HLA genes, immunoglobulin genes and human disease.
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Results for “Genes, Immunoglobulin”
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Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes.
Immunoglobulin genotyping of Epstein-Barr virus (EBV)-positive posttransplantation lymphoproliferative disease has suggested that such lesions often arise from atypical post-germinal center B cells, in some cases carrying functionally inactivated immunoglobulin genes. To investigate whether EBV can rescue cells that are failed products of the somatic hypermutation process occurring in germinal centers (GCs), we isolated GC cells from tonsillar cell suspensions and exposed them to EBV in vitro. Screening more than 100 EBV-transformed cell lines of GC origin identified 6 lines lacking surface immunoglobulin, a phenotype never seen among lines derived from circulating naive or memory B cells. Furthermore, 3 of the 6 surface immunoglobulin-negative GC lines carried inactivating mutations in the immunoglobulin H (IgH) variable gene sequence. The ability of EBV to rescue aberrant products of the germinal center reaction in vitro strengthens the probability that a parallel activity contributes to EBV's lymphomagenic potential in vivo.
Amino Acid Sequence↗
DNA elements are asymmetrically joined during the site-specific recombination of kappa immunoglobulin genes.
Immunoglobulin K genes are constructed during lymphocyte differentiation by the joining of two DNA elements, VK and JK, to form both a VKJK coding unit and a reciprocal recombination product. The two products formed in single VK-to-JK joining events can be directly isolated through the use of a retrovirally introduced recombination substrate. The structural analysis of a number of recombinants and the derivation of secondary recombination products define some of the basic features of the mechanism of immunoglobulin gene assembly.
Animals↗
A lymphoid-specific protein binding to the octamer motif of immunoglobulin genes.
Immunoglobulin gene promoters are active only in lymphoid cells and this tissue-specific activity requires an octamer sequence, ATTTGCAT. Paradoxically, this same octamer motif seems to be a transcriptional control element in promoters which are active in all tissues. Using an electrophoretic mobility shift assay to identify DNA binding proteins, we have now detected two species of nuclear proteins which bind specifically to this octamer. One previously characterized form (NF-A1) was found in all cell lines tested while the other form (NF-A2) was restricted to lymphoid cell lines. NF-A2 was found in cell lines representing all stages of B-cell differentiation and in half of the T-lymphoma cell lines tested. The identification of a lymphoid-specific octamer binding protein may account for the lymphoid-specific activity of immunoglobulin promoters.
Animals↗
A novel cytidine deaminase AIDs in the delivery of error-prone polymerases to immunoglobulin genes.
Immunoglobulin genes undergo somatic hypermutation in activated B lymphocytes. The mutations are targeted to the variable region of the gene, apparently by co-transcriptional deposition of a mutation complex. The novel activation induced deaminase (AID) gene is required for this process and recent work indicates that it is the cytidine deaminase activity of the AID protein rather than an associated RNA editing function that is required [Curr. Biol. 12 (2002) 1748; Nature 419 (2002) 1; Nature 418 (2002) 99]. The authors review the implications of this work and argue that deamination of deoxy-cytidine to deoxy-uracil seems to initiate several pathways in which error-prone polymerases are postulated to create mutations.
Animals↗
Recombination events that activate, diversify, and delete immunoglobulin genes.
Immunoglobulin kappa light-chain diversity arises, in large part, from an array of germ-line V-region genes that undergo somatic recombination with one of four active J-region segments. The diversity provided by this combinational system is increased by a recombination mechanism that allows variation of crossover points so as to generate additional diversity at a critical region of the light chain. The elaborate mechanism for generating diversity is accompanied not only by considerable waste, in terms of unused V and J regions in a given cell, but also by a range of aberrant recombinants that fail to produce active immunoglobulin genes.
Animals↗
Poor correlation between clonal immunoglobulin gene rearrangement and immunoglobulin gene transcription in Hodgkin's disease.
It recently has been suggested that some cases of Hodgkin's disease (HD) are derived from B lymphocytes. We therefore examined immunoglobulin heavy chain gene rearrangement and transcription by polymerase chain reaction in 30 cases of HD and compared them with 25 cases of non-Hodgkin's B-cell lymphoma. Clonal VDJ gene rearrangements were observed in 6 cases of HD. Of these 6 cases, clonal VDJ gene transcription was found by RNA-dependent polymerase chain reaction in only 2 cases. One of these 2 cases histologically showed composite lymphoma of HD and diffuse large B cell lymphoma. We performed in situ hybridization with a clonal VDJ gene probe in this case to determine the localization of the genetic clonality. The large lymphoma cells reacted positively, but Hodgkin's and Reed-Sternberg cells showed only nonspecific staining. No discrepancy between immunoglobulin gene rearrangement and transcription was observed in 24 of the 25 cases of non-Hodgkin's B-cell lymphoma. The discordance between clonal gene rearrangement and transcription in HD contrasts sharply with the high correlation of those processes in non-Hodgkin's B-cell lymphoma.
Gene Rearrangement↗
Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes.
Immunoglobulin rearrangement from variable heavy chain (V(H)) to diversity (D)-joining heavy chain (J(H)), which occurs exclusively in B lineage cells, is impaired in mice deficient for the B lineage-specific transcription factor Pax5. Conversely, ectopic Pax5 expression in thymocytes promotes the rearrangement of D(H)-proximal V(H)7183 genes. In exploring the mechanism for Pax5 regulation of V(H)-to-DJ(H) recombination, we have identified multiple Pax5 binding sites in the coding regions of human and mouse V(H) gene segments. Pax5 bound to those sites in vitro and occupied V(H) genes in early human and mouse B lineage cells. Moreover, Pax5 interacted with the recombination-activating gene 1 (RAG1)-RAG2 complex to enhance RAG-mediated V(H) recombination signal sequence cleavage and recombination of a V(H) gene substrate. These findings indicate a direct activating function for Pax5 in RAG-mediated immunoglobulin V(H)-to-DJ(H) recombination.
Animals↗
Requirement of the activation-induced deaminase (AID) gene for immunoglobulin gene conversion.
Three phenotypically distinct processes-somatic hypermutation, gene conversion, and switch recombination-remodel the functionally rearranged immunoglobulin (Ig) loci in B cells. Somatic hypermutation and switch recombination have recently been shown to depend on the activation-induced deaminase (AID) gene product. Here, we show that the disruption of the AID gene in the chicken B cell line DT40 completely blocks Ig gene conversion and that this block can be complemented by reintroduction of the AID complementary DNA. This demonstrates that the AID master gene controls all B cell-specific modifications of vertebrate Ig genes.
Alleles↗
Structure and function of immunoglobulin genes and immunoglobulin precursors.
To gain information on the origin of antibody diversity (somatic mutation or germ line hypothesis) it is necessary to determine the number of V region genes. For this purpose the capacity of a distinct V region probe to hybridize and quantify V genes of the same and different subgroups should be established. Relevant information on this issue was obtained from the extent of cross-hybridization of a distinct L chain cDNA with mRNAs coding for L chains of the same and different subgroups. The results indicated that: (1) V regions of similar amino acid sequence are coded by similar nucleotide sequence (this is not self-evident because of the degeneracy of the genetic code); (2) the nucleic acid probe to one V region may anneal and quantify V genes of members of the same subgroup. Molecular hybridizations of the cDNA probe with nuclear DNA showed that: (1) the number of kappa type C genes is small (about 2 per haploid genome); (2) the number of V genes presumably is also small; (3) there is no amplification of these genes in myeloma cells that produce large amounts of the Ig. These results support the somatic mutation model for the generation of antibody diversity. New information on the structure and controlled expression of Ig genes was obtained from the study of L chain precursors, which are the immediate product of L chain mRNA translation in vitro. In the precursors extra peptide segments (19-22 residues in length) precede the N-terminus of the mature L chain. Amino acid sequence analyses of the precursors provide evidence that: (1) the gene coding for the V region is larger than hitherto known; (2) duplication of a short DNA segment occurred in the structural gene coding for the MOPC-321 precursor; (3) translation of the L chain mRNA may be contingent on the nucleotide sequence coding for the extra piece; (4) cleavage of the extra piece may regulate secretion of mature L chain; (5) the extra piece is remarkably hydrophobic, suggesting that the role of the extra piece is to anchor the precursor in cell membranes, in a manner similar to the function of the "hydrophobic domain" of membrane bound proteins. We propose that most precursor molecules are directed to the endoplasmic reticulum where the extra piece is cleaved to yield mature Ig destined for secretion; a few precursor molecules escape cleavage and are anchored by means of the hydrophobic extra piece in the cell-surface membrane to serve as the antigen-recognizing receptor.
Amino Acid Sequence↗
The ubiquitous octamer-binding protein(s) is sufficient for transcription of immunoglobulin genes.
All immunoglobulin genes contain a conserved octanucleotide promoter element, ATGCAAAT, which has been shown to be required for their normal B-cell-specific transcription. Proteins that bind this octamer have been purified, and cDNAs encoding octamer-binding proteins have been cloned. Some of these proteins (referred to as OTF-2) are lymphoid specific, whereas at least one other, and possibly more (referred to as OTF-1), is found ubiquitously in all cell types. The exact role of these different proteins in directing the tissue-specific expression of immunoglobulin genes is unclear. We have identified two human pre-B-cell lines that contain extremely low levels of OTF-2 yet still express high levels of steady-state immunoglobulin heavy-chain mRNA in vivo and efficiently transcribe an immunoglobulin gene in vitro. Addition of a highly enriched preparation of OTF-1 made from one of these pre-B cells or from HeLa cells specifically stimulated in vitro transcription of an immunoglobulin gene. Furthermore, OFT-1 appeared to have approximately the same transactivation ability as OTF-2 when normalized for binding activity. These results suggest that OTF-1, without OTF-2, is sufficient for transcription of immunoglobulin genes and that OTF-2 alone is not responsible for the B-cell-specific regulation of immunoglobulin gene expression.
Base Sequence↗
Detection of two distinct malignant B cell clones in a single patient using anti-idiotype monoclonal antibodies and immunoglobulin gene rearrangement.
Immunoglobulin gene rearrangement analysis and somatic cell hybridization techniques were used to examine the malignant cell population in an unusual patient with hairy cell leukemia and macroglobulinemia (N Engl J Med 296:92, 1977). Although previous investigations suggested that the IgM macroglobulin was secreted by the circulating leukemia cells, anti-idiotype monoclonal antibodies raised to the IgM macroglobulin failed to react with the malignant cells in the circulation and bone marrow. In contrast, approximately 50% of the mononuclear cells from an enlarged inguinal lymph node reacted strongly with the anti-idiotype antibodies. Subsequent reanalysis of all cell populations demonstrated that whereas the circulating and bone marrow cells were IgM kappa-bearing, the macroglobulin was IgM gamma-bearing and the lymph node cells were evenly divided among IgM kappa-bearing and IgM gamma-bearing. Immunofluorescence flow cytometry indicated that those lymph node cells that reacted strictly with the anti-idiotype antibody were IgM gamma-bearing, demonstrating that they were the source of macroglobulin. An analysis of immunoglobulin gene DNA confirmed the coexistence of two distinct malignant B cell populations in the lymph node and indicated that the IgM kappa-bearing lymph node cells were identical to the circulating and bone marrow leukemic cells.
Aged↗
Detection of immunoglobulin gene rearrangement in B lymphoid malignancies by polymerase chain reaction gene amplification.
Immunoglobulin heavy chain gene rearrangement serves as a marker of cell lineage and clonality in B lymphoproliferative disorders. We have used polymerase chain reaction (PCR) gene amplification to detect immunoglobulin gene rearrangements involving VH251, a heavy chain variable region preferentially utilized in B lymphoproliferative disorders. Using synthetic amplimers derived from VH251 and the heavy chain joining region, under conditions of high stringency, a homogeneous VH251-specific fragment of approximately 350 bp could be amplified from leukaemic DNA. Of 53 cases of B lineage acute lymphoblastic leukaemia screened for VH251 rearrangement by PCR, 10 were positive. A background level of VH251 rearrangement could also be amplified from normal peripheral blood and bone marrow DNA, but a VH251 rearranged leukaemic clone representing 0.01% of bone marrow mononuclear cells could be readily detected. The application of PCR to detect immunoglobulin gene rearrangement involving VH251 and potentially other preferentially utilized V regions provides a sensitive method both for tracking malignant B cells and for the study of normal B cell developmental pathways through which B lineage malignancies arise.
Blotting, Southern↗
Cmu gene rearrangement of mouse immunoglobulin genes in normal B cells occurs on both the expressed and nonexpressed chromosomes.
We have examined the organization of heavy-chain immunoglobulin genes on both the expressed and nonexpressed chromosomes of normal B lymphocytes from allotype heterozygous (BALB/c X C57BL/J)F1 mice. The C mu genes of BALB/c mice are on 12.4-kilobase EcoRI and 13.1-kilobase Kpn I restriction fragments, whereas those of C57BL/J mice are on 13.6-kilobase EcoRI and 14.3-kilobase Kpn I restriction fragments, allowing the examination of rearrangements on each chromosome independently. B lymphocytes from spleen and Peyer's patches expressing both IgD and IgM of the BALB/c allotype were isolated with a fluorescence-activated cell sorter. EcoRI and Kpn I restriction digests were hybridized with a C mu gene-containing probe. The C mu gene is present on both chromosomes. DNA rearrangements occur on both the expressed and nonexpressed chromosome within the 3.6-kilobase Kpn I/EcoRI restriction fragment containing the joining (JH) gene locus. We conclude that allelic exclusion of heavy-chain immunoglobulin gene expression is not mediated by JH-region DNA rearrangement of the expressed chromosome only. In contrast, analysis of the C kappa gene region from the same sorted B-cell DNA reveals a substantial quantity of germ-line context DNA. We also demonstrate that the deletions observed on the Eco RI fragment containing the C mu gene in myeloma cells and in C mu gene-containing recombinant DNAs do not usually occur in normally differentiating B lymphocytes and are likely to be confined to myeloma tumor cells.
Animals↗
Detection of cells with clone-specific immunoglobulin gene rearrangements in the peripheral blood of myeloma patients using immunoglobulin gene fingerprinting.
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Clone Cells↗
Differentiation of a precursor cell with the germline context immunoglobulin gene into immunoglobulin-producing cells in vitro.
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Animals↗
Gene conversion in human rearranged immunoglobulin genes.
Over the past 20 years, many DNA sequences have been published suggesting that all or part of the V(H) segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial V(H) replacements with no addition of untemplated nucleotides at the V(H)-V(H) joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of V(H) replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion.
Base Sequence↗
Structure of the T15 VH gene subfamily: identification of immunoglobulin gene promotor homologies.
We have sequenced and analyzed the flanking and coding regions of four closely related mouse VH gene segments referred to as the T15 gene subfamily. We have found that although the sequence homologies between the four members of this family are greatest in the coding region, significant homologies extend into the leader sequences and the flanking regions as well. Sequence comparisons of the promoter regions of other VH gene segments indicate that the octamer promoter sequence is part of a larger conserved sequence that may play an important role in immunoglobulin gene transcription. Analysis of the lambda clones containing the members of this subfamily indicate that despite the close linkage of two of the members, the average number of kilobases of DNA between the germ-line gene segments of this family is likely to be very great.
Animals↗