Biomedical subjects

A Durandy

Publications and source records attributed to A Durandy.

At least 19 recordsLinked to original sources

PubMed2000

A syndrome involving intrauterine growth retardation, microcephaly, cerebellar hypoplasia, B lymphocyte deficiency, and progressive pancytopenia.

We report a new complex syndrome involving profound failure to thrive with severe intrauterine growth retardation, cerebellar abnormalities, microcephaly, a complete lack of B lymphocyte development, and secondary, progressive marrow aplasia. B cell differentiation was found to be blocked at the pro-B cell stage. Although not strictly proven, a genetic origin is likely, according to similar cases reported in the literature. Three candidate genes, PAX5, encoding B cell-specific activator protein, a factor involved in B cell lineage commitment, stromal cell-derived factor 1, and CXCR4, encoding a chemokine and its receptor, respectively, were thought to be responsible for this disease, given the similarity between the phenotype of the corresponding knock-out mice and the clinical features of the patient. However, the genomic DNA sequences of these 3 genes were normal, and normal amounts of stromal cell-derived factor 1 and CXCR4 were present. These data strongly suggest that another molecule is involved in early B cell differentiation, hematopoiesis, and cerebellar development in humans.

Agammaglobulinemia↗

PubMed1999

Activation of the Janus kinase 3-STAT5a pathway after CD40 triggering of human monocytes but not of resting B cells.

CD40/CD40 ligand interactions play a key role in the immune responses of B lymphocytes, monocytes, and dendritic cells. The signal transduction events triggered by cross-linking of the CD40 receptor have been widely studied in B cell lines, but little is known about signaling following CD40 stimulation of monocytes and resting tonsillar B cells. Therefore, we studied the CD40 pathway in highly purified human monocytes and resting B cells. After CD40 triggering, a similar activation of the NF-kappaB (but not of the AP-1) transcription factor complex occurred in both cell preparations. However, the components of the NF-kappaB complexes were different in monocytes and B cells, because p50 is part of the NF-kappaB complex induced by CD40 triggering in both monocytes and B cells, whereas p65 was only induced in B cells. In contrast, although the Janus kinase 3 tyrosine kinase was associated with CD40 molecules in both monocytes and resting B cells, Janus kinase 3 phosphorylation induction was observed only in CD40-activated monocytes, with subsequent induction of STAT5a DNA binding activity in the nucleus. These results suggest that the activation signals in human B cells and monocytes differ following CD40 stimulation. This observation is consistent with the detection of normal CD40-induced monocyte activation in patients with CD40 ligand+ hyper IgM syndrome in whom a defect in CD40-induced B cell activation has been reported.

B-Lymphocytes↗

PubMed1999

TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells.

TGF-beta 1 is critical for differentiation of epithelial-associated dendritic Langerhans cells (LC). In accordance with the characteristics of in vivo LC, we show that LC obtained from human monocytes in vitro in the presence of TGF-beta 1 1) express almost exclusively intracellular class II Ags, low CD80, and no CD83 and CD86 Ags and 2) down-regulate TNF-RI (p55) and do not produce IL-10 after stimulation, in contrast to dermal dendritic cells and monocyte-derived dendritic cells. Surprisingly, while LC exhibit E-cadherin down-regulation upon exposure to TNF-alpha and IL-1, TGF-beta 1 prevents the final LC maturation in response to TNF-alpha, IL-1, and LPS with respect to Class II CD80, CD86, and CD83 Ag expression, loss of FITC-dextran uptake, production of IL-12, and Ag presentation. In sharp contrast, CD40 ligand cognate signal induces full maturation of LC and is not inhibited by TGF-beta 1. The presence of emigrated immature LCs in human reactive skin-draining lymph nodes provides in vivo evidence that LC migration and final maturation may be differentially regulated. Therefore, due to the effects of TGF-beta 1, inflammatory stimuli may not be sufficient to induce full maturation of LC, thus avoiding potentially harmful immune responses. We conclude that TGF-beta 1 appears to be responsible for both the acquisition of LC phenotype, cytokine production pattern, and prevention of noncognate maturation.

Antigens, CD↗

PubMed1999

CD40 ligand expression deficiency in a female carrier of the X-linked hyper-IgM syndrome as a result of X chromosome lyonization.

We report on the case of a girl with an immune deficiency characterized by recurrent infections of the upper and lower respiratory tract, low IgG and IgA serum levels as well as deficiency of the in vivo antibody response. Since this patient is the sister of a boy affected with a hyper-IgM syndrome due to a defect in CD40 ligand (CD40L) expression, the involvement of CD40L in this phenotypic expression was investigated. A very low fraction of activated T cells (5%) in this female patient expressed CD40L. This resulted from the presence of a heterozygous CD40L nonsense mutation associated with a skewed pattern of X chromosome inactivation as determined by methylation pattern analysis. Although carriers of X-linked hyper-IgM are considered to be asymptomatic, this study indicates that extreme lyonization of the normal X can lead to a mild expression of the hyper-IgM syndrome which is similar to common variable immune deficiency (CVID). Therefore, it is possible that some cases of CVID in females represent partial deficiency of CD40L expression in carriers of the CD40L mutation.

CD40 Antigens↗

PubMed1998

Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection.

Interferon-gamma receptor ligand-binding chain (IFN-gammaR1) or signaling chain (IFN-gammaR2) deficiency, like interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency, predispose to severe infections due to poorly virulent mycobacteria and salmonella. A child with bacille Calmette-Guérin and Salmonella enteritidis infection was investigated. Mutations in the genes for IFN-gammaR1, IFN-gammaR2, IL-12Rbeta1, and other molecules implicated in IL-12- or IFN-gamma-mediated immunity were sought. A large homozygous deletion within the IL-12 p40 subunit gene was found, precluding expression of functional IL-12 p70 cytokine by activated dendritic cells and phagocytes. As a result, IFN-gamma production by lymphocytes was markedly impaired. This is the first discovered human disease resulting from a cytokine gene defect. It suggests that IL-12 is essential to and appears specific for protective immunity to intracellular bacteria such as mycobacteria and salmonella.

BCG Vaccine↗

PubMed1998

Anti-B-cell monoclonal antibody treatment of severe posttransplant B-lymphoproliferative disorder: prognostic factors and long-term outcome.

B-lymphoproliferative disorder (BLPD) is a rare but severe complication of organ and bone marrow transplantation (BMT). Profound cytotoxic T-cell deficiency is thought to allow the outgrowth of Epstein-Barr virus-transformed B cells. When possible, reduction of immunosuppressive treatment or surgery for localized disease may cure BLPD. Therapeutic approaches using chemotherapy or antiviral drugs have limited effects on survival. Adoptive immunotherapy with donor T-cell infusions has given promising results in BMT recipients. We previously reported that administration of two monoclonal anti-B-cell antibodies (anti-CD21 and anti-CD24) could contribute to the control of oligoclonal BLPD. Here we report the long-term results of treatment with these monoclonal anti-B-cell antibodies for cases of severe BLPD. In an open multicenter trial, 58 patients in whom aggressive B-cell lymphoproliferative disorder developed after BMT (n = 27) or organ (n = 31) transplantation received 0.2 mg/kg/d of specific anti-CD21 and anti-CD24 murine monoclonal antibodies (MoAbs) for 10 days. The treatment was well tolerated. Thirty-six of the 59 episodes of BLPD in the 58 patients presented complete remission (61%). The relapse rate was low (3 of 36, 8%). Multivariate analysis identified the following risk factors for partial or no response to anti-B-cell MoAb therapy: multivisceral disease (P </= .005), central nervous system involvement (P </= .05), and late onset of BLPD (P </= .005). The overall long-term survival was 46% (median follow-up, 61 months); it was lower among BMT patients (35%) than organ transplant patients (55%). None of the patients who had received BMT for hematological malignancy survived for 1 year. Eight of these 11 patients presented monoclonal BLPD. Tumor burden was the only other variable that contributed significantly to poor survival. Thus, as assessed from this long-term study, the use of anti-B-cell MoAbs therefore appears to be a safe and relatively effective therapy for severe posttransplant BLPD.

Adolescent↗

PubMed1998

Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency.

In humans, interferon gamma (IFN-gamma) receptor deficiency leads to a predisposition to mycobacterial infections and impairs the formation of mature granulomas. Interleukin-12 (IL-12) receptor deficiency was found in otherwise healthy individuals with mycobacterial infections. Mature granulomas were seen, surrounded by T cells and centered with epithelioid and multinucleated giant cells, yet reduced IFN-gamma concentrations were found to be secreted by activated natural killer and T cells. Thus, IL-12-dependent IFN-gamma secretion in humans seems essential in the control of mycobacterial infections, despite the formation of mature granulomas due to IL-12-independent IFN-gamma secretion.

Animals↗

PubMed1998

Amino-acid change in the Epstein-Barr-virus ZEBRA protein in undifferentiated nasopharyngeal carcinomas from Europe and North Africa.

Different Epstein-Barr-virus(EBV) variants were found to be associated with nasopharyngeal carcinoma (NPC). The type-C variant lacks the BamHI site between the BamHI W1* and I* regions and the type-f variant has an extra BamHI site in the BamHI F fragment. The BNLF1 gene (which encodes the LMP1 protein) from a nude-mouse-passaged CAO strain and from NPC biopsies from Taiwanese patients also exhibits variations resulting in structural and functional differences in the protein. The BZLF1 gene encodes the ZEBRA protein which triggers the EBV lytic cycle. A difference has been observed in 8 amino acids in the ZEBRA sequence in B95-8 (Z95) and P3HR1 (ZP3) cell lines. EBV found in NPC biopsies and peripheral-blood cells from Asians was predominantly of the ZP3 type (72%), while 81% of samples from different EBV-associated diseases and peripheral-blood cells from North Africa or Europe were of the Z95 type. We found that an alanine 206 had been replaced by a serine in the Z95 sequence in 72% of the NPC biopsies from European and North African patients. The Zser206 variant is found in a significantly lower percentage (p < 0.001) of other EBV-positive tissues from individuals in the same region (10-33%). In contrast, a 30-bp deletion is observed near the 3' end of the LMP1 gene in the majority of EBV (86%) from NPC and peripheral-blood cells from Asians, whereas a significantly lower percentage (p < 0.001) of NPC biopsies from European and North African patients (56%) have this deletion, as do lymphocytes from control individuals from the same region (36 and 55% respectively).

Africa, Northern↗

PubMed1998

Normal CD40-mediated activation of monocytes and dendritic cells from patients with hyper-IgM syndrome due to a CD40 pathway defect in B cells.

Patients with X-linked hyper-IgM syndrome [CD40 ligand (CD40L) deficiency] are prone to infections by intracellular parasites. It has been suggested that this susceptibility is caused by defective macrophage activation through the CD40L-CD40 pathway. We studied the CD40-mediated activation of monocytes and dendritic cells from patients affected with a CD40L+ hyper-IgM syndrome characterized by a defect of B lymphocyte responses to CD40 agonists. We show that the CD40-induced production of IL-6, IL-8 and TNF-alpha by monocytes, and IL-12 by dendritic cells, and expression of the activation markers CD83, the costimulatory molecules CD86 and CD80, and HLA-DR antigens were all similar in patient and control cells. This observation is consistent with the clinical characteristics of the syndrome: a defect of immunoglobulin switch but no susceptibility to opportunistic infections, as observed in CD40L-deficient patients. These observations suggest that CD40-mediated activation pathways could be, at least in part, different in B and monocytic/dendritic cell lineages.

Antigens, CD↗

PubMed1997

Abnormal CD40-mediated activation pathway in B lymphocytes from patients with hyper-IgM syndrome and normal CD40 ligand expression.

The CD40-mediated activation pathway of B cells from 10 patients with hyper-IgM syndrome and normal expression of CD40 ligand was studied. In all 10 cases, B cells were found to be defective for IgG, IgA, and IgE production after stimulation by anti-CD40 mAbs and cytokines. In the patients tested, neither B cell proliferation (n = 6) nor CD23 molecule expression (n = 5) were observed in cultures stimulated with anti-CD40 mAb. These results point to an intrinsic B cell deficiency and a defect in the CD40-triggered B cell activation pathway; this conclusion was supported by a lack of detectable germinal centers in the spleen of two patients. CD40-triggered activation events, i.e., phosphatidylinositol 3 (PI3) kinase activation and induction of transcription factors NF-kappaB and AP-1, were next analyzed in B cell lines derived from five patients. Three distinct patterns were observed: an absence of detectable abnormalities (n = 1), defective PI3 kinase activation with normal induction of NF-kappaB and AP-1 (n = 3), and defects in both PI3 kinase activation and induction of NF-kappaB and AP-1 (n = 1). In three B cell lines, each exhibiting one of the CD40-mediated activation patterns, sequences of CD40 and CD40 binding protein coding regions were normal. The coding region of TNF receptor-associated factor 2 (TRAF2), which is known to interact with CD40 for NF-kappaB induction, was also found to be normal in B cell lines deficient in NF-kappaB induction. Altogether, these results suggest that CD40 ligand-positive hyper-IgM syndrome could be genetically heterogeneous, although phenotypic variability is not excluded, and that an early defect in the CD40-triggered activation cascade can account for defective Ig class switching in some patients with CD40 ligand-positive hyper-IgM syndrome.

Adolescent↗

PubMed1997

Epidermal Langerhans' cells in children with primary T-cell immune deficiencies.

Dendritic cells are the major antigen-presenting cells, especially for naive T lymphocytes; it is conceivable therefore that their absence or dysfunction may induce an immune deficiency (ID). Few data are available, however, concerning dendritic cells in human primary ID. Langerhans' cells (LC) are intraepidermal dendritic cells which express specific markers and may therefore be studied by immunohistochemistry on paraffin-embedded skin samples. Skin samples of nine children with primary ID were studied and compared with five age-matched controls. LC were present within the epidermis of two children with X-linked severe combined ID, a condition related to the lack of the common gamma-chain of interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors. LC were also present in skin samples of a child with Omenn syndrome and in three children with combined ID. By contrast, no LC were detected in the skin samples of two children with alymphocytosis and of a child with reticular dysgenesis, a condition characterized by the absence of peripheral blood leukocytes.

Antigens, CD1↗

PubMed1997

Sensitivity of Epstein-Barr virus-induced B cell tumor to apoptosis mediated by anti-CD95/Apo-1/fas antibody.

Epstein-Barr virus (EBV) can induce uncontrolled B lymphocyte proliferation leading to fatal lymphoma in immunocompromised patients. The sensitivity to apoptosis of B lymphoid cell lines (LCL) derived from EBV-induced lymphoproliferative disorders was investigated. In vitro and in vivo, these B LCL strongly express CD95/Apo-1/fas antigen and undergo apoptosis upon stimulation with anti-Apo-1 monoclonal antibody. When inoculated into severe-combined immunodeficient (scid) mice, human B cells lines developed into rapidly growing tumors. Administration of an agonistic anti-Apo-1 antibody significantly delayed tumor progression. Relapses were frequent, but were not caused by selection of resistant B cells, since B cells from relapsing tumors underwent apoptosis on re-exposure. Induction of apoptosis by an anti-C95/Apo-1/fas-specific antibody could be applied for therapy of EBV-induced B cell tumors and contribute to our understanding of the mechanisms of T cell-mediated elimination of EBV lymphomas in immunodeficient patients.

Animals↗

PubMed1997

Production and roles of IL-6, IL-10, and IL-13 in B-lymphocyte malignancies and in B-lymphocyte hyperactivity of HIV infection and autoimmunity.

We analyzed the production and the roles of IL-6, IL-10, and IL-13 in B-lymphoid malignancies and in specific diseases with B-lymphocyte hyperactivity. Both IL-13 and IL-10 genes are expressed in B-cell lymphomas. However, their contribution to tumor progression is unclear. In certain lymphoproliferative disorders that develop in transplanted patients, IL-6 is produced by malignant cells and is a major factor of their proliferation. In other lymphomas, the IL-6 gene is expressed only in malignancies where differentiated malignant cells are present. In these lymphomas, IL-6 is produced by stromal cells, and the malignant cells express the IL-6 receptor. In patients with HIV infection, the level of production of IL-6, IL-10, and IL-13 is not higher than those of other conditions with immune activation. However, IL-6 contributes to increased production of IgG and IgA in vivo. In Castleman's disease, IL-6 is produced in the lymph node germinal centers, partly originating from follicular dendritic cells, which may explain some of the pathogenesis of this disease. In systemic lupus erythematosus, the critical cytokine is IL-10, which is produced in large amounts by B lymphocytes and monocytes and is responsible for autoantibody production. Taken together, these data emphasize the roles of IL-6 and IL-10, usually produced by nonlymphoid cells, on B lymphocytes, either malignant or hyperactivated.

Acquired Immunodeficiency Syndrome↗

PubMed1997

[Antiviral immunodeficiency: EBV, CMV, adenovirus].

Patients undergoing bone marrow transplantation are susceptible to many different bacterial, fungal and viral infections. Among the viral pathogens, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus cause the greatest morbidity and mortality and have been the most common infectious causes of death following the grafting of allogeneic marrow. This great susceptibility to viral infections is due to the immunodeficiency in cellular and humoral immune responses lasting for months to years. Contributing factors are high-dose chemo/radiotherapy, graft-versus-host disease (GVHD) prophylaxis/treatment, GVHD itself, the degree of HLA disparity between donor and recipient and the underlying disease. Defects of T cell helper and cytotoxic functions contribute to the great incidence of viral infections. We described here the kinetic of immunological reconstitution and the role of T cell immunodeficiency. At day 30 to 40 after BMT, a minority of patients had recovery of virus-specific CD8+ T-cell response. Between day 40 and day 90 recovery of deficient CD8+ and CD4+ T cell responses occurred in the majority of the recipients of HLA identical BMT but only in the minority of the recipients of HLA partially incompatible BMT. New approaches should therefore be envisaged either to preserve donor T-cell-mediate immunity or tho accelerate immune reconstitution. Add-back of unmanipulated T-cells, or virus-specific T cells could improve antimicrobial defenses after BMT.

Adenoviruses, Human↗

PubMed1997

[Therapeutic prospects and lymphoproliferative syndromes related to EBV].

The B lymphoproliferative disorders are a major (10%) and severe (70% mortality) complication of immunosuppression required for HLA-mismatched bone marrow or organ transplantation. An experimental model was developed in which patients infected EBV-B cells are inoculated into scid mice and develop into tumors, allowing evaluation of treatment efficacy: monoclonal antibodies directed to membrane antigens of tumoral cells (monoclonal antibodies anti-B), monoclonal antibodies neutralizing interleukins (and especially IL6), cytotoxic T cells. Results obtained with these three different approaches are herein reported.

Animals↗

PubMed1996

Hyper-IgM syndrome associated with rheumatoid arthritis: report of RA in a patient with primary impaired CD40 pathway.

We studied a patient who had a typical seronegative rheumatoid arthritis (RA) and an immunodeficiency with hyper-IgM (HIM syndrome). CD40L was normally expressed by activated T cells, but CD40-mediated signal transduction was defective in B cells, preventing heavy chain switching (CD40L+ type of the HIM syndrome). These data suggest that a typical RA can develop in at least some patients with dysfunction of the CD40 pathway, i.e. in the absence of a normal co-operation between T and B cells. Accordingly, the blockade of CD40L-CD40 interactions, which has been proposed as a treatment of RA, might not be adapted to all patients.

Adult↗

PubMed1995

Recombinant soluble trimeric CD40 ligand is biologically active.

CD40 ligand (CD40L) is expressed on the surface of activated CD4+ T cells, basophils, and mast cells. Binding of C40L to its receptor, CD40, on the surface of B cells stimulates B cell proliferation, adhesion and differentiation. A preparation of soluble, recombinant CD40L (Tyr-45 to Leu-261), containing the full-length 29-kDa protein and two smaller fragments of 18 and 14 kDa, has been shown to induce differentiation of B cells derived either from normal donors or from patients with X-linked hyper-IgM syndrome (Durandy, A., Schiff, C., Bonnefoy, J.-Y., Forveille, M., Rousset, F., Mazzei, G., Milili, M., and Fischer, A. (1993) Eur. J. Immunol. 23, 2294-2299). We have now purified each of these fragments to homogeneity and show that only the 18-kDa fragment (identified as Glu-108 to Leu-261) is biologically active. When expressed in recombinant form, the 18-kDa protein exhibited full activity in B cell proliferation and differentiation assays, was able to rescue of B cells from apoptosis, and bound soluble CD40. Sucrose gradient sedimentation shows that the 18-kDa protein sediments as an apparent homotrimer, a result consistent with the proposed trimeric structure of CD40L. This demonstrates that a soluble CD40L can stimulate CD40 in a manner indistinguishable from the membrane-bound form of the protein.

Amino Acid Sequence↗

PubMed1995

Undetectable CD40 ligand expression on T cells and low B cell responses to CD40 binding agonists in human newborns.

IgG, IgA, and IgE production by newborn B cells is limited both in vivo and in vitro in various activation conditions, whereas IgM production is readily detectable. It has been suggested that the Ig heavy chain switch inability could be the consequence of T and B cell immaturity. As the interaction between CD40 (expressed on B cells) and its ligand CD40-L (expressed on activated T cells) triggers a key signal required for isotype switching, we studied the expression and function of these two components in normal fetuses, newborns, and infants, compared with adults. CD40-L expression was not inducible in 28 of 30 specimens of newborn cord-blood T cells following incubation with PMA and ionomycin, whereas activation markers such as CD69 were inducible. CD40-L expression was triggered by activation of T cells from infants > 3 wk of age. Surprisingly, T cells from 19- to 28-wk-old fetuses also expressed CD40-L following activation. CD40-L expression on newborn T lymphocytes was induced on T cell lines generated in the presence of PHA and maintained with IL-2 following further stimulation with PMA and ionomycin. CD40-L mRNA transcripts and intracytoplasmic protein expression following activation of newborn T cells were strongly decreased, leading to undetectable protein membrane detection. These results point to a possible transcriptional down-regulation of CD40-L expression by neonatal T lymphocytes. In addition, fetal and cord-blood B cells were poorly able to switch to IgG or IgA by stimulation with CD40 agonists (Ab or soluble CD40-L) in the presence of IL-4 or IL-10 as also detected with surface IgD+ adult B cells. Both phenomena could contribute to the neonatal Ig switch inability, although distinct underlying regulatory mechanisms are probably involved, as suggested by different in vivo time courses.

Adult↗