The structure of an entire noncovalent immunoglobulin kappa light-chain dimer (Bence-Jones protein) reveals a weak and unusual constant domains association.
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Monoclonal free light chains secreted in immunoproliferative disorders are frequently involved in renal complications, including a specific proximal tubule impairment, Fanconi's syndrome. The latter is characterized in most cases by intracellular crystallization including a light-chain variable-domain fragment which resists lysosomal proteases. Bence-Jones protein (BJP) DEL was isolated from a patient with myeloma-associated Fanconi's syndrome. The crystal structure of this human kappa immunoglobulin light-chain noncovalent dimer was determined using molecular replacement with the structure of molecule REI, as the variable domain, and that of BJP LOC as the constant domain. To our knowledge, DEL is the first complete kappa BJP structure described to date. The R-factor is 20.7% at 2.8 A resolution. The BJP DEL dimer was compared with other light-chain dimers and with Fab fragments with a kappa light chain. Although the domain-folding pattern was similar, the relative positions of the constant domains differed. BJP DEL showed a noncanonical quaternary structural arrangement which may be attributable to the poor CL-CL affinity and lack of an interchain disulfide bridge, combined with the conformational editing effect of the crystal-packing forces. Our results suggest that, in the absence of a disulfide bridge, most BJP CLs are probably mobile in solution. This may explain their high susceptibility to proteases and the absence of naturally occurring crystals for these dimers. Furthermore, these findings of an unusual quaternary structure of an immunoglobulin light-chain association extend our knowledge about the large and highly diverse structures of the immunoglobulin superfamily. (+info)
Antitumor activity of thalidomide in refractory multiple myeloma.
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BACKGROUND: Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease. METHODS: Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by 200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks. RESULTS: The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone marrow did not change significantly in patients with a response. At least one third of the patients had mild or moderate constipation, weakness or fatigue, or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare. As of the most recent follow-up, 36 patients had died (30 with no response and 6 with a response). After 12 months of follow-up, Kaplan-Meier estimates of the mean (+/-SE) rates of event-free survival and overall survival for all patients were 22+/-5 percent and 58+/-5 percent, respectively. CONCLUSIONS: Thalidomide is active against advanced myeloma. It can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy. (+info)
Structural relationship of kappa-type light chains with AL amyloidosis: multiple deletions found in a VkappaIV protein.
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Two amyloidogenic Bence Jones proteins (Am37 VkappaIV and NIG1 VkappaI) and one non-amyloidogenic protein (NIG26 VkappaIII) were characterized. The protein Am37 had four deletions when compared with the translated germ-line gene sequence: two Ser residues following position 27 (27e, 27f) in CDR1 and two amino acids Pro-44, and Tyr-49 in FR2 were deleted. A strictly conserved salt-bridge-forming amino acid, Asp-82, was replaced by the hydrophobic residue Leu. In a comparative study of amyloidogenic and non-amyloidogenic proteins, five amino acids (Ser-10, Ala-13, Ser-65, Gln-90, and Ile-106) were found to be unique to NIG1 and several other amyloidogenic proteins. Additional substitutions also occur within these proteins. These substitutions might be significant in altering protein folding as well as in contributing to their aggregation as amyloid fibrils. (+info)
Some Bence-Jones proteins enter cultured renal tubular cells, reach nuclei and induce cell death.
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Eighteen monoclonal Bence-Jones proteins (BJPs) were examined for their effects on cultured LLC-PK1 (porcine kidney proximal tubule) cells as well as for their amidase and DNase activities. Five proteins were found to enter the cell and to gain access to the nucleus without degradation of epitopes. Intranuclear BJPs ultimately induced DNA fragmentation and cell death. BJPs with relatively high amidase activity were cytotoxic. On the other hand, three of four BJPs with DNase activity had a cytocidal effect on cultured cells; the remaining BJP, which had a relatively high DNase activity but a very low amidase activity, failed to enter the cell and was not cytotoxic in vitro. These results suggest that catalytic and cytotoxic activities of some BJPs may make a significant contribution, in a substantial proportion of myeloma patients, to the development and/or deterioration of the disease. (+info)
Thermodynamic modulation of light chain amyloid fibril formation.
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To obtain further insight into the pathogenesis of amyloidosis and develop therapeutic strategies to inhibit fibril formation we investigated: 1) the relationship between intrinsic physical properties (thermodynamic stability and hydrogen-deuterium (H-D) exchange rates) and the propensity of human immunoglobulin light chains to form amyloid fibrils in vitro; and 2) the effects of extrinsically modulating these properties on fibril formation. An amyloid-associated protein readily formed amyloid fibrils in vitro and had a lower free energy of unfolding than a homologous nonpathological protein, which did not form fibrils in vitro. H-D exchange was much faster for the pathological protein, suggesting it had a greater fraction of partially folded molecules. The thermodynamic stabilizer sucrose completely inhibited fibril formation by the pathological protein and shifted the values for its physical parameters to those measured for the nonpathological protein in buffer alone. Conversely, urea sufficiently destabilized the nonpathological protein such that its measured physical properties were equivalent to those of the pathological protein in buffer, and it formed fibrils. Thus, fibril formation by light chains is predominantly controlled by thermodynamic stability; and a rational strategy to inhibit amyloidosis is to design high affinity ligands that specifically increase the stability of the native protein. (+info)
Extramedullary plasmacytoma in a horse with ptyalism and dysphagia.
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A Clydesdale mare was examined for weight loss, inappetence, ptyalism, and dysphagia. The main abnormality revealed by serum biochemistry was a marked hyperglobulinemia, and protein electrophoresis revealed a monoclonal gammopathy in the gamma region. The urine was positive for Bence Jones proteins. These findings suggested a plasma cell tumor. The neoplasm could not be located with extensive antemortem examination. At postmortem, neoplastic cells morphologically compatible with plasma cells and positive for equine IgG with imunoperoxidase staining infiltrated the pericardium, mediastinal stromal tissues, adrenal glands, meninges, atrioventricular valves, aorta, abdominal and thoracic fat, and nerves, including the trigeminal nerve. The neoplastic cells invading the cranial nerves were responsible for many of the presenting signs. (+info)
A surgical case of solitary plasmacytoma of rib origin with biclonal gammopathy.
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Localized solitary plasmacytoma of the bone (SPB) is a rare disease and is characterized by only one or two isolated bone lesions with no evidence of disease dissemination. A previously healthy 44-year-old male was admitted for evaluation of an abnormal radiographic shadow in the left middle lung field with symptoms of left back pain. Radiological evaluation revealed a peripheral opacity in the left chest wall, which was highly suspected to be a chest wall tumor. CT-guided transcutaneous needle biopsy of the tumor was performed and the specimens showed a monomorphous population of mature plasma cells. The bone marrow biopsy findings revealed no evidence of myeloma and bone scanning revealed only abnormal accumulation in the left seventh rib. He had mild M-proteins in a urine sample and Bence-Jones protein was detected. Immunoelectrophoresis revealed mild biclonal gammopathy of Bence-Jones protein of both the kappa and lambda light-chain types. Under a diagnosis of solitary bone plasmacytoma, preoperative radiation therapy with doses of 40 Gy for the tumor was performed. He underwent complete en bloc resection of the chest wall, including one-third of the left sixth and seventh ribs, the intercostal muscle and the parietal pleura. The protein abnormalities in the urine sample disappeared following surgical resection. Adjuvant chemotherapy using melphalan and prednisolone was performed. He is doing well without evidence of tumor recurrence 2 years following his initial diagnosis. (+info)
A case of gamma 3 heavy chain disease with vacuolated plasma cells: a clinical, immunological, and ultrastructural study.
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A patient with lambda Bence-Jones proteinuria, Waldenstrom's macroglobulinaemia, and Franklin's disease (gamma HCD), but without clinical evidence of a lymphoproliferative disorder, is presented. The serum contained two distinct immunoglobulin abnormalities: a monoclonal immunoglobulin M (IgM) of lambda type, and a protein fragment which was immunologically related to immunoglobulin G (IgG) and devoid of light chain activity. This gamma HCD protein belongs to the gamma 3 subclass with a molecular weight of approximately 60,000 daltons. The urine contained a Bence-Jones lambda protein as well as the gamma HCD fragment. The two paraproteins were probably secreted by two different malignant clones. Ultrastructural study revealed pathological vacuolated plasma cells of a sort that has hitherto been principally described in association with micron HCD. The mechanism of the intracellular storage of pathological immunoglobulins is discussed in the light of the ultrastructural study. (+info)