Heavy chain deposition disease: an overview.

Heavy chain deposition disease (HCDD) is one of three entities of monoclonal immunoglobulin deposition disease, characterized histopathologically by the presence of nodular glomerulosclerosis and glomerular and tubular deposition of monoclonal heavy chains without associated light chains. Although HCDD is an extremely rare disease, >30 cases have been reported to date in the literature. Of these cases, only three cases have been reported in Japan. The majority of the patients presents with nephrotic syndrome, hematuria, and hypertension, and develop progressive renal failure with or without the complication of multiple myeloma. Some cases have been treated successfully using chemotherapy. Because of its rarity, a thorough understanding of HCDD is essential for both accurate diagnosis and adequate subsequent treatment.

Where disease pathogenesis meets protein formulation: renal deposition of immunoglobulin aggregates.

Aggregation is one of the important issues encountered during the development of immunoglobulin-based drugs. The aim of the current review is to discuss the causes and consequences of immunoglobulin aggregation as well as the relevance of immunoglobulin aggregation to disease pathogenesis. Extracellular deposition of immunoglobulins, either monoclonal light chains or intact polyclonal antibodies, induces renal failure in various nephropathies. The aggregates can present fibrillar or amorphous structures. In this review, factors known to influence protein aggregation, such as the primary structure of the protein, local environment and glycosylation are assessed, as well as the subsequent altered clearance, fibril formation and toxicity. The role of the protein local environment is emphasized. Even if the local environment causes only minor perturbations in the protein structure, these perturbations might be sufficient to trigger aggregate formation. This fact underlines the importance of choosing appropriate formulations for protein drugs. If the formulation provides a slightly destabilizing environment to the protein, the long-term stability of the drug may be compromised by aggregate formation.

[Development of gamma-heavy chain disease during the course of diabetic nephropathy].

We reported a rare case of gamma-heavy chain disease. A 63-year-old man had been given a diagnosis of diabetes mellitus at the age of 30 and had received hemodialysis since the age of 55. The patient presented with swollen lymph nodes in the neck. Lymph node biopsy findings suggested immunoblastic lymphadenopathy. The patient was admitted to Kitasato University hospital. Serum protein electrophoresis showed an increase of beta-fraction peak, and immunoelectrophoresis revealed an increase of gamma-heavy chain protein. Further studies of the gamma-heavy chain protein showed that it contained three different components and that the molecular weight of the main component was 34,000 Da. The patient died on the 11th day of hospitalization. The diagnosis at autopsy was unclassified malignant lymphoma.

[Gamma-heavy chain disease associated with MALT lymphoma of the duodenum].

We report a case of a 63-year-old woman with gamma heavy chain disease (HCD) associated with mucosa-associated lymphoid tissue (MALT) lymphoma of the duodenum. She was suffering from drug-resistant tonsillitis with high fever. Examination on admission showed leukocytopenia and thrombocytopenia. Bone marrow aspirate revealed granulocytosis and a hypocellular marrow with no increase in plasma cells or atypical lymphocytes. Serum electrophoresis disclosed, in addition to hypogamma-globulinemia, an abnormal band due to the presence of gamma HCD protein. This abnormal protein was a molecular weight of approximately 40 kd as determined by Western blots technique, and belonged to the IgG1 subclass as determined by ELISA with monoclonal antibodies against IgG. An endoscopic examination of the patient's duodenum found a small tumorous lesion, which was confirmed pathologically to be MALT lymphoma. HCD is known to be associated with lymphoproliferative diseases. In this case, gamma HCD had developed as a secondary complication of MALT lymphoma. gamma HCD associated with MALT lymphoma of the duodenum is rare in the literature.

A case of mu-heavy chain disease: combined features of mu-chain disease and macroglobulinemia.

A case of mu-heavy chain disease (HCD) is described. The patient, a 40-year-old man, presented with an intracranial tumor. The bone marrow of this patient showed infiltration with both plasma cells and lymphocytes. The majority of plasma cells were vacuolated and the result of immunoelectrophoresis of serum protein revealed an arc with anti-IgM antiserum and an additional rapid migrating arc of different mobility with anti-kappa antiserum. The urine contained a kappa-type Bence Jones protein. An enzyme-linked antibody study showed that the majority of plasma cells in bone marrow contained both mu and kappa antigenic determinants in their cytoplasm. On Sephadex G-200 gel filtration, the monoclonal IgM-kappa protein and the mu-chain fragment were detected in the serum, suggesting the combined features of mu-HCD and macroglobulinemia. The molecular weight of the mu-chain fragment was approximately 45,000 daltons. The intracranial tumor completely disappeared after irradiation therapy. However, he died 1 year later after development of a huge abdominal tumor.

Oncogenic potential of the B-cell antigen receptor and its relevance to heavy chain diseases and other B-cell neoplasias: a new model.

Some growth factor receptor genes can be activated to become oncogenic as a result of various mutations. The receptors that are encoded by these genes may deliver constitutive signals independent of ligand binding. The model which is presented here assumes that alterations in the B-cell antigen receptor could have similar effects. Evidence that membrane immunoglobulin alterations contribute to oncogenesis in vivo comes from studies of heavy chain diseases. Moreover, this model could have also implications for other B-cell neoplasias.

Gamma heavy chain disease associated with Hodgkin's disease. Clinical, pathologic, and immunologic features of one case.

This report describes the clinical, pathologic, and immunologic features of a patient with gamma heavy chain disease (gamma-HCD) associated with Hodgkin's disease (HD). The diagnosis of gamma-HCD was established by serum electrophoresis and immunoelectrophoresis and confirmed by biochemical analysis of patient's serum showing the presence of an incomplete gamma chain, with an approximate molecular weight of 40 kilodaltons. The diagnosis of HD rested upon the presence of systemic lymphadenopathy, the typical histologic pattern and reactivity of Reed-Sternberg cells with the LeuM1-CD15 monoclonal antibody. The two diseases developed independently, in the absence of any immunosuppressive treatment. Furthermore, there was some evidence suggesting that HD tissue was not responsible for the production of the incomplete gamma chain. This and similar cases may provide a model for a better understanding of the events leading to the simultaneous outgrowth of two lymphoid neoplasias in the same patient.

Colonic lymphoma producing alpha-chain disease protein.

Alpha-chain disease with involvement of small intestine-resulting in characteristic villus atrophy and malabsorption has not been reported in this country. We studied a 57-yr-old male who presented with a polypoid tumor of the hepatic flexure of the colon. There was no evidence of malabsorption as manifested by a normal fat balance, serum carotene, and D-xylose absorption studies and the small bowel biopsy did not show villus atrophy. The tumor in the colon was surgically removed and diagnosed as a malignant lymphoma of lymphocytic type. Tumor tissue infiltrated in the mesentery could not be excised. Alpha-chain disease protein was demonstrated in serum and urine, and also in tumor tissue by immunoperoxidase techniques. The alpha-chain disease protein was further purified and classified as subclass 1. The patient had a good clinical response to cyclophosphamide and prednisone, but still has intraabdominal lymphoma with gastric involvement, and his serum alpha-chain protein persists. This case report may represent a distinct variant of alpha-chain disease.

Atypical intestinal alpha-chain disease evolving into selective immunoglobulin a deficiency in a Finnish boy.

The clinical course of alpha-chain disease in a Finnish boy is described. The disease presented with growth retardation and gastrointestinal symptoms at age 10 yr. Tests performed between the ages of 15 and 21 yr showed varying intestinal involvement including the large bowel, ileum, and distal jejunum. Alpha-chain disease protein was present in serum in fluctuating concentrations for at least 5 yr; it was produced by plasmacytoid cells found in the affected parts of the large bowel mucosa. The patient was treated with sulfasalazine and melphalan, but it is not clear that the clinical remission and the subsequent disappearance of the alpha-chain disease protein should be ascribed to this treatment. Concomitant with the normalization of the condition, a selective immunoglobulin A deficiency became apparent. The possibility is raised that an immunoglobulin A deficiency could have been the original defect in the patient, predisposing to intestinal infections; topical overstimulation of a defective immunoglobulin A system due to impaired mucosal defense might thus have explained the emergence of alpha-chain disease cells in the gut.

Chronic lymphocytic leukaemia and IgG heavy chain disease.

A 64-year-old woman who has suffered from chronic lymphocytic leukaemia since 1976 is discussed. In 1978, an abnormal protein component was found in her serum by means of immunoelectrophoresis. Using the techniques of immunoselection of the serum immunoglobulins and immunofluorescence of the bone marrow cells, it was demonstrated that this component consists of IgG1 heavy chains only. The native protein, COL, consisted of a dimer linked by disulphide bonds of a molecular weight of 80 000 daltons. Its monomeric unit had a molecular weight of 40 000 daltons, as determined by SDS-polyacrylamide gel electrophoresis after reduction with 2-mercaptoethanol. Protein COL was not produced by the leukaemic cells (which bore IgM-lambda on their membrane) but by a morphologically distinct clone of lymphoid cells. After therapy with chlorambucil, the level of the heavy chain disease protein in the serum decreased substantially.

A case report of the immunodysplasia syndrome and heavy chain disease associated with subacute bacterial endocarditis.

A 36-year-old man was admitted to Saitama Medical School Hospital, because of a remittent fever which had continued for approximately 6 months, hepatosplenomegaly and lymphadenopathy. He had direct Coombs' test positive auto-immune hemolytic anemia associted with subacute bacterial endocarditis (SBE). The lymphnode demonstrated focal diffuse proliferation of immunoblasts and arborizing vessels with a few small germinal centers, which resembled histological features of the immunoblastic lymphadenopathy. The immunochemical analysis revealed the presence of free IgG Fc fragments in serum. From the above results the patient was diagnosed as immunodysplasia syndrome (IDS) and heavy chain disease (HCD) associated with SBE. It was suggested that the chronic antigenic stimulation due to SBE might have some role in the mechanism of the development of the IDS and HCD in our patient.