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PubMed1982

gamma Heavy chain disease in man: cDNA sequence supports partial gene deletion model.

Human gamma heavy chain disease (HCD) is characterized by the presence in serum of a short monoclonal Ig gamma chain unattached to light chains. Although most HCD proteins have internal deletions, in some the defect is NH2-terminal. The OMM gamma 3 HCD serum protein is of the latter type, having undergone an extensive NH2-terminal deletion with a sequence starting within the hinge. A cell line synthesizing the OMM protein has enabled us to study the biogenesis of the abnormal molecule. In vitro translation of isolated mRNA yields a protein containing a hydrophobic NH2-terminal leader sequence. In the intact cell, the precursor molecule is processed normally to yield a protein with an NH2-terminal sequence homologous to the beginning of the variable (V) region. The nucleotide sequence of cDNA prepared from the OMM mRNA encodes a 19-amino acid leader followed by the first 15 residues of the V region. An extensive internal deletion encompasses the remainder of the V and the entire CH1 domain. Immediately following the short V region, there is information in the cDNA for the entire normal hinge. The primary synthetic product is thus an internally deleted molecule that undergoes postsynthetic degradation to yield the NH2-terminally deleted serum protein. The structure of the OMM mRNA suggests that the protein abnormality results from a partial gene deletion rather than defective splicing.

Amino Acid Sequence↗
PubMed1997

Cast nephropathy in mu heavy chain disease.

The occurrence of kidney diseases was very rarely reported in heavy chain diseases (HCD). At variance with gamma and alpha HCD in which there is no free light chain secretion, about two-thirds of mu HCD patients have urinary Bence Jones (BJ) proteins. We report on a 66 year-old man affected with typical mu HCD who developed renal failure after a 3-year follow-up. He had presented with chronic lymphocytic leukemia with bone marrow vacuolated plasma cells, serum mu HCD protein and serum and urine BJ protein. After an apparent hematological remission following fludarabine therapy, anemia and blood hyperlymphocytosis recurred together with microscopic hematuria, proteinuria and increased creatininemia. Kidney biopsy showed numerous tubular eosinophilic casts which stained for kappa chain determinants by immunofluorescence and an interstitial infiltration by lymphocytes and plasma cells. The hematological and renal condition improved after reinitiation of chemotherapy. This appears to be the first documented report of a light chain-dependent visceral complication in HCD.

Aged↗
PubMed1979

Celluar immunoglobulins in human gamma- and alpha-heavy chain diseases.

Proliferating cells from twenty-four patients with alpha- or gamma-heavy chain disease (HCD) were studied by direct immunofluorescence and in several cases by biosynthesis experiments with 14C-amino acid incorporation. In twenty-two patients, the cells contained the HCD proteins only and no light chain synthesis could be detected. Conversely, apparently non-secreted monotypic light chains were found in one case of gamma-HCD and one case of alpha-HCD. The proportion of proliferating cells containing cytoplasmic heavy chains, their appearance and the presence or not of surface heavy chains showed great variation from patient to patient. In some cases, the proliferation predominantly affected either plasma cells or lymphocytes whereas in others the disease seemed to correspond to a proliferation of HCD protein-bearing lymphocytes with persistent maturation into plasma cells. Large cell lymphomas supervening on alpha-HCD belonged to the same proliferating clone as the clone secreting the HCD protein, as shown by surface markers and biosynthesis experiments which demonstrated synthesis but no secretion of HCD proteins. In one patient with gamma-HCD, the cells carried surface gamma and delta chains.

Adult↗
PubMed1978

Pathological studies on a long-term survived case of gamma heavy chain disease--a brief review of 30 reported cases and a proposal for histological typing.

A pathological and brief clinical study on the eleventh case of gamma heavy chain (gamma-chain) disease who died at the age of 44 after a long course of 12 years from the assumed onset of the disease was presented. Clinicopathological observations of the case showed a neoplastic nature which caused her death complicated by asthmatic attacks. Autopsy findings were characterized by diffuse infiltration of lymphoplasmacytoid cells and a few large immunoblastic cells into various organs. Literatures of 30 cases reported in the past, and the modern concept of lymphoma strongly suggest that the classificatory position of gamma-chain disease as well as Waldenström's macroglobulinemia should be placed between multiple myeloma and classic malignant lymphoma as an independent disease entity belonging to the same category. A proposal of histological typing of the disease was made in order to simplify various diagnostic designations in the literatures:--gamma-chain disease, 1) reticular type, 2) lymphocytic predominance, 3) plasmacytic predominance, 4) lymphoplasmacytoid cell type, 5) immunoblastic type. The present case belongs to type 4.

Adolescent↗
PubMed1993

An insertion-deletion event in murine immunoglobulin kappa gene resembles mutations at heavy-chain disease loci.

The analysis of spontaneous somatic mutants gives insights into the regulation of gene expression. Human heavy-chain disease (HCD) is a monoclonal lymphoproliferative disorder characterized by the presence of truncated immunoglobulin (Ig) heavy chains without associated light chains. To better understand the molecular mechanisms leading to the loss of light-chain production, we have examined a murine cell line model of heavy-chain disease. R15, a spontaneous mutant of the IgA, kappa-producing myeloma cell line W3129, produces heavy chain but no light chain. The variant delta 15 derived from R15 resembles human HCD in that it secretes a shortened heavy chain with no associated light chain. Cloning and analysis of the R15 kappa light-chain gene revealed that a 358-nucleotide insertion of unknown origin replaced 22 bases of the wild-type leader-variable region (L-V) intron (IVS). Although this genomic change left the light-chain exons and known regulatory elements intact, it altered the mRNA processing pathway, yielding two alternative RNA products, neither of which encodes a functional protein. This mutant therefore provides new insights into how genomic changes can influence gene expression.

Animals↗
PubMed1987

[Gamma 1 heavy chain disease with immune vasculitis and rheumatoid arthritis].

We are reporting about a case of gamma heavy-chain disease (Franklin's disease) with immunovasculitis and rheumatoid arthritis. The diagnosis was confirmed by the results of immunoelectrophoresis of the patient's serum and also by evidence of stimulated lymphocytes without light chain, but having gamma heavy-chain surface proteins. The immunofixation of the serum showed two protein bands of gamma heavy-chains with different loads. These results are confirmed by a two dimensional electrophoresis and isoelectric focussing of the serum proteins. The pathologic protein consists of at least two different heavy-chain proteins (mol wt 40,000 and 80,000) with isoelectric points between pH 5.5 and 7.3. In the urine of the patient pathological gamma heavy chain-protein was found only in a very low concentration. The predominant clinical symptom of the patient was a necrotizing vasculitis which became a therapeutical problem. In the immunofluorescence examination of the skin biopsy specimens, immunoglobulins and C3-complement could be detected in the stratum papillare. This fact would be compatible with the development of antibodies or immune complexes against deposited heavy-chain proteins. The arthropathy and the positive rheumatoid factor could similarly be explained by an immune complex mechanism.

Antigen-Antibody Complex↗
PubMed1978

Murine heavy chain disease.

Using cultured mouse myeloma cells, it has been possible to derive cells which are now synthesizing products similar to human heavy chain disease proteins. An initial mutant was isolated which snythesized a heavy chain with an internal deletion and a normal light chain. In a subsequent step, a variant was identified in which the synthesis of the heavy chain with the deletion persisted in the absence of light chain synthesis. These experiments also demonstrate that in the MPC-11-derived cultured cell line, the continued synthesis of heavy chain does not require the synthesis of light chain.

Animals↗
PubMed1988

Rapid evolution in the immunochemical findings of a gamma heavy chain disease.

We noted the following major immunochemical changes in the final course of a gamma heavy-chain disease associated with a myelomonocytic leukemia: an important oligoclonal increase of IgG1/kappa, during sepsis development, whereas the lambda molecules decreased and IgG2 and IgG3 completely disappeared in a one-month interval. Initial concentrations of IgG4 were stable during that period, and gamma 1 heavy chains were slightly increased. This is a very unusual observation of the successive immunochemical events terminating a gamma heavy-chain disease.

Aged↗
PubMed1981

Follicular centre cell lymphoma with alpha heavy chain disease. A histopathological and immunohistological study.

The first recorded case of a small intestinal lymphoma with alpha heavy chain disease occurring in Hungary is reported. The clinical manifestation of the disease and the focal distribution of mucosal alterations do not fulfill the criteria to make a diagnosis of Mediterranean type lymphoma (MTL) but the lymphomatous segments of the jejunum show the same pathological and immunohistological characteristics as seen in MTL. One of the basic features of MTL, the so called lympho-histiocytic nodules, which have been suspected by previous authors to represent an incipient neoplastic process involving histiocytic cells, is identified as follicular centroblastic/centrocytic malignant lymphoma. The cytogenetical connection between the massive proliferation of abnormal alpha chain producing plasma cells and neoplastic germinal centres is substantiated by direct immunohistological evidence using a combined immunofluorescent and immunoperoxidase technique to detect heavy and light chains within the same cell. The sarcomatous-appearing pleomorphic cell proliferation is interpreted as an anaplastic change in the centroblastic/centrocytic lymphoma. Unequivocal evidence for an abnormal IgA production in this pleomorphic component has not been obtained. Our observations suggest that in alpha heavy chain disease the neoplastic cell population originates in the germinal centres.

Heavy Chain Disease↗
PubMed1979

A new case of gamma heavy chain disease: clinical, immunochemical and structural characterization.

A new case of gamma heavy chain disease (gamma HCD) is described in a 77-year-old woman. The serum and urine contain an M-component and electrophoretic, antigenic and ultracentrifugal properties resembling those of the Fc fragment of IgG globulin. Analysis on SDS-polyacrylamide gel electrophoresis and ultracentrifugal studies show that gamma HCD portein is present in the serum as a dimer with a molecular weight of 58,000 daltons. Analysis of isotypic and allotypic markers along with the structural studies show that this HCD protein belongs to the IgG subclass and that deletion includes the total VH and CH1 regions with sequence starting at residue 225 in the middle of the hinge region.

Aged↗
PubMed1978

Gamma heavy chain disease in man: translation and partial purification of mRNA coding for the deleted protein.

Lymphoid cells obtained from the peripheral blood of a patient with heavy chain disease have been established in long-term culture. They continue to produce a protein antigenically identical to the deleted gamma3 heavy chain disease protein found in the patient's serum. The availability of the cell line has made it possible to analyze the mRNA coding for this protein. The primary in vitro translation product is 1500-2000 daltons larger than the polypeptide portion of the cytoplasmic or secreted protein and has methionine at the amino terminus. The mRNA sediments at 15.5 S on sucrose gradients and therefore appears to be smaller than the 17S message coding for normal-sized mouse gamma chains. It contains a base sequence that codes for a hydrophobic amino-terminal peptide not found in the cytoplasmic protein. There was no evidence for the synthesis of translatable light chain message by these cells. The present data suggest that this protein results from a primary somatic genetic event that gave rise to a cell product bearing a normal aminoterminus sensitive to limited proteolytic digestion. The serum protein thus appears to begin in the hinge region but, in fact, contains a normal heavy chain initiation site.

Cells, Cultured↗
PubMed1978

Gamma heavy chain disease in man: synthesis of a deleted gamma3 immunoglobulin by lymphoid cells in short and long term tissue culture.

Bone marrow cells were obtained from a patient with gamma heavy chain disease (HCD) whose serum contained a deleted immunoglobulin heavy chain. Incubation of the marrow cells with radioactive amino acids in short term tissue culture resulted in the synthesis of the labelled HCD protein. A permanent cell line was established from the peripheral blood of the patient. Similar labelling studies with the cell line and its cloned progeny demonstrated the synthesis of a protein identical in size and antigenicity to that synthesized by the marrow cells and found in the patient's serum. These experiments clearly demonstrated that, in this case of heavy chain disease, the deleted protein was the synthetic product of a clone of malignant lymphoid cells.

Amino Acids↗
PubMed1991

[Gamma-1 heavy chain disease with the demonstration of Bence-Jones proteins].

We describe a 61-year-old patient suffering from gamma-1-heavy-chain disease (gamma 1-HCD) associated with Bence-Jones-lambda proteinemia and proteinuria. The analysis of the patients gamma 1-HCD protein (WIN) shows a deletion of the complete Fd fragment. The N-terminal seven amino-acid residue does not resemble any of the known immunoglobulin-heavy-chain variable regions. Unexpectedly, in PBL-DNA and in DNA from EBV-immortalized cells we found in addition to the expected predominantly rearranged Ig-lambda-light-chain gene a predominant rearrangement of an Ig-kappa gene. These findings show that the gamma-1-heavy-chain disease of the patient involves a defective regulation of Ig-light-chain-gene activation as well.

Amino Acid Sequence↗
PubMed1980

[Gamma-heavy chain disease with autoimmune abnormalities and peripheral neuropathy (author's transl)].

The authors report the case of a 72 year old woman affected by gamma heavy chain disease in whom the heavy chain was detected in the serum and the urine as well. Further study of the paraprotein showed that it belonged to the gamma 1 subclass. This observation was unusual because of the presence of a 15 year-long peripheral neuropathy and the existence of various auto-antibodies, especially intrinsic factor antibody.

Aged↗
PubMed1989

Genomic alterations in a case of alpha heavy chain disease leading to the generation of composite exons from the JH region.

Human alpha heavy chain disease (HCD) is characterized by the presence in patient's serum of a short Ig alpha chain devoid of light chains. We analyzed the serum protein, the alpha HCD mRNA and the productive rearranged H chain gene from the leukemic cells of a new case (YAO) of alpha HCD. The abnormal YAO alpha 1 Ig was devoid of VH and CH1 domains and started at the beginning of the hinge region. The alpha HCD mRNA was shorter than normal alpha mRNA and the cDNA prepared from YAO mRNA encoded a leader sequence, an insert of 70 nucleotides and the CH2 and CH3 exons. The origin of the inserted sequence was assessed by cloning and sequence analysis of the alpha 1 productive gene. It started with a leader exon, a leader-VH intron and the first 11 bp of a VH exon. Then the VH region was deleted and replaced by a 19-nucleotide sequence that turned out to correspond to the 3' part of a modified JH5 exon. It was followed by a 221-bp sequence homologous to the JH5-psi JH3 intron and by an inserted sequence of unknown origin. The 3' part of this insertion and the remnant of a JH6 exon delineated a third exon that was followed by a relatively conserved JH6-C alpha intron. These two composite exons were flanked by splicing sites and accounted for the 70-nucleotide insert of the cDNA. The genomic nucleotide sequence also revealed a large deletion in the switch CH1 region which eliminated normal splicing sites and resulted in splicing of the third exon directly to the CH2 exon.

Amino Acid Sequence↗
PubMed1993

[Alpha heavy chain disease. Molecular analysis of a new case].

The NH2-terminal structure of serum abnormal protein, as well as the sequence of the corresponding mRNA, were determined in a new case of alpha heavy chain disease. The patient presented with typical clinical features of the disease. Intestinal and mesenteric lymphoplasmic infiltration was monoclonal as assessed by the study of the configuration of heavy and light chain genes. The serum abnormal alpha chains included two molecular species: one starting at the beginning of the hinge region and the other being two amino acids shorter, missing the two first amino acids of the hinge region. The sequence of the mRNA displayed a leader exon, a 93 bp sequence of unknown origin and the second and third constant exons of human alpha 1 chain. These data are discussed in the light of previously reported molecular studies in heavy chain diseases.

Adult↗