During fetal development, murine and hu- Although VH genes apparently undergo gene rearrangements at random in the adult mouse (3), data from studies in mice and humans indicate that the functional repertoire of VH genes in the fetus is highly restricted. In mice there is a strong bias toward rearrangement and expression of those VH genes that are most proximal to the JH locus during early B-cell ontogeny (4, 5). Also, the expressed human fetal VH repertoire at 130 days ofgestation may contain only 9-39 genes (6).Ig V gene rearrangement and expression in chronic lymphocytic leukemia (CLL) also is nonrandom. Recent studies with murine B-cell clonal expansions and lymphomas that in part resemble human CLL or small lymphocytic (SL) lymphoma indicate that these lymphoproliferative disorders may utilize a highly restricted repertoire of Ig V genes (7-9). In humans, 20%o of all CLL patients may have leukemic cells that rearrange a particular VH gene belonging to the VH5 subgroup (10). We discovered (11) that nearly 20% ofpatients with K-light-chain-expressing CLL may produce Ig reactive with a murine monoclonal anti-idiotypic antibody, designated 17.109. Generated against an IgM rheumatoid factor (RF) from a patient with mixed cryoglobulinemia, this monoclonal antibody (mAb) detects a K-light-chain-associated crossreactive idiotype (CRI) present on >33% of all human IgM RF paraproteins and many other IgM autoantibodies (12, 13). We found that mAb 17.109-reactive leukemic cells from unrelated CLL patients express homologous K light chain V region (VK) genes that share 99% homology with Humkv325 (14), a VKIII gene isolated from placental DNA (15). Thus, frequent expression of the mAb 17.109 CRI in CLL suggests that CLL B cells express V genes nonrandomly and without somatic mutation.We have detected expression of other autoantibodyassociated CRIs in CLL and associated B-cell malignancies. Approximately 20% of the CLL patients examined were found to have leukemic cells reactive with another anti-CRI mAb, designated G6 (16). mAb G6 recognizes an Ig heavychain-associated CRI that also is present on many IgM paraproteins with RF activity (17). In a more recent survey, mAb G6 was found to react with =10% of all cases of CD5-positive SL non-Hodgkin lymphoma (NHL) (18).The G6 CRI may be a serologic marker for a VH1 gene(s) expressed during early B-cell development. G6-reactive RFs, for which amino acid sequence data are available, share considerable homology in the first, second, and fourth framework regions (FRs) of the VH, and all derive from the VH1 region subgroup (19). Furthermore, the two most recently sequenced G6-reactive RFs, BOR and KAS, share >92% homology with the deduced amino acid sequence of 51pl, a VH1 gene expressed at high frequency in the restricted fetal repertoire (6).To examine the molecular basis for the high-frequency expression of the G6 CRI in CD5 B-cell malignancies, we determined the nucleic acid sequences of the VH genes rearranged and expressed by G6-reactive CLL. Our data indicate that th...
SummaryNatural autoantibodies are primarily immunoglobuhn M (IgM) antibodies that bind to a variety of self-antigens, including self-IgG. Accounting for a large proportion of the early B cell repertoire, such polyspecific autoantibodies are speculated to contribute to the homeostasis and/or competence of the primary humoral immune system. Recent studies indicate that the leukemia cells from most patients with chronic lymphocytic leukemia (CLL) also express such IgM autoantibodies. Similarly, the leukemia cells from many CLL patients react with murine monoclonal antibodies (mAbs) specific for crossreactive idiotypes (CtLIs) associated with human IgM autoantibodies. In particular, leukemic cells frequently react with G6, a mAb specific for an Ig heavy chain (H chain)-associated CRI, and/or with 17.109, a mAb that defines a K light chain (L chain)-associated CRI. Generated against IgM rheumatoid factor (RF) paraproteins, G6 and 17.109 each recognize a major CRI that is present in many IgM RF paraproteins. Furthermore, over 90% of the IgM paraproteins found to bear both H and L chain-associated CtLls also are found to have tLF activity. Molecular characterization of these CILIs demonstrates that each is a serologic marker for expression of a highly conserved Ig V gene. As such, the frequent production of IgM polyspecific autoantibodies in CLL simply may reflect the frequent use of such highly conserved autoantibody-encoding Ig V genes with little or no somatic mutation. To test this hypothesis, we generated murine transfectomas to pair the 17.109-reactive K L chain of SMI, a 17.109/G6-reactive CLL population, with the Ig H chain of SMI or other G6-reactive leukemia cells or tonsillar lymphocytes. Cotransfection of vectors encoding the Ig H and L chains of SMI generated transfectomas that produce IgM~ RF autoantibodies reactive with human IgG1 and IgG4. In contrast to G6/17.109-reactive IgM~ ILF Waldenstrom's paraproteins, the SMI IgM~ also reacts with several other self-antigens, including myoglobin, actin, and ssDNA. However, cotransfection of the SMI L chain with a vector encoding any one of 10 different G6-reactive Ig H chains generated transfectomas that produce IgM~ antibodies without detectable polyspecific autoantibody activity. These results indicate that polyspecific antiself-reactivity of G6/17.019-reactive Ig is dependent on the somatically generated Ig third complementarity determining region. Collectively, these studies imply that selection may be responsible for the frequent expression of polyspecific autoantibodies in CLL and early B cell ontogeny. r'~he leukemia cells from many patients with chronic lym-1 .IL phocytic leukemia (CLL) produce polyspecific IgM autoantibodies. Early studies by Prend'homme and Seligmann (1) indicated that CLL patients have leukemia cells that frequently bear surface membrane IgM that has RF activity, or binding activity for human IgG. In another limited survey, four of thirteen CLL patients were found to have leukemia cells that expressed surface IgM (slgM) with binding a...
Objective Identify novel genes and pathways specific to superficial (SZ), middle (MZ) and deep zones (DZ) of normal articular cartilage. Methods Articular cartilage was obtained from knees of 4 normal human donors. The cartilage zones were dissected on a microtome. RNA was analyzed on human genome arrays. Data obtained with human tissue were compared to bovine cartilage zone specific DNA arrays. Genes differentially expressed between zones were evaluated using direct annotation for structural or functional features, and by enrichment analysis for integrated pathways or functions. Results The greatest differences were observed between SZ and DZ in both human and bovine cartilage. The MZ was transitional between the SZ and DZ and thereby shared some of the same pathways as well as structural/functional features of the adjacent zones. Cellular functions and biological processes enriched in the SZ relative to the DZ, include most prominently ECM receptor interactions, cell adhesion molecules, regulation of actin cytoskeleton, ribosome-related functions and signaling aspects such as Interferon gamma, IL4, CDC42Rac and Jak-Stat. Two pathways were enriched in the DZ relative to the SZ, including PPARG and EGFR/SMRTE. Conclusion These differences in cartilage zonal gene expression identify new markers and pathways that govern the unique differentiation status of chondrocyte subpopulations.
We examined human tonsillar B cells for expression of autoantibody heavy-chain or kappa light-chain cross-reactive idiotypes (CRIs), respectively defined by murine MAbs G6 or 17.109. We find 17.109 or G6 each specifically binds a subpopulation of B cells, respectively reacting with 3.8±3% (mean±SD) or 2.0±1.2% of all tonsillar lymphocytes. Cells reactive with both 17.109 and G6 comprise only 0.4±0.3% of tonsillar lymphocytes. Although each tested specimen had 17.109-positive cells, 2 of 19 tonsils (11%) did not have any G6-reactive cells. We find that CRI-positive cells and CD5 B cells both co-express slgD but fail to bind peanut agglutinin or MAbs specific for CD10, indicating that both cell types reside in the mantle zones of secondary B cell follicles. However, less than half of the B cells bearing one or both of these CRIs express detectable levels of CD5. Nevertheless, we find that G6-reactive lymphocytes constitute a multiclonal population of cells that express homologous heavy chain variable region genes, each rearranged to one of several distinct and apparently nonmutated D and JH gene segments. Collectively, these studies indicate that expression of nondiversified autoantibody-encoding variable region genes may not be an exclusive property of B cells that bear detectable levels ofthe CD5 surface antigen. (J. Clin.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.