Perturbations of the CD8+ T-cell repertoire in CVID patients with complications

AbstractA higher chronic expansion of effector cytotoxic CD8+DR+ T-lymphocytes has been reported in common variable immunodeficiency (CVID) patients with complications such as splenomegaly, autoimmune disease and/or granulomatous disease. In order to document the features associated with this T cell activation involving the CD8+ T-compartment, we examined the diversity of the alpha/beta TCR repertoire of the patient's CD8+ T-lymphocytes using the qualitative analysis of the CDR3 lengths (Immunoscope).Ten CIVD patients were enrolled in this study, four without complications (Group 1), six with complications (Group 2). All patients exhibited non-gaussian altered CDR3 length distributions, albeit to different extent within the different Vβ families. CVID patients with activated CD8+ T-cells show a reduction of their TCR repertoire diversity which is more severe in patients with complications. Viral reactivations such as CMV are suspected to be part of the mechanisms underlying immunosenescence

Altered dendritic cell distribution in patients with common variable immunodeficiency

Recent data suggest a critical role for dendritic cells (DCs) in the generation of immunoglobulin-secreting plasma cells. In the work reported herein, we analyzed the frequency of peripheral blood plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) in a cohort of 44 adults with common variable immunodeficiency (CVID) classified according to their CD27 membrane expression status on B cells. A deep alteration in the distribution of DC subsets, especially of pDCs, in the peripheral blood of CVID patients was found. Patients with a reduced number of class-switched CD27(+)IgD(-)IgM(- )memory B cells and patients with granulomatous disease had a dramatic decrease in pDCs (P = 0.00005 and 0.0003 vs controls, respectively) and, to a lesser extent, of mDCs (P = 0.001 and 0.01 vs controls, respectively). In contrast, patients with normal numbers of switched memory B cells had a DC distribution pattern similar to that in controls. Taken together, our results raise the possibility that innate immunity contributes to pathogenesis in CVID

Immunological markers after long-term treatment interruption in chronically HIV-1 infected patients with CD4 cell count above 400 x 10(6) cells/l.

OBJECTIVE: To analyse immunological markers associated with CD4+ lymphocyte T-cell count (CD4+) evolution during 12-month follow-up after treatment discontinuation. METHOD: Prospective observational study of chronically HIV-1 infected patients with CD4+ above 400 x 10(6) cells/l. RESULTS: CD4+ changes took place in two phases: an initial rapid decrease in the first month (-142 x 10(6) cells/l on average), followed by a slow decline (-17 x 10(6) cells/l on average) The second slope of CD4+ decline was not correlated with the first and only baseline plasma HIV RNA was associated with it. The decline in CD4+ during the first month was steeper in patients with higher CD4+ and weaker plasma HIV RNA baseline levels. Moreover, the decline was less pronounced (P < 10(-4)) in patients with CD4+ nadir above 350 x 10(6) cells/l (-65 x 10(6) cells/l per month) in comparison with those below 350 x 10(6) cells/l (-200 x 10(6) cells/l per month). A high number of dendritic cells (DCs) whatever the type was associated with high CD4+ at the time of treatment interruption and its steeper decline over the first month. Moreover, the myeloid DC level was stable whereas the lymphoid DC count, which tended to decrease in association with decrease in CD4+, was negatively correlated with the HIV RNA load slope. CONCLUSIONS: The results support the use of the CD4+ nadir to predict the CD4+ dynamic after treatment interruption and consideration of the CD4+ count after 1-month of interruption merely reflects the 12-month level of CD4+. Although DCs seem to be associated with the CD4+ dynamic, the benefit of monitoring them has still to be defined

First description of an IgM monoclonal antibody causing αIIb β3 integrin activation and acquired Glanzmann thrombasthenia associated with macrothrombocytopenia

BACKGROUND: Acquired Glanzmann thrombasthenia (GT) is a bleeding disorder generally caused by anti-αIIb β3 autoantibodies. OBJECTIVES: We aimed to characterize the molecular mechanism leading to a progressive GT-like phenotype in a patient with chronic immune thrombocytopenia. PATIENT, METHODS AND RESULTS: The patient suffered from repeated episodes of gastrointestinal bleedings and further studies indicated a moderate platelet aggregation defect. Few months later, platelet function showed abolished aggregation using all agonists, but normal agglutination with ristocetin. No platelet-bound antibodies were detected, but the presence of large amounts of an IgM type antibody detected together with αIIb β3 in the patient's permeabilized platelets suggested that this IgM was an autoantibody causing the internalization of the complex. This was confirmed by the fact that the patient's IgM bound to normal platelets but not to platelets from GT type I patients. Moreover, patient's plasma activated αIIb β3 on controls' platelets as evidenced by increased PAC-1 binding. We also demonstrated that the patient's plasma triggered αIIb β3 outside-in signaling, as β3 Tyr773 and FAK were phosphorylated, and increased the rate of actin polymerization in resting platelets reflecting an impairment of cytoskeletal reorganization. As different signs of dysmegakariopoiesis were also observed in our patient, we evaluated the ability of its serum to impair proplatelets formation and showed that it significantly decreased the number of proplatelet-bearing megakaryocytes in controls' bone marrow stem cells culture as compared to normal serum. CONCLUSIONS: We present the case of a patient with a progressive and severely perturbed platelet function associated with the presence of an IgM activating autoantibody directed against αIIb β3 . This article is protected by copyright. All rights reserved

The Expression of Myeloproliferative Neoplasm-Associated Calreticulin Variants Depends on the Functionality of ER-Associated Degradation

BACKGROUND: Mutations in CALR observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase - Signal Transducer and Activator of Transcription (JAK-STAT) pathway. However, little is known on the impact of those variant CALR proteins on endoplasmic reticulum (ER) homeostasis. METHODS: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 (XBP1), and the expression level of endogenous lectins. Pharmacological and molecular (siRNA) screens were used to identify mechanisms involved in CALR mutant proteins degradation. Coimmunoprecipitations were performed to define more precisely actors involved in CALR proteins disposal. RESULTS: We showed that the expression of CALR mutants alters neither ER homeostasis nor the sensitivity of hematopoietic cells towards ER stress-induced apoptosis. In contrast, the expression of CALR variants is generally low because of a combination of secretion and protein degradation mechanisms mostly mediated through the ER-Associated Degradation (ERAD)-proteasome pathway. Moreover, we identified a specific ERAD network involved in the degradation of CALR variants. CONCLUSIONS: We propose that this ERAD network could be considered as a potential therapeutic target for selectively inhibiting CALR mutant-dependent proliferation associated with MPN, and therefore attenuate the associated pathogenic outcomes

Intérêt du Rituximab dans le Purpura Thrombopénique immunologique réfractaire (à propos de douze observations)

BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Etude de l'activation lymphocytaire au cours des anémies hémolytiques auto-immunes

Les anémies hémolytiques auto-immunes (A.H.A.I.) sont classées selon deux entités opposées : les A.H.A.I. dites "chaudes" et les A.H.A.I. "froides" ou maladies des agglutinines froides. Elles s'opposent l'une à l'autre par leurs mécanismes physiopathologiques sous-jacents, par leur présentation clinico-biologique, et par leur prise en charge thérapeutique. Leurs mécanismes physiopathologiques responsables du processus d'hémolyse restent à l'heure actuelle mal connus. Toutefois, la recherche fondamentale sur les A.H.A.I. tire profit des résultats des études portant sur certaines maladies auto-immunes, en particulier le lupus érythémateux disséminé et le purpura thrombopénique idiopathique, dont un des axes de recherche actuel a pour objet l'étude de l'activation lymphocytaire T. Nous rapportons une étude rétrospective d'une cohorte de 84 patients suivis pour une A.H.A.I. au centre hospitalier universitaire de Bordeaux. Les patients atteints d'une A.H.A.I. "chaude" présentent une hémolyse plus sévère avec une anémie plus profonde et une splénomégalie significativement plus fréquente, site de prédilection de l'hémolyse au cours de ce type d'A.H.A.I. L'étude de l'activation lymphocytaire T est définie par la mesure de l'expression membranaire du marqueur HLA-DR à la surface des lymphocytes T. A la 1ère mesure du marqueur HLA-DR, on observe une activation lymphocytaire T significativement plus importante au cours des A.H.A.I. "froides" comparées aux A.H.A.I. "chaudes". L'évolution de la maladie hémolytique vers un état de rémission semble s'associer à une majoration lymphocytaire T, concernant en particulier la sous population lymphocytaire T CD8 (+). De la même façon que l'implication des lymphocytes T CD4 (+) régulateurs a été démontrée dans le contrôle de certaines maladies auto-immunes, ces résultats tendent à évoquer l'existence d'une population lymphocytaire T CD8 (+) à activité régulatrice favorisant l'évolution des A.H.A.I. vers un état de rémission. Il est néanmoins nécessaire de compléter ces travaux par l'étude de l'expression des marqueurs de régulation (facteur de transcription Foxp3 et du marqueur de régulation CTLA4) au niveau des lymphocytes T CD8 (+) HLA-DR (+) afin de confirmer les résultats obtenus.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Lupus érythémateux aïgu disséminé (étude comparative des paramètres cliniques, biologiques, immunologiques chez 157 patients en fonction de leur taux de lymphocytes T doubles négatifs)

BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF