CD40 is an integral membrane protein found on the surface of B lymphocytes, dendritic cells, follicular dendritic cells, hematopoietic progenitor cells, epithelial cells, and carcinomas. It is a 45-50 kDa glycoprotein of 277 aa, which is a member of the tumor necrosis factor receptor superfamily. The CD40 gene maps to human chromosome 20q11-2-q13-2. CD40 binds to a ligand (CD40-L) which is an approximately 35 kDa glycoprotein of 261 aa, a member of the tumor necrosis factor superfamily. The CD40-L gene maps to human chromosome Xq24. This CD40-L is expressed on activated T cells, mostly CD4+ but also some CD8+ as well as basophils/mast cells. The CD40-L is defective in the X-linked hyper-IgM syndrome. Cross-linking of CD40 with immobilized anti-CD40 or cells expressing CD40-L induces B cells to proliferate strongly, and addition of IL-4 or IL-13 allows the generation of factor-dependent long-term normal human B cell lines and the secretion of IgE following isotype switching. Addition of IL-10 results in very high immunoglobulin production with limited cell proliferation. IL-10 induces naive B cells to produce IgG3, IgG1, and IgA1, and further addition of TGF beta permits the secretion of IgA2. Several evidences suggest that CD40-dependent activation of B cells is important for the generation of memory B cells within the germinal centers: (i) CD40 activated germinal center B cells cultured in the presence of IL-4 acquire a memory B cell phenotype, (ii) CD40 activated B cells can undergo isotype switching, (iii) the deficit of CD40-L results in the hyper-IgM syndrome characterized by lack of germinal centers in secondary lymphoid organ follicles and lack of IgG, IgA, and IgE, and (iv) CD40-L positive T cells are present in secondary follicles. Thymic epithelial cells, activated monocytes, and dendritic cells express CD40 antigen which may be involved in an enhanced cytokine production by these cells, allowing an amplification of T cell proliferation. Finally, as other members of the tumor necrosis factor receptor family have been shown to bind several ligands, it is possible that CD40 may bind other ligands that may trigger CD40 on different cell types such as hematopoietic cells or epithelial cells.

The CD40 Antigen and its Ligand

Most physicians and immunologists, if they think of the mast cell at all, regard it as something of a pariah. Other cells of hematopoietic origin, such as neutrophils, macrophages, and platelets, are clearly important in host defense, hemostasis, or both. In contrast, the contributions of the mast cell to pathologic conditions come to mind much more readily than any role it may have in the maintenance of health. Indeed, some would argue that an entire branch of medicine -- allergy -- deals in large part with the adverse effects produced by activation of the mast cell and the basophil, a . . .

New concepts about the mast cell.

Until recently, the expression and primary function of the cell surface receptor CD40 and its ligand CD154 were considered restricted to B and T lymphocytes, and their interactions required for the thymus-dependent humoral response. However, current work from several groups challenges this view of the CD40/CD154 dyad as a mere mediator of lymphocyte communication. A variety of non-lymphocytic cell types express both receptor and ligand, including hematopoetic and non-hematopoetic cells, such as monocytes, basophils, eosinophils, dendritic cells, fibroblasts, smooth muscle, and endothelial cells. Accordingly, ligation of CD40 mediates a broad variety of immune and inflammatory responses, such as the expression of adhesion molecules, cytokines, matrix-degrading enzymes, prothrombotic activities, and apoptotic mediators. Consequently, CD40 signaling has been associated with pathogenic processes of chronic inflammatory diseases, such as autoimmune diseases, neurodegenerative disorders, graft-versus-host disease, cancer, and atherosclerosis. This review focuses on the synthesis and structure of CD40 and outlines CD154/CD40 signaling pathways, and emphasizes the previously unexpected importance of the CD40/CD154 receptor/ligand dyad in a spectrum of immunoregulatory processes and prevalent human diseases.

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The CD40/CD154 receptor/ligand dyad.

Cd40-cd40 ligand : a multifunctional receptor-ligand pair

CD40 was originally described as a functionally significant B cell surface molecule. However, CD40 is also expressed on monocytes, dendritic cells, epithelial cells, and basophils. We now report that synovial membrane (SM) or dermal fibroblasts also express cell surface CD40 in vitro. Fibroblast CD40 expression declines with increasing time in culture and recombinant interferon-gamma (rINF-gamma) induces fibroblast CD40 up-regulation. This effect of rINF-gamma is augmented by recombinant interleukin-1 alpha or recombinant tumor necrosis factor-alpha. CD40 expression on fibroblasts is functionally significant because CD40L-CD40 interactions induce SM fibroblast CD54 (intercellular adhesion molecule-1) and CD106 (vascular cell adhesion molecule-1) up-regulation. Moreover, ligation of CD40 augments IL-6 production by SM fibroblasts and induces fibroblasts to proliferate. In addition, rINF-gamma enhances the effect of CD40L-CD40 interactions on fibroblast proliferation. Taken together, these studies show that fibroblasts can express CD40, cytokines can regulate fibroblast CD40 expression, and CD40 ligation induces fibroblast activation and proliferation.

Ligation of CD40 on fibroblasts induces CD54 (ICAM-1) and CD106 (VCAM-1) up-regulation and IL-6 production and proliferation.

Recently, we were able to establish the immunologic surface marker profile of human basophils and mast cells. In the present study, the characterization of these cell types was extended by the use of monoclonal antibodies (mAbs) to hemopoietic differentiation antigens. Basophils and mast cells were enriched by mAbs and complement from chronic myeloid leukemia blood (n = 5) and dispersed lung tissue (n = 4), respectively. A panel of 80 mAbs was tested for being reactive with purified cell populations using flow cytometry and/or a combined toluidine blue-immunofluorescence staining procedure. In addition to previous findings, basophils were found to react with mAbs directed against the 126-kilodalton dipeptidylpeptidase IV (CD26), platelet glycoprotein IIa (CD31), CD40 antigen known to share sequence homology with nerve growth factor receptor, leukosialin (CD43), CD44 antigen, the ICAM-1 antigen (CD54) and VIM2-reactive gangliosides involving the sialofucooligosaccharide sequence (CDw65L). Bsp-1 was found to be a specific marker for human basophils, whereas mast cells were not stained by this reagent. Basophils apparently lack CD22 antigen, gangliosides detected by CDw65 mAbs (except CDw65L) and CD71 antigen (transferrin receptor). Mast cells were found to express CD43 and CD44 antigen. In contrast, mast cells lack CD22, CD26, CD31, CD40 and CDw65 antigen. These results provide further evidence that both blood basophils and mast cells express a unique immunologic surface marker profile including binding sites for a variety of immunomodulating ligands and adhesion molecules.

Further characterization of surface membrane structures expressed on human basophils and mast cells.

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Further characterization of surface membrane structures expressed on human basophils and mast cells.