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Biomedical subjects

J Y Muller

Publications and source records attributed to J Y Muller.

At least 37 records · Page 2Linked to original sources
PubMed1996

The hereditary pancreatitis gene maps to long arm of chromosome 7.

Hereditary pancreatitis (HP) is an autosomal dominant disorder with incomplete penetrance characterized by recurring episodes of severe abdominal pain often presenting in childhood. Although this disorder has only been recently described, about 100 families have been documented worldwide. The pathophysiology of this disorder is unknown. Here, a large French family of 147 individuals (47 of whom were affected) from a four-generation kindred with HP has been examined and a genome segregation analysis of highly informative microsatellite markers has been performed. Linkage has been found between HP and six chromosome 7q markers. Maximal two point lod scores between HP and D7S 640, D7S 495, D7S 684, D7S 661, D7S 676 and D7S 688 were 4.00 (theta = 0.143), 5.85 (theta = 0.143), 4.91 (theta = 0.156), 8.58 (theta = 0.077), 8.28 (theta = 0.060), 4.40 (theta = 0.169), respectively. Multipoint linkage data combined with recombinant haplotype analysis indicated that the most likely order is: D7S 640-D7S 495-D7S 684-D7S 661-D7S 676-D7S 688, with the HP gene situated in the underlined region. As in all families reported in the literature, the clinical presentation of the disease is identical to the presentation of sporadic cases, one could expect that the knowledge of the HP gene could be a clue to pancreatitis in general. Based on its map position, this is the first step towards the positional cloning of the Hereditary Pancreatitis Gene (HPG).

Chromosome Mapping↗
PubMed1996

1,25 Dihydroxyvitamin D3 exerts regional effects in the central nervous system during experimental allergic encephalomyelitis.

1,25-dihydroxyvitamin D3 (1,25-D3) is already known to prevent clinical signs of experimental allergic encephalomyelitis when animals are treated during the immunization phase. In the present work we have evaluated the ability of 1,25-D3 to inhibit chronic relapsing experimental allergic encephalomylitis (EAE) of the Lewis rat, when administered after the beginning of clinical signs. We observed a significant clinical improvement in 1,25-D3-treated rats. This effect was accompanied by a profound inhibition of CD4 antigen expression by central nervous system (CNS) infiltrating monocytes/macrophages and parenchymal microglia. In addition, immunohistochemical analysis performed at the time of the second attack evidenced a region-specific distribution of inflammatory cells. In the same way, some aspects of the effects exerted by 1,25-D3 appeared to vary depending on the region considered, namely spinal cord, brainstem, cerebellum, midbrain or anterior brain. Thus, in 1,25-D3-treated rats, we observed an almost complete inhibition of CD4 antigen expression in the granule cell layer and the adjacent white matter of the cerebellum as well as a marked decrease in the number of OX42-positive cells (macrophages and activated microglia) in anterior brain sections. We conclude that 1,25-D3 can exert immunomodulatory effects inside the CNS during an ongoing immune process and may thus represent a promising therapy for multiple sclerosis.

Animals↗
PubMed1996

Inheritance of abnormal glycophorin C of the Gerbich and Yussef type in a French family.

The discovery of a natural Gerbich antigen (anti-Ge2) in the serum of a propositus prompted us to study his red blood cells (RBCs) by using monoclonal anti-bodies (mAbs) directed against glycophorin (GP) C and GPD. An mAb directed against the Ge4 antigen (mAb NaM10-7G11) agglutinated both untreated and trypsin-treated cells, demonstrating the expression of a trypsin-resistant GPC (namely, GPC of the Gerbich type: GPCGe). Surprisingly, an anti-Ge3 antibody (mAb NaM19-3C4) agglutinated untreated cells, showing that they also express the Ge3 antigen that may be carried by normal GPC and CPD or by the abnormal GPC of the Yussef (Yus) type (GPCYus). Immunoblotting analysis performed with an mAb directed against the C-terminal portion of GPC showed that the propositus' RBCs do not contain normal GPC and GPD but both GPCGe and GPCYus. Analysis of RBCs from the family demonstrated that, like the propositus, 2 of the 3 sisters had inherited both the GYPCGe and the GYPCYus alleles from the parents, who carried either the GYPCGe or the GYPCYus allele. The third sister had inherited the normal GYPC alleles from her parents, whereas the child of the propositus had inherited the GYPCGe allele. Interestingly, natural anti-Ge2 antibodies were identified in the serum of 2 of the 3 Ge-negative individuals.

Agglutination Tests↗
PubMed1996

Expression of glycosyl-phosphatidylinositol-linked glycoproteins in blood cells from paroxysmal nocturnal haemoglobinuria patients: a flow cytometry study using CD55, CD58 and CD59 monoclonal antibodies.

We used CD55 and CD59 monoclonal antibodies (mAbs) for the investigation of peripheral blood cells from sixteen patients with paroxysmal nocturnal haemoglobinuria (PNH) by flow cytometry. Mixed-field populations of erythrocytes, platelets, monocytes or granulocytes were visualized in all cases but, due to the extended half-life of unaltered erythrocytes and blood transfusions, the GPI-linked protein deficiency was more obvious for white blood cells, especially granulocytes, and platelets. In contrast, a minority of altered lymphocytes was observed in only five patients. The expression of CD55 and CD59 antigens was grossly correlated but quantitative differences were observed for patients whose cells were only partially deficient in GPI-linked proteins. Patients with PNH secondary to aplastic anaemia exhibited a significantly lower percentage of altered cells compared with "classical" PNH patients. In addition, we found that CD58 normally bound to deficient white blood cells and platelets, showing the LFA-3 molecule is expressed as a transmembrane protein in these cells.

Adult↗
PubMed1995

Effects of MHC-encoded TAP1 and TAP2 gene polymorphism and matching on kidney graft rejection.

The products of TAP1 and TAP2 genes, recently mapped within the MHC class II region, are involved in antigen presentation by MHC class I molecules, especially in the transport of endogenous peptides. As for most MHC genes, a polymorphism has been described and the possibility that it could influence the recipient immune response by modulating antigen presentation in kidney transplantation has been tested. The aim of our study was to compare TAP1 and TAP2 gene polymorphism and matching in 53 couples of kidney donors and recipients without any rejection episodes and in 55 other couples who had experienced at least 2 acute cellular rejection episodes; 70 healthy individuals served as controls. Our results showed that allelic variant frequencies of TAP1 alleles (1A to 1C) and TAP2 alleles (2A to 2E), as assessed by amplification refractory mutation system-polymerase chain reaction, were similar among "rejection" and "no rejection" populations. Furthermore, there were no differences of TAP1 and/or TAP2 matching between donors and recipients in the 2 groups. In contrast, we showed that the recipients of the no rejection group were better matched with their corresponding donors for the HLA-DR genes than those of the rejection group. These results suggest that the currently described polymorphism in the limited coding region of TAP1 and TAP2 genes does not influence the incidence of kidney allograft rejection episodes and seems not to be a strong link to the adjacent DR/DQ subregion. Moreover, the observed increase frequency of TAP1B allele in the whole recipient's group as compared with controls (16.2% vs. 7.1% in the healthy individuals; P < 0.02) was not linked to the rejection occurrence but to the presence of glomerulonephritis as initial disease. Our study suggests that, in the clinical conditions tested, neither TAP polymorphism nor TAP matching influences the renal graft outcome.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Lack of evidence for a role of HLA-DP in unexplained recurrent spontaneous abortion.

Using the "Polymerase Chain Reaction-Sequence Specific Oligoprobes" (PCR-SSOp) technique, we studied the HLA-DPB locus in both partners of 59 couples with a history of three spontaneous abortions, and of 38 control couples in order to determine the role of this centromeric region of the major histocompatibility complex (MHC) in the immune reaction needed for a favorable course of pregnancy. As no particular phenotypes were noted, and also neither excessive HLA-DP homozygosity in sterile women nor excessive HLA-DP allele sharing between sterile partners, this MHC class II sub-region would seem to play no role either directly or by linkage disequilibrium, in the development of normal pregnancy.

Abortion, Habitual↗
PubMed1995

Flow cytometry analysis of dual red blood cell populations after bone marrow transplantation.

Flow cytometry represents an alternative method to agglutination assays for the accurate quantification of mixed field populations of erythrocytes observed after bone marrow transplantation. Murine monoclonal antibodies directed against the blood group ABH antigens were selected and processed in order to prepare ready-to-use fluorescent reagents. Anti-A (NaM87-1F6; IgG3), anti-B (NaM9-2E11; IgG3) and anti-H (NaM19-7E11; IgM) were purified, labelled with fluorescein isothiocyanate, and used in a direct flow cytometry assay. Anti-A1 (NaM1-1C9; IgG3) was no longer active after FITC-labelling and then was used in an indirect assay. The agglutination was prevented by formaldehyde pretreatment of erythrocytes. Using artificially-made double populations of erythrocytes, measured values with mixtures of 1-100% of cells were very closely related to expected values, showing both the sensitivity and the accuracy of the method. From careful investigation of a series of bone-marrow transplanted patients, we conclude that engraftments could be demonstrated earlier by flow cytometry than by agglutination, because minor populations (1-10%) of cells could be determined accurately only with labelled reagents. In addition, the disappearance of the donor cells on a long-term follow-up of patients enabled an earlier detection of graft failure in one case. The proposed method provides appreciable help to follow engraftment in patients and may have more general applications for the study of other haemopoietic chimaeras.

ABO Blood-Group System↗
PubMed1994

Susceptibility to alloimmunization to platelet HPA-1a antigen involves TAP1 polymorphism.

The alloimmunization against platelet HPA-1a antigen in mothers of thrombocytopenic neonates is strongly associated with HLA class II structures (DR3 and DR13) and especially with HLA-DR52a antigen (98% of the cases reported here). Because new genes have recently been mapped within the MHC class II region, we typed TAP1 and TAP2 gene polymorphisms by ARMS-PCR in order to characterize more effectively MHC genes involved in this alloimmunization. Our results showed that TAP1*0102 allele was significantly associated with NAIT only in the population of HLA-DR 13-DR52a-immunized women (50%) versus HLA-DR 13-DR52a controls (20%) (p < 0.05), and not in HLA-DR3-DR52a-immunized women versus HLA-DR3-DR52a controls. There is no linkage disequilibrium between TAP1*0102 and DRB1*13 alleles (delta = -0.0063) that could account for this result. The higher frequency of TAP1*0102 allele among HLA-DR 13-DR52a-immunized women suggests that HPA-1a antigen presentation and recognition may be influenced by nonclassic HLA class II gene polymorphisms, or that other linked but yet unknown genes could interfere.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Characterization of new murine monoclonal antibodies directed against glycophorins C and D.

Six new murine monoclonal antibodies (mAbs) directed to the erythrocyte membrane glycophorins C (GPC) and D (GPD) were obtained from splenocytes of different BALB/c mice immunized with human red blood cells, and fully characterized. The mAbs were selected by agglutination tests with control and Gerbich-negative cells, and by immunoblotting analysis. They showed specificity for the N-terminal domain(s) of GPC (and GPD) and were classified into three categories by competitive analysis using 125I-labelled antibodies and real-time biospecific interaction. The first group (NaM10-7G11, NaM70-1G4 and NaM77-7B6) compete for epitope(s) located at the N-terminal portion of GPC. Agglutination-inhibition tests revealed that the 7G11 epitope involves the amino group of Met1 and sialic acid residue(s) whereas the 1G4 and 7B6 epitopes contain O-glycans. NaM89-2G11 belongs to a second group; its epitope is located in a region including Glu17, Asp19 and (an) O-glycan(s). The third group comprises mAbs NaM19-3C4 and NaM98-3C1 which bind to both GPC and GPD in proximity of the binding site of human anti-Ge:3 antibodies. In addition, mAb 3C4 (anti-GPC/GPD) was found to bind to approximately 125,000 sites per red cell. Considering that the ratio of the GPC to GPD is about 3-4 to 1, the number of GPC and GPD molecules was estimated as 95,000 and 35,000, respectively.

Animals↗
PubMed1994

Production of a new murine monoclonal antibody with Fy6 specificity and characterization of the immunopurified N-glycosylated Duffy-active molecule.

A murine monoclonal antibody (mAb i3A; IgG1, kappa light chain) was obtained using human red blood cells as immunogen. The antibody showed Fy6 specificity since it agglutinated all but Fy(a-b-)-untreated red cells and failed to agglutinate chymotrypsin-treated cells. An erythrocyte membrane protein of 42-46 kD was revealed as the major component recognized by the antibody on immunoblots. The antibody also bound to 92- to 95- and 200-kD proteins, tentatively identified as oligomers of the 42- to 46-kD monomeric form. The affinity-purified Fy6-active protein was converted to a sharp band of 35 kD after N-glycanase treatment. The molecule appeared as a slightly broadly band after neuraminidase treatment but was not further altered by O-glycanase. The i3A mAb bound to 6,000 +/- 1,000 receptor sites on either Fy(a-b+), Fy (a+b+) and Fy(a+b-) red cells with an affinity constant in the range of 3-6 x 10(8) M-1. No binding was observed to other blood cells nor to several cells (B, T, myelomonocytic and erythro-leukemia cell lines). Also, the bulk of i3A-Fy6 immune complexes could be dissociated from the red cell membrane with as low as 0.2% Triton X-100, showing that the Fy6-active glycoprotein is not tightly associated with the membrane skeleton. Our data obtained with a new monoclonal antibody directed to the Fy6 antigen demonstrate that the blood group Duffy-active component is a red cell-specific glycoprotein carrying one or more N-linked oligosaccharides.

Animals↗
PubMed1993

[Paroxysmal nocturnal hemoglobinuria. Diagnosis aided by a monoclonal antibody directed against the decay accelerating factor glycoprotein].

The laboratory diagnosis of paroxysmal nocturnal haemoglobinuria (also called Marchiafava-Micheli disease) is based on the sensitivity of the patient's red cells to complement-induced lysis. In view of the clonal expression of the disease, haemolysis tests are difficult to interpret when the abnormal red cell population is small. The sensitivity of abnormal red cells to haemolysis is due to the absence of proteins attached to the cell membrane by a phosphatidyl-inositol link, which intervene in the regulation of the complement-induced lysis mechanism. Using a monoclonal antibody directed against one of these proteins, the decay accelerating factor (DAF, protein CD 55), makes it possible to diagnose paroxysmal nocturnal haemoglobinuria. DAF expression on patients' blood cells was measured by quantitative agglutination and by indirect flow cytometry. The agglutination test using polybren is a fast detection method, but it may be uninterpretable, notably in cases with positive antiglobulin (Coombs') test. In contrast, DAF expression measured by indirect flow cytometry correlates perfectly with measurement of red cell sensitivity by haemolysis tests. Using the monoclonal antibody by indirect flow cytometry is the method of choice to confirm the diagnosis of paroxysmal nocturnal haemoglobinuria and to measure the proportions of normal and abnormal red cells in case of haematological disorder.

Adolescent↗
PubMed1993

Lack of binding of peptides carrying the human platelet antigen 1 (HPA-1) dimorphism to purified HLA-DRw52a molecules.

The strong association between anti-HPA-1a alloimmunization and DR3, DRw52a phenotype in HPA-1b homozygous women suggests that these class II molecules play a crucial role in the immune response against HPA-1a. The diallelic system HPA-1 results in a single amino acid polymorphism at the residue 33 of the glycoprotein IIIa. So, we tested the binding of peptides from the 25-42 region of the GPIIIa to purified HLA-DR3 and -DRw52a molecules, using a solid phase assay and a liquid phase peptide binding assay. No binding was demonstrated, indicating that either the crucial region for binding to class II molecules is not the 25-42 region, or that other events only occurring "in vivo" are required for binding. These results may also suggest an indirect role of the residue 33 for T-cell stimulation.

Amino Acid Sequence↗
PubMed1993

[Rapid diagnosis of paroxysmal nocturnal hemoglobinuria by gel test agglutination].

Murine monoclonal antibodies (MoAbs) directed against DAF (Decay Accelerating Factor, CD55 antigen) and MIRL (Membrane Inhibitor of Reactive Lysis, CD59 antigen) were used to identify the affected red cells (CD55-/CD59-) of PNH patients. MoAbs NaM16-4D3 (CD55, IgG2a) and NaM77-1E5 (CD59, IgG3) weakly agglutinate red cells and represent powerful tools to quantitate normal (PNHI) and abnormal (PNHII and PNHIII) cells from PNH patients by indirect flow cytometry. MoAbs NaM125-7H10 (CD55) and NaM123-6G12 (CD59), both IgM, were selected for their agglutinating properties and used for the separation of PNHI from PNHII and PNHIII red cells by the gel test technology. From analysis of artificial mixtures of DAF+ and DAF- cells, a direct relationship was established between fluorescent cells detected by flow cytometry, and erythrocytes agglutinated in microtyping cards. The method was further confirmed by analysis of ten blood samples from PHN patients and represent an alternative to classical hemolysis tests. On the basis of our experience we propose the following for the diagnosis of PNH: 1) agglutination test with NaCl microtyping cards using IgM CD55 and CD59; 2) flow cytometry analysis for accurate quantitation of CD55-/CD59- red cells.

Agglutination Tests↗
PubMed1993

[Kidney transplantation and HLA-DR compatibility evaluated by genomic analysis: one center study].

The actual effect of HLA-DR matching in renal transplantation remains controversial. Since DNA analysis has been shown to be more reliable than serological typing, a re-evaluation of the impact of DR-matching on graft prognosis is required. In this study, 224 cadaver kidney transplantations performed in our center were retrospectively matched according to Restriction Fragment Length Polymorphism DR incompatibilities and compared to prospective serological DR-matching. Transplant outcome was evaluated using graft survival, first rejection onset and rejection frequency. In 18.8% individuals, a discrepancy between serology and DNA typing for at least one antigen was noted. Serology particularly failed to type recipients (21.7%) and 43.2% of the total missed antigens were serologically "blank" or unidentified ("X") alleles. A graft survival rate of 100% after one year was observed for transplantations with no DNA DR mismatch (n = 31). Furthermore, there was a definite correlation between DNA matching and (i), the percentage of individuals with one or more than one acute rejection episode (18% and 41.8% at one year for O incompatibility and pooled 1 and 2 incompatibilities respectively, p < 0.05); (ii), the mean of acute rejection per individual (p < 0.001); and (iii), the rejection onset time (p < 0.01). No correlation between serological matching and the acute rejection episodes parameters was noted. Since HLA typing could be performed in less than 2 hrs using new molecular biology techniques, we conclude that prospective DNA typing should improve kidney transplantation outcome in the near future.

Graft Rejection↗
PubMed1993

[Immunologic aspects of bone marrow transplantation].

Allogeneic bone marrow transplantation is concerned by immunology by at least two aspects: the first one is the acceptance of the graft by the host and reciprocally and the second one is that it constitutes an unique human model of immune reconstitution. In this review of the immunological aspects, we deal with the selection of the bone marrow donor (related or not) especially on the base of HLA compatibility and the graft-versus-host disease (GVH) with the clinical manifestations, the usual treatments, the supposed cellular mechanisms and the risk factors of developing such complications. The graft versus leukemia effect (GVL) which may be linked to the GVH disease and the mechanisms of rejection and take of the graft are also reviewed as well as the immune reconstitution following the immune deficiency due to the conditioning treatment and the occurrence of a GVH disease.

Bone Marrow Transplantation↗
PubMed1993

Pentoxifylline inhibits experimental allergic encephalomyelitis.

Pentoxifylline, a widely used methylxanthine, has been proven to inhibit the production and action of the cytokine TNF alpha. Since it has been suggested that TNF alpha is the major cytokine involved in the pathogenesis of multiple sclerosis, we tested pentoxifylline for its capacity to prevent experimental allergic encephalomyelitis (EAE). 26 Lewis rats with acute EAE were treated with either pentoxifylline or saline. The pentoxifylline treated rats showed a significantly lower incidence of clinical signs as well as significantly lower histological inflammation. The exact mechanism of this preventive effect remains to be clarified but it might be mainly related to inhibition of TNF alpha release from central nervous system macrophages.

Animals↗
PubMed1993

[Immunological treatment of spontaneous repeated abortions. The value of transfusing the partner's leukocytes in the third week of gestation].

Twenty-two nulli- all primipara who had had previous repeated spontaneous abortions and who did not have anti-HLA antibodies for the partner, received immunological treatment consisting of a single transfusion of the partner's lymphocytes in the third week of pregnancy, and giving natural progesterone supplements after the kinetic of Beta-HCG in the plasma had been assessed. The number of pregnancies which went to terme (94% success) was significantly better than those obtained in our first protocol which was to give one to three transfusions of the partner's lymphocytes before the pregnancy started (58% success rare after 24 treatments). Apart from obtaining much better results the second protocol made it possible to avoid giving a significant number of useless transfusions (22% of pre-conceptual transfusions were not followed by a pregnancy at all).

Abortion, Habitual↗