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Biomedical subjects

J Banchereau

Publications and source records attributed to J Banchereau.

At least 91 records · Page 5Linked to original sources
PubMed1997

B-cell-derived IL-10: production and function.

In vitro and in vivo studies identify IL-10 as a key cytokine that inhibits cell-mediated immunity and inflammation while promoting humoral responses. The present review summarizes our studies regarding the ability of B cells to secrete IL-10. When established lines are considered, the production of human IL-10 is restricted to mature B-cell lines and correlates with Epstein-Barr Virus (EBV) expression. Accordingly, EBV infection induces purified tonsil B lym phocytes to produce high levels of human IL-10, whereas viral IL-10 (encoded by EBV) remains undetectable. Exogenous IL-10 enhances EBV-induced B-cell growth, while a neutralizing anti-IL-10 antibody inhibits it, suggesting that IL-10 acts as an autocrine growth factor for EBV-infected B lymphocytes. Normal B lymphocytes secrete lower levels of human IL-10 following activation through B-cell receptor or CD40 antigen. While addition of exogenous IL-4 diminishes CD40-induced secretion of IL-10, addition of Staphyloccocus aureus Cowan I (SAC) particles increases it. Neutralization of endogenous IL-10 does not alter growth of CD40-activated B cells but inhibits their IgG, IgA, and IgM secretion, especially when costimulated with SAC particles. Finally, the simul taneous blocking of both endogenous IL-10 and IL-6 inhibits two-thirds of the production of the three isotypes when B cells were triggered through CD40 in the presence of SAC particles, suggesting that IL-10 synergizes with IL-6 to sustain differentiation of CD40-activated B lymphocytes. Overexpression of B-cell-derived IL-10 is likely to contribute in vivo to different pathologies such as B-lymphoproliferative disorders and autoimmune diseases.

Antibodies↗
PubMed1997

Regulation of B-cell commitment to plasma cells or to memory B cells.

During humoral immune responses, B-lymphocyte activation is followed by differentiation along either the plasma cell pathway or the memory B-cell pathway. Recent studies suggest that CD40-CD40 ligand, OX-OX40 ligand, a group of cytokines and intracellular transcriptional factors may all contribute to B-lymphocyte differentiation control.

Animals↗
PubMed1997

Normal human B cell sub-populations and their malignant counterparts.

Seven tonsillar B cell sub-sets have been isolated according to cell surface molecular markers. The molecular characteristics of their phenotype, cell cycle, survival, somatic mutations and isotype switch status permit their inter-relationships to be followed up until the plasma cell stage. Different lymphoma types correlate with all except one of the stages and only two out of nine non-Hodgkin's B cell lymphomas cannot be presently associated to a normal peripheral B cell sub-set. The assignment of lymphomas to their normal human B cell counterparts will facilitate the identification of the causative event(s) responsible for the malignant transformation.

B-Lymphocyte Subsets↗
PubMed1997

Functions of CD40 on B cells, dendritic cells and other cells.

CD40 is a cell surface receptor that belongs to the tumor necrosis factor receptor family. It was first identified and functionally characterized on B lymphocytes; however, in recent years it has become clear that CD40 expression is much broader, as it is found on monocytes, dendritic cells, hematopoietic progenitors, endothelial cells and epithelial cells. Although initially identified for its activation properties, CD40 is also able to transduce negative signals in various cell types. It is presently accepted that CD40 plays a critical role in the regulation of immune responses. The past year has seen considerable progress in the identification of intracellular molecules mediating CD40 signaling. Furthermore, it has been established that ligation of CD40 ligand (CD40L) delivers signals to the CD40L bearing cells themselves. Finally, the critical role of CD40-CD40L interactions in the development of various disease states has been fully appreciated.

Animals↗
PubMed1997

Dendritic cells: therapeutic potentials.

Dendritic cells (DCs) are leukocytes that are specialized to capture antigens and initiate T-cell-mediated immune responses. After capture of antigens, DCs, then in an immature stage, leave their tissue of residence and migrate through the lymph/blood into secondary lymphoid organs where they differentiate into mature cells. Because DCs can prime animals in the absence of any other adjuvant, they have been termed 'nature's adjuvant'. Large numbers of DCs can now be generated from circulating monocytes or from CD34 hematopoietic progenitors in response to GM-CSF in combination with either IL4 or TNF alpha. In mice, tumor antigen loaded DCs have been shown to prevent the development of tumors and even to induce the regression of established tumors. DCs therapy represents a very promising approach to the treatment of cancer and infectious diseases. Early studies indicate the existence of DC populations that can induce tolerance and may prove useful in organ transplantation.

Animals↗
PubMed1997

Induction of somatic mutation in a human B cell line in vitro.

Both the B cell-surface trigger(s) and the intracellular molecular mechanism(s) of somatic hypermutation in immunoglobulin (Ig) variable region genes remain unknown, partly because of the lack of a simple and reproducible in vitro model. Here, we show that upon surface immunoglobulin cross-linking followed by co-culture with activated cloned T cells, the Burkitt's lymphoma cell line BL2 is induced to mutate its IgV(H) gene. Repeated activation of BL2 cells increased the frequency of mutation. The in vitro-induced mutations, which do not affect the IgM constant region, are point mutations distributed over the entire V(H)DJ(H) gene segment and do not show evidence of antigen-driven selection.

Amino Acid Sequence↗
PubMed1997

Possible role for CD40-CD40L in the regulation of interstitial infiltration in the kidney.

Interstitial infiltration by mononuclear cells is a hallmark of most inflammatory kidney diseases, and the degree of infiltration is associated with disease progression. It has been demonstrated that proximal tubular epithelial cells (PTEC) are an important source of different cytokines/chemokines and thereby play a central role in the regulation of the local inflammatory response. CD40 is a cell surface receptor involved in immune regulation for which the ligand is expressed on activated T cells. By different staining methods, CD40 was found expressed in cryosections on the basolateral side of tubuli, as well as on the surface of an SV40-transformed PTEC line (PTEC-TRL) and on primary PTEC cultures. Cross linking CD40 receptor on these cultured cells, using a CD40L-transfected mouse fibroblast, resulted in strong up-regulation of the production of the chemokines IL-8, MCP-1 and RANTES. For IL-8 and MCP-1 production, the stimulation index after CD40 activation ranged from two- to sevenfold. Much stronger effects were observed for RANTES production, where levels remained undetectable (< 0.1 ng/ml) in non-stimulated cultures, whereas CD40 activation resulted in a strong production reaching 5 ng/ml in a 72-hour culture period. These data suggest that CD40L-CD40 interactions between infiltrating activated T cells and PTEC might be an important factor in the regulation of interstitial infiltration within the kidney.

Animals↗
PubMed1997

Cross-linking of antigen receptor via Ig-beta (B29, CD79b) can induce both positive and negative signals in CD40-activated human B cells.

Antigen-dependent activation of B lymphocytes is mediated through surface immunoglobulins and their associated molecules Ig-alpha (CD79a, Mb1) and Ig-beta (CD79b, B29). Here we show that an antibody directed against the extracellular part of human Ig-beta can, when cross-linked by CD32-transfected L cells, induce an IL-2-dependent proliferation of tonsil B cells. With the use of L cells stably transfected with both CD32 and CD40L, anti-Ig-beta activation of B cells was combined with CD40 triggering, an important component of the T cell-dependent B cell activation. This dual cellular activation resulted in two different phases, with initially synergistic proliferative effects, both without and with IL-2 or IL-10. Then, after 5-6 days of culture, cells stimulated with both anti-Ig-beta and CD40L underwent massive cell death, in contrast to B cells activated with CD40L alone. Cell death was not prevented by the addition of IL-2 or IL-10, but was prevented by the addition of IL-4. These results are discussed in the context of positive and negative selection of mature B cells.

Animals↗
PubMed1997

High levels of neutralizing autoantibodies against IL-1 alpha are associated with a better prognosis in chronic polyarthritis: a follow-up study.

Neutralizing autoantibodies to interleukin (IL)-1 alpha were detected in a subset of chronic polyarthritis patients characterized by an increased proportion of patients with primary Sjögren's syndrome or self-limiting inflammatory arthritis, diseases with a much better prognosis than rheumatoid arthritis (RA). The evolution of anti-IL-1 alpha antibody levels was followed over 3 years. Incidence and levels were higher in patients with a benign form of polyarthritis. In these patients levels remained stable or increased over the follow-up period. In contrast, incidence and levels were lower and some RA patients became negative. Negative correlations were observed between the levels of anti-IL-1 alpha antibodies and the clinical and biological indices of disease activity. The relative risk factor of developing RA was 12 in the absence of high anti-IL-1 alpha antibody levels and 18.2 when associated with the presence of HLA-DR4. In conclusion, the presence of anti-IL-1 alpha autoantibodies appears to be protective and their detection could represent a marker of good prognosis for destruction.

Adult↗
PubMed1997

CD40 ligation counteracts Fas-induced apoptosis of human dendritic cells.

Dendritic cells (DC) are cells of the hematopoletic system specialized in capturing antigens and initiating T cell-mediated immune responses. We show here that human DC generated in vitro by culturing CD34+ cord blood progenitor cells in granulocyte macrophage colony stimulating factor plus tumor necrosis factor-alpha express the Fas antigen (APO-1, CD95) and undergo apoptosis upon triggering of Fas by mAb. However, only a proportion of the cells die in response to Fas ligation, an observation that may be related to the virtual absence of the bcl-2 protein in about half of the cells. Ligation of DC CD40 by culture on CD40L-transfected fibroblastic cells up-regulates the expression of bcl-2 and, concomitantly, renders DC virtually resistant to Fas-induced apoptosis. Parallel experiments with mature, interdigitating dendritic cells (IDC) isolated from tonsils revealed that IDC express Fas but do not enter into apoptosis following Fas ligation, a finding that may be explained by their high levels of bcl-2. Thus, upon encountering antigen-specific T cells, DC become resistant to Fas-induced apoptosis, as a consequence of CD40 ligation and possibly by mechanisms associated to the up-regulation of bcl-2 protein expression.

Antibodies, Monoclonal↗
PubMed1997

Functional role of CD40 and its ligand.

CD40, a cell surface receptor which belongs to the TNF-R family, was first identified and functionally characterized on B lymphocytes. In recent years, CD40 has been found expressed on other cells, including monocytes, dendritic cells, endothelial cells and epithelial cells and is now thought to play a more general role in immune regulation. The present paper reviews recent developments about CD40, with main emphasis on: (1) structure and expression of CD40 and its ligand; (2) CD40 signal transduction; (3) in vitro function of CD40 on different cell types, and (4) in vivo functions of CD40/CD40L interactions.

Antibody Formation↗
PubMed1997

Low-grade B cell lymphomas of mucosa-associated lymphoid tissue (MALT-type) require CD40-mediated signaling and Th2-type cytokines for in vitro growth and differentiation.

To investigate the mechanisms of T cell dependence underlying the development of extranodal mucosa-associated lymphoid tissue (MALT)-type B cell lymphomas, the activation, proliferation, and differentiation of lymphoma B cells were studied using ligand binding to the CD40 membrane receptor. The activation and proliferative response of all investigated low-grade MALT-type lymphomas (n = 6) was strongly dependent on anti-CD40-mediated signals and was complemented by cytokines produced by T helper cells of the Th2 type (interleukin-4 (IL-4) and/or IL-10). Th1 cytokines (IL-2 and/or interferon-gamma) bad little effect. Low-grade, but less so high-grade, MALT-type lymphoma B cells were induced to secrete large amounts of tumor immunoglobulin in response to IL-10. In contrast, high-grade MALT-type lymphomas (n = 5) proliferated in response to both Th2- and Th1-type cytokines and CD40 stimulation, whereas Burkitt lymphomas (n = 3) could not be rescued from apoptosis by CD40 stimulation with or without cytokines. These results suggest that CD40 signaling in combination with Th2 cytokines are essential for the development and progression of low-grade MALT-type B cell lymphoma. We conclude that T cells, which activate B cells in a CD40-dependent fashion, may contribute to lymphoma pathogenesis.

B-Lymphocyte Subsets↗
PubMed1997

An update on interleukin-4 and its receptor.

Interleukin-4 (IL-4) exhibits many biological and immunoregulatory functions on B lymphocytes, monocytes, dendritic cells and fibroblasts. The IL-4 gene is located on chromosome 5 and displays several cell-specific regulatory sequences in its promoter, which explain its restricted secretion pattern to activated T cells and mast cells. The IL-4 receptor is multimeric and is constituted by at least IL-4Ralpha, a chain common to other cytokine receptors. Two types of IL-4 receptors have been defined: one constituted by the IL-4Ralpha and the gamma(c) chain, and a second constituted by the IL-4Ralpha and the IL-13Ralpha, which is able to transduce both IL-4 and IL-13 signals. Major events of IL-4 transducing signal have now been elucidated and are known to be mediated through JAK/IRS-2 and STAT6 pathways. Numerous studies have also demonstrated the key regulatory role of IL-4 in allergic responses as well as its anti-tumor and anti-inflammatory effects.

Animals↗
PubMed1996

Epstein-Barr virus latent membrane protein (LMP1) is not sufficient to maintain proliferation of B cells but both it and activated CD40 can prolong their survival.

Epstein-Barr virus (EBV) infects human primary B lymphocytes and induces and maintains proliferation of these cells efficiently in vitro. Mutants of Epstein-Barr virus which express EBV nuclear antigen 2 (EBNA2) in a conditional fashion allow dissection of individual contributions of viral genes to B cell immortalization. EBNA2 is a transcriptional activator of cellular and viral genes, including the viral latent membrane protein 1 (LMP1), which is essential for B cell immortalization and has oncogenic effects in non-lymphoid cells. To analyze the role of this gene in B cell immortalization, LMP1 was constitutively expressed in B cells infected with EBV carrying a conditional EBNA2 allele. In the absence of functional EBNA2, LMP1 was incapable of sustaining B cell proliferation in two independent assays but induced a phenotype consistent with prolonged cell viability. Activation of CD40 displayed a comparable phenotype. These data indicate that both CD40 activation and LMP1 expression may use a common pathway for B cell activation. Proliferation of human B cells, however, requires one or more additional signals triggered by EBNA2.

B-Lymphocytes↗
PubMed1996

Dendritic cells capable of stimulating T cells in germinal centres.

The B cells within the germinal centres of lymphoid organs undergo affinity maturation of their antigen receptors, a critical event for antibody memory. Follicular dendritic cells within the germinal centres retain immune complexes that select the developing B cells for which they have a higher affinity. We have now identified a subset of CD4+ CD11c+ CD3- dendritic cells in the germinal centres. These are strong antigen-presenting cells for T cells, but do not co-stimulate CD40-activated B cells. These dendritic cells probably stimulate germinal centre T cells and aid the complicated processes that are required for the generation of memory B cells.

Antigen Presentation↗