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Biomedical subjects

J Y Muller

Publications and source records attributed to J Y Muller.

At least 19 recordsLinked to original sources
PubMed2005

[TRALI: from diagnosis to prevention].

Transfusion-Related Acute Lung Injury (TRALI) is a post-transfusion acute respiratory distress syndrome (ARDS). TRALI is a non-cardiogenic lung oedema occurring within 6 hours following the infusion of a blood component. Its frequency has been estimated from 1 in 5.000 to 1 in 500.000 injected blood products. Its aetiology is still controversial. Antibodies against HLA class I molecules or granulocyte surface molecules recognizing recipient leukocyte antigens were implicated at first. More recently anti HLA class II were involved in some cases. Finally granulocyte activating lipids released from cells during blood storage were claimed to account for cases in which no antibody were detected. Nevertheless, in most cases, none of these triggering factors alone seems sufficient to induce a TRALI. A predisposing condition, associated with leucostasis in pulmonary vessels, is required. Whatever the mechanism, the pulmonary lesion is eventually due to release of neutrophil granule content in contact with endothelial cells of lung micro-capillary vessels. The basement membrane damages leads to fluid and cell extravasations in interstitial and alveolar spaces. Among blood donors multiparous women are the most frequently involved. Up to now there are neither definite guidelines regarding detection of harmful antibodies nor regulation for deferral of potentially dangerous blood donors.

Basement Membrane↗
PubMed2001

A point mutation in the cysteine-rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb-IIIa (alphaIIbbeta3) integrin receptor locked in a high-affinity state and a Glanzmann thrombasthenia-like phenotype.

This article reports a Glanzmann thrombasthenia (GT) patient, N.M., with a point mutation in the third cysteine-rich repeat of beta3-integrin or platelet glycoprotein (GP) IIIa, leading to the expression of a constitutively activated fibrinogen receptor. The diagnosis of GT was based on a severely reduced platelet-aggregation response to a series of agonists and approximately 20% of surface-expressed GPIIb-IIIa. The patient's GPIIb-IIIa constitutively expressed epitopes recognized by antibodies to ligand-induced binding sites (LIBS) and also spontaneously bound the fibrinogen-mimetic antibody, PAC-1. Furthermore, significant amounts of bound fibrinogen were detected on his platelets ex vivo. No signs of platelet activation were observed on sections of unstimulated platelets from N.M. by electron microscopy. Immunogold labeling highlighted the presence of surface-bound fibrinogen but revealed platelet heterogeneity with regard to the surface density. When the patient's platelets were stimulated by thrombin-receptor activating peptide, amounts of surface-expressed GPIIb-IIIa increased and the aggregation response improved, although it failed to normalize. Platelets from N.M. were able to adhere and spread on immobilized fibrinogen. Sequence analysis of genomic DNA from N.M. revealed a homozygous g1776T>C mutation in GPIIIa, leading to a Cys560Arg amino acid substitution. A stable Chinese hamster ovary (CHO) cell line was prepared expressing surface GPIIb-Arg560IIIa. Like platelets from the patient, GPIIb-Arg560IIIa-transfected CHO cells constitutively bound LIBS antibodies and PAC-1. They also showed an enhanced ability to adhere on surface-bound fibrinogen. Overall, these data demonstrate that a gain-of-function mutation can still be associated with a thrombasthenic phenotype even though platelets show spontaneous fibrinogen binding.

Adult↗
PubMed1999

Flow cytometric monitoring of red blood cell chimerism after bone marrow transplantation.

Chimerism after bone marrow transplantation (BMT) was investigated by flow cytometry analysis of red blood cells (RBCs) and of reticulocytes using a series of selected monoclonal or polyclonal antibodies directed against ABO, Rhesus, Kell, Duffy or MNSs antigens. The method allows the routine detection of less than 0.1% of positive cells in artificial mixed field populations. Blood samples from 135 patients undergoing BMT were investigated around days 15, 30, 45, 60, 90, 180, and then every 6 months after transplantation. Characteristic patterns showing expression of donor red blood cell antigens (expansion markers) and concomitant decrease of recipient specific antigens (depletion markers) within days 16-20 were observed for 125 successfully engrafted patients. Distinct patterns were obtained in 10 patients. A delay in engraftment was evidenced in four patients by the absence of chimerism during the first 6 months without any sign of relapse. Re-appearance of recipient RBCs and reticulocytes was observed in five patients; it was consistent with relapse that was later confirmed by clinical, haematological and cytogenetic studies. Finally, a stable and partial chimerism with 20% of RBCs expressing a marker from the recipient was observed in one patient without any sign of relapse. The reported investigation demonstrated that flow cytometry of RBCs and reticulocytes represents a powerful method to efficiently monitor bone marrow transplanted patients on a long-term basis.

Adolescent↗
PubMed1998

New method for quantitative determination of fetal hemoglobin-containing red blood cells by flow cytometry: application to sickle-cell disease.

A new method to quantify red blood cells (RBCs) containing fetal hemoglobin (HbF), or F cells, by flow cytometry was developed. The use of formaldehyde as fixative agent and sodium dodecyl sulfate (SDS) to permeabilize fixed RBCs resulted in a low staining background, a negligible Hb leakage, and minimal cell clumping. HbF was detected by immunofluorescence with a murine monoclonal antibody directed to the gamma chain of human Hb. The accuracy of the F-cell count was evaluated on mixed-field populations of adult and cord RBCs. The results of flow cytometry were highly correlated with HbF dosage in the hemolysate by high-pressure liquid chromatography (HPLC) (R > 0.99). The sensitivity of the method allowed the study of HbF distribution at the single-cell level in normal controls and patients with sickle-cell disease (SCD). All patients exhibited a heterocellular distribution of HbF, with highly variable percentages of F cells and non-F cells. As an additional and valuable biological parameter in SCD, the mean HbF content per F cell could be deduced from the measurement of HbF level by HPLC and F-cell count by flow cytometry. Results were unchanged after storing the cells for several weeks in an optimized resuspending solution. Since it does not need uncommon reagents or devices and allows the simultaneous detection of membrane antigens by two-color flow cytometry, this method is convenient for routine laboratories as well as for research purposes.

Adult↗
PubMed1998

Impact of the MHC-encoded HLA-DMA, DMB, and LMP2 gene polymorphisms on kidney graft outcome.

We previously studied the relationship between TAP1 and TAP2 gene polymorphism and compatibility in kidney graft outcome and reported that the currently described TAP1 and TAP2 gene polymorphisms did not influence the incidence of acute rejection episodes. In this study, we report on the effect of polymorphism and matching of HLA-DMA, -DMB, and LMP2 genes on kidney graft outcome. This study was performed on 102 selected kidney recipients who experienced two or more acute rejection episodes (rejection group) during follow up and who were compared to a group of 150 patients who never had rejection (non rejection group). Although a significant effect of HLA-DR matching was observed between these two groups, our data suggest that matching for all the new genes located in the HLA class II region (TAP1, TAP2, LMP2, HLA-DMA and -DMB) does not influence the kidney graft outcome. However, a significant increase (pc < 0.05) of DMA*0102 allele was observed in the recipients of the rejection group as compared to those of the non rejection group. This effect was not due to a linkage disequilibrium between DMA and HLA-DR loci and suggests that this specific HLA-DMA allele could play a role in the indirect pathway of class II presentation of donor antigens.

Adult↗
PubMed1998

Investigation of the survival of paroxysmal nocturnal hemoglobinuria red cells through the immunophenotyping of reticulocytes.

BACKGROUND: Complement-mediated lysis of red cells (RBCs) is a classic feature of paroxysmal nocturnal hemoglobinuria (PNH) that is traditionally studied with a combination of radiolabeling of RBCs and in vitro hemolysis tests. Phenotyping of reticulocytes was used as an alternative method for the evaluation of the relative life span of normal RBCs (PNH I) and RBCs that were partially (PNH II) or completely (PNH III) deficient in CD59. STUDY DESIGN AND METHODS: Murine monoclonal antibodies CD55, CD58, and CD59 and thiazole orange were used to phenotype reticulocytes by two-color flow cytometry in nine PNH patients. RBC survival could be calculated from the ratio of CD59- or CD59low mature RBCs to CD59- or CD59low reticulocytes obtained from these patients who had not received a transfusion. RESULTS: The life span of PNH III RBCs varied from about 17 to 60 days. PNH II reticulocytes were found in the four patients with PNH II RBCs. The life span of PNH II RBCs varied with their residual expression of CD59, and cells with 15 to 20 percent of the normal amount of CD59 were protected against in vivo hemolysis. CONCLUSION: Phenotyping of reticulocytes is a convenient and reliable tool for evaluating the relative survival of normal and PNH RBCs. PNH II and PNH III reticulocytes are phenotypically distinct, and some PNH II RBCs may be sensitive to complement-mediated lysis in vitro, but normally they are complement-resistant in vivo.

CD55 Antigens↗
PubMed1997

Treatment of graft-versus-host disease by extracorporeal photochemotherapy: a pilot study.

BACKGROUND: Graft-versus-host disease (GVHD) is a major complication after bone marrow transplantation, which may be refractory to immunosuppressive drugs. As preliminary case reports suggested that extracorporeal photochemotherapy (ECP) using a Therakos device might be beneficial, we conducted a pilot study to assess the efficacy and safety of a new ECP method that does not require administration of 8-methoxypsoralen (8-MOP) to the patient. METHODS: ECP was performed three times a week for 3 weeks and then tapered according to the patient's course. Soluble 8-MOP was added ex vivo to an enriched mononuclear cell suspension obtained by a cell separator. This cellular suspension was then ultraviolet A irradiated and reinfused into the patient. Evaluation was performed using specific objective tests depending on clinical conditions. RESULTS: The two patients in the study with acute GVHD and severe liver dysfunction resistant to steroid pulse showed no improvement with ECP treatment. The five patients with chronic GVHD (c-GVHD) had the following clinical features: three patients had myositis and two patients had severe cutaneous c-GVHD, including one patient with sclerodermoid lesions, one with bronchiolitis obliterans, one with bronchitis, and one with liver involvement. Immunosuppressive drugs were either prohibited or ineffective. The number of procedures for each patient ranged from 13 to 30. Cytapheresis required the use of a double-lumen catheter (4/5) or an arteriovenous fistula (1/5). No side effects were related to 8-MOP or ultraviolet A irradiation. Four of five patients improved after ECP; one patient with bronchiolitis obliterans, a fibrotic condition, remained stable. CONCLUSIONS: ECP treatment may be helpful for the treatment of severe c-GVHD and the avoidance of increased immunosuppression.

Acute Disease↗
PubMed1997

Anti-native and recombinant myeloperoxidase monoclonals and human autoantibodies.

Myeloperoxidase (MPO) is one of the main antigen targets of anti-neutrophil cytoplasmic antibodies (ANCA) in systemic vasculitides. It has been suggested that anti-MPO antibodies may recognize a single epitope on recombinant MPO. If confirmed on native MPO, this might allow specific therapeutic intervention with anti-idiotypic MoAbs to prevent antibody antigen interaction which is thought to cause activation of neutrophils and vasculitis. We searched for restriction in the epitope recognition profile in 50 patients with anti-MPO autoantibodies, using both native and recombinant MPO. Mouse monoclonals were purified and tested in competition assays. At least four epitopes were identified on native MPO using these monoclonals and only two were conserved on recombinant MPO. We found that human MPO autoantibody response was not restricted to a single epitope on native MPO, as all sera tested did not show the same profile in competitive studies with monoclonals. Furthermore, 30% of human anti-native MPO sera failed to recognize rMPO.

Animals↗
PubMed1997

Expression of blood group i antigen and fetal hemoglobin in paroxysmal nocturnal hemoglobinuria.

BACKGROUND: The mechanism by which the paroxysmal nocturnal hemoglobinuria (PNH) clone progressively takes over normal hematopoietic cells remains unknown. The respective in vivo differentiation of normal and PNH erythroid progenitors was investigated through the expression of two fetal erythroid markers (i antigen and fetal hemoglobin [HbF]) whose expression in adult red cells is associated with altered erythropoiesis. STUDY DESIGN AND METHODS: Murine monoclonal antibodies directed against HbF and i and CD59 antigens were used to phenotype red cells of 10 PNH patients. A multiparametric flow cytometry assay of red cells and reticulocytes was designed to assess a possible association of i and HbF with PNH or normal red cells. RESULTS: Most patients exhibited greater expression of i and HbF than did normal controls. In each case, the percentages of i-positive or HbF-positive cells within CD59-deficient and CD59-positive red cells were very close, clearly showing a lack of preferential association of these markers with normal or PNH cells. CONCLUSION: In PNH patients, normal and PNH erythroid progenitors have the same ability to promote HbF and i antigen expression, which suggests that normal and PNH erythroid progenitors (burst-forming units-erythroid, colony-forming units-erythroid, erythroblasts) behave similarly in response to bone marrow stress.

Adolescent↗
PubMed1997

Idiopathic and secondary membranous nephropathy and polymorphism at TAP1 and HLA-DMA loci.

In a previous study on the effects of TAP1 and TAP2 gene polymorphism in kidney allograft recipients, we found no association between graft outcome and recipient/donor TAP1 and TAP2 allele polymorphism or compatibility, but we observed a surprising increased frequency of the TAP1*0201 allele among kidney recipients. This increase was restricted to patients with glomerulopathy. We now report on a larger cohort of 178 patients with membranous nephropathy who were typed for their HLA-DPB1, -DRB1, -DMA, -DMB, LMP2, LMP, TAP1 and TAP2 genes compared with 100 random ethnically matched and healthy unrelated individuals used as controls. The results show a significant increased frequency of two markers in membranous nephropathy patients as compared with controls: firstly the previously recognized increase in HLA-DR3 (59% vs 18%: Pc < 1 x 10(-9), RR = 6.6), secondly a new association with two TAP1 amino acid variants displaying respectively a valine in amino acid position 333 (TAP1-Val-333) and consequently a glycine in position 637 (TAP1Gly-637) due to its strong linkage disequilibrium with Val-333. No linkage disequilibrium was found between TAP1-Val-333 and HLA-DR3. Moreover, we also noticed a decrease of the DMA*0102 phenotype in membranous nephropathy patients. The other HLA-DPB, -DMB, LMP2, LMP7 and TAP2 phenotype frequencies were roughly similar between patients and controls. These results show that the TAP1-Val-333 like HLA-DR3 phenotype is positively associated with membranous nephropathy and that these two risk factors are not cumulative in membranous nephropathy pathophysiology.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Anti-lactoferrin autoantibodies: relation between epitopes and iron-binding domain.

Anti-neutrophil cytoplasm antibodies (ANCA) have been found in the sera of patients presenting systemic necrotizing microscopic vasculitis, i.e. Wegener's granulomatosis and microscopic polyangiitis. Lactoferrin (LF) is one of the antigens rarely recognized by ANCA, and anti-LF autoantibodies are found in several autoimmune conditions, including rheumatoid vasculitis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, primary sclerosing cholangitis and Crohn's disease. We analysed the epitopes recognized by human anti-LF antibodies to test whether the heterogeneity of clinical presentation might be due to a different epitope recognition profile. Several monoclonal antibodies were raised and used in competition studies with six human sera. Four distinct epitopes were identified on LF, and LF binding of only one of six sera was inhibited by one of the monoclonals. Thus, anti-LF autoreactivity appears to be polyclonal and not restricted to an immunodominant epitope. Specific epitope profiles cannot be determined in these autoimmune conditions. We hypothesized that the interaction of anti-LF antibodies with the LF iron binding domain might contribute to pathogenesis by inhibiting iron chelation after neutrophil activation, thereby providing increased iron availability for endothelial cell damage. The relation of anti-LF mouse monoclonals or polyclonal human or rabbit antibodies to the LF iron-binding domain was studied in competition assays between 59Fe and these antibodies. Preincubation of LF with monoclonals or anti-LF human sera did not affect the binding of 59Fe on LF. 59Fe-binding kinetic studies showed that rabbit anti-LF polyclonal, but not mouse monoclonals or human anti-LF positive sera, was capable of inhibiting iron binding on LF. Therefore, anti-LF autoantibodies did not appear to modulate LF iron-binding activity. We conclude that LF is a rare antigen specificity for ANCA and that the clinical and pathophysiological relevance of anti-LF autoreactivity remains uncertain.

Antibodies, Monoclonal↗