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Biomedical subjects

Michel Cogné

Publications and source records attributed to Michel Cogné.

At least 19 recordsLinked to original sources
PubMed2006

Polyclonal IgG4 hypergammaglobulinemia associated with plasmacytic lymphadenopathy, anemia and nephropathy.

Marked polyclonal immunoglobulin (Ig)G4 hypergammaglobulinemia has exceptionally been reported. Here we report on two Algerian patients who presented a syndrome characterized by anemia, plasmacytic lymphadenopathy, renal manifestations, and a marked polyclonal IgG4 hypergammaglobulinemia leading to a hyperviscosity syndrome in one case. The IgG4-expressing cell percentage was significantly increased in the peripheral blood lymphocytes collected from the two patients upon diagnosis. Moreover, in contrast with normal sera, both patients' sera significantly increased the percentage of IgG4-expressing cells when incubated with CD40-stimulated normal B lymphocytes. Similar effects were obtained with the culture supernatants of the patients' activated T cells. Anti-interleukin (IL) 4 and/or anti-IL-13 antibodies were unable to antagonize the IgG4 production. IL-4 and IL-13 serum concentrations were found to be normal in the two patients. The increased IgG4 production was found to be mediated by soluble factor(s), most probably secreted by activated T cells, which did not require the signal transducer and activator of transcription 6 signaling pathway.

Adolescent↗
PubMed2006

Role of the monoclonal kappa chain V domain and reversibility of renal damage in a transgenic model of acquired Fanconi syndrome.

Acquired Fanconi syndrome (FS) is a complication of monoclonal gammopathies featuring a generalized dysfunction of the proximal tubule of the kidney, due to the storage within proximal tubular cells of a monoclonal immunoglobulin light chain. We engineered transgenic mice in which the endogenous mouse Jkappa cluster was replaced by a human VkappaJkappa rearranged gene cloned from a patient with smoldering myeloma-associated FS. The V region belonged to the VkappaI subgroup and was related to the O2-O12 germ-line gene, a V segment previously found associated with FS and light-chain crystallization in several patients with myeloma. Association of the human VkappaI domain with a mouse kappa constant domain in transgenic animals yielded a nephrotoxicity pattern similar to that observed in patients, strongly suggesting that the whole pathogenic effect of FS light chains can be ascribed to a peculiar structure of the V domain. Morphologic alterations of the kidney tubular cells, which contained rhomboid-shape crystals, were observed in mice, together with alterations of the proximal tubule reabsorption function. Moreover, the number of renal crystalline inclusions was dramatically reduced after conditional deletion of the human VkappaI transgene, showing that proximal tubular lesions are reversible upon suppression of the nephrotoxic light chain secretion.

Animals↗
PubMed2006

Germ line transcription in mice bearing neor gene downstream of Igamma3 exon in the Ig heavy chain locus.

Class switch recombination (CSR) is preceded by germ line transcription that initiates from promoters upstream of switch (S) sequences and terminates downstream of associated constant genes. Previous work showed that germ line transcripts and their processing are required for CSR and that germ line transcription is regulated in a major part by a regulatory region located downstream of the Ig heavy chain locus. This long-range, polarized effect can be disturbed by inserting an expressed neomycine resistance (neo(r)) gene. To contribute to a better understanding of the mechanism of such a long-distance regulation, we generated knock-in mice in which a neo(r) gene was inserted downstream of Igamma3 exon leaving intact all the necessary elements for germ line transcription and splicing. We show that the expressed neo(r) gene interferes with transcription initiation from Igamma3, and that it impairs but does not block S recombination to Cgamma3. Moreover, we show for the first time that the neo(r) gene provides through chimeric neo(r)-Cgamma3 transcripts the necessary elements for splicing of germ line transcripts by activating two novel cryptic splice sites, one in the coding region of the intronless neo(r) gene and the other in the Igamma3-Cgamma3 intron.

Alternative Splicing↗
PubMed2006

Interallelic class switch recombination can reverse allelic exclusion and allow trans-complementation of an IgH locus switching defect.

The predominant path of immunoglobulin class switch recombination follows the paradigm of intra-chromosomal deletion enabling expression of another heavy chain instead of micro and delta. This was, however, challenged by observations of inter-allelic class switch recombination in rabbit or mouse IgG3- or IgA-producing B cells. Assuming that the conditions of inter-chromosomal exchange are likely present at any target S regions in stimulated B cells, we explored trans-association of VH and C genes in a model allowing all C genes to be checked simultaneously. Heterozygous mutant mice are thus studied, which carry one non-functional IgH allele inactivated by a non-translatable mutation of VDJ-CH transcripts, while the functional allele is deficient for class switching due to a truncated 3'regulatory region. A fair level of switching to all Ig classes is restored in heterozygous mice despite the fact that cis-recombination is either non productive on one allele or deficient on the other. Molecular evidence at the DNA level of trans-CSR to IgG3 was demonstrated by cloning and sequencing Smu-Sgamma3 hybrid junctions. These data demonstrate that inter-allelic recombination may broadly rescue the production of various class-switched isotypes and allow complementation between mutations located at both ends of the IgH constant gene cluster.

Alleles↗
PubMed2005

Interallelic class switch recombination contributes significantly to class switching in mouse B cells.

Except for the expression of IgM and IgD, DNA recombination is constantly needed for the expression of other Ig classes and subclasses. The predominant path of class switch recombination (CSR) is intrachromosomal, and the looping-out and deletion model has been abundantly documented. However, switch regions also occasionally constitute convenient substrates for interchromosomal recombination, since it is noticeably the case in a number of chromosomal translocations causing oncogene deregulation in the course of lymphoma and myeloma. Although asymmetric accessibility of Ig alleles should theoretically limit its occurrence, interallelic CSR was shown to occur at low levels during IgA switching in rabbit, where the definition of allotypes within both V and C regions helped identify interchromosomally derived Ig. Thus, we wished to evaluate precisely interallelic CSR frequency in mouse B cells, by using a system in which only one allele (of b allotype) could express a functional VDJ region, whereas only interallelic CSR could restore expression of an excluded (a allotype) allele. In our study, we show that interchromosomal recombination of V(H) and Cgamma or Calpha occurs in vivo in B cells at a frequency that makes a significant contribution to physiological class switching: trans-association of V(H) and C(H) genes accounted for 7% of all alpha mRNA, and this frequency was about twice higher for the gamma3 transcripts, despite the much shorter distance between the J(H) region and the Cgamma3 gene, thus confirming that this phenomenon corresponded to site-specific switching and not to random recombination between long homologous loci.

Alleles↗
PubMed2005

Fanconi's syndrome induced by a monoclonal Vkappa3 light chain in Waldenstrom's macroglobulinemia.

Fanconi's syndrome (FS) is a disorder of sodium-dependent proximal tubule reabsorption, which may complicate plasma cell disorders producing a free monoclonal light chain (LC). FS often occurs in the setting of smoldering myeloma and features cytoplasmic crystalline inclusions of monoclonal kappa LC in proximal tubular cells and malignant plasma cells. Although the clinical and pathological presentation may vary, including lack of crystal formation, monoclonal kappa LCs that underlie FS show a striking genetic and biochemical homogeneity: they almost always belong to the Vkappa1 subgroup of variability and originate from 2 germline genes, O2/O12 or O8/O18. Their variable domain sequences present unusual hydrophobic residues, responsible for the resistance to proteolysis, which leads to LC accumulation in the endocytic compartment of proximal tubule cells. We report a patient with slowly progressive Waldenstrom's macroglobulinemia and full-blown FS with accumulation of a monoclonal kappa LC within proximal tubules, but no detectable crystalline organization. This LC, which belonged to the unusual Vkappa3 subgroup and derived from the L2/L16 germline gene, showed no common substitution with previously described FS kappaI LC and was sensitive to trypsin digestion. These data show that molecular and biochemical characteristics of kappa LCs in patients with FS are more heterogeneous than initially suspected. Mechanisms other than resistance of LCs to endosomal proteolysis probably are involved in the pathogenesis of FS-associated plasma cell dyscrasias.

Aged↗
PubMed2005

Indolent lymphoplasmacytic and marginal zone B-cell lymphomas: absence of both IRF4 and Ki67 expression identifies a better prognosis subgroup.

BACKGROUND AND OBJECTIVES: Small B-cell indolent lymphomas postulated to be of a post-germinal center origin include marginal zone lymphomas of the spleen (S-MZL) or lymph nodes (N-MZL) and mucosa-associated lymphoid tissue (MALT) lymphomas and lymphoplasmacytic lymphomas (LPL). The existence of rather aggressive cases stresses the need for new biological prognostic markers. DESIGN AND METHODS: We analyzed 90 tumors (20 LPL, 41 MALT lymphomas, 12 N-MZL, 17 S-MZL), investigating the expression of CD5, CD10, CD20, CD23, CD27, CD38, CD79a, CD138, Bcl6, cyclin D1, IRF4 and Ki67 antigens by immunohistochemistry. Results were compared to the histology, the standard clinical and biological parameters, and the global survival. RESULTS: Tumors were all positive for CD20 and CD79a, occasionally positive for CD5, CD23, CD138 and cyclin D1, and all negative for Bcl-6 and CD10. CD38, CD27 and IRF4 expression was heterogeneous. IRF4 expression was correlated with plasma-cell differentiation (p=0.0017). Ki67 expression was increased mainly in N-MZL (66%) and LPL (45%). In terms of overall survival, Ki67, IRF4 and C-reactive protein levels were found to be the 3 independent parameters associated with a worse outcome. Lack of both Ki67 and IRF4 expression was associated with a longer survival (median overall survival 9.8+/-1.1 years versus 3.6+/-1.3 years in the other group) (p=0.0011). INTERPRETATIONS AND CONCLUSIONS: Absence of expression of both Ki67 and IRF4 is likely to define a group of memory B-cell lymphomas with a better prognosis. This may have an important impact in the staging of patients since expression of these markers is easily assessed in routine diagnosis.

Adult↗
PubMed2004

Transcription-dependent somatic hypermutation occurs at similar levels on functional and nonfunctional rearranged IgH alleles.

Allelic exclusion of IgH chain expression is stringently established before or during early B cell maturation. It likely relies both on cellular mechanisms, selecting those cells in which a single receptor allows the best possible Ag response, and on molecular restrictions of gene accessibility to rearrangement. The extent to which transcriptional control may be involved is unclear. Transcripts arising from nonfunctional alleles would undergo nonsense-mediated degradation and their virtual absence in mature cells cannot ensure that transcription per se is down-regulated. By contrast, somatic hypermutation may provide an estimate of primary transcription in Ag-activated cells since both processes are directly correlated. For coding regions, the rate and nature of mutations also depend upon Ag binding constraints. By sequencing intronic sequence downstream mouse VDJ genes, we could show in the absence of such constraints that somatic hypermutation intrinsically targets nonfunctional rearranged alleles at a frequency approaching that of functional alleles, suggesting that transcription also proceeds on both alleles at a similar rate. By contrast and confirming the strong dependency of somatic hypermutation upon transcription, we show that artificial blockade of transcription on the nonfunctional allele by a knock-in neomycin resistance cassette keeps the VDJ region unmutated even when its promoter is intact and when it is fully rearranged.

Alleles↗
PubMed2004

The polymorphism of the locus control region lying downstream the human IgH locus is restricted to hs1,2 but not to hs3 and hs4 enhancers.

In human, three transcriptional enhancers called hs1,2, hs3 and hs4 were identified downstream the 3' Ig heavy (IgH) locus. We previously reported by PCR and Southern blotting the existence of various allelic forms for the hs1,2 enhancer, one allele being associated with a higher efficiency of switching to IgA in IgA nephropathy (IgAN) patients. Since it is strongly suggested in the mouse that the whole 3' regulatory region is broadly involved in the regulation of class switch recombination (CSR), we wondered if the reported hs1,2 polymorphism was the sole difference possibly accounting for the varying ability to produce non-IgM antibodies in the human population. In this study, we report the absence of additional polymorphism of the hs3 and hs4 enhancers either by using a PCR method or by Southern blotting. DNA sequence analysis confirmed the existence of an invariant core sequence for human hs3 and hs4 enhancers, featuring multiple nuclear factor potential binding sites. In conclusion, human hs3 and hs4 enhancers are not polymorphic, a result that markedly contrasts with the hs1,2 enhancer for which the generation of multiple alleles in both rodents and humans has likely been favored by its central position within a large palindromic region.

Base Sequence↗
PubMed2004

Immunologic basis for the rare occurrence of true nonsecretory plasma cell dyscrasias.

Lymphocytes and plasma cells are major actors of the adaptive immune response and can rightly be considered as human health keepers. However, recombination and mutation events occurring at high rate in the B cell lineage also expose these cells to gene alterations, potentially resulting in uncontrolled and life-threatening cell proliferation. Although in cultured cell lines, such gene alterations frequently generate nonsecretory variants, most immunoproliferative B cell disorders feature in vivo immunoglobulin (Ig) secretion. In this paper, we review the molecular mechanisms involved in various instances of the rare, nonsecretory myelomas, in light of current notions about the molecular control of Ig production, assembly, and secretion in normal B cells. We finally document the attractive hypothesis that B cell clones, which retain nonsecretable, intracellular Igs, may be ideal, in vivo targets for efficient anti-idiotypic immune responses, and clones featuring an abundant secretion may by contrast easily induce T cell anergy and escape the anti-tumoral immune surveillance.

Animals↗
PubMed2004

RNA surveillance down-regulates expression of nonfunctional kappa alleles and detects premature termination within the last kappa exon.

Random V(D)J junctions would generate nonfunctional and/or out-of-frame sequences in about two-thirds of cases and result in abundant transcripts encoding truncated proteins. Although allelic exclusion at the DNA recombination level ensures that a single allele is functional, the frequent biallelic rearrangements need additional mechanisms to down-regulate aberrant transcripts in those cells with both a functionally and a nonfunctionally rearranged allele. The process of nonsense-mediated decay targets aberrantly rearranged Ig heavy-chain transcripts, but the situation of light-chain mRNAs is more complex, because they do not meet the usual requirements for nonsense-mediated decay and most often lack a spliceable intron downstream of the premature termination. We studied immunoglobulin heavy-chain -/- pro-B cells in which light chain genes get rearranged and expressed in the absence of any selection for the assembly of a functional B cell receptor. Using this model, we show that the whole kappa locus is accessible in pro-B cells and allows the assembly of a broad spectrum of VkappaJkappa segments, most of which are out-of-frame. This model provides an evaluation of the in vivo efficiency of RNA surveillance toward aberrant kappa mRNAs produced in pro-B cells. Our data show that nonfunctional kappa transcripts are excluded from the mature mRNA pool not only by detecting termination in an upstream exon but also by detecting changes in the position of termination within the last exon. Similar mechanisms efficiently down-regulate nonfunctional kappa transcripts arising in normal mature B cells due to the biallelic transcription of rearranged kappa genes.

Alleles↗
PubMed2004

Immunoglobulin class-switch recombination in mice devoid of any S mu tandem repeat.

Immunoglobulin heavy-chain class-switch recombination (CSR) occurs between highly repetitive switch sequences located upstream of the constant region genes. However, the role of these sequences remains unclear. Mutant mice were generated in which most of the I mu -- C mu intron was deleted, including all the repeats. Late B-cell development was characterized by a severe impairment, but not a complete block, in class switching to all isotypes despite normal germ line transcription. Sequence analysis of the I mu -- C mu intron in in vitro activated-mutant splenocytes did not reveal any significant increase in activation-induced cytidine deaminase (AID)-induced somatic mutations. Analysis of switch junctions showed that, in the absence of any S mu repeat, the Imicro exon was readily used as a substrate for CSR. In contrast to the sequence alterations downstream of the switch junctions, very few, if any, mutations were found upstream of the junction sites. Our data suggest that the core E mu enhancer could be the boundary for CSR-associated somatic mutations. We propose that the core E mu enhancer plays a central role in the temporal dissociation of somatic hypermutation from class switching.

Amino Acid Sequence↗
PubMed2004

Induction of somatic hypermutation by antigen-specific B cell receptors in the human BL2 cell line.

The role of the B cell antigen receptor in the induction of somatic hypermutation is presently unclear. We established stable transfectants of the human BL2 cell line expressing hen-egg lysozyme-specific IgM or IgA and compared their ability to induce somatic hypermutation of the endogenous rearranged heavy-chain gene. We found that IgM and IgA were both able to induce somatic hypermutation in an antigen dose-independent manner. The mutations displayed most of the characteristics of somatic hypermutation in vivo. Notably, some replacements introduced stop codons in the coding region. Our data suggest that class-switched memory B cells may undergo somatic hypermutation. They also suggest that the transmembrane/cytoplasmic domains of the class-switched isotypes modulate the signaling and down-modulation activities of the BCR in an antigen dose-dependent manner.

Amino Acid Sequence↗
PubMed2003

The beta-globin HS4 insulator confers copy-number dependent expression of IgH regulatory elements in stable B cell transfectants.

Locus control regions (LCR) were first defined by their theoretical ability to enhance the expression of linked genes in a tissue-specific, position-independent and copy-number dependent manner. In fact, few of the so-called LCR identified completely fulfil this definition. For example, the regulatory elements located in 5' (Emu) and 3' (HS3a; HS1,2; HS3b; HS4) of the IgH locus display some properties of a LCR but lack a copy-number dependence and sometimes display position effects in transgenes. In order to study whether addition of insulators would allow to overcome such problems in transgenes, we studied constructs harboring a V(H) promoter-green fluorescent protein reporter gene linked to the 3' and/or 5' IgH elements, surrounded or not with the chicken beta-globin 5'HS4 insulator. When flanked with insulators it appeared that either 3' IgH and 5' IgH regulatory elements now behave as true LCR elements and noticeably display copy-number dependence in transfected pre-B or B cell lines.

B-Lymphocytes↗
PubMed2003

Combination of 3' and 5' IgH regulatory elements mimics the B-specific endogenous expression pattern of IgH genes from pro-B cells to mature B cells in a transgenic mouse model.

To ensure the B cell differentiation stage specificity of the intronic Emu element and of the locus control region (LCR) that lies downstream of the IgH chain locus, we generated transgenic mice harboring a V(H) promoter-GFP reporter gene linked to the 3'LCR region and the Emu element. By flow cytometry, GFP(+) lymphocytes were observed amongst pro-B cells (B220(+)CD43(+)CD117(+)) and at all stages of differentiation up to mature B cells (B220(+)IgM(+)IgD(+)). Expression was strictly confined to cells committed to the B lymphocyte lineage as judged by the lack of GFP(+)Thy1,2(+) cells (T lymphocytes) and GFP(+)B220(-)CD117(+)CD43(+) cells (uncommitted lymphohematopoietic progenitors). Therefore, the Emu-GFP-3'LCR transgene is not expressed by hematopoietic stem cells, begins its expression in pro-B cells and is specifically active at all stages of B cell maturation. The combination of 3' and 5' IgH regulatory elements thus appears as a potentially useful cassette in transgenes that require a stringent and early B lineage-specific expression.

Animals↗