Original Article
Nephrotoxic Potential of Bence Jones Proteins
N Engl J Med 1991; 324:1845-1851June 27, 1991
- Abstract
- Abstract
Background.
The renal manifestations of diseases associated with the production of monoclonal light chains—myeloma (cast) nephropathy, light-chain deposition disease, and amyloidosis AL—result from the deposition of certain Bence Jones proteins as tubular casts, basement-membrane precipitates, or fibrils, respectively. For unknown reasons, the severity of the renal manifestations of these diseases varies greatly from patient to patient. We employed an experimental in vivo model to determine the pathologic importance of various Bence Jones proteins.
Methods.
Mice were injected intraperitoneally with 300 mg of Bence Jones protein from 40 patients with multiple myeloma or amyloidosis AL and killed 48 hours later. The mouse kidneys were examined by light and electron microscopy, and light-chain deposits were identified immunohistochemically with highly specific antihuman light-chain antiserum.
Results.
Of the 40 different human Bence Jones proteins studied, 26 were deposited in the mouse kidneys predominantly as tubular casts, basement-membrane precipitates, or crystals; no light-chain deposits were detected in the kidneys of the mice that received the other 14 Bence Jones proteins. Of the 18 patients for whom renal tissue was available for study, the findings in 14 were comparable to those in the mice. Furthermore, the proteins obtained from 22 of the 27 patients whose serum creatinine concentrations equaled or exceeded 168 μmol per liter (1.9 mg per deciliter) were deposited in the mouse kidneys, whereas protein deposition occurred after the injection of proteins from only 4 of the 13 patients with serum creatinine concentrations below 168 μmol per liter. The repeated injection of Bence Jones proteins from two patients who had amyloidosis AL resulted in deposition of the protein in the mouse kidneys as amyloid.
Conclusions.
Particular Bence Jones proteins are primarily responsible for producing the distinctive types of protein deposition in renal tissue and the clinical manifestations that occur in patients with light-chain—associated diseases. This experimental model has potential value for the identification of nephrotoxic or amyloidogenic light chains. (N Engl J Med 1991; 324:1845–51.)
Media in This Article
Figure 1
Forms of Renal Light-Chain Deposition Observed Experimentally in Mice and Clinically in Patients with Multiple Myeloma or Amyloidosis AL.Table 1
Clinical and Experimental Observations of the Renal Deposition of Bence Jones Proteins from Patients with Multiple Myeloma or Amyloidosis AL.Article Activity
- Article
BENCE Jones proteins are of pathophysiologic importance in renal and systemic diseases associated with increased production of light chains. These diseases include myeloma (cast) nephropathy, light-chain deposition disease, and amyloidosis AL.1 Their renal manifestations are characterized by the deposition of monoclonal light chains — i.e., Bence Jones proteins — as casts within tubules (in myeloma nephropathy), linear precipitates or nodules in tubular, glomerular, and vascular basement membranes and mesangial tissue (in light-chain deposition disease), or fibrils located in blood-vessel walls and glomeruli as well as interstitially (in amyloidosis AL).2 3 4 5 6 7 8 These light-chain deposits ultimately result in the impairment of renal function and account for much of the morbidity and mortality in patients with these disorders.9 10 11
Although a number of host factors may contribute to renal damage in patients with Bence Jones proteinuria, there is evidence that differences in the physical and chemical properties of the proteins themselves12 13 14 15 16 17 18 19 20 21 22 23 24 account for the apparently "benign" nature of certain Bence Jones proteins, as opposed to the "malignant" propensity of others to form casts, linear precipitates, fibrils, or other types of deposits.25 Heretofore, the ability to recognize potentially nephrotoxic or amyloidogenic light chains has been limited. The availability of an experimental model to identify Bence Jones proteins of pathologic import could have prognostic relevance. In addition, the model would be useful in elucidating the factors that affect light-chain deposition and could thus be of therapeutic value.
Several types of in vivo experimental systems have been employed to demonstrate the nephrotoxicity of human Bence Jones proteins.12 , 14 , 17 , 22 23 24 , 26 27 28 In one such study, Koss et al.26 reported that the intraperitoneal injection of a human Bence Jones protein into mice resulted in the extensive deposition of the administered protein in the form of casts within the distal tubules of the recipient animals; in contrast, two other proteins failed to induce such deposits. Whether these experimental findings were related to the presence or absence of myeloma (cast) nephropathy in the three patients could not be established because of the lack of clinical information about the patients. However, because the experimentally induced Bence Jones protein nephropathy in the mice closely resembled the pathologic features of myeloma (cast) nephropathy in humans, and because both species metabolize light chains similarly,29 we used the mouse model to assess the nephrotoxic potential of a large number of well-characterized human Bence Jones proteins obtained from patients for whom renal functional and pathological data were available. We demonstrated the capacity of certain of these human monoclonal light chains to deposit in mouse kidneys not only in the form of tubular casts, but also as basement-membrane precipitates, crystals, or amyloid fibrils. Furthermore, the similarities between the experimental and clinical forms of light-chain deposition demonstrate the predictive value of the mouse model in differentiating malignant from benign Bence Jones proteins.
Methods
Clinical Data
We studied 40 patients with multiple myeloma or amyloidosis AL and Bence Jones proteinuria. The diagnosis of multiple myeloma or amyloidosis was established by appropriate clinical and laboratory criteria, and the initial serum creatinine concentrations recorded. Renal tissue from 18 of these patients was available for study; specimens from 5 patients were obtained by biopsy before chemotherapy, and the remaining 13 were obtained at autopsy from previously treated patients (Table 1Table 1
Clinical and Experimental Observations of the Renal Deposition of Bence Jones Proteins from Patients with Multiple Myeloma or Amyloidosis AL.). Bence Jones proteins were identified in urine specimens by immunoelectrophoretic and immunofixation analyses with monospecific anti-κ and anti-λ light-chain antiserum.30 The protein concentration of the urine specimens was measured by a sulfosalicylic acid turbidity method, and the amount of Bence Jones protein relative to that of other urinary proteins was determined by agarose-gel electrophoresis and densitometry.31 Isolation and Characterization of Protein
Twenty-four-hour urine specimens were dialyzed extensively against deionized, distilled water and lyophilized. The Bence Jones proteins were isolated by preparative zone electrophoresis as described elsewhere.30 The purity, molecular weight, and isoelectric points of the Bence Jones proteins were determined by electrophoresis in agarose, sodium dodecyl sulfate–polyacrylamide, and isoelectric-focusing gels, respectively. The light-chain variable-region (VL) subgroup of the proteins was determined by immunodiffusion analysis.30
Experimental Protocol
Six-week-old C3H/HEJ mice (weighing 15 to 20 g) were injected intraperitoneally with a 3-ml Luer-Lok Monoject syringe (Sherwood Medical, St. Louis) and a 25-gauge needle with reconstituted, sterile filtered solutions of Bence Jones proteins. The Bence Jones protein was suspended in 1 ml of a sterile physiologic buffer solution, pH 7.1, prepared by adding 0.5 ml of 4 percent sodium bicarbonate (Neut, Abbott Laboratories, North Chicago) to 10 ml of preservative-free 0.9 percent sodium chloride (Abbott), and the suspension was centrifuged at 3580×g for 15 minutes. The supernatant was passed through wetted 0.45-μm and 0.22-μm filters (Millipore, Bedford, Mass.). Maximal recovery of protein was ensured by washing the filters with an additional 0.5 ml of buffer. A sufficient amount of Bence Jones protein was dissolved initially to yield, after centrifugation and filtration, the requisite final concentration of protein, as determined by a modification of the Folin—Ciocalteau method.30 The desired volume of fluid injected was approximately 1.5 ml (maximal volume, 3 ml), and it contained up to 300 mg of protein. Urine collected from the mice before and after the injection was examined for protein electrophoretically and immunochemically with use of agarose-gel membranes (Paragon SPE and IFE Electrophoresis Systems, Beckman Instruments, Brea, Calif.). Blood was obtained from the retro-orbital plexus for the determination of urea nitrogen levels (BUN-Endpoint-20, Sigma Chemical, St. Louis) 24 to 48 hours after the injections, after which the mice were killed by cervical dislocation and the organs removed. The kidneys were processed in two ways. For light microscopy and immunohistochemical analysis, sections were placed in 10 percent buffered formalin and embedded in paraffin; for electron microscopy, sections were placed in 2.5 percent glutaraldehyde—0.05 M sodium cacodylate buffer, pH 7.2, transferred after one to two hours to the cacodylate buffer, and then embedded in Epon.
Histopathology
For light microscopy, 4-to-6-μm tissue sections were cut and stained with hematoxylin–eosin, periodic acidSchiff, and periodic acid—methenamine stains. For the detection of amyloid, tissue sections were treated with a freshly prepared alkaline Congo red solution and examined under polarized light with a Leitz filter polarizer with a gypsum plate and a filter analyzer. For electron microscopy, Epon-embedded sections were examined with a Zeiss 9S transmission electron microscope and photographed.
immunohistochemistry
The methods used for the detection of light-chain deposits by the immunoperoxidase technique with primary rabbit antihuman light-chain antiserum have been described elsewhere.32 The antiserum used recognized antigenic determinants30 of light-chain variable regions and constant regions (CL).32 Immunoperoxidase-stained slides were examined microscopically. To define the predominant form of mouse and human renal pathology, we examined 10 fields with a 20× objective and a 10× ocular lens. Each field was divided into quadrants and scored from 0 to 4, depending on the presence of light-chain deposition in each quadrant. The predominant nature of the deposition was established on the basis of averaged data from the 10 studied fields. One of us reviewed the coded clinical and experimentally derived tissue sections without knowledge of the respective patients' renal histopathological features.
Results
Light-Chain Deposition: Casts
To determine both the potential of human Bence Jones proteins to be deposited in mouse kidneys and the clinical value of the experimental model, we initially studied monoclonal light-chain proteins from two patients. One protein was obtained from Patient 18, who excreted approximately 25 g of a κ-chain Bence Jones protein daily and who had uremia (serum creatinine level, 796 μmol per liter [9 mg per deciliter]). The second protein was from a patient with multiple myeloma (not included in Table 1) who had excreted approximately 50 g of a κ-chain Bence Jones protein daily for more than three years but whose serum creatinine concentration was normal. Pairs of mice were injected with 50, 100, 200, or 300 mg of the Bence Jones proteins or comparable amounts of ovalbumin. One of each pair was killed at 24 hours, and the second at 48 hours; the kidneys were processed for histologie examination.
The lumens of virtually all the distal tubules of the kidneys of the mice that received 200 or 300 mg of protein from Patient 18 were filled with homogeneous casts negative on periodic acidSchiff staining. The amorphous, dense nature of the casts was apparent on electron microscopy. The pathological alterations were similar in the 24-hour and 48-hour specimens, although in the latter the lesions were more extensive and involved both proximal and distal tubules, and the mice that had received more protein had more extensive lesions. The tubular casts in the mice injected with protein from Patient 18 were similar to those in the renal-biopsy specimen from this patient, as determined by light (Fig. 1AFigure 1
Forms of Renal Light-Chain Deposition Observed Experimentally in Mice and Clinically in Patients with Multiple Myeloma or Amyloidosis AL.) and electron microscopy. Immunohistochemical studies with antihuman light-chain antiserum (anti-idiotype and anti-isotype) confirmed that the tubular deposits in the mouse kidneys represented the intact human Bence Jones protein and were antigenically similar to the light chains found in the renal tubules of Patient 18. In nine separate experiments involving injections of 300 mg of protein from the two patients, the formation of renal tubular casts was induced only with the injection of protein from Patient 18.On the basis of these initial studies, we tested the capability of the Bence Jones proteins from 38 additional patients to induce cast formation within 48 hours of a 300-mg injection of the protein. The sections of mouse kidney were examined immunohistochemically with an anti-κ-chain or an anti-λ-chain antiserum, depending on the light-chain type of the injected protein. The injected light chains from 14 of these 38 patients (8 κ and 6 λ) were deposited predominantly as intraluminal casts, although other forms of light-chain deposits were evident after the injection of protein from 6 of these 14 patients. The location and extent of cast formation were varied. For example, in some cases casts were evident throughout the tubular system, but in others they were limited to the loop of Henle and either proximal or distal tubules. Typically, the casts containing Bence Jones protein appeared homogeneous, but occasionally they were more flocculent or grainy. Extensive deposition of such casts in the mouse kidneys often resulted in tubular dilatation and was occasionally associated with interstitial mononuclear-cell infiltrates and tubular atrophy. Among the 14 patients whose Bence Jones proteins induced tubular casts in mouse kidneys, renal tissue (obtained at biopsy or autopsy) was available for analysis from 7. As shown in Table 1, the kidneys in all seven patients contained light-chain casts morphologically and immunologically comparable with those found in the mouse kidneys (as noted in the case of Patient 18). Regardless of the presence or absence of tubular casts in the mice, Bence Jones protein was invariably detected in mouse urine collected for 24 hours after the injection; after 48 hours it was no longer present, and the electrophoretic pattern of excreted urinary protein was identical to that found before the injection.
Light-Chain Deposition: Basement-Membrane Precipitates
Certain human Bence Jones proteins, when injected into mice, were deposited not as tubular casts but as basement-membrane precipitates. One such protein was obtained from Patient 13, who excreted approximately 3 g of a κ-chain Bence Jones protein daily and who also had uremia (serum creatinine level, 424 μmol per liter [4.8 mg per deciliter]). Mice injected with 300 mg of this protein were killed 48 hours later. The sections of the mouse kidneys stained with hematoxylin–eosin showed only occasional tubular casts. No histologic alterations were noted in sections stained with periodic acid—methenamine or Congo red, nor were electron-dense deposits identified in the mouse tubular, glomerular, or vascular basement membranes or mesangia. Immunohistochemical analysis, however, revealed striking focal deposition of the Bence Jones protein in renal tubular and capillary basement membranes and in blood-vessel walls. That the linear precipitates found in these structures were composed of the injected monoclonal κ chain was demonstrated with a specific antihuman κ-chain antiserum. Microscopical examination of renal tissue obtained post mortem from Patient 13 showed few tubular casts, as in the specimens from mice; in addition, thickening of the tubular and glomerular basement membranes was noted in the specimens stained with periodic acid—methenamine. Immunohistochemical studies of renal tissue from this patient revealed changes comparable to those found in the kidneys of mice injected with the Bence Jones protein from the patient — namely, deposition of κ chains within the tubular and endothelial basement membranes (Fig. 1B). No electron-dense basement-membrane deposits were found in the patient's kidneys. In addition to intact Bence Jones protein, the urine of the mice contained a fragment of the native light chain that was approximately 18,000 daltons; this fragment was also present in the urine of Patient 13.
Among the other 39 Bence Jones proteins, 13 (4 κ chain and 9 λ chain) were also deposited in basement membranes (vascular, tubular, or both) of the mouse kidneys similar to that found with the protein from Patient 13 (Table 1). In five of these cases, light-chain basement-membrane precipitates and tubular casts were equally prominent. Renal tissue was available from 5 of the 13 patients whose Bence Jones proteins induced basement-membrane deposition experimentally; two of these (Patients 11 and 16) had comparable renal lesions. Ultrastructural analysis of the renal-biopsy specimen from Patient 11 revealed no electron-dense deposits.
Light-Chain Deposition: Crystals
The injection into mice of the κ-chain Bence Jones protein from Patient 12, who had a serum creatinine concentration of 398 μmol per liter (4.5 mg per deciliter), resulted in yet another type of experimentally induced light-chain deposit —namely, the extensive intraluminal precipitation of the human protein in the form of long, rodlike crystals. The crystal-inducing nature of this λ chain was demonstrated in multiple experiments, and the morphologic appearance and location of the protein crystals within the renal tubules of the mouse were virtually identical to those of the crystals found in the patient's kidney (Fig. 1C). Among the other 39 human Bence Jones proteins studied, 2 (1 λ chain and 1 κ chain) were deposited in the mouse kidneys as rhomboid and ovoid crystals, respectively. These proteins were obtained from Patients 6 and 17, whose renal tissue, as in the case of Patient 12, contained light-chain—related intratubular crystals identical to those induced experimentally (Table 1).
Light-Chain Deposition: Amyloid
On the basis of our demonstration that λ light chains of a particular variable-region subgroup —VλVI — are preferentially found in patients with amyloidosis AL,15 we selected a λVI-chain Bence Jones protein from one such patient for study in mice. Initial attempts to produce human light-chain—related amyloid lesions within 48 hours by single 300-mg injections of this protein (or any of the other 39 proteins studied) were unsuccessful. Green birefringent Congo red—positive deposits were readily evident, however, in mice that received a number of doses of the λVI light chain. After four weeks, biweekly 200-mg injections of Bence Jones protein from this patient produced birefringent Congo red—positive deposits in the walls of the renal arteries of the mice (Fig. 1D). Electron microscopy revealed vascular deposits of non-branching 8-to-10-nm fibrils, confirming the amyloid nature of this material. Immunohistochemically, the experimentally induced amyloid represented the injected human light chain. Furthermore, the amyloid deposits in the mouse did not contain the amyloid A protein, as shown by their lack of reactivity with a specific anti-A antiserum. This patient had a vascular form of amyloidosis AL, as demonstrated by rectal-valve and bone marrow biopsies. Although renal tissue was not available, the fibrillar Congophilic vascular lesions induced in the mice were similar in appearance to those found in the kidneys of a different patient who also had λVI-chain Bence Jones protein—associated amyloidosis AL (Fig. 1D).
In an additional study, we investigated in mice the amyloidogenic potential of a κ-type Bence Jones protein obtained from Patient 2, who also had renovascular and systemic amyloidosis AL. As with the λVI-type Bence Jones protein, the prolonged injection of the κ chain from this patient resulted in its deposition as birefringent Congophilic fibrils in the blood-vessel walls of the mouse kidneys.
Experimental and Clinical Correlates
Of the 40 patients whose Bence Jones proteins (23 κ chain and 17 λ chain) were injected into mice, renal tissue (obtained by biopsy or autopsy) was available for immunohistochemical study from 18 patients. In four of the five patients from whom renal-biopsy specimens were obtained at the time of diagnosis, the morphologically predominant form or forms of light-chain deposition (casts, basement-membrane precipitates, or crystals) were identical to those induced experimentally; in the fifth patient (Patient 15), the mouse kidney contained basement-membrane deposits in addition to casts. Among 7 of the 13 specimens obtained at autopsy, there was also agreement with respect to the presence or absence of the pathological forms of light-chain deposits detected clinically and experimentally. In the remaining six patients, the specimens obtained from two contained basement-membrane deposits in addition to casts, whereas in four the clinical and experimental results differed (Table 1).
The nephrotoxicity of certain injected human Bence Jones proteins was also reflected in the urea nitrogen concentrations in the samples of mouse blood obtained 48 hours after the injection. Among the 25 mice in which such measurements were possible, the average blood urea nitrogen value in the 18 mice in which human light-chain deposits were present was 16 μmol per liter (43 mg per deciliter) (range, 8 to 24 μmol per liter), as compared with an average value of 9 μmol per liter (25 mg per deciliter) (range, 5 to 13 μmol per liter) in the 7 mice with no evident pathological features and 9 μmol per liter (range, 8 to 10) in uninjected mice. In general, the highest blood urea nitrogen values were found in the mice with the most extensive human light-chain deposits.
Twenty-seven of the 40 Bence Jones proteins studied (16 κ chain and 11 λ chain) were obtained from patients whose serum creatinine concentrations at the time of diagnosis equaled or exceeded 168 μmol per liter (1.9 mg per deciliter). Twenty-two of these 27 proteins, when injected into mice, were deposited in the kidney as casts, basement-membrane precipitates, or crystals. Whether the azotemia in the five remaining cases was due to other factors (e.g., nephrosclerosis) could not be established. In contrast, of the 13 Bence Jones proteins obtained from patients whose serum creatinine values were below 168 μmol per liter, only 4 were deposited in the mouse kidneys (Table 2Table 2
Nephrotoxicity of Urinary Bence Jones Proteins from 40 Patients with Multiple Myeloma or Amyloidosis AL.).There was no apparent relation between either the amount of Bence Jones protein excreted by the patients or the chemical properties of the protein (κ chain vs. λ chain, monomer vs. dimer, or anionic vs. cationic) and the presence or absence of light-chain deposits found clinically or experimentally.
Discussion
We used an in vivo animal model26 to investigate the nephrotoxic potential of urinary Bence Jones proteins from 40 patients with multiple myeloma or amyloidosis AL. Under the experimental conditions employed, certain of the proteins were deposited in a reproducible fashion within the mouse kidneys as tubular casts, basement-membrane precipitates, crystals, or amyloid fibrils. In most cases, the form of light-chain deposition induced in the mouse kidney was similar to that found in the patient. In certain instances, more than one type of light-chain deposition was induced experimentally; this phenomenon, also noted in several of our patients, has been described elsewhere.3
Myeloma (cast) nephropathy has long been considered the hallmark of the renal disease found in patients with multiple myeloma and Bence Jones proteinuria.2 , 4 We found that Bence Jones proteins obtained from patients who had myeloma (cast) nephropathy also precipitated within the renal tubules of mice. The long-term effects of intraluminal Bence Jones protein deposition — e.g., giant-cell reaction and pronounced tubular atrophy — were not present in the mice, presumably because of the short interval between the time of protein injection and the killing of the animals (such histologic changes were observed by Koss et al. 5 to 14 days after the protein injection26).
Light-chain deposition disease is characterized by the deposition of monoclonal light chains (usually κ type) as nodular or diffuse precipitates along the basement membranes of renal tubules, glomeruli, and blood vessels and in mesangium.2 , 3 , 33 34 35 36 37 Such deposition may be suspected on the basis of special tissue staining (e.g., periodic acid—methenamine) and the ultrastructural identification of punctate electron-dense deposits. Because of the variation in pathological features, however, including the absence of the characteristic electron-dense deposits,3 the definitive diagnosis of light-chain deposition disease is made immunohistochemically. The injection into mice of Bence Jones proteins obtained from patients with immunologically confirmed light-chain deposits in the basement membranes induced similar lesions in the mouse kidneys. The finding that 14 of the 40 Bence Jones proteins studied were deposited as basement-membrane precipitates suggests that such deposition may be more prevalent than was previously suspected, that it can involve λ-type as well as κ-type monoclonal light chains, and that it does not necessarily occur as electron-dense deposits.
The deposition of monoclonal light chains as crystals within renal tubular cells and lumens has been reported in patients with the multiple myeloma—associated (acquired) Fanconi's syndrome2 , 7 8 and in association with both human and experimentally induced tubular (cast) nephropathy.4 , 26 Renal deposition of Bence Jones proteins as crystals was the predominant histologic feature in two of our patients and was also found in a third patient who had cast nephropathy as well; the urinary protein from all three patients induced the formation of similar light-chain crystals in mice. None of these patients had an acquired Fanconi's syndrome, but the crystalline deposits may have accounted for their impaired renal function.
The injection into mice of Bence Jones proteins obtained from two patients who had amyloidosis AL resulted in the deposition of the human proteins as amyloid. The amyloid induced in the mice had the characteristic tinctorial, ultrastructural, and immunohistochemical features of light-chain—derived amyloid. In contrast to the relatively rapid induction in mice of other forms of light-chain deposits, the experimental production of amyloidosis AL required repeated injections of protein.
The fact that under similar experimental conditions some but not all Bence Jones proteins were deposited in the mouse kidneys implicates the protein as being primarily responsible for the pathological features observed. In addition, the finding that a given light chain was selectively deposited within the renal parenchyma in a particular form (i.e., as a cast, basement-membrane precipitate, crystal, or fibril) indicates that the nature of light-chain deposition is determined by structurally distinctive characteristics of individual proteins. Although certain physicochemical and serologic properties of the light chain — isoelectric point, molecular weight, and κ or λ isotype — have been associated with Bence Jones protein nephrotoxicity,12 13 14 15 16 17 18 19 20 21 22 23 24 we and other investigators9 10 11 , 38 39 40 41 have found no such relation. As yet, the specific molecular features responsible for the renal deposition of certain Bence Jones proteins are unknown. The ability to identify nephrotoxic or amyloidogenic light chains and the clinical relevance of the mouse model provide investigators a unique opportunity to learn more about the pathogenesis and more effective treatment of the light-chain—associated diseases.
From the Human Immunology and Cancer Program, Department of Medicine (A.S., D.T.W.), and the Department of Pathology (A.A.K.), University of Tennessee Medical Center/Graduate School of Medicine, Knoxville. Address reprint requests to Dr. Solomon at the university of Tennessee Medical Center at Knoxville, 1924 Alcoa Hwy., Knoxville, TN 37920.
Supported by a grant (CA-10056) from the National Cancer Institute of the U.S. Public Health Service, an I.M.A. Barger Memorial Grant for Cancer Research (IM-430) from the American Cancer Society, and the Stein Cancer Research Fund.
This paper is dedicated to the late Dr. Emilio Machado. We are indebted to Ms. Julie Ottinger for her role in the preparation of the manuscript; to Ms. Teresa K. Williams, Ms. Mildred F. Conley, and Ms. Bobbie J. Rush for their technical assistance; to Dr. David Girard for the electron photomicrographs; to Mr. Charles Burger, Mr. Dan McCammon, and Mr. Joe Chen, University of Tennessee medical students who participated in these studies; to Dr. Blas Frangione for furnishing the anti—amyloid A antiserum; and to Dr. William M. Murphy, Dr. Conrad L. Pirani, and Dr. Gloria R. Gallo for their helpful discussions.
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