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Biomedical subjects

M Cogné

Publications and source records attributed to M Cogné.

At least 19 recordsLinked to original sources
PubMed2002

Molecular study of an IgG1kappa cryoglobulin yielding organized microtubular deposits and glomerulonephritis in the course of chronic lymphocytic leukaemia.

Glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits (GOMMID) and glomerulonephritis related to type I cryoglobulin are well-known but rare complications of B cell derived chronic lymphocytic leukaemia. In these disorders, monoclonal Ig have never been studied at the molecular level. We conducted a pathological and molecular analysis in a patient with chronic lymphocytic leukaemia, glomerulonephritis and a single circulating monoclonal Ig. Unusual IgG1kappa kidney deposits were observed. The heavy and light chain variable region sequences of that cryoprecipitating monoclonal Ig were characterized. Light microscopy revealed glomerulonephritis typical of cryoglobulinaemia, with neutrophil and macrophage infiltration, endocapillary hyperplasia and few protein thrombi. Electron microscopic study clearly evidenced numerous subepithelial mixed granular and organized deposits with a unique microtubular organization, reminiscent of the GOMMID. The Ig molecule sequence revealed alterations of charge and hydrophobicity potentially promoting a crystal-like aggregation and the aggregation of microtubules. This description suggests that common mechanisms are involved in various forms of precipitation and/or deposition of complete Ig molecules, with a variable extent of organization and with a possible overlap between pathological patterns of either glomerulonephritis with microtubular deposits or type I cryoglobulinic glomerulonephritis.

Amino Acid Sequence↗
PubMed2002

GM-CSF and IL-12 production by malignant plasma cells promotes cell-mediated immune responses against monoclonal Ig determinants in a light chain myeloma model.

Immune responses towards malignant plasma cells have clearly been demonstrated in the course of monoclonal B cell dyscrasias and shown to be mostly specific for idiotypic determinants of the monoclonal immunoglobulin (Ig). These responses are specifically efficient against lymphoma cells expressing a membrane form of the monoclonal Ig. In myeloma, such immune responses are often weak and a number of strategies are currently assayed in order to boost the cell-mediated responses against the secreted monoclonal Ig. The use of cytokines promoting Th1 responses could be helpful for the induction of anti-tumour immunity and the control of residual disease in patients treated with myeloablative therapy, and such strategies need to be evaluated. In a light chain myeloma model where the monoclonal Ig can only be secreted, we tried to induce protective immune responses through immunization of animals with transfected malignant plasma cells. An expression plasmid encoding GM-CSF and IL-12 proved to be highly efficient for the induction of both cytotoxic and proliferative responses after immunization of animals with transfected and irradiated tumour cells. Anti-tumour immunization according to this protocol was successful in protecting 93.4% of the animals against a subsequent tumour challenge.

Animals↗
PubMed2002

Analysis of three genetic markers in IgA nephropathy patients from a single region.

BACKGROUND: IgA nephropathy (IgA-N) is the most common glomerular disease. Various genetic factors have been suspected to influence the disease, but they never have been studied in the same cohort of patients. METHODS: In 125 IgA-N biopsy-proven cases, we studied by DNA techniques the allele distribution of 3 polymorphic loci: the angiotensin-converting enzyme (ACE) gene, the specific HLA-DQB1 gene and the hs1,2 enhancer of the alpha1 gene of the IgH locus. Patients were classified as progressive and non-progressive based on a creatininemia above 150 microl/ml or/and a deterioration of the clearance greater than 3 ml/min/year. We analyzed the influence of the polymorphism on the development and the progression of the disease. The control group consisted of 83 heathly subjects. RESULTS: The frequency of HLA-DQB1*0602 was decreased in IgA-N patients (3.6% vs 10.2%, Pc = 0.04, RR = 0.36), suggesting a protective effect of this allele for IgA-N. Kaplan-Meyer analysis with the Cox-proportional hazard model revealed a shorter time between diagnosis and renal failure in patients with the B allele for the al gene hs1,2 enhancer (p = 0.04). ACE polymorphism did not influence the development or the progression of the disease. CONCLUSION: Genes controlling the immune response, such as HLA DQB1 and the alpha1 transcriptional enhancer gene, may influence the development and/or the progression of IgA-N nephropathy. Patients who develop an IgA-N nephropathy have a higher risk of severe evolution if they have a profile of high IgA humoral responder.

Adolescent↗
PubMed2001

An elevation in the concentration of HLA class I molecules in human blood due to ageing.

The quantification of plasmatic HLA class-I molecules (sHLA-I) was realized by a sandwich ELISA using a monomorphic mAb (W6/32). sHLA-I concentration is significantly increased in the elderly group (>50 years, 0.429+/-0.301 microg ml(-1)) as compared to the young group (<50 years, 0.126+/-0.085 microg ml(-1)). The variation of sHLA-I content could contribute to the unresponsiveness of ageing immune system.

Aging↗
PubMed2001

Characterization of the murine gene for subunit VIIaL of cytochrome c oxidase.

Mammalian cytochrome c oxidase consists of thirteen subunits, ten encoded by the nuclear genome and three by the mitochondrial DNA. In several species, two isoforms have been isolated for nuclear-encoded subunits VIa, VIIa and VIII: an ubiquitous L (liver) form and a heart- and skeletal-muscle specific H form. The gene for murine cytochrome c oxidase subunit VIIa-L (Cox7aL) and its promoter region were isolated, sequenced and analysed. The coding region is split in four exons spanning 4.1 kbp and the promoter carries potential binding sites for Sp1, NRF1 and NRF2 transcription factors. Transcriptional activity of the promoter in reporter assays suggested an ubiquitous expression in mouse tissues.

Animals↗
PubMed2001

Localization of the 3' IgH locus elements that effect long-distance regulation of class switch recombination.

Four transcriptional enhancers lie downstream of the immunoglobulin heavy chain locus: Calpha3'/hs3a, hs1,2, hs3b, and hs4. Although individually weak, these elements have strong transcriptional synergies when combined and they altogether behave as a locus control region. Previous knockout experiments in the 3' region have shown that both hs3a and hs1,2 are dispensable for normal expression and rearrangement of the IgH locus but that their replacement with a transcribed neo gene severely affects class switch recombination. Here we show that even in the absence of a neo gene, joint deletion of the last two 3' enhancers, hs3b and hs4, severely impairs germline transcription and class switching to most isotypes and may in addition affect mu gene expression in resting B cells.

Animals↗
PubMed2001

HLA-A and HLA-B transcription decrease with ageing in peripheral blood leucocytes.

Immunosenescence involves modifications of humoral and cellular immunity. In a previous study, we have shown a locus-dependent reduction of HLA class-I cell surface expression on peripheral lymphocytes and monocytes with advancing age. Here we report the quantitative analysis of HLA-A and -B transcripts from PBL of 54 healthy subjects aged 21-90 years. Using a competitive RT-PCR method, we observed a significant decrease of HLA-A (P < 0.0001) and -B (P = 0.0025) mRNA contents with increasing age. Secondly, to investigate this locus-dependent alteration of HLA class-I transcription, we performed EMSA using nuclear extracts from PBL of five young (24-31-year-old) and 5 elderly (58-69 years old) donors with locus A and B sequences of the Enh-A as probes. No qualitative variation of EMSA profiles appeared between the two groups of donors with 6 and 4 bandshift for the locus A and B, respectively. Quantitatively, we observed a significant increase of B4 intensity in the elderly group compared to the young group (P < 0.05). These results suggest that the variation of DNA binding protein could contribute to the lower transcription of HLA-A and -B with ageing. These alterations of HLA class-I expression at the transcriptional level could lead to the unresponsiveness of CD8 T cells due to default of antigen presentation with ageing.

Adult↗
PubMed2001

Polymorphism of the human alpha1 immunoglobulin gene 3' enhancer hs1,2 and its relation to gene expression.

We studied the hs1,2 transcriptional enhancer identified downstream of the human alpha1 gene of the immunoglobulin H (IgH) locus, for which two different allelic configurations (a and b) were previously reported by Southern blotting. By using a polymerase chain reaction (PCR) method we amplified minisatellites within the hs1,2 core enhancer, with variable numbers of tandem repeats (VNTR) defining three 'PCR alleles' alpha1A, alpha1B and alpha1C (including one, two and three repeats, respectively). Five different alpha1 h1,2 genotypes were encountered in a population of 513 donors, representing 13.8, 34.5, 49.7, 1.3 and 0.6% for the AA, BB, AB, AC and BC genotypes, respectively. Luciferase assays showed that increasing the number of minisatellites increased the transcriptional strength of the alpha1 hs1,2 enhancer. Simultaneous determination of Southern blot alleles and VNTR alleles only showed a partial linkage between both types of polymorphism, altogether defining at least six different allelic forms of the 3'alpha1 region. In conclusion, the present study further demonstrates the genetic instability of the 3'alpha region, for which multiple alleles have been generated through inversions and internal deletions and/or duplications. This study also strengthens the hypothesis that the polymorphism at the IgH 3' regulatory region of the alpha1 gene could play a role in the outcome of diseases involving immunoglobulin secretion.

3' Untranslated Regions↗
PubMed2000

Heavy and light chain primary structures control IgG3 nephritogenicity in an experimental model for cryocrystalglobulinemia.

Crystal formation by monoclonal immunoglobulins is a well-known but rare complication of B-cell neoplasia. We have designed an in vivo model of cryocrystalglobulinemia by grafting to mice hybridoma clones producing a pathogenic monoclonal immunogloblulin (Ig) G3kappa. One clone, 8A4, secreted a singular IgG3 that formed crystals both in the proliferating plasma cells and as mesangial and subendothelial deposits in the kidney glomeruli. Morphologic analysis of kidneys revealed neutrophil infiltration and endocapillary hyperplasia, while the morphology of deposits was reminiscent of those in cryocrystalglobulinemia patients. A variant clone that only differed from 8A4 by a 3-amino acid deletion in the V(kappa) CDR1 increased its secretion level by 7-fold and produced an abundant bona fide serum monoclonal cryoglobulin in mice, without crystal formation within tumoral cells; it yielded no subendothelial deposits but only amorphous precipitates in capillary lumens of kidney glomeruli, reminiscent of those seen in the human hyperviscosity syndrome, without other glomerular lesions. A limited variation in the V(kappa) domain thus proved able to increase secretion, to abrogate crystallization, and to modify patterns of glomerular lesions and deposits. Both the crystallizing and noncrystallizing IgG3kappa sequences were related to previously reported murine cryoglobulins, all including a gamma3 chain and canonical VH sequences. Two additional variants of 8A4 with identical VH and VL domains but having switched to IgG1 also lost crystal formation, further showing this feature of 8A4 to result from a unique 3-dimensional conformation of the complete immunoglobulin, relying on V and C domain primary structures of both chains.

Amino Acid Sequence↗
PubMed2000

CTLA4 exon 1 dimorphism in bullous and cicatricial pemphigoid.

The human cytotoxic T-lymphocyte antigen 4 (CTLA4) gene encodes proteins regulating the immune response. The polymorphism of this gene is associated with some autoimmune diseases. In this study, we analysed the distribution of the dimorphisms of exon 1 (+ 49 A/G) in bullous pemphigoid (BP) and cicatricial pemphigoid (CP), two types of autoimmune bullous skin diseases that occur in elderly people. The frequency of the exon 1 A-G genotype was marginally decreased in patients (36.4%; n = 55) compared with controls (52.8%, n = 53), but the results were not statistically significant (P = 0.09).

Abatacept↗
PubMed2000

Alleles of the alpha1 immunoglobulin gene 3' enhancer control evolution of IgA nephropathy toward renal failure.

BACKGROUND: IgA nephropathy is the most common glomerular disease. Mechanisms leading to its occurrence and controlling the evolution of the disease remain largely unknown. Various genetic factors have been found, mostly implicating immunologically relevant genes (IgH, TCR, human lymphocyte antigen, and complement loci). A regulatory region recently identified downstream, the alpha1 gene of the IgH locus, was a likely candidate for the control of IgA1 production in patients. Alleles of this region, differing by size, sequence, and orientation of the alpha1 hs1,2 transcriptional enhancer, were first identified through Southern blot hybridization. METHODS: We established a polymerase chain reaction (PCR) method suitable for routine testing that amplifies minisatellites within the alpha1 hs1, 2 enhancer, with variable numbers of tandem repeats (VNTR) defining the two alleles. This assay allowed the typing of 104 patients with IgAN and 83 healthy volunteers. Results from typing of alpha1 hs1,2 alleles were compared with long-term clinical outcome in patients. Enhancer alleles were compared in a luciferase reporter gene assay. RESULTS: The alpha1 hs1,2 alleles do not constitute a predictive factor for IgA nephropathy, since similar allelic frequencies were observed in healthy individuals and in unrelated European patients. In contrast, among patients, homozygosity for the weakest enhancer allele (AA genotype) was significantly correlated with a milder form of the disease, whereas the allele B was associated with severe evolution. The minisatellite region within the alpha1 hs1,2 enhancer carried potential transcription factor-binding sites, and its duplication increased the transcriptional strength of the alpha1 hs1, 2 allele B over that of allele A. CONCLUSION: Altogether, these alleles may constitute a risk factor for the prognosis of IgA nephropathy.

3' Untranslated Regions↗
PubMed2000

Deregulated platelet-activating factor levels and acetylhydrolase activity in patients with idiopathic IgA nephropathy.

BACKGROUND: Platelet-activating factor (PAF) is a phospholipid mediator with potent inflammatory activities. PAF stimulates IgA synthesis by B cells while IgA aggregates enhance PAF production by neutrophils and mesangial cells. These results led us to investigate blood PAF levels and plasma acetylhydrolase (AHA, the PAF catabolic enzyme) activity in patients with idiopathic IgA nephropathy (IgAN). METHODS: PAF and AHA levels were investigated using the platelet aggregation assay and degradation of (3)H-labelled PAF, respectively. The genotype of AHA with regard to the G994-->T mutation in exon 9 was assessed by an allele-specific polymerase chain reaction. RESULTS: Blood PAF levels were significantly (P:=0.003, Mann-Whitney U:-test) elevated in IgAN patients (50.6+/-6.8 pg/ml, n=33) compared with healthy controls (18+/-5 pg/ml, n=18). In contrast, plasma AHA levels were significantly (P:=0.0001, Mann-Whitney U:-test) reduced in patients with IgAN (61+/-2 nmol/ml/min, n=51) compared with healthy controls (78+/-4 nmol/ml/min, n=53). G994-->T transversion in exon 9 of AHA was not found in any of the IgAN patients. CONCLUSION: Elevated circulating levels of PAF in IgAN patients might result from an insufficient AHA probably related to environmental factors rather than genetic ones. The mechanism and the precise role of the PAF/AHA deregulation in IgAN patients remain to be clarified.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1999

Mutational analysis in murine models for myeloma-associated Fanconi's syndrome or cast myeloma nephropathy.

We have designed an in vivo model in which murine hybridoma cell clones producing human Ig light chains (LC) are administered to mice. Depending on which monoclonal LC is expressed, this model mimics either cast myeloma nephropathy or the pathological condition defined as myeloma-associated Fanconi's syndrome (FS) with LC crystallization. Morphological alterations of the kidney cells are thus obtained in mice. All studied LC are closely related human monoclonal VkappaI proteins, which differ by a limited number of substitutions within the variable region. In the case of an FS monoclonal LC, we show that limited changes introduced through site-directed mutagenesis in the variable domain may suppress formation of intracellular crystals within tubular cells. We also show that multiple peculiarities of the variable region are simultaneously needed to allow LC crystallization; this property thus likely results from a unique LC tridimensional conformation imposed by concomitant somatic mutations of a specific germinally encoded framework.

Amino Acid Sequence↗
PubMed1999

Cutting edge: Ig heavy chain 3' HS1-4 directs correct spatial position-independent expression of a linked transgene to B lineage cells.

The Ig H chain locus is regulated by a set of cis-acting elements. Hypersensitive sites (HS) located 3' of the IgH, HS1-4, has been suggested to act as a locus control region (LCR) in cell lines. To assess the proposed role of HS1-4 acting as an LCR, we generated transgenic mice harboring a VH promoter-beta-globin reporter gene linked to the Ig H chain HS1-4 3'regulatory sequences. Transgene expression is strictly confined to B lymphocytes, with no detectable expression outside the B cell lineage in all transgenic founder lines. Furthermore, reporter gene activity is integration independent but not copy number dependent. Thus, additional sequences are required to allow the HS1-4 regulatory region to act as a classical LCR in mice. Our data are discussed in the context of tissue-specific gene expression in B lineage cells.

3' Untranslated Regions↗
PubMed1999

Optimisation of HLA-B27 testing by association of flow cytometry and DNA typing.

HLA-B27 typing contributes to the diagnosis of ankylosing spondylitis. The classical technique of microlymphocytotoxicity is costly and can give false-negative results. We have compared 304 samples using two relatively new methods - flow cytometry and PCR-SSP - and evaluated their respective uses in routine analysis. Flow cytometric HLA-B27 testing was performed using three monoclonal anti-B27 antibodies (HLA-ABC-m3, GS145.2 and FD705 clones). Cut-off values were established to differentiate HLA-B27-positive from HLA-B27-negative samples with ROC curves. Although flow cytometric analysis with a reliable monoclonal antibody (mAb) is valuable for HLA screening, none of the HLA-B27 flow cytometry protocols was sufficient on its own to ascertain the HLA phenotype in 100% of samples. Two false negatives were observed with the FD705 mAb and the use of two different monoclonal antibodies did not increase the accuracy of HLA-B27 typing. HLA-B27 typing using molecular biology is a reliable but costly technique. Therefore we suggest that DNA typing could be used as a complementary technique and applied to samples whose HLA-B27 phenotype cannot be determined by flow cytometry. The association of flow cytometry and DNA typing is, in our experience, an economical and reliable approach.

Antibodies, Monoclonal↗
PubMed1999

HLA-G and classical HLA class I transcripts in various components of the adult human eye.

HLA-G transcripts have previously been detected in the ocular cell line HS738, in foetal eyes and in global ocular extract. Using RT-PCR and hybridization, we searched for HLA-G and classical HLA class I transcripts in the corneas of eye donors (n = 6) and in various components of eyes collected at time of surgery: lens (n = 3), iris (n = 2), vitreous body (n = 2) and retina (n = 2). Whereas HLA class I mRNA was abundant in the ocular tissues of all donors, we could not find HLA-G transcript in any ocular tissues obtained from subjects in vivo. The absence of HLA-G in adult eye cornea limits its interest as a possible target in corneal transplantation. Classical HLA class I transcripts were abundant in the cornea and other components of the eye. These results highlight the role of classical HLA class I antigen in eye immunity and corneal transplantation.

Cornea↗