Ig amyloidosis is usually a systemic disease with multisystem involvement. However, in a significant number of cases amyloid deposition is limited to one specific organ. It has not been determined if the Ig light chain (LC) amyloid precursor protein in localized amyloidosis is synthesized by circulating plasma cells with targeting of the amyloid fibril-forming process to one specific organ, or whether the synthesis of Ig LC and fibril formation occurs entirely as a localized process. In the present study local synthesis of an amyloid fibril precursor LC was investigated. Amyloid fibrils were isolated from a ureter that was obstructed by extensive infiltration of the wall with amyloid. Amino acid sequence analysis of the isolated fibril subunit protein proved it to be derived from a λII Ig LC. Plasma cells within the lesion stained positively with labeled anti-λ Ab and by in situ hybridization using an oligonucleotide probe specific for λ-LC mRNA. RT-PCR of mRNA extracted from the tumor and direct DNA sequencing gave the nucleotide sequence coding specifically for the λII amyloid subunit protein, thus confirming local synthesis of the LC protein.

Immunoglobulin (AL) amyloidosis is characterized by the extracellular deposition of amyloid fibrils containing monoclonal Ig light chain (LC)4 protein. It is usually a systemic disease with multiorgan involvement, and it is generally accepted that the monoclonal Ig protein is the product of a circulating B-lymphocyte clone that may have malignant features (multiple myeloma, Waldenström’s macroglobulinemia) or lack malignant characteristics (benign monoclonal gammapathy, monoclonal gammapathy of unknown significance) (1). More than 80% of subjects with AL amyloidosis have a circulating monoclonal protein detectable in the serum or urine by immunological techniques. Several studies characterizing the circulating monoclonal protein have shown a precursor product relationship with the amyloid fibril subunit protein of the deposits (2, 3, 4, 5). While deposition in blood vessel walls throughout the systemic circulation is common, deposition of amyloid fibrils in specific organs is variable. The reason for this “tissue tropism” is not clear, but the occurrence of selected organ involvement in cases where there is a circulating monoclonal protein suggests that localized forms of AL amyloidosis may also be the result of targeting of the precursor protein to a specific organ rather than local synthesis of that protein.

Localized AL amyloidosis has been described involving the larynx and tracheobronchial tree, orbital tissues, the genitourinary tract, and subcutaneous tissue. Except in the case of extra medullary plasmacytomas with amyloid deposition, it has not been clear whether the amyloid precursor protein is synthesized by plasma cells in the localized amyloid lesion or whether monoclonal LC protein is targeted to a specific organ because of characteristics of that LC protein (1). To prove local synthesis and deposition of amyloid fibril protein, the amyloid fibril subunit protein from a ureteral mass was characterized, and mRNA from plasma cells within the lesion was shown to code for the specific amyloid precursor protein.

The distal portion of the left ureter of a 68-yr-old woman was resected because of obstruction by extensive infiltration of amorphous material. Tissue sections were stained with hematoxylin and eosin, and with Congo red.

Immunohistochemistry.

After tryptic digestion of paraffin-embedded 5-μm tissue sections, the sections were blocked with 5% milk in 1× PBS, (pH 7.2) for 20 min and then incubated overnight at 4°C in a moisture chamber with mouse monoclonal IgG anti-human λ-LC (1:50) (Dako, Carpinteria, CA). Endogenous alkaline phosphatase activity was quenched by incubation in 1 mM levamisole for 20 min. Goat anti-mouse IgG conjugated with alkaline phosphatase (Biosource International, Camarillo, CA) diluted at 1:100 was used as the secondary Ab. The substrate and coupler used were NBT-BCIP (nitroblue tetrazolium and 5-bromo-4-chloro-indolyl phosphate) (Bio-Rad, Richmond, CA). Appropriate controls were treated similarly to test sections.

In situ hybridization.

λ-LC-specific mRNA was detected by using a commercial oligonucleotide probe (Novocastra/Vector Laboratories, Burlingame, CA) complementary to the λ-C region (6, 7). This technique is based on the demonstration of total polyadenylated mRNA in formalin-fixed paraffin sections by using a oligonucleotide probe labeled with FITC.

Paraffin-embedded sections of ureteral tumor, 5 μm thick, were deparaffinized and rehydrated before treatment with proteinase K. Incubation with the λ fluorescein-conjugated probe was followed by incubation with an anti-fluorescein isothiocyanate-alkaline phosphatase antiserum (FITC-AP) and visualization after the addition of specific substrate. Sections of human tonsil served as a positive control. Sections without the addition of specific λ probe served as negative control.

Fibrils were isolated from 200 mg of tumor as previously described (8). Briefly, tissue was homogenized in sodium citrate and sodium chloride in a Tenbroeck tissue grinder (Fisher Scientific, Pittsburgh, PA) and centrifuged at 12,000 RPM for 30 min in a Beckman Instruments (Torrence, CA) J2-21 centrifuge. The supernatant was discarded and the above steps repeated four times. The final pellet was dialyzed against water and lyophilized. Fibrils were solubilized with 6 M guanidine hydrochloride (GuHCl) (pH 8.5), reduced with DTT, and alkylated with iodoacetic acid as previously described (8). Insoluble material was removed by centrifugation, and the supernatant was recovered by lyophilization after dialysis against water. Samples were analyzed by SDS-PAGE using the Tricine system of Schägger and Von Jagow (9).

GuHCl solubilized material was digested with trypsin (2% by weight) in 0.1 M ammonium bicarbonate and recovered by lyophilization (8). The digest was dissolved in 50% acetic acid and fractionated on a Beckman Ultrasphere ODS column (4.6 × 250 mm) equilibrated with 0.1% trifluoroacetic acid in water and eluted with a linear acetonitrile gradient. Separated fractions were dried in a Savant (Farmingdale, NY) Speed Vac Concentrator. Peptide T5 was digested with Staphylococcus protease (5% by weight) in 0.1 M ammonium bicarbonate at 37°C. GuHCl solubilized material was digested with pyroglutamate aminopeptidase as previously described (10). Samples were analyzed by Edman degradation on an Applied Biosystems (Foster City, CA) model 473A protein sequencer using the manufacturer’s standard cycles.

Approximately 200 mg of tissue stored at −80°C since excision were homogenized without any preparation using Polytron homogenizer (Brinkmann, Westbury, NY). Total RNA was extracted by a standard method (11) and served as template for first strand synthesis of cDNA using SuperScript (Life Technologies, Grand Island, NY). Specific primers were made using a DNA synthesizer (model 391-PCR MATE, Applied Biosystems). PCR of cDNA was conducted by using the λII 5′ primer (P1) (5′-CAGCAGTGACGTTGGTGGTC-3′), corresponding to the peptide sequence of residues 27–29 of λ-LC, and the λII3′ primer (P2) (5′-TCAGCCTGGAGCCCAGAGAT-3′) corresponding to residues 75–80. PCR was also performed using the above λII 5′ primer (P1) and 3′ primer, (P3) (5′-CTTGTTGGCTTGAAGCTCCTC-3′), corresponding to the peptide sequence of residues 123–129 in the C region. PCR was performed in a final volume of 50 μl containing 10× PCR buffer (100 mM Tris-HCl (pH 8.3), 500 mM KCl, 12 mM MgCl2), 200 mM of each dNTP, 25 pmol of each primer, 2.5 U AmpliTaq Gold DNA polymerase (Perkin-Elmer, Norwalk, CT) and 0.5 μg of cDNA as template. After 12 min preheating at 95°C, amplification was performed using a Perkin-Elmer thermal cycler for 35 cycles consisting of denaturation at 95°C for 1 min, annealing at 60°C for 1 min, and extension at 72°C for 1 min. To verify the presence of PCR products of the expected size (168 bp and 309 bp, respectively), 8 μl aliquots of the amplified DNA fragments were electrophoresed through 2% Nusieve GTG agarose (FMC Bioproducts, Rockland, ME) gel with appropriate m.w. standards at 90 V for 1 h, stained with 1 μg/ml ethidium bromide, and visualized under UV light.

After pretreatment of 1 μl of PCR product with a combination of exonuclease I and shrimp alkaline phosphatase, 7 μl of reaction were used directly for sequencing by Thermo Sequenase [α-33P] radiolabeled terminator cycle sequencing technique (Amersham Life Science, Arlington Heights, IL). Samples were electrophoresed on a 6% polyacrylamide gel at 48 W for 2 h using a glycerol tolerant gel buffer. The gel was dried and exposed to Kodak (Rochester, NY) X-Omat film.

Histological sections of the ureteral tumor stained with hematoxylin and eosin revealed extensive submucosal deposition of amorphous eosinophilic material surrounded by collections of plasma cells without architectural features of lymph node follicles (Fig. 1). Congo red staining revealed the typical green birefringence of amyloid upon polarization (Fig. 2). There was no evidence of malignancy. Bone marrow aspirate from the patient was normal without evidence of plasmacytosis. Immunoelectrophoresis of serum and urine did not detect a circulating monoclonal Ig protein.

FIGURE 1.

Ureteral section stained with hematoxylin and eosin showing amorphous amyloid deposition surrounded by plasmacytes.

FIGURE 1.

Ureteral section stained with hematoxylin and eosin showing amorphous amyloid deposition surrounded by plasmacytes.

Close modal
FIGURE 2.

Congo red staining of ureteral section visualized under polarized light showing green birefringence pathognomonic for amyloid.

FIGURE 2.

Congo red staining of ureteral section visualized under polarized light showing green birefringence pathognomonic for amyloid.

Close modal

Analysis on SDS-PAGE of solubilized amyloid fibrils from the tumor showed several broad bands corresponding to molecular mass below 30 kDa. The most prominent band below 30 kDa was ∼17–18 kDa, with weaker bands of 25–27 kDa, 12–13 kDa, and 7–9 kDa (data not shown). Sequence analyses of these bands after transfer to polyvinylidene difluoride membrane yielded no changes in phenylthiohydantoin amino acids, suggesting a blocked N terminus. Analysis of the GuHCl-soluble fraction from the fibrils also gave low yields and no discernible sequence, suggesting a blocked N terminus. After incubation with pyroglutamate aminopeptidase, however, sequence analysis identified 18 residues of the N terminus (Fig. 3). The fact that treatment with pyroglutamate aminopeptidase yielded a sequencable protein identified the blocked N terminus of the amyloid protein as pyroglutamic acid. The sequence was homologous to the N terminus of λII-LCs and identified the Ig origin of the amyloid.

FIGURE 3.

Amino acid sequence of amyloid protein ATK. The arrows indicate the peptides used to determine the sequence. Parentheses indicate residues tentatively identified, while (X) in peptide T6 indicates residues not identified. Peptides identified with a T were isolated after digestion with trypsin. Peptide SP was obtained from a Staphylococcus protease digest of peptide T6. <Q - AP denotes the sequence from the GuHCl soluble fraction after pyroglutamate aminopeptidase treatment. <Q denotes pyroglutamic acid. The residues are numbered as in Ref. 12, which has no amino acid at position 10 in λ-LCs.

FIGURE 3.

Amino acid sequence of amyloid protein ATK. The arrows indicate the peptides used to determine the sequence. Parentheses indicate residues tentatively identified, while (X) in peptide T6 indicates residues not identified. Peptides identified with a T were isolated after digestion with trypsin. Peptide SP was obtained from a Staphylococcus protease digest of peptide T6. <Q - AP denotes the sequence from the GuHCl soluble fraction after pyroglutamate aminopeptidase treatment. <Q denotes pyroglutamic acid. The residues are numbered as in Ref. 12, which has no amino acid at position 10 in λ-LCs.

Close modal

The complete sequence of the amyloid subunit protein ATK (Fig. 3) was determined by analysis of tryptic peptides separated on HPLC. Peptides T2 to T7 identified residues 17–110 of the V region except for residues 92–103. Residues 95A-103 were identified from peptide T6a. Sequence analysis of peptide SP derived from a Staphylococcus protease digest of peptide T6 confirmed the remaining tentatively identified residues. In addition to full-length T8 and T9 peptides, minor amounts of peptides corresponding to residues 111–123 and 111–125, and 130–142, 130–143, 130–145, and 130–146 were present, suggesting that the C terminus of the amyloid protein was heterogeneous. No evidence for glycosylation was found on sequence analysis of all tryptic peptides.

Numerous additional peptides were present in the tryptic digest that had Gly at every third residue, and Pro and/or hydroxy-Pro adjacent to Gly. Such repeats are indicative of collagen sequences and suggest that higher m.w. material in the GuHCl-soluble fraction may be collagen derived.

Comparison of the ATK protein residues 1–110 sequence with known λ-LC sequences revealed the protein was most homologous to λII-LCs (12). However, several residues of protein ATK (Arg16, Asn27, His30, Glu38, Phe65, Ser74, Val85) were unique compared with known λII proteins.

Immunohistochemical analysis of paraffin-embedded tissue with anti-λ-LC Ab did not stain amyloid deposits. However, plasma cells in the submucosa showed positive staining, suggesting the presence and possible local synthesis of λ-LCs (Fig. 4). In situ hybridization of tissue sections with an oligonucleotide probe complementary to λ-LC C region mRNA showed a strong cytoplasmic signal in the plasmacytes, suggesting local synthesis of LCs was occurring (Fig. 5). The specificity of the hybridization was confirmed by using appropriate controls.

FIGURE 4.

Immunohistochemistry of ureteral section using mouse anti-human λ-LC Ab showing immunoreaction of plasma cells in the submucosa.

FIGURE 4.

Immunohistochemistry of ureteral section using mouse anti-human λ-LC Ab showing immunoreaction of plasma cells in the submucosa.

Close modal
FIGURE 5.

In situ hybridization on paraffin-embedded ureteral section with λ-LC C region of mRNA oligonucleotide probe showing the presence of mRNA coding for λ-LC.

FIGURE 5.

In situ hybridization on paraffin-embedded ureteral section with λ-LC C region of mRNA oligonucleotide probe showing the presence of mRNA coding for λ-LC.

Close modal

To determine whether plasma cells in the tumor were synthesizing protein ATK, total RNA was extracted from the tumor and a first strand cDNA library of the mRNA was made. Primers for PCR analysis were based on the known cDNA sequence of an expressed λII-LC (13). The nucleotide sequence of 5′ primer (P1) corresponded to the cDNA sequence for residues 27–29, which differs from protein ATK with Ser instead of Asn at residue 27, plus C at the 3′ end to select cDNA coding for His (CAT) at position 30 instead of the most common Tyr (TAT) in λII-LCs. The 3′ primer (P2) was complementary to the nucleotide sequence for residues 75–80, identical to protein ATK, plus the first two bases for residue 81. PCR analysis of tumor derived cDNA library with P1 and P2 yielded a 168-bp product. Sequence analysis identified the nucleotide sequence encoding residues 35–74 of a λ-LC (Fig. 6). The deduced amino acid sequence was identical to protein ATK with the unique Glu38, Phe65, and Ser74 residues.

FIGURE 6.

cDNA nucleotide sequence encoding for residues 35–111 of λII-LC and its translated protein sequence. The arrows denote the nucleotide sequence determined using (P1 + P2) and (P1 + P3) primers.

FIGURE 6.

cDNA nucleotide sequence encoding for residues 35–111 of λII-LC and its translated protein sequence. The arrows denote the nucleotide sequence determined using (P1 + P2) and (P1 + P3) primers.

Close modal

Since both of these primers were designed for the V region of the λ-LC gene, it was possible that the template for the PCR was contaminating genomic DNA. To exclude this possibility, another 3′ primer (P3) was synthesized complementary to the DNA sequence for residues 123–129 of the C region of λ-LC (14). PCR analysis with P1 and P3 yielded a 309-bp product. Sequence analysis identified the nucleotide sequence encoding residues 50–111 of a λ-LC, whose deduced amino acid sequence was identical to protein ATK including the unique Phe65, Ser74, and Val85 residues (Fig. 6). The PCR product thus contains contiguous DNA sequences corresponding to the V, J, and C region, confirming that the cDNA for rearranged λ-LC mRNA was the PCR template as opposed to contaminating genomic DNA.

Localized amyloidosis and primary extramedullary plasmacytoma with amyloidosis are rare diseases of unknown pathogenesis defined as amyloid deposition isolated to a specific organ without any systemic distribution. While primary extramedullary plasmacytoma with amyloid deposition is considered a malignant cell disease with local production of monoclonal protein and subsequent amyloid formation, the origin of the amyloid protein in the more common localized forms of amyloidosis has not been established (15). Organ limited tumor-like amyloidosis has been described in various areas in the body, but mainly in the skin, respiratory and the genitourinary tract, eye, and orbital tissues. Localized amyloidosis of the genitourinary tract is uncommon and has often been mistaken for urothelial carcinoma. While all areas of the urinary tract may be involved, the bladder, ureters, and urethra are the most frequent sites of amyloid deposition (16, 17, 18). Amyloid deposition in the ureteral localized form is usually restricted to one area of a ureter, but bilateral presentation with anuria has been described (19).

In 1981, Fujihara and Glenner (16) suggested that isolated amyloid deposition in the genitourinary tract is probably due to a local, tissue based immunocyte dyscrasia. Later Bhagwandeen and Taylor (17) confirmed the monoclonality of plasma cells by immunohistochemistry. As part of the pathogenic mechanism of amyloid deposition, it has been postulated that recurrent and chronic mucosal and submucosal inflammation causes an influx of plasmacytes followed by a local overproduction of Ig protein. The local metabolic modification of this Ig produces an insoluble form of fibrils that deposit as a nodule (16, 17). However in the reported cases in the literature as well as in our case there was no evidence of chronic urogenital infection. In addition, factors related to the monoclonality of the amyloid process have not been defined.

Recently we reported a primary amyloidosis localized to the urethra in a 29-yr-old male (8). Biochemical analysis demonstrated the Ig λVI subgroup in the amyloid fibrils. In systemic AL amyloidosis patients, λ monoclonal Ig proteins predominate although the ratio of κ/λ plasma cells in the normal immune system is 2:1, which suggests that λ-LCs are more amyloidogenic. This appears to be true for localized AL amyloidosis as well. In systemic forms, the possible presence of free λ-LC in plasma as covalent dimers, unlike the monomeric form of κ molecules, may reduce the renal catabolism of λ components (20). This would probably not be a factor in localized amyloidosis, and suggests that primary protein structure leading to aggregation may be of greater importance to fibril formation. It is not known which residues or substitutions are responsible for the amyloidogenicity of these subgroups. In 1995, Stevens et al. (21), by comparing the primary structure of 180 human monoclonal LCs identified particular residues and positions in the V domain that distinguish amyloidogenic from nonamyloidogenic molecules, suggesting the crucial role of the primary structure of the LC.

Due to technical difficulties for obtaining unfixed material required for protein purification, only a few structures of AL localized amyloid have been described. In the present study the availability of fresh amyloid-laden tissue allowed combined immunohistochemical, biochemical, and molecular analysis of the primary localized amyloidosis. Based on the amino acid sequence of the extracted amyloid protein and published cDNA sequence of the λ-LC proteins, primers P1 and P3 were designed to anneal to mature rearranged mRNA (spanning the V region, J minigene, and C region), thus allowing the amplification of RNA/cDNA, which originated strictly from the committed plasmacyte clone and not genomic DNA. Moreover, the presence of sequence encoding residues Glu38, Phe65, Ser74, and Val85, unique to amyloid protein ATK λII-LC, provides definitive proof that the organ-limited ureteral amyloid deposits arise in relation to tissue based plasma cells.

The locally synthesized amyloid subunit protein consisted of V region and the first two tryptic peptides from the C region. This is comparable to the size of AL amyloid proteins isolated from systemic amyloidosis and indicates that similar proteolytic events may occur in localized amyloidosis.

Immunohistochemistry of paraffin embedded tissue using mouse monoclonal IgG anti-human λ-LC showed positive staining of plasmacytes surrounding submucosal deposits. In situ hybridization showed a strong signal in the sections of the isolated tumor, allowing the detection of nucleic acid target sequences. This result provides additional evidence that the mRNA for the specific λ-LC is encoded at the local level and does not originate in bone marrow. This conclusion is supported by the fact that bone marrow aspirate in this case showed no evidence of a plasma cell dyscrasia and no M component was present in serum or urine.

The respiratory, digestive, and genitourinary tracts are protected immunologically by subepithelial accumulations of lymphoid tissue that are not constrained by a connective tissue capsule. This may occur as a diffuse concentration of plasmacytes, lymphocytes, and macrophages throughout the interstitial wall of lungs or genitourinary tract. The urinary tract resident B-lymphocytes are stimulated and, after activation, drain to lymph nodes and thoracic duct, and then pass via bloodstream into the urinary mucosal surface where they become IgA-forming cells. The presence of specific homing receptors could explain the absence of dissemination in this type of amyloidosis. The amyloid deposition is the consequence of transformation and secretion of monoclonal LC by a committed B-lymphocyte clone. However, several attempts by in situ hybridization using a J-chain probe and by immunohistochemistry to demonstrate the presence of IgA in the ureteral mass have so far been unsuccessful.

The present study provides definitive evidence that organ-specific or localized AL amyloid deposition represents de novo production of amyloid with the presence at the local level of those factors necessary for fibrillogenesis. This finding is against the hypothesis that LCs produced in systemic amyloidosis might be processed at remote sites and then transported via the bloodstream to the target organ. We still do not understand the tropism of amyloid LCs for specific organs, but the study of the localized forms has given insight into this process. Better understanding of the pathogenesis of this type of LC amyloidosis may provide directions for future therapeutic research and prevention of AL amyloidosis.

1

This work was supported by Veteran Affairs Medical Research Grant MRIS583-0888, U.S. Public Health Service Grants RR-00750, DK49596, and DK42111, the Marion E. Jacobson Fund, and the Machado Family Research Fund.

2

The nucleotide and protein sequences reported in this paper have been deposited in the GenBank database under accession no. AF0099676, Bankit 230834

4

Abbreviations used in this paper: LC, light chain; GuHCl, guanidine hydrochloride.

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