pneumoniae) or gram-negative enteric organisms in nephrotic populations suggests a defect of complement-mediated inflammatory function at the time that infections are acquired [1, 2, 5-7]. Enhanced susceptibility to these pathogens by nephrotic children could be explained by aberrations of alternative complement pathway function, because capsular polysaccharide and/or endotoxin selectively activate this pathway in vitro and presumably in vivo in the absence of specific antibody [27]. Increased susceptibility to bacterial infections in part related to diminished activation of alternative-pathway C3 has been documented in other pathologic entities such as sickle cell anemia [33] and combined C2-factor B deficiency [28] and in neonates [15,30,36]. Our findings have confirmed previous observations by Mcf.ean et al. in a comparable nephrotic population [10]. Serum factor B values were significantly lower in patients during relapse than values during remission or values for controls. Decreased values were noted in steroidresponsive as well as steroid-resistant patients, and a highly significant correlation between serum factor B and serum albumin values was noted. An association of decreased concentrations of serum factor B and impaired opsonic function in relapsing nephrotic patients reported by Mcl..ean et al. [10] was also observed in our investigations using different functional assays. Diminished serum opsonic activity for E. coli as demonstrated by bactericidal and radiolabel-uptake techniques in the former report [10] in addition to impaired zymosan opsonization as shown by CL and immunofluorescence techniques suggests the possibility of impaired alternative pathway function in active nephrotic states. Norman and Miller [37] previously investigated chemotactic function in a small group of steroid-sensitive "nil lesion" nephrotic patients in clinical remission. They reported that "spontaneous" serum chemotactic activity (defined as activity generated from heat-treated sera [56 C, 60 min]) was significantly elevated in comparison with control values. Although test sera in

Infections in Nephrotic Children

Table 4. Clinical and laboratory features of six "nil lesion" nephrotic patients investigated during exacerbations and remissions of their disease.

Day of determination, clinical status

Serum factor B (mg/dl)

Peak serum CL activity (cpm)"

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6.8 12.4

42,000 81,000

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1.13 1.93

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our investigation were not similarly heat-treated, counts in Boyden chemotaxis chambers containing sera from patients in remission also were elevated, although not significantly so, when com pared with controls. As in the investigation by Norman and Miller [37], we noted no significant correlation of chemotactic function in our patients with respect to duration of disease or to regimen of corticosteroid treatment. Our observations in steroid-sensitive "nil lesion" nephrotic patients during relapse states revealed significant alterations in the results of the Boyden assay. Counts in chemotaxis chambers containing sera from relapsing nephrotic patients were decreased significantly. We were unable to document abnormal behavior in the patients' granulocytes or evidence for an inhibitor of chemotaxis or cellular motility. The association of decreased levels of serum factor B and decreased counts in chemotactic assays utilizing patient sera or zymosan-activated patient sera in relapse states could suggest a functional disorder of serum complement. Diminished values for serum factor B despite normal serum concentrations of other complement proteins, lower

counts for zymosan-activated serum, and the correlative opsonic data in this report and in the investigation of Mel.can et al. [10] support the possibility of impaired activity of the alternative pathway. Diminished counts in Boyden chemotaxis chambers demonstrated in this report may be due to factors unrelated to serum complement function. A highly significant correlation of diminished counts and serum albumin values was noted in our investigation. Wilkinson [38] recently reported the possible importance of albumin in potentiating in vitro chemotactic activity of a variety of cytotoxins. The role of serum albumin in altering granulocyte adherence to micropore filters in Boyden chambers is currently under investigation in our laboratory.' Reconstitution studies designed to evaluate selectively a possible pathologic role of serum albumin as well as serum complement in relapsing nephrotic patients will be of critical importance. 1 T. L. York, J. C. Hollers, R. A. Patrick, and C. W. Smith, "Alterations of Human Polymorphonuclear Leukocyte Adhesiveness: Effect on Motility in Vitro," manuscript in preparation.

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17. References 1. Feigin, R. D., Shearer, W. T. Opportunistic infection in children. II. In the compromised host. J. Pediatr. 87:677-694,1974. 2. Speck, W. T., Dresdale, S. S., McMillan, R. W. Primary

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peritonitis and the nephrotic syndrome. Am. J. Surg. 127:267-269, 1974. Giangiacomo, J., Cleary, T. G., Cole, B. R., Hoffsten, P., Robson, A. M. Serum immunoglobulins in the nephrotic syndrome. A possible cause of minimalchange nephrotic syndrome. N. Engl. J. Med. 293:812,1975. Lawson, D., Moncrieff, A., Payne, W. W. Forty years of nephrosis in childhood. Arch. Dis. Child. 35:115-126, 1960. Pahmer, M. Pneumococcus peritonitis in nephrotic and non-nephrotic children. A comparative clinical and pathologic study with a brief review of the literature. J. Pediatr. 17:90-106, 1940. Wilfert, C., Katz, S. Etiology of bacterial sepsis in nephrotic children, 1963-1967. Pediatrics 42:840-843, 1968. Fowler, R. Primary peritonitis: changing aspects 19561970. Aust. Paediatr. J. 7:73-83,1971. Bose, B., Keir, W. R., Godberson, C. V. Primary pneumococcal peritonitis. Can. Med. Assoc. J. 110:305307,1974. Squire, J. R. The nephrotic syndrome. Br. Med. J. 2: 1389-1399, 1953. McLean, R. H., Forsgren, A., Bjorksten, B., Kim, Y., Quie, P. G., Michael, A. F. Decreased serum Factor B concentration associated with decreased opsonization of Escherichia coli in the idiopathic nephrotic syndrome. Pediatr. Res. 11:910-916, 1977. McLean, R. H., Michael, A. F. Properdin and C3 proactivator: alternate pathway components in human glomerulonephritis. J. Clin. Invest. 52:634-644, 1973. Smith, C. W., Hollers, J. C., Duprees, E., Goldman, A. S., Lord, R. A. A serum inhibitor of leukotaxis in a child with recurrent infection. J. Lab. Clin. Med. 79:878-885, 1972. Hemming, V. G., Hall, R. T., Rhodes, P. G., Shigeoka, A. 0., Hill, H. R. Assessment of group B streptococcal opsonins in human and rabbit serum by neutrophil chemiluminescence. J. CIin. Invest. 58: 1379-1387, 1976. Anderson, D. C., Huntsberger, J., Marquez, V. Luminol enhanced chemiluminescence of neonatal granulocytes and monocytes [abstract no. 677]. Pediatr. Res. 12:476,1978. Hill, H. R., Hogan, N. A., Bale, J. F., Hemming, V. G. Evaluation of non-specific (alternate pathway) opsonic activity by neutrophil chemiluminescence. Int. Arch. Allergy Appl. Immunol. 53:490-497,1977. Routh, J. I., Knapp, E. L., Kobayashi, C. K. Electrophoretic studies of plasma and urinary proteins in children with lipoid nephrosis. J. Pediatr. 33:688697, 1948. Longsworth, L. G., MacInnes, D. A. An electrophoretic study of nephrotic sera and urine. J. Exp. Med. 71: 77-82,1940. Momma, K. Immunochemical semiquantitative estimation of ')1M and ')IA immunoglobulins in healthy and diseased children. Acta Paediatr. Jpn. 7:13-22, 1965. Conn, H. 0., Fessel, J. M. Spontaneous bacterial peri-

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The precise relationship between concentrations of serum factor B and functional activity of the alternative complement pathway is uncertain. In our investigation and that of Mcl.ean et al. [10], most but not all patient sera deficient in factor B were also opsonically deficient. Hill et al. [15] demonstrated deficient opsonic activity for zymosan in approximately two-thirds of sera from full-term and premature infants; this deficiency was generally related to diminished concentrations of serum factor B. In an additional investigation of healthy neonates, serum concentrations of properdin and factor B and activity of C3-C9 were markedly depressed. CH 50 titers for rabbit erythrocytes (the amount of complement that lyses 50~~ of sensitized cells) in 75% of cord sera samples studied were significantly diminished below mean values for adult sera. Addition of excess purified C3-C9, factor B, or properdin independently was only partially effective in reconstitution of CH 50 titers [36]. Since serum concentrations of properdin, C3, C4, and other classic complement components are normal in relapsing nephrotic patients [10, 39], the defect in nephrotic syndrome is more selective than that of the neonate. Although urinary loss and secondary depletion of serum factor B has been well documented [10], the possibility of enhanced complement activity with consumption of specific components also must be considered. Elevated "spontaneous" activity in the nephrotic populations studied by Norman and Miller [37, 40] supports the possibility of enhanced serum complement activity at least in nephrotic patients in remission. Levinsky et al. [24] and Poston et al. [41] have documented the presence of circulating IgG immune complexes in steroid-responsive nephrotic patients, especially during early relapse stages of their disease. Levinsky et al. [24] have speculated that since IgG immune complexes in their patient population did not bind Clq, the antigens and/or antibodies in those complexes may have activated the alternative complement pathway.

Infections in Nephrotic Children

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39.

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41.

nate: humoral and cellular aspects. Pediatr. Res. 5: 487-492, 1971. Miller, M. E., Nilsson, U. R. A familial deficiency of the phagocytosis-enhancing activity of serum related to a dysfunction of the fifth component of complement (C5). N. Engl J. Med. 282:354-358, 1970. Stossel, T. P., Alper, C. A., Rosen, F. S. Opsonic activity in the newborn: role of properdin. Pediatrics 52: 134-137,1973. Johnston, R. B., Jr., Newman, S. L., Struth, A. G. An abnormality of the alternate pathway of complement activation in sickle-cell disease. N. Eng!. J. Med. 288: 803-808, 1973. Alper, C. A., Bloch, K. J., Rosen, F. S. Increased susceptibility to infection in a patient with type II essential hypercatabolism of C3. N. Eng!. J. Med. 288: 601-606,1973. Alper, C. A., Abramson, N., Johnston, R. B., Jr., Jandl, J. H., Rosen, F. S. Increased susceptibility to infection associated with abnormalities of complementmediated functions and of the third component of complement (C3). N. Engl. J. Med. 282:349-354, 1970. Adamkin, H., Stitzel, A., Urmson, J., Farnett, M. L., Post, E., Spitzer, R. Activity of the alternative pathway of complement in the newborn infant. J. Pediatr.93:604-608,1978. Norman, M. E., Miller, M. E. Spontaneous chemotaxis in patients with glomerulonephritis and the nephrotic syndrome. J. Pediatr. 83:390-398, 1973. Wilkinson, P. C. A requirement for albumin as a carrier for low molecular weight leukocyte. Chemotactic factors. Exp, Cell. Res. 103:415-418, 1976. Norman, M. E., Mandel, R., Nilsson, U. R. Further studies of a humoral chemotactic abnormality in glomerulonephritis. Int. Arch. Allergy Appl. Immu1101. 56:144-154,1978. Norman, M. E., Miller, M. E. Spontaneous chemotaxis in acute glomerulonephritis: demonstration of a positive correlation with disease activity. J. Pediatr. 85: 20-24,1974. Poston, R. N., Cerio, R., Cameron, J. S. Circulating immune complexes in minimal-change nephritis. N. Engl. J. Med. 298:1089,1978.

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toni tis in cirrhosis: variations on a theme. Medicine (Baltimore) 50: 161-197,1971. Peterson, P. A., Berggard, I. Urinary immunoglobulin components in normal, tubular and glomerular proteinuria: quantities and characteristics of free light chains, IgG, IgA and Fc 'Y fragment. Eur. J. Clin. Invest. 1:255-264, 1971. Shalhoub, R. J. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2:556-560, 1974. Michael, A. F., McLean, R. H., Roy, L. P., Westberg, N. G., Hoyer, J. R., Fish, A. J., Vernier, R. L. Immunologic aspects of the nephrotic syndrome. Kidney Int. 3:105-115,1973. Ooi, B. S., Orlina, A. R., Masaitis, L. Lymphocytotoxins in primary renal disease. Lancet 2: 1348-1350, 1974. Levinsky, R. J., Malleson, P. N., Barratt, T. M., Soothill, J. F. Circulating immune complexes in steroid-responsive nephrotic syndrome. N. Eng!. J. Med. 298: 126-129, 1978. Smith, M. D., Barratt, T. M., Hayward, A. R., Soothill, J. F. The inhibition of complement-dependent lymphocyte rosette formation by the sera of children with steroid-sensitive nephrotic syndrome and other renal diseases. Clin. Exp. Immunol. 21:236-243, 1975. Groshong, T., Mendelson, L., Mendoza, S., Bazaral, M., Hamburger, R., Tune, B. Serum IgE in patients with minimal-change nephrotic syndrome. J. Pediatr, 83: 767-771,1973. Stossel, T. P. Phagocytosis (in three parts). N. Eng!. J. Med.290:717-723, 774-780,833-839,1974. Newman, S. L., Vogler, L. B., Feigin, R. D., Johnston, R. B., Jr. Recurrent septicemia associated with congenital deficiency of C2 and partial deficiency of Factor B and the alternate complement pathway. N. Engl. J. Med. 299:290-292,1978. Gewurz, H., Page, A. R., Pickering, R. J., Good, R. A. Complement activity and inflammatory neutrophil exudation in man: studies in patients with glomerulonephritis, essential hypocomplementemia, and agammaglobulinemia. Int. Arch. Allergy Appl. Immunol. 32:64-90, 1967. Miller, M. E. Chemotactic function in the human neo-

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Assessment of serum factor B, serum opsonins, granulocyte chemotaxis, and infection in nephrotic syndrome of children.

THE JOURNAL OF INFECTIOUS DISEASES. VOL. 140, ]\0. 1 • JULY 1979 © 197!} by The University of Chicago. 0022-1899179/4001-0001$01.02 MAJOR ARTICLES As...
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