Heavy Chain Disease Research Articles

Primary lymphomas of the small intestine: East‐west contrast

Primary small intestinal lymphoma (PSIL) represents a heterogenous group of disorders with variable clinical and pathologic features and a characteristic age, socioeconomic, and geographic distribution. In developed countries, PSIL usually occurs as a localized ileal tumor, shows a bimodal age distribution, and most frequently presents with abdominal pain and obstructive symptoms. Histologically, most of these tumors are diffuse histiocytic, lymphocytic, or undifferentiated lymphomas. Other variants of PSIL, collectively referred to as immunoproliferative small intestinal disease, occur most often among young patients of poor socioeconomic status in Third World countries, mostly in the Middle East and Mediterranean area. They are characterized by involvement of long loops of the upper small intestine and commonly present with abdominal pain, diarrhea, malabsorption, and clubbing of the fingers. A subgroup of these patients shows a serological abnormality with the appearance of part of the alpha heavy chain of IgA in the serum. Histologically, the lesion appears as a dense diffuse lymphoplasmacytic infiltrate of the mucosa of the upper jejenum or duodenum. A form of malignant lymphoma of true histiocytic origin complicates long-standing celiac disease. The contrasting clinical, epidemiological, histopathological, and immunological features of these variants of PSIL raise interesting questions about the pathogenesis of small bowel lymphoma.

Immunohistochemistry of primary gastrointestinal lymphomas: a study of 76 cases.

A retrospective study of 76 primary gastrointestinal lymphomas utilizing an avidin: biotinylated horseradish peroxidase complex (ABC) technique demonstrated 22 B-cell lymphomas, including two associated with alpha-heavy chain disease. Seven cases were classified as true histiocytic lymphomas based on a positive reaction for one or more of three histiocytic enzyme markers utilized, predominantly alpha-1-antitrypsin and alpha-1-antichymotrypsin. However, in 20 cases, an intense admixture of reactive histiocytes was noted and these cells stained preferentially for the enzyme, lysozyme. Twenty cases, which stained for both kappa and lambda light chains and positively or negatively for albumin, could not be classified and 27 cases failed to stain with any of the antisera utilized.

A DNA insertion/deletion necessitates an aberrant RNA splice accounting for a mu heavy chain disease protein.

The human heavy chain disease protein BW is an immunoglobulin mu-chain variant whose amino terminus is initiated at the fifth amino acid of the first constant region domain. We cloned and analyzed both rearranged heavy chain alleles from BW leukemic cells to determine the molecular basis for this deleted protein. The phenotypically excluded heavy-chain allele possessed two intermediate recombinations of separate variable-diversity (V-D) and diversity-joining (D-J) junctions, neither of which were expressed. The productive allele, responsible for the mu chain, had a complete V-D-J4 recombination but as a result of a single-base deletion possessed stop codons within the variable region. More important, a small DNA insertion/deletion eliminated the J4 donor splice site. This necessitated an aberrant RNA splice between the leader region and the first constant region domain creating a shortened 2.35-kilobase muRNA. A recognition sequence for signal peptidase predicted a cleavage at the fifth amino acid of the first constant region domain. These molecular events are responsible for the truncated mu chain that lacks a variable region and fails to assemble light chains.

The role of gastrointestinal endoscopy in a developing country.

Eight-thousand-six-hundred-and-eighty patients were examined endoscopically over a period of six years. Significant pathological lesions were detected in 79.6% of the cases. While duodenal ulcers were seen at the same frequency as in the West, the number of gastric ulcers were considerably fewer, the ratio of gastric to duodenal ulcer being 1:8.4. Gastric cancer was also observed less commonly than in the West, but gastric lymphoma constituted 21% of all gastric malignancies. By endoscoping all bleeders within 24 hours we were able to identify the source of bleeding in 90.9% of the cases, and a lesion was detected in 96.8%. Direct visualisation of the duodenal and jejunal mucosa supported by histological examination was of paramount importance in the early detection of Immunoproliferative Small Intestinal Disease (IPSID) and its differentiation from other diseases such as tuberculosis, bilharzial jejunitis and Crohn's disease which are seen in our population.

Données récentes sur les Gammapathies monoclonales

Monoclonal gammopathies (M.G.) are a group of disorders characterized by the proliferation of a single clone of plasma-cells that produce a Monoclonal Immunoglobulin (M-Ig). The presence of M-Ig can be demonstrated by electrophoresis in the patient' serum and identified by immunoelectrophoresis as a molecule containing two heavy chains of a single class and two light chains of a single type. In M.G. of malignant origin, free light chains (Bence Jones Proteins) can be evidenced in the concentrated urines. The fact that M.G. may be more frequent in certain families show the existence of a familial predisposition of this disease whereas its origin is still unknown. M.G. are often associated with malignant proliferation of B lymphocytes such as multiple myeloma, Waldenström's macroglobulinemia, heavy chain disease as well as some other lymphoproliferative disorders. However, in a certain number of cases, the malignant origin of the M.G. was not proved, because M-Ig can occur in the serum of people apparently in good health and without clinical or hematological features (asymptomatic "benign" M.G.). Asymptomatic benign M.G. have been detected in increasing numbers during the last decade due to use of cellulose acetate electrophoresis for the routine examination of patients or in the course of systemic screening in normal populations such as blood donors. At the present time, a malignant origin of M.G. cannot be proved in more than thirty per cent of case and these "asymptomatic M.G." must be follow-up by a yearly clinical, hematological and electrophoretical check-up in order to detect a possible malignant evolution. In other cases, M.G. can be associated with neoplasms of cells types not known to produce M-Ig, in cold chronic agglutinin disease, and during the course of some auto-immune disorders.

Small intestinal lymphoma

AbstractThis paper reviews small intestinal lymphoma. Although a major emphasis is placed on primary small intestinal lymphoma of the “Western” type, the important topic of lymphoma in celiac disease is discussed. Our own recent experience of 7 patients with lymphoma in celiac disease is presented. The lymphoma of immunoproliferative small intestinal disease (“Mediterranean” lymphoma) and the associated α‐chain disease are also reviewed, with emphasis on the differences from the “Western” type of primary small intestinal lymphoma.

Immunoproliferative small intestinal disease and primary small intestinal lymphoma. Relation to alpha chain protein.

Forty-three patients with immunoproliferative small intestinal disease and primary small intestinal lymphoma were studied prospectively. Eighteen patients in whom alpha-chain protein was detected in the serum had significantly more features of malabsorption, and disease was localized more commonly in the jejunum. In all of these patients, a diffuse lymphoplasmacytic infiltrate was found in the intestine; in three patients lymphoma was found only in mesenteric lymph nodes. Twenty-five patients with lymphoma in whom alpha-chain protein failed to be detected had significantly more features of intestinal obstruction, and disease was found more commonly in the ileum. Five of these patients had lymphoma associated with a diffuse mucosal infiltrate that was indistinguishable from the first group. In patients available for follow-up, no difference was found in cumulative survival over 30 months in the two groups, with approximately 40% mortality at 6 months.

Plasma cell infiltration of the small bowel: lack of evidence for a non-secretory form of alpha-heavy chain disease.

Eight patients with diffuse plasma cell infiltration of the small bowel who had the clinical features of immunoproliferative small intestinal disease (IPSID), but whose serum was negative for free alpha-heavy chains, were investigated for evidence of a non-secretory form of alpha-chain disease (alpha-CD). Molecular sieving and immunoblotting of serum, immunoperoxidase staining of biopsy specimens, and in vitro protein synthesis studies utilising an immunoprecipitation technique and polyacrylamide gel electrophoresis, failed to detect any new cases of alpha-CD. Four of the eight cases were found to have diffuse intestinal lymphoma. The remaining four patients, who were unsuccessfully investigated for evidence of a significant abnormality in cellular immunity, have not developed detectable alpha-CD protein or lymphoma over a mean of 143 months. Despite continuing exposure to possible environmental stimuli, it is concluded that not all cases of IPSID elaborate detectable alpha-CD protein or evolve to lymphoma.

Primary gastrointestinal lymphoma in Kuwait. An 11-yr retrospective analysis of 108 cases

One hundred and eight cases of primary gastrointestinal lymphoma from the files of Kuwait Cancer Control Centre over a period of 11 yr were analysed retrospectively. The occurrence was 47 in the proximal small intestine, 38 in the stomach, 18 in the distal ileum and five in the colon and rectum. The majority of the patients were in stage III. Using a modified Rappaport's classification, lymphocytic lymphoma was the commonest histologic type (60%) as compared to histiocytic lymphoma (19%). Four patients had early IPSID (immunoproliferative small intestinal disease). The ‘Western’ type of lymphoma occurred in the fourth decade while the ‘Mediterranean’ type occurred in the third decade of life. The latter occurred more commonly among people of low socioeconomic background. Chemotherapy was the single most effective mode of treatment. Addition of surgery, radiotherapy or both did not improve the 2-yr survival but did improve the 5-yr survival.

Peripheral neuropathies associated with monoclonal proteins: a clinical review.

Over the last decade, the increasing use of serum and urine protein electrophoretic screening of patients with idiopathic peripheral neuropathy has led to greater recognition of peripheral neuropathy syndromes that are associated with monoclonal proteins and plasma cell dycrasias. After careful evaluation, most of these patients have benign monoclonal gammopathy, followed in frequency by primary systemic amyloidosis and osteosclerotic myeloma, with occasional cases associated with osteolytic multiple myeloma, Waldenstrom's macroglobulinemia, gamma heavy chain disease, and other rare disorders. Several of these syndromes have distinctive presentations and are recognizable clinically, whereas others (especially multiple myeloma neuropathy) are diverse clinically and are not clearly distinguishable from other chronic neuropathies. The discovery of IgM-kappa monoclonal proteins directed at myelin antigens in some patients with benign monoclonal gammopathy and the delineation of the syndrome of neuropathy and multiorgan involvement in osteosclerotic myeloma are important developments which may shed light on the mechanism of the remote effects of malignancies on the nervous system.

Gamma heavy chain disease: Report of a case associated with trisomy of chromosome 7

A case of gamma heavy chain disease is reported in a 52-year-old white male who presented with fever and generalized lymphadenopathy. A lymph node biopsy showed malignant lymphoma. A partial transient response was obtained with cyclophosphamide, vincristine, prednisone, and doxorubicin. He died 3 months after diagnosis from disease progression and infectious complications. Chromosome analysis of cells from an involved lymph node showed the presence of trisomy 7. Chromosome abnormalities have been reported in three of ten previously published cases of gamma heavy chain disease. Trisomy of chromosome #7 has not previously been reported.

Gamma heavy chain disease studied by two-dimensional electrophoresis and immuno-blotting techniques.

We used two-dimensional polyacrylamide gel electrophoresis and immunoblotting techniques to study serum proteins from a patient with a monoclonal gammopathy. Two-dimensional electrophoresis was optimized for serum proteins with two main goals: (a) to allow the resolution of many serum proteins in both directions, with penetration of the maximum number of proteins in the first dimension; and (b) to obtain the best reproducibility from one experiment to another, within the limits of the current technique. These analyses, combined with immunoblotting, permitted us to characterize a gamma heavy chain disease protein of 34 000-Da molecular mass. Moreover, two-dimensional mapping of the patient's serum proteins allowed demonstration of the microheterogeneity of this monoclonal component.

Immunoproliferative small intestinal disease in Algerians. II. Ultrastructural studies in alpha-chain disease.

The plasma cell infiltrate of the small intestine in alpha-chain disease has been studied ultrastructurally in an attempt to determine whether there is a significant nuclear-cytoplasmic asynchrony that could be used as evidence for the neoplastic nature of the disease, even in its early stages. No such asynchrony was identified. In the early stages of the disease, the infiltrate was mainly of slightly immature plasma cells indistinguishable from those of coeliac disease. Later stages were marked by the presence of less differentiated immunoblastic cells arising in the deep mucosa and infiltrating into glands. Multinucleate plasmacytoid cells were thought to be degenerate cells. The significance of these findings is discussed in relation to the nature of alpha-chain disease and immunoproliferative small intestinal disease in general.

Immunoproliferative small intestinal disease in algerians. II. Ultrastructural studies in alpha-chain disease

Immunoproliferative small intestinal disease in algerians. II. Ultrastructural studies in alpha-chain disease

Loss of a consensus splice signal in a mutant immunoglobulin gene eliminates the CH1 domain exon from the mRNA.

A series of mouse myeloma mutants, derived from a cell line of the murine MPC-11 tumor (gamma 2b, kappa), resemble human heavy-chain disease in their loss of an internal domain (exon). In these mutants, most of the gamma 2b CH1 exon was present in the nuclear RNA but was removed during splicing to form the mature cytoplasmic RNA. Amino acid sequence studies of one mutant (10.1) are consistent with the loss of the complete CH1 domain. A second mutant cell line (I17) derived from 10.1 and containing the same CH1 alteration was shown by S1 nuclease protection experiments to have an additional mRNA deletion spanning the CH2-CH3 domain boundary. This second deletion was shown to result from a genomic alteration that provided a marker for the isolation of the expressed H-chain allele. To determine the basis of the CH1 splicing defect, the 117 genome-expressed gamma 2b constant region DNA was cloned. Sequence studies showed a deletion of 99 nucleotides around the 3' end of the CH1 domain, which removed the splice site and flanking DNA, apparently causing the aberrant splicing of the RNA transcript. The sequence deleted in the mutant is flanked by short repeats of the octameric sequence CCAGCCAG in the wild-type gene. In the mutant, one copy of the repeat, in addition to the sequences between the repeats, has been lost.

Loss of a consensus splice signal in a mutant immunoglobulin gene eliminates the CH1 domain exon from the mRNA.

A series of mouse myeloma mutants, derived from a cell line of the murine MPC-11 tumor (gamma 2b, kappa), resemble human heavy-chain disease in their loss of an internal domain (exon). In these mutants, most of the gamma 2b CH1 exon was present in the nuclear RNA but was removed during splicing to form the mature cytoplasmic RNA. Amino acid sequence studies of one mutant (10.1) are consistent with the loss of the complete CH1 domain. A second mutant cell line (I17) derived from 10.1 and containing the same CH1 alteration was shown by S1 nuclease protection experiments to have an additional mRNA deletion spanning the CH2-CH3 domain boundary. This second deletion was shown to result from a genomic alteration that provided a marker for the isolation of the expressed H-chain allele. To determine the basis of the CH1 splicing defect, the 117 genome-expressed gamma 2b constant region DNA was cloned. Sequence studies showed a deletion of 99 nucleotides around the 3' end of the CH1 domain, which removed the splice site and flanking DNA, apparently causing the aberrant splicing of the RNA transcript. The sequence deleted in the mutant is flanked by short repeats of the octameric sequence CCAGCCAG in the wild-type gene. In the mutant, one copy of the repeat, in addition to the sequences between the repeats, has been lost.

The gamma 1 heavy-chain disease FOR protein is present in two molecular forms.

Heavy chain disease proteins (FOR) were isolated from human plasma. These proteins were also detected immunochemically in the urine of the patient. The proteins were disulphide-linked Fc-like dimers with molar mass 64.2 kg/mol and sedimentation rate S020,W = 0.356 ps (3.56 S). Similar amounts of aspartic acid and pyroglutamic acid were found at the N-terminus. After cyanogen bromide cleavage of the FOR proteins, three peptides were isolated and their amino acid composition and partial amino acid sequence was determined. We suggest that two Fc-like proteins of similar sizes are present in the plasma: (1) the first with N-terminal aspartic acid corresponding to position 221 of gamma 1 EU chain and (2) the second with N-terminal pyroglutamic acid. The first protein and small amounts of related low-molar mass fragments found also in the plasma could be degradation products of the second protein. Evidence is given on structural differences between the FOR proteins and the corresponding portion of the gamma 1 EU chain.

Long survival in a patient with alpha-chain disease

A patient with evidence at presentation of alpha-heavy chain disease and an immunoblastic lymphoma is presented, who had remained in clinical, histologic, and immunologic remission for more than 12 years following initial radiotherapy and corticosteroids. The suggested management of this condition and its prognosis is discussed.

The primary structure of mu-chain-disease protein BOT. Peculiar amino-acid sequence of the N-terminal 42 positions.

The complete primary structure of the mu heavy-chain disease (mu-HCD) protein BOT has been determined. The monomeric HCD-mu-chain consists of 391 amino-acid residues, lacking the VH and mu CH1 domains but including the entire CH2, CH3 and CH4 domains (349 residues). The sequence of the preceding 42 N-terminal residues which we designate as the "pre-C-part" presents no homology to any known variable or constant immunoglobulin sequence, but contains an internal homology of positions 10-19 to positions 20-29. The origin of the "pre-C-part" structure and the deletion of the mu CH1 domain of protein BOT are discussed.

Immunoproliferative Small-Intestinal Disease

Six patients had the clinical and pathological features of immunoproliferative small-intestinal disease (IPSID). All were female with malabsorption or growth retardation in whom testing for alpha-heavy chains was repeatedly negative. They were followed for a mean of 7.5 years, during which time no significant alteration in the jejunal biopsy appearances of five patients has occurred, none have developed lymphomas.