Heavy Chain Disease Research Articles

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.

An Unusual Case of a Plasma Cell Neoplasm With an IgG3λ Myeloma and a γ3 Heavy Chain Disease Protein

A unique case of gamma3 heavy chain disease with two related serum proteins is reported. One molecule appears to be an IgG3lambda myeloma protein. The second molecule is a dimer of a shortened gamma3 heavy chain that has an unblocked amino terminus and lacks the VH and CH1 domains. Its probable origin as a synthetic product is discussed. The clinical and pathologic features of this patient resemble those of other patients with gamma heavy chain disease more than those of patients with multiple myeloma. It seems likely that the heavy chain disease protein is the result of a mutational event in the malignant clone originally producing the myeloma protein.

An unusual case of a plasma cell neoplasm with an IgG3lambda myeloma and a gamma3 heavy chain disease protein

A unique case of gamma3 heavy chain disease with two related serum proteins is reported. One molecule appears to be an IgG3lambda myeloma protein. The second molecule is a dimer of a shortened gamma3 heavy chain that has an unblocked amino terminus and lacks the VH and CH1 domains. Its probable origin as a synthetic product is discussed. The clinical and pathologic features of this patient resemble those of other patients with gamma heavy chain disease more than those of patients with multiple myeloma. It seems likely that the heavy chain disease protein is the result of a mutational event in the malignant clone originally producing the myeloma protein.

A New Case of Gamma-Heavy Chain Disease

The first case of gamma-heavy chain disease described in Spain is here reported. The patient, a 36-year-old woman, presented fever, enlarged regional lymph nodes, and hepatosplenomegaly, without bone marrow abnormalities but with lymphopenia. Serum electrophoresis did not disclose any M-component. The abnormal gamma-chain protein had a alpha2-globulin mobility and was immunochemically related to the Fc fragment. It belonged to the IgG 4 subclass, its molecular weight was about 60,000. Proteinuria was minimal but the electrophoresis of concentrated urine showed a homogeneous peak of alpha2-globulin mobility constituted by the gamma-chain fragment. Biopsy of an axillary lymph node disclosed features of immunoblastic sarcoma. The course was malignant, resulting in death in 8 months.

“Mediterranean abdominal lymphoma,” or immunoproliferative small intestinal disease.Part I: Clinical aspects

The pathology of 25 cases of Mediterranean abdominal lymphoma, better designated as immunoproliferative small intestinal disease (IPSID), are reported from the American University of Beirut Hospital. The series includes nine cases with documented alpha heavy chain disease (alpha-HCD). The disease is characterized by the presence of a diffuse and compact bandlike lymphoplasmacytic infiltration of the proximal small intestinal mucosa. The presence of a concomitant malignant lymphoma in the intestine and/or mesenteric lymph nodes, and of alpha-heavy protein in the serum is commonly encountered. Two histopathologic variants of IPSID are present. The first is characterized by the diffuse infiltration of the mucosa, at sites away from tumoral masses, by either pure plasmacytic infiltration, or mixed lymphoplasmacytic infiltration. This variety is associated with the immunoblastic sarcoma type of malignant lymphoma, and with alpha chain disease (alpha-HCD). The second variant is characterized by a diffuse follicular lymphoid hyperplasia pattern in the small intestinal mucosa. The associated malignant lymphoma is diffuse and undifferentiated often having a starry-sky pattern. This variety is not associated with alpha-HCD. Both histologic variants share the same clinical antecedents. In five patients, mesenteric lymph nodes harbored immunoblastic sarcoma while the intestinal mucosae of the same patients were involved with a benign appearing lymphoplasmacytic infiltration. This finding stresses the need for staging laparatomy. Three patients, with alpha-HCD, had peripheral lymph node involvement with immunoblastic sarcoma. The disease apparently evolves in two stages: an immunoproliferative phase, probably reversible, and a later development of malignant lymphoma. The term immunoproliferative small intestinal disease accurately describes the nature of the entity.

Alpha heavy-chain disease in Southern Iran

A prospective study of 32 patients with primary upper small intestinal lymphoma in our region revealed 10 cases of alpha heavy-chain disease. Patients were mostly in the second and third decades of life and males predominated. Weight loss, diarrhea, and abdominal pain were the most common complaints and clubbing the most frequent physical findings. Laboratory tests revealed a malabsorption pattern on intestinal x-rays, and malabsorption of xylose, fat, and vitamin B12 was frequently noted. Dense plasmacytic infiltrate of the lamina propria of small bowel was the most frequent pathologic finding while true neoplasm of the lymphoid system (ie, immunoblastic sarcoma) was encountered in 20% of the cases.

μ-Chain secretion by peripheral blood lymphocytes in μ-chain disease; functional and ultrastructural characterization of cells associated with μ-chain production

The course of secretion of immunoglobulin (Ig) μ-chain secretion by cultured peripheral blood lymphocytes in a case of heavy chain disease has been studied. It has been found that μ-chain protein is secreted primarily as a monomer. Dimers and polymers of μ-chain protein found in the serum of this patient are of secondary i.e. post-synthetic origin. By comparison of cytoplasmic and culture supernatant protein it has been found that metabolically inert deposits of μ-chain protein in aggregated form are present within the cultured cells. By ultrastructure studies these cells were classified as small lymphoid cells. The cells associated with μ-chain secretion in this patient exhibit distinct functional and ultrastructural features and possibly are arrested at a differentiation stage at which surface Ig synthesis is initiated.

Gamma Heavy Chain Disease: Clinical Aspects and Characterization of a Deleted, Noncovalently Linked γ1 Heavy Chain Dimer (BAZ)

This report describes the clinical and immunoglobulin features of a patient with gamma heavy chain disease (HCD), who presented with a clinical picture suggestive of an underlying malignancy rather than the usual picture of lymphoma or granulomatous disease. A unique clinical feature was the nearly total replacement of the submaxillary glands by plasma cells. The patient's serum and urine contained a paraprotein, gammaHCD protein BAZ, which belongs to the gamma1 subclass and forms noncovalently linked dimers with a molecular weight of approximately 60,000 daltons. This mutant protein exhibited a deletion which encompassed most of the variable (V) region, the first constant domain (CH 1), and the hinge region. In addition, preliminary structural analyses demonstrated the replacement of alanine by glycine in position 431 of the carboxyterminal octadecapeptide. This substitution may possibly represent another allotypic marker on IgG1 proteins.

Gamma heavy chain disease: clinical aspects and characterization of a deleted, noncovalently linked gamma1 heavy chain dimer (BAZ)

This report describes the clinical and immunoglobulin features of a patient with gamma heavy chain disease (HCD), who presented with a clinical picture suggestive of an underlying malignancy rather than the usual picture of lymphoma or granulomatous disease. A unique clinical feature was the nearly total replacement of the submaxillary glands by plasma cells. The patient's serum and urine contained a paraprotein, gammaHCD protein BAZ, which belongs to the gamma1 subclass and forms noncovalently linked dimers with a molecular weight of approximately 60,000 daltons. This mutant protein exhibited a deletion which encompassed most of the variable (V) region, the first constant domain (CH 1), and the hinge region. In addition, preliminary structural analyses demonstrated the replacement of alanine by glycine in position 431 of the carboxyterminal octadecapeptide. This substitution may possibly represent another allotypic marker on IgG1 proteins.

Gamma Heavy Chain Disease—Presenting as Pancytopenia and Splenomegaly

A patient with gamma heavy chain disease (Franklin's disease) was discovered during evaluation for pancytopenia and splenomegaly. Lymphadenopathy, palatal edema, and infiltration of the bone marrow palatal edema, and infiltration of the bone marrow with abnormal cells were all absent. Serum and urine protein electrophoresis demonstrated a monoclonal protein migrating in the beta region. Immunoelectrophoresis showed that it reacted with antibodies against the Fc fragment of IgG heavy chains (gamma chains) but not with antibodies against kappa and lambda but not with antibodies against kappa and lambda light chains of Fab fragments. In the first year after detection of the disease, the patient had acute cholecystitis and disseminated herpes zoster. Sixteen months after diagnosis he died of overwhelming pneumonia caused by Pseudomonas aeruginosa and lebsiella neumoniae. A striking feature of his illness was his asymptomatic presentation, with pancytophenia and splenomegaly the only indication of this disease.

III. Non-epithelial Large Intestine

Non-epithelial tumors of the gastrointestinal tracts are very rare. Its incidence is about 1-5% of the all neoplasmas of the gastrointestinal tract. Benign non-epithelial tumors in the small intestine are occupied about 60% of all benign tumors. But there is very low frequency in the stomach, colon and rectum. The incidence of the malignant non-epithelial tumors (sarcoma) is very rare, 1-2% of all malignant tumors in stomach and large intestine. However, in the small intestine, it is showed to be over 40% in sarcoma. Of all benign non-epithelial tumors, histologically leiomyoma and benign lipoma are very common. Most of sarcoma are malignant lymphoma and leiomyosarcoma, and other tumors are very rare.It is very important to differentiate leiomyosarcoma from neurogenic sarcoma. Almost cases which were previously reported as neurogenic tumor, especially neurinoma or neurogenic sarcoma of the gastrointestinal tract, are probably leiomyosarcoma and leiomyoma. In this paper we emphasized the importance of histological differential diagnosis between leiomyosa-rcoma and neurogenic tumors in the gastrointestinal tract. And we reported a case of solitary neurogenic sarcoma of the small intestine.Recently, lymphoid-plasmacytic disorders associated with appearance of a unique serum and urinary protein, which is Fc-fragment of the counterpart of the heavy chain of Ig-G, are known as heavy chain disease. We have experienced a case of heavy chain disease, which was involved the gastrointestinal tract. We cannot find any reports of heavy chain disease involving the gastrointestinal tract. Histologically heavy chain disease features (reticulum cell sarcoma like and Hodgkin desease like) but malignant lymphoma, and remarkable plasma cell infiltration was noted. This feature is very characteristic of this disease. Ig-A heavy chain disease (α-chain disease) arises from small intestine. The characteristical histoligical findings is diffuse plasma cell infiltration and clinically associated with malabsorption.

Mediterranean lymphomas with alpha heavy chain monoclonal gammopathy.

Nine cases of Mediterranean lymphoma with alpha heavy chain disease are described. All patients were young, aged between 11 and 22 years. Neither sex predominated in the series. The clinical presentation of the disease was either gastrointestinal, with chronic diarrhea and malabsorption, or neoplastic, with tumors frequently associated with either obstructive or perforative complications. Finger clubbing and retardation of physical growth (height and weight) and secondary sexual maturation were usually evident. The laboratory manifestations of the malabsorption syndrome were scant and generally not specific. The intestinal lesions predominated in the beginning of the small bowel, and their gross appearance varied from one case to another: diffuse thickening of the intestinal wall, alone or associated with tumors, or isolated segmentary tumors. Massive mesenteric lymph node enlargement was present in all cases; in some cases hepatic, splenic, or extra-abdominal lymph node spread was noted. Histologically, these lesions demonstrated a varied cellular morphology, but seemed to belong constantly to the B-lymphocytic line. The secretion and excretion by these cells of an abnormal IgA (devoid of light chains), which was revealed by immunoelectrophorectic study of the patients' sera, was the main biochemical abnormality of the disease. This disease presents several problems: 1) its relationship with other intestinal lymphomas; 2) the nature and the degree of malignancy of the intestinal cellular infiltrates; and 3) its identification as a clinicopathologic entity, with the possibility that infectious and genetic factors are significant in its etiology and pathogenesis.

The amino acid sequence of “heavy chain disease” protein ZUC. Structure of the Fc fragment of immunoglobulin G3

The sequence of the Fc fragment of human IgG3 was studied, using a naturally-occurring γ3 heavy chain variant (ZUC). Though the molecule is internally deleted, it contains 248 residues, including the entire Fc fragment. The almost complete sequence of the C H2 and C H3 domains (position 234 to 446) indicates an extremely close evolutionary relationship with γ1 and γ4 chains. There is a 95% homology between IgG3 and IgGl and 92% between IgG3 and IgG4 in the C H2 in the C H3 domains.

Mutations in mouse myeloma cells: implications for human multiple myeloma and the production of immunoglobulins.

Multiple myeloma raises a number of puzzling questions about the production of immunoglobulins and the malignant transformation of lymphoid cells. Some of these questions can be approached by studying mouse plasmacytomas and by genetic and biochemical studies of mouse myeloma cells in culture. The synthesis, assembly, glycosylation, and secretion of immunoglobulin has been analyzed in detail using the mouse myeloma system. The development of a technique that detects variants in clones of cultured mouse myeloma cells has led to the demonstration of a unique genetic instability in these cells. Based on these results a model is presented to explain the high frequency of ligh-chain producing (Bence Jones) myelomas in patients. Finally, mutant cell lines have been recovered which produce defective immunoglobulins similar to those found in heavy-chain disease and some other lymphoproliferative disorders.

Mu heavy-chain disease--a defect in immunoglobulin assembly. Structural studies of the kappa chain.

Mu-chain protein GLI is a pentameric molecule with an amino-terminal deletion comprising 130 residues. The half-cysteine residue (position 140) which forms the H-L disulfide bridge in normal IgM is present. Instead of being joined to the L chain, it presumably exists as an additional inter-H-H disulfide bridge. The kappa Bence Jones protein is of normal size and present in two forms: as monomers and dimers. The carboxy-terminal half-cysteine of the monomer is bound to cysteine. Possible reasons for failure of assembly between mu and L chains are briefly discussed.

A new immunoglobulin variant: gamma3 heavy chain disease protein CHI.

Protein CHI is a defective human gamma3 heavy chain immunoglobulin with a deletion encompassing a portion of the variable and constant regions. Joining of the two pieces takes place at the beginning of an extra fragment (Fh) in the constant region where repetitive sequences are found, apparently as the result of gene duplications and/or unequal crossover between gamma genes. It is postulated that a 45 nucleotide fragment is the repetitive unit coding for the extra fragment.

The evolution of alpha heavy chain disease

Two patients with alpha heavy chain disease are described. In the first patient, treatment with cyclophosphamide, prednisone and doxycycline was associated with a 28 month-long remission and the disappearance of the paraprotein and lymphoplasmocytic infiltration of the intestine. Shortly afterwards, a retroperitoneal immunoblastic lymphoma was found associated with an immunoglobulin G-kappa-paraproteinemia, and gamma heavy and kappa-light chains in the urine; the intestinal biopsy specimen was normal. In the other patient, the alpha chain only appeared two years after the malabsorption syndrome. The fact that in the first, apparently cured patient, a tumor of different anatomic site and secretory capacity appeared, suggests the existence of a B-cell neoplasia of different clone from that which gave rise to the original disease. In the second patient, it is probable that only the increase in the mass of neoplastic cells led to the detection of the protein abnormality, or alternatively the antigenic-oncogenic stimulus led to the abnormal secretion only after two years.

The evolution of alpha heavy chain disease : Guardia J, Rubiés-Prat J, Gallart MT, Moragas A, Martínez-Vásquez JM, Bacardi R, Vilaseca J: Am J Med 60: 596–602, 1976

The evolution of alpha heavy chain disease : Guardia J, Rubiés-Prat J, Gallart MT, Moragas A, Martínez-Vásquez JM, Bacardi R, Vilaseca J: Am J Med 60: 596–602, 1976

The Defect in µ Heavy Chain Disease Protein GLI

Summary Amino acid sequence studies of µHCD protein GLI reveal the absence of the amino terminal 130 residues. The molecule starts at Ala 131 and contains Cys 140, normally involved in the H-L disulfide bridges. Except for the deletion and presumably an extra H-H disulfide bridge involving Cys 140, the remainder of the µ-chain appears normal.

Giemsa-SEM Method to Observe the Surface Structure of Plasmocytoid Cell in a Heavy Chain Disease

Giemsa-SEM Method to Observe the Surface Structure of Plasmocytoid Cell in a Heavy Chain Disease