Les reseaux franco-hongrois et la France, de 1896 a 1914: auxiliaires d'une decouverte ou marchands d'illusions?

The article stresses the importance of networks in the shaping of French public opinion on Hungary. Three groups can be distinguished: professionals of "French-Hungarian friendship", Hungarian personalities involved in making Hungary popular in France, and "French friends of Hungary". In contrast to the common idea of a domination of Romanian or Slavic networks in France at the turn of the century, the analysis of events such as the Millenium Exposition of 1896 in Budapest, the Universal Exposition of 1900 in Paris, or more generally the international congresses flourishing all over Europe at this time, shows a significant increase of (most of time very positive) information transfers from Hungary to France. The specific task of French-Hungarian networks in this "Discovery of Hungary" was to link together Hungarian political illusions, such as defined by Istvan Bibo (Hungary as an independent nation-state on the French model) and their French counterparts (French as a universal model, especially for the small nations of East Central Europe struggling with German domination). The information transfers were controlled by a small group of "brokers". The internal and international crisis of 1905-1906 between Budapest and Vienna gave to the French-Hungarian networks a new importance. They used the hope of an alliance between Hungarians and Slaves against German influence to increase political and cultural contacts between France and Hungary. The real turning point is to be situated between 1908 and 1910: the new political course in Budapest led to both the bankruptcy of French political illusions and the division of French-Hungarian networks. Hardly concurrent "brokers" lost their influence, and French observers began to build their own information networks. For most of French observers, Hungary was not any more a modern, Francophile, but an archaic and hostile nation. The First World War confirmed the failure of French-Hungarian networks

Early growth response genes 2 and 3 regulate the expression of Bcl6 and differentiation of T follicular helper cells

T follicular helper (Tfh) cells support differentiation of B cells to plasma cells and high affinity antibody production in germinal centers (GC) and Tfh differentiation requires the function of B cell lymphoma 6 (Bcl6). We have now discovered that early growth response gene (Egr) 2 and 3 directly regulate the expression of Bcl6 in Tfh cells which is required for their function in regulation of GC formation. In the absence of Egr2 and 3, the expression of Bcl6 in Tfh cells is defective leading to impaired differentiation of Tfh cells resulting in a failure to form GCs following virus infection and defects in production of anti-viral antibodies. Enforced expression of Bcl6 in Egr2/3 deficient CD4 T cells partially restored Tfh differentiation and GC formation in response to virus infection. Our findings demonstrate a novel function of Egr2/3 which is important for Tfh cell development and Tfh cell mediated B cell immune responses.This work was supported by Arthritis Research UK. The authors declare that they have no conflicts of interest with the contents of this article

IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses

During T cell–dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell–intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell–autonomous effect of IL-21 receptor (R) signaling throughout all stages of the GC response. IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1+ GC B cells but did not affect formation of early memory B cells. IL-21R was required on GC B cells for maximal expression of Bcl-6. In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21

A High Frequency of HIV-Specific Circulating Follicular Helper T Cells Is Associated with Preserved Memory B Cell Responses in HIV Controllers

Follicular helper T cells (Tfh) play an essential role in the affinity maturation of the antibody response by providing help to B cells. To determine whether this CD4+ T cell subset may contribute to the spontaneous control of HIV infection, we analyzed the phenotype and function of circulating Tfh (cTfh) in patients from the ANRS CO21 CODEX cohort who naturally controlled HIV-1 replication to undetectable levels and compared them to treated patients with similarly low viral loads. HIV-specific cTfh (Tet+), detected by Gag-major histocompatibility complex class II (MHC-II) tetramer labeling in the CD45RA- CXCR5+ CD4+ T cell population, proved more frequent in the controller group (P = 0.002). The frequency of PD-1 expression in Tet+ cTfh was increased in both groups (median, >75%) compared to total cTfh (<30%), but the intensity of PD-1 expression per cell remained higher in the treated patient group (P = 0.02), pointing to the persistence of abnormal immune activation in treated patients. The function of cTfh, analyzed by the capacity to promote IgG secretion in cocultures with autologous memory B cells, did not show major differences between groups in terms of total IgG production but proved significantly more efficient in the controller group when measuring HIV-specific IgG production. The frequency of Tet+ cTfh correlated with HIV-specific IgG production (R = 0.71 for Gag-specific and R = 0.79 for Env-specific IgG, respectively). Taken together, our findings indicate that key cTfh-B cell interactions are preserved in controlled HIV infection, resulting in potent memory B cell responses that may play an underappreciated role in HIV control.IMPORTANCE The rare patients who spontaneously control HIV replication in the absence of therapy provide a unique model to identify determinants of an effective anti-HIV immune response. HIV controllers show signs of particularly efficient antiviral T cell responses, while their humoral response was until recently considered to play only a minor role in viral control. However, emerging evidence suggests that HIV controllers maintain a significant but "silent" antiviral memory B cell population that can be reactivated upon antigenic stimulation. We report that cTfh help likely contributes to the persistence of controller memory B cell responses, as the frequency of HIV-specific cTfh correlated with the induction of HIV-specific antibodies in functional assays. These findings suggest that T follicular help may contribute to HIV control and highlight the need for inducing such help in HIV vaccine strategies that aim at eliciting persistent B cell responses

ICOS regulates the generation and function of human CD4+ Treg in a CTLA-4 dependent manner

Inducible co-stimulator (ICOS) is a member of CD28/Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) family and broadly expressed in activated CD4+ T cells and induced regulatory CD4+ T cells (CD4+ iTreg). ICOS-related signal pathway could be activated by the interaction between ICOS and its ligand (ICOSL). In our previous work, we established a cost-effective system to generate a novel human allo-antigen specific CD4hi Treg by co-culturing their naïve precursors with allogeneic CD40-activated B cells in vitro. Here we investigate the role of ICOS in the generation and function of CD4hi Treg by interrupting ICOS-ICOSL interaction with ICOS-Ig. It is found that blockade of ICOS-ICOSL interaction impairs the induction and expansion of CD4hi Treg induced by allogeneic CD40-activated B cells. More importantly, CD4hi Treg induced with the addition of ICOS-Ig exhibits decreased suppressive capacity on alloantigen-specific responses. Dysfunction of CD4hi Treg induced with ICOS-Ig is accompanied with its decreased exocytosis and surface CTLA-4 expression. Through inhibiting endocytosis with E64 and pepstatin A, surface CTLA-4 expression and suppressive functions of induced CD4hi Treg could be partly reversed. Conclusively, our results demonstrate the beneficial role of ICOS-ICOSL signal pathway in the generation and function of CD4hi Treg and uncover a novel relationship between ICOS and CTLA-4. © 2013 zheng et al.published_or_final_versio

Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome

Hypomorphic RAG mutations, leading to limited V(D)J rearrangements, cause Omenn syndrome (OS), a peculiar severe combined immunodeficiency associated with autoimmune-like manifestations. Whether B cells play a role in OS pathogenesis is so far unexplored. Here we report the detection of plasma cells in lymphoid organs of OS patients, in which circulating B cells are undetectable. Hypomorphic Rag2R229Q knock-in mice, which recapitulate OS, revealed, beyond severe B cell developmental arrest, a normal or even enlarged compartment of immunoglobulin-secreting cells (ISC). The size of this ISC compartment correlated with increased expression of Blimp1 and Xbp1, and these ISC were sustained by elevated levels of T cell derived homeostatic and effector cytokines. The detection of high affinity pathogenic autoantibodies toward target organs indicated defaults in B cell selection and tolerance induction. We hypothesize that impaired B cell receptor (BCR) editing and a serum B cell activating factor (BAFF) abundance might contribute toward the development of a pathogenic B cell repertoire in hypomorphic Rag2R229Q knock-in mice. BAFF-R blockade reduced serum levels of nucleic acid-specific autoantibodies and significantly ameliorated inflammatory tissue damage. These findings highlight a role for B cells in OS pathogenesis

Primary B-Cell Deficiencies Reveal a Link between Human IL-17-Producing CD4 T-Cell Homeostasis and B-Cell Differentiation

IL-17 is a pro-inflammatory cytokine implicated in autoimmune and inflammatory conditions. The development/survival of IL-17-producing CD4 T cells (Th17) share critical cues with B-cell differentiation and the circulating follicular T helper subset was recently shown to be enriched in Th17 cells able to help B-cell differentiation. We investigated a putative link between Th17-cell homeostasis and B cells by studying the Th17-cell compartment in primary B-cell immunodeficiencies. Common Variable Immunodeficiency Disorders (CVID), defined by defects in B-cell differentiation into plasma and memory B cells, are frequently associated with autoimmune and inflammatory manifestations but we found no relationship between these and Th17-cell frequency. In fact, CVID patients showed a decrease in Th17-cell frequency in parallel with the expansion of activated non-differentiated B cells (CD21lowCD38low). Moreover, Congenital Agammaglobulinemia patients, lacking B cells due to impaired early B-cell development, had a severe reduction of circulating Th17 cells. Finally, we found a direct correlation in healthy individuals between circulating Th17-cell frequency and both switched-memory B cells and serum BAFF levels, a crucial cytokine for B-cell survival. Overall, our data support a relationship between Th17-cell homeostasis and B-cell maturation, with implications for the understanding of the pathogenesis of inflammatory/autoimmune diseases and the physiology of B-cell depleting therapies

Follicular Helper T Cells are Essential for the Elimination of Plasmodium Infection

CD4+ follicular helper T (Tfh) cells have been shown to be critical for the activation of germinal center (GC) B-cell responses. Similar to other infections, Plasmodium infection activates both GC as well as non-GC B cell responses. Here, we sought to explore whether Tfh cells and GC B cells are required to eliminate a Plasmodium infection. A CD4 T cell-targeted deletion of the gene that encodes Bcl6, the master transcription factor for the Tfh program, resulted in complete disruption of the Tfh response to Plasmodium chabaudi in C57BL/6 mice and consequent disruption of GC responses and IgG responses and the inability to eliminate the otherwise self-resolving chronic P. chabaudi infection. On the other hand, and contrary to previous observations in immunization and viral infection models, Signaling Lymphocyte Activation Molecule (SLAM)-Associated Protein (SAP)-deficient mice were able to activate Tfh cells, GC B cells, and IgG responses to the parasite. This study demonstrates the critical role for Tfh cells in controlling this systemic infection, and highlights differences in the signals required to activate GC B cell responses to this complex parasite compared with those of protein immunizations and viral infections. Therefore, these data are highly pertinent for designing malaria vaccines able to activate broadly protective B-cell responses

Pouvoir, Eglise et société en Hongrie communiste, 1944-1964 : histoire intérieure d’une domination

This thesis reconstructs the development of relations among the Communist regime, the Church, and the Catholic laity in Hungary, from the arrival of the Red Army at the end of 1944 through the signing of the Partial Agreement between the Holy See and the Hungarian government on 15 September 1964. The thesis takes as its task the reconstruction of a process under whose auspices Communist domination was deeply internalized, as much by members of the clergy as by the faithful themselves. It seeks also to understand the manner in which that domination was able to shape the development of ecclesiastical and religious life. Finally, it aims to reconstruct the political dynamics that brought about this bid for domination and the manner in which that bid was subsequently transformed, particularly following the shock of the Revolution of 1956. The thesis is based on a large body of unpublished and published sources, hailing from the Party-State apparatus (political police, Office of Ecclesiastical Affairs, the Party agit-prop department) as well as the Church (collections of the Episcopate, religious orders, and parishes), supplemented by oral history testimony gathered both before and after the fall of the Communist regime.Cette thèse retrace l’évolution des rapports entre le pouvoir communiste, l’institution ecclésiastique et les laïcs catholiques en Hongrie, de l’arrivée de l’Armée rouge, à la fin de l’année 1944, jusqu’à la signature de l’Accord partiel entre le Saint-Siège et le gouvernement hongrois, le 15 septembre 1964. Elle retrace le processus au terme duquel la domination communiste a été profondément intériorisée, aussi bien par les membres du clergé que par les fidèles eux-mêmes. Elle cherche aussi à comprendre de quelle manière cette domination a pu influer sur l’évolution de la vie ecclésiale et religieuse. Elle vise enfin à reconstituer la dynamique politique qui a porté cette volonté de domination, et la manière dont elle s’est transformée, notamment après le choc de la révolution de 1956. La thèse s’appuie sur un large corpus de sources inédites ou publiées, issues aussi bien de l’appareil de l’Etat-Parti (police politique, Bureau des Affaires ecclésiastiques, département de l’agit-prop du Parti) que de celui de l’Eglise (archives épiscopales, des ordres religieux ou des paroisses), corpus complété par des témoignages et des archives orales, produits avant comme après la chute du régime communiste. La thèse est divisée en trois grandes parties chronologiques : les années d’après-guerre, de 1944 à 1948 ; les années staliniennes, de 1948 à 1956 ; les premières années du kadarisme, de 1956 à 1964. A ce découpage chronologique se superpose une structure qui distingue les trois points de vue étudiés dans la thèse : celui de l’appareil communiste, celui de l’institution ecclésiastique et de la société cléricale, et enfin celui des laïcs