Heavy Chain Disease Research Articles

Hematologic disorders in rheumatic disease

The 1990 literature relating to hematologic disorders in rheumatic disease is reviewed. Two main subject areas of general interest are identified. The anemia of chronic disease has been reviewed and shown to be associated with a variety of medical conditions. Generalized reticuloendothelial hyperplasia associated with heavy-chain disease is a poorly recognized complication associated with rheumatoid arthritis and may be mistaken for underlying sepsis in these patients.

Plasma postheparin diamine oxidase in patients with small intestinal lymphoma

Diamine oxidase (DAO) is an enzyme located almost exclusively in villus tip enterocytes. Its plasma activity is enhanced by intravenous heparin which releases the enzymes from small bowel enterocytes into the blood. Plasma postheparin DAO (PHD) values have been shown to be significantly lower in patients with malabsorption and villous atrophy, thus suggesting that PHD reflects the mature enterocytic mass. In this study we have assayed PHD in five patients with small bowel lymphoma (two with immunoproliferative small intestinal disease [IPSID] and three with non-IPSID lymphoma) associated with malabsorption syndrome and small bowel mucosa atrophy. The PHD test was performed at diagnosis, after partial or complete remission induced by chemotherapy, and during the follow-up. The PHD values, very low at diagnosis (0.66 +/- 0.12 U/ml), increased during chemotherapy and reached the normal range (greater than 3.7 U/ml) when complete remission occurred. The PHD values rapidly and consistently decreased whenever the disease relapsed. Our data indicate that in patients with small bowel lymphoma PHD test is a sensitive marker of small bowel mucosa damage and suggest that it could be useful in monitoring the recovery of mucosal lesions induced by chemotherapy.

A filter affinity transfer method for the analysis of rheumatoid factors

Transfer of serum proteins separated by thin layer agarose electrophoresis onto nitrocellulose sheets precoated with purified human polyclonal IgG followed by revelation with enzyme-coupled anti-mu or anti-alpha antisera resulted in the specific detection of rheumatoid factors (RF) belonging to the IgM or IgA classes. Mono- or polyclonality of such RF can be evaluated from the patterns of the blots (sharp bands). In addition, their light chain type can be determined using affinity filters coated with a gamma heavy chain disease protein or with IgG Fc fragments. This simple and rapid procedure allows an easy characterization of monoclonal RF, even if they are present in minute amount amongst polyclonal RF as in certain sera from rheumatoid arthritis patients.

Differential mRNA stabilities affect mRNA levels in mutant mouse myeloma cells

A series of mouse myeloma cell lines producing mutant gamma 2b immunoglobin heavy chains, which resemble heavy chain disease proteins, were analyzed for messenger RNA abundance as a function of mRNA alterations. A mutation effectively deleting the gamma 2b-CH1 domain of the mRNA had little or no effect on Ig heavy chain mRNA abundance on half-life (mutant 10.1). A mutation in the gamma 2b-CH2 and CH3 domain, causing premature termination of translation, had more deleterious effects on Ig heavy chain mRNA abundance and half-life (mutant I17). Substitution of the deleted portions of the gamma 2b mRNA with gamma 2a sequences by subclass switching in the cells (mutants K23 and K25) resulted in increased heavy chain abundance and half-life relative to the parent I17. In contrast, kappa light chain mRNA levels and half-lives remain constant among the mutants. The wild-type and mutant cell lines transcribed the Ig heavy chain gamma 2b locus equally when compared with an internal beta-actin standard by transcription run on studies. Therefore, half-life of the Ig heavy chain mRNA seems to be the principal determinant in cytoplasmic mRNA abundance in this system.

The value of double-contrast study of the small intestine in immunoproliferative small intestinal disease

Radiological findings of 2 patients with immunoproliferative small intestinal disease were studied. One of the cases was associated with alpha-chain disease. Both patients complained of severe diarrhea, and diagnosis was made by endoscopic biopsy of the duodenum and jejunum. Double-contrast studies of the small intestine and hypotonic duodenographies in these patients revealed thickened folds and innumerable fine granular elevations without ulcerations or luminal narrowings. Double-contrast studies are one of the most important examinations in the diagnosis of this disorder.

Alpha heavy chain disease of patient MAL: structure of the non‐functional rearranged α gene translocated on chromosome 9

Alpha heavy chain diseases (HCD) are lymphoproliferative disorders characterized by the production of truncated alpha immunoglobulin heavy chain without associated light chains, alpha HCD MAL is featured by multiple structural alterations of the alpha 1 productive gene and on original t(9;14)(p11;q32) translocation involving the other rearranged alpha 1 allele. We present here the structure of the der(9) chromosome. Sequence analysis provides evidence that the translocation occurred after local pairing of the two chromosomes mediated by an almost perfect nonameric sequence, followed by a staggered double-strand break of chromosome 14. This translocation occurred on a V(D)J rearranged locus; unexpectedly, there were a deletion of the 3' part of the VH gene, several insertions of non-immunoglobulin-related genes and multiple mutations, i.e. alterations reminiscent of those occurring on the HCD productive genes.

Oral Manifestation of Immunoproliferative Small Intestinal Disease. A Case Report

A patient with a previous medical history of immunoproliferative small intestinal disease (IPSID) presented with persistent red and ulcerated lesions on her attached gingiva. Despite the obvious long standing gingival inflammation, minimal destruction of alveolar bone had occurred. Following failure of the tissues to respond to routine periodontal therapy, a gingival biopsy was taken. Histological assessment of the specimen revealed several features in common with the intestinal lesions seen in IPSID. In particular, a large plasma cell infiltrate subjacent to the gingival epithelium was noted. There was a marked loss of normal connective tissue morphology and evidence of epithelial degeneration. Treatment has since consisted of palliative measures only. While this is a relatively rare condition, it (as well as other disorders of the immune system) provides a useful insight into the role that the immune system plays in the inflammatory periodontal diseases.

A new extra sequence at the amino terminal of a μ heavy chain disease protein (DAG)

The primary structure of a human μ heavy chain (DAG) protein is described. The native protein is a circular decamer with a molecular weight ( Mr) of 500 kDa, each decamer being constituted of the constant domainsC μ 2, C μ 3 and C μ 4 and interlinked by 15 disulfide bridges. At its NH 2-terminal each monomeric chain starts with an “extra sequence”. The amino acid sequence of this segment is Arg-Gln-Ser-Asp-Asp-Pro-Val-Leu-Arg-Gly-Thr-Thr-Val-Pro-Val-Thr-Glu and its reinitiation point is located at Val 223 (Gal numbering), at the beginning of Cμ 2. This sequence has no homology with any other protein included in the present databases.

Immunoproliferative small intestinal disease: A study of 13 cases with alpha heavy‐chain disease

The pathology of 13 cases of immunoproliferative small intestinal disease (IPSID) associated with alpha-heavy-chain disease--one an apparent non-secretor and another with localized infiltration--is described. Four cases exhibited immunohistological light-chain monotypia. In one of these, evolution of a light-chain negative cell population was observed over a 7-year period. In the intestine, centrocyte-like cells produced lympho-epithelial lesions in 11 cases and enlarged lymphoid follicles in three. In lymph nodes, perifollicular infiltration was observed in 11 cases and abnormal follicles in six. Of three patients with high-grade lymphoma at presentation, one died untreated at 2 months, and two are alive at 34 and 91 months. Of 10 patients with low-grade disease at presentation, two died--one at 76 months, the other after transforming to high-grade lymphoma at 73 months. Eight patients with low-grade disease are alive, an average of 67 months after presentation. Four of five conservatively treated low-grade cases (including three in remission) showed evidence of monoclonality at presentation (light-chain monotypia in two and gene rearrangement in two), while two of the five exhibited DNA aneuploidy. It is concluded that IPSID with alpha-heavy-chain disease is neoplastic in all its stages and is a variant of mucosa-associated lymphoma. The role of centrocyte-like cells and the response to conservative therapy are discussed.

Immunoproliferative small intestinal disease (IPSID): Relationships with ?-chain disease and ?Mediterranean? lymphomas

Immunoproliferative small intestinal disease (IPSID): Relationships with ?-chain disease and ?Mediterranean? lymphomas

Gamma heavy chain disease associated with Hodgkin' 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.

A Case of Heavy Chain Disease: Diagnosis and Monitoring Using Assays of Immunoglobulin Heavy and Light Chains

Heavy chain diseases (HCD) are uncommon. We report the first use of recently developed analytical techniques for the assay of immunoglobulin heavy and light chains in the diagnosis and monitoring of a patient with gamma-HCD.

Gammapathies monoclonales en Tunisie

Protein electrophoresis and immunoelectrophoresis carried out on 4805 sera and 93 urine samples from Tunisian patients over 8 years, and a monoclonal protein was detected in 198 cases. The distribution of the monoclonal compounds to the clinical diagnosis was studied. 115 (58%) were classified as multiple myeloma (MK), 34 (17%) as alpha heavy chain disease (MCL a), 34 (17%) as monoclonal gammapathy associated to various diseases (GMOD), 11 (6%) as benign essential monoclonal gammapathies (GMBE), 4 (2%) as Waldenström's macroglobulinemia (MW). The relationship between the monoclonal immunoglobulin and the clinical diagnosis, the distribution of the monoclonal compounds according to the heavy chain class and the identification of the light chains were studied. The results obtained are in line with the principal data in literature concerning monoclonal gammapathy. However there is a particularity about monoclonal gammapathy observed in the Tunisian's population studied: Higher percentage of alpha heavy chain diseases, monoclonal IgD and monoclonal light chain. Lower percentage of monoclonal IgM in GMBE or GMOD, as in MW.

An Immunohistochemical Study

We performed a detailed histological and immunohistological study on both fresh-frozen and paraffin-embedded tissue from full-thickness jejunal biopsy specimens taken from three patients with immunoproliferative small-intestinal disease (IPSID). In all three patients, the mucosal infiltrate consisted of "centrocyte-like" (CCL) cells forming lymphoepithelial lesions and plasma cells. In one patient, the mucosal infiltrate was strikingly follicular. Immunohistochemistry showed alpha 1 heavy chain, but no light chain, in the perinuclear space and cytoplasm of the CCL cells and in the plasma cells. In two patients, the plasma cells (but not the CCL cells) also contained alpha 2 heavy chain. In the case showing a follicular pattern, the extrafollicular CCL cells and most of the cells within the mucosal follicles expressed alpha 1 heavy chain, but a minor and variable population of cells expressed polytypic IgM. The dendritic reticulum cells stained for alpha 1 (but not alpha 2) heavy chain, mu chain, and both light chains. In all cases, the CCL cells did not stain for common acute lymphoblastic leukaemia antigen (CALLA); in the follicles, CALLA negative cells displaced a residual CALLA-positive population to the periphery and merged with the CALLA negative cells outside the follicles. These findings confirm the homology between IPSID and low-grade B-cell "Western" lymphomas arising in mucosa-associated lymphoid tissue; they suggest that the follicular pattern sometimes seen in these lymphomas is caused by selective colonization of reactive follicles by CCL tumor cells.

Monoclonal and biclonal immunoglobulin‐producing disorders

Monoclonal gammopathies are B lymphocyte-derived disorders producing a specific monoclonal immunoglobulin. The group includes multiple myeloma, Waldenström's macroglobulinaemia, monoclonal gammopathy of undetermined significance (MGUS) and heavy-chain disease. In 1% of the cases a double M-component is present which is referred to as a biclonal gammopathy. The pathogeneses of these disorders are unknown, but several possibly related environmental factors have been identified. In multiple myeloma, an increased incidence and mortality rate has been noted during the last 20 years. Strong lines of evidence are presented showing that, in monoclonal gammopathies, the cell clone consists of B lymphocytes in different stages of maturation. In most cases of biclonal gammopathy there is probably a common cellular origin.

Immunochemical and structural characterization of an IgG1 heavy chain disease

The immunochemical and structural analysis of an IgG1 heavy chain disease is reported. The abnormal component is characterized by extensive deletion including the CH1 domain and most or all of the VH region.

Gamma Heavy Chain “Disease”

This review underscores the diversity of the clinical manifestations and hematopathological features of gamma heavy chain disease based on the detailed report of 16 patients evaluated in our chemical department, the analysis of 12 cases diagnosed in our laboratory, and the study of 81 cases previously reported. This condition is defined by the presence in the serum of immunoglobulin molecules composed of deleted gamma heavy chains devoid of light chains. The production by the monoclonal B cells of these peculiar proteins appears to result from multiple defects (deletions, insertions, and mutations) in both heavy and light chain genes leading to abnormal mRNA splicing. Gamma heavy chain disease is currently underdiagnosed. The diagnosis established by immunoelectrophoresis using specific antisera combined, in some instances, with the immunoselection procedure, can easily be missed on serum electrophoretic patterns: a narrow abnormal band suggestive of a monoclonal component was found in only 10 of our 28 cases. The amount of heavy chain disease protein in urine ranges from trace to 20 g/day and is usually moderate. Gamma heavy chain disease most often presents as a lymphoproliferative disorder featured by lymphadenopathies, splenomegaly, and constitutional symptoms. Extra-hematopoietic tumor localizations, such as cutaneous or subcutaneous involvement or thyroid tumor, may occur. Autoimmune disorders, notably rheumatoid arthritis and autoimmune hemolytic anemia or thrombocytopenic purpura, are frequent (26% of cases). There is no specific histological pattern. The most frequent is a pleomorphic malignant lymphoplasmacytic proliferation mainly seen in bone marrow and lymph nodes. Some cases present with a predominantly plasmacytic proliferation or chronic lymphocytic leukemia. Other patients are affected with non-Hodgkin lymphoma of various morphologic types. Immunocytologic studies showed that a gamma heavy chain disease protein may occur in the context of a double monoclonal lymphoproliferative process or in various B or T cell malignancies that are not directly involved in the production of the abnormal immunoglobulin. In some patients, the histologic appearance of the enlarged lymphoid organs showed only a moderate lymphoplasmacytic infiltration of uncertain malignancy. More important, some patients showed no evidence of an underlying lymphoproliferative disorder after several years of follow-up. The clinical course of gamma heavy chain disease varies from an asymptomatic state to a rapidly progressive malignancy. The choice of therapy should entirely rely on the underlying clinicopathologic features, without taking into account the presence of the abnormal protein.(ABSTRACT TRUNCATED AT 400 WORDS)

Genomic alterations in a case of α 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.

Nonsecretory α-Chain Disease with Immunoproliferative Smallintestinal Disease

HEAVY-CHAIN diseases in humans, which have been described for the three main classes of immunoglobulins, are B-cell disorders in which proliferating cells produce truncated monoclonal heavy chains that lack associated light chains.1 The abnormal proteins have deletions of part or all of the variable region and of one or two constant domains, usually CH1. The normal sequence resumes at a position corresponding to the beginning of an exon.2 The heavy chains are synthesized as abnormally short chains.3 , 4 Recent studies in a few cases of μ–heavy-chain and γ-heavy-chain diseases have shown that the messenger RNA (mRNA) was short and . . .

Gamma heavy chain disease and rheumatoid arthritis

G AMMA HEAVY CHAIN disease (7HCD). is characterized by the presence of incomplete immunoglobulin heavy chains in serum and/or urine’; although often described as a lymphoproliferative disorder, it has a wide variety of clinical and pathologic features.*-5 More than 60 cases have been reported”’ since Franklin et al first described this condition in 1964.3 A substantial number of cases yHCD are associated with autoimmune disorders such as rheumatoid arthritis (RA), systemic lupus erythematosus, Sjogren’s syndrome, and myasthenia gravis.2 yHCD varies in severity, whether associated with RA or not, from a benign condition, to one leading to progressive deterioration and death.4 We report a patient with severe RA preceding by 4 years the development of THCD, followed by recurrent sepsis, progressive deterioration, and death. At autopsy a non-Hodgkin’s lymphoma was found. The literature on the association between yHCD and RA is reviewed.