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Www Modelmature Model Mature W Model Mature Obama Th 1 Model Mature Immunoproliferative small intestinal disease (IPSID): a model for mature B-cell neoplasms--《血液学杂志》--医学期刊频道--首席医学网

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    IPSID affects mainly older children and young adults (range, 10-35 years; mean, 25-30 years) of low socioeconomic status in developing countries. It is uncommon in young children and older adults. Geographically, the majority of cases reported were from the Middle East, North and South Africa, and the Far East.14-18 Sporadic cases have been reported from other countries and continents, especially in immigrants from the Middle East and North Africa.19 Clinically, intermittent diarrhea and colicky abdominal pain are the most frequent symptoms.20-22 Other symptoms and signs are mainly related to malabsorption. Intestinal obstructions, abdominal masses, and ascites are common in advanced stage (Table 1). The differential diagnosis usually includes chronic infections, parasitic infestations, sprue, tropical sprue, and lymphomas other than IPSID. Although the clinical, laboratory, and radiologic findings are pathognomonic, the final diagnosis is usually established by endoscopic biopsies and/or laparotomy. Upper gastrointestinal endoscopy shows abnormalities in the second, third, and fourth parts of the duodenum and upper jejunum in all patients except those with very early disease. Thickening, erythema, and nodularity of the mucosal folds are noted.16,17 As the disease progresses, tumors appear usually in the proximal small intestine and rarely in the stomach.

    Pathology and evolution

    The main pathologic feature of IPSID is the presence of dense mucosal infiltrate of "centrocyte-like" and many plasma cells involving long segments of the small bowel mucosa, predominantly the proximal parts.2,14 The overlying epithelial cells are usually intact, and the crypts are sparse (Figure 1C-D). Progression to higher grade large-cell lymphoplasmacytic and immunoblastic lymphoma is characterized by increased plasmacytic atypia with the formation of aggregates and later sheets of dystrophic plasma cells and immunoblasts invading into the submucosa and the muscularis propria. This large-cell component seems to evolve within the diffuse "low-grade" IPSID and is clonally related to it (Figure 1E-F). 2,25 The rate of evolution of IPSID from low-grade to higher grade is not known. Most patients are diagnosed at the time of this transformation due to the severe symptoms of abdominal pain and obstruction. However, they usually have mild IPSID-related symptoms dating back up to 5 or even 10 years earlier. Patients with IPSID-associated large-cell lymphomas are 6 years older than those with pure IPSID, a statistically significant difference.2 Hepatic, splenic, or peripheral lymph node involvement are uncommon except in the late stages of disease. Bone marrow involvement and leukemic manifestations are rare.26,27

    Heavy chain protein: diagnosis, structure, synthesis, and secretion

    The immunologic hallmark of IPSID is the presence of anomalous  heavy chain protein in the serum detected in 20% to 90% of patients.5,17,20,28-30 The higher detection rate reflects recent improvement in immunologic technique, especially the use of immunoselection.31,32 Immunoelectrophoresis into gel containing especially developed anti-Fab alpha serum provides the most sensitive and specific detection system for HCD protein (Figure 1A). Alternatively, immunoselection is performed in 1% agarose gel incorporated with 30% vol/vol antikappa and antilambda antisera. Upon immunoelectrophoresis, normal immunoglobulin A (IgA) precipitates around the trough, while HC protein migrates freely toward the anode producing various abnormal precipitation lines.31 In our own experience in Iraq, this latter immunoselection technique detected HC protein in 42% of patients with a clinicopathologic picture of IPSID. This ratio was much higher (about 70%) if only the noninvasive low-gradephase patients are considered (Table 2).32 In some apparently HC-negative patients, the abnormality can be identified through immunohistochemical or immunofluorescence staining of the small bowel biopsies.33,34 These stains demonstrate positivity for HC, while the light chain stains are negative.

    HCD proteins are almost always 1 species and appear to consist largely of multiple polymers of different sizes.14 The molecular weight of the basic monomeric unit varies between 29 000 and 35 000. Allowance is usually made in these figures for carbohydrate, since the carbohydrate content of many of these HCD proteins is unusually high. Thus, the length of the basic polypeptide subunit varies from patient to patient and in most instances it is between half and three fourths the size of its normal counterpart.35 Sequenced data showed that the HCD protein lacked the variable heavy chain (VH) and the first constant domain. Normal sequence resumed at the beginning of the hinge region, with a valine residue corresponding to position 222 of a normal 1 chain. The carboxy terminal structure and conformational integrity remain intact.35,36 The HCD protein has various deletions, insertions, and mutations similar to those observed in the much less common  and μ heavy chain diseases (Figure 2).35

    As expected, the HCD messenger RNA lacks the VH and constant heavy chain 1 (CH1) sequences. It also contains an in-frame insert of unknown origin between the leader peptide and the normal CH2 and CH3 coding sequences.36,37 These inserts are of variable length (42 to 105 base pair [bp]), and they are unrelated to each other. Their structure suggests that they result from alternative splicing process. These sequences do not resemble any normal human genomic DNA. The absence of homology between these insertions could not support the hypothesis of infectious nonhuman DNA, either. They may represent highly altered sequences from human Ig locus. Since the amino acid sequence of HCD proteins begins with a CH2 domain, it is most likely that the amino acid terminal sequence encoded by these insertions is cleaved intracellularly before secretion.38

    The complete gene sequence encoding 3 HCD proteins, MAL,37 YAO,39 and SEC has been determined.40 These 3 genes show a striking similarity in their position and extent of the 2 main deletions, which encompass sequences in the V/J and the switch/CH1 regions. In all cases, most, or all, of the V region is deleted as is the sequence starting in the switch region and extending through part, or all, of the CH1 domain.41 These findings are also similar to those present in the 2  heavy chain proteins gene sequenced (OMN42 and RIV43). Taken together, the analysis of  and HCD proteins and nucleic acids seems to show the emerging pattern of 2 large noncontiguous deletions in the heavy chain genes and the expression of low levels of light chain constant regions.42

    Analysis of the DNA from IPSID tumors showed monoclonal heavy and light chain gene rearrangement even in the early stages of the disease.44 Southern blot analysis established that in all cases one or both  genes were rearranged in tumor DNA, whereas the  genes were in germ-line configuration. In some cases, the truncated mRNA was shorter than a normal kappa mRNA. This finding was interpreted as indicating the occurrence of genomic alterations in both heavy and light chain loci in HCD, as demonstrated by the analysis of the sequence of rearranged  gene in a case of  HCD.45 As a characteristic of  and  HCD, there are no light chains detected in the serum or associated with the heavy chain fragments in most cases. Studies reported from various laboratories suggested that independent structural gene abnormalities are at least partially responsible for the uniform absence of detectable light chain production in HCD. In contrast to most normal and neoplastic Ig-producing cells, there is excess of heavy to light chain mRNA as well as protein. The elegant experiments by Teng et al41 demonstrated that this excess is a function of the cell independent of structural gene abnormality and is due to a low level of light chain transcription. Transcription can be increased by fusing the HCD cell line to murine myeloma cell line or transfecting the defective light chain gene into a murine plasma cell. Other findings suggested that the examined HCD cells either lack a transcription factor present in mature plasma cells or have a functional repressor of light chain transcription.41

    The synthesis of HCD protein by the proliferating cells has been demonstrated by immunofluorescence and/or immunohistochemical method and by biosynthesis studies.14,35 These studies and those of the membrane-bound Ig have shown that the immunoblastic cells in late-stage disease do not synthesize HCD protein.46 In all cases studied, the HCD protein was found in the jejunal juice when it was already present in the serum. HC protein was found in the intestinal or gastric lumen in some cases, although it was undetectable in the sera of these patients in spite of the use of the most sensitive technique.14 The concentration of HCD protein in urine is low and Bence Jones proteinuria has never been found. It was also noted that in rare cases the HCD protein is absent from the serum, urine, and jejunal juice, but can be demonstrated by immunohistochemical staining of small bowel biopsies33 or that the Ig gene is rearranged by molecular studies.47 It has been demonstrated that gene deletions force "nonsecretory" HCD plasma cells to produce membrane form chain only.40 In the vast majority of HCD, however, secretion of truncated HC could be demonstrated by various techniques.

    Normal mammalian  chains are 50 kDa and contain 1 variable and 3 constant region domains. Plasma cells in mucosal tissue assemble polymeric IgA intracellularly from monomeric IgA. Normal plasma IgA is monomeric, while mucosal IgA is dimeric or tetrameric. It contains joining (J) chains that help recognize the receptor (pIgR) expressed on basolateral surfaces of adjacent epithelial cells.48 Light chains have been shown to play a critical role in the Ig molecule secretions by the plasma cells.49 In HCD mutations in both the heavy and the light chains seem to result in the secretions of the truncated  heavy chains by the neoplastic plasma cells in spite of the absence of light chains. J chains are present in the majority of HCD proteins.16 However, the production of these truncated HCD proteins probably outpace the synthesis of the secretory component by the enterocytes. This could be expected because in IPSID the crypts are atrophic and highly dispersed in contrast to celiac disease where they are hyperplastic (Figure 1C-D). Thus, large amounts of polymeric HCD protein can usually be demonstrated in the serum and also in the jejunal and gastric fluids.14

    Cytogenetics of IPSID