PubMed · 7991944
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J P Di Santo, G de Saint Basile, A Durandy, A Fischer. Hyper-IgM syndrome.. https://doi.org/10.1016/s0923-2494(94)80185-1
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beta-chemokines play an important role in the development of immunologic reactions. Macrophages are major beta-chemokine-producing cells during T-cell directed, delayed-type hypersensitivity reactions in tissues, and have been reported to be important producers of beta-chemokines in the lymph nodes of HIV-1-infected individuals. However, the physiological signals responsible for inducing macrophages to produce beta-chemokines have not been established. Two soluble T cell products, interferon-gamma and granulocyte-macrophage colony stimulating factor, were added to cultured macrophages, but failed to stimulate the production of macrophage inflammatory protein-1alpha and -1beta; regulated upon activation, normal T cell expressed and secreted (RANTES); or monocyte chemoattractant protein-1. Instead, direct cell-cell contact between macrophages and cells engineered to express CD40L (also known as CD154) resulted in the production of large amounts of macrophage inflammatory protein-1alpha and -1beta, and RANTES (all ligands for CCR5), and monocyte chemoattractant protein-1 (a ligand for CCR2). Supernatants from CD40L-stimulated macrophages protected CD4(+) T cells from infection by a nonsyncytium-inducing strain of HIV-1 (which uses CCR5 as a coreceptor). These results have implications for granulomatous diseases, and conditions such as atherosclerosis and multiple sclerosis, where CD40L-bearing cells have been found in the macrophage-rich lesions where beta-chemokines are being produced. Overall, these findings define a pathway linking the specific recognition of antigen by T cells to the production of beta-chemokines by macrophages. This pathway may play a role in anti-HIV-1 immunity and the development of immunologic reactions or lesions.
The molecular mechanisms underlying Hodgkin's disease remain obscure, but it has been recognized that the neoplastic cells display high levels of constitutively active nuclear NF-kappaB. Here we demonstrate that although nuclear NF-kappaB is transcriptionally active, the Hodgkin cells fail to activate NF-kappaB dependent transcription in response to CD40 ligand. In three Hodgkin cell lines examined each had abnormalities in expression of IkappaBalpha which could account for the deregulated NF-kappaB. Although all three cell lines had greater than normal levels of IkappaBalpha mRNA no IkappaBalpha protein could be detected in the KM-H2 cells, while the L428 cell line contains a C-terminally truncated IkappaBalpha species that fails to associate with NF-kappaB. The HDLM-2 cell line contains a more slowly migrating form of IkappaBalpha that can associate with NF-kappaB, but increasing the level of this protein within the cell fails to inhibit nuclear NF-kappaB. Addition of recombinant IkappaBalpha to nuclear extracts from all three cell lines resulted in complete inhibition of NF-kappaB DNA binding activity and introduction of a plasmid expressing IkappaBalpha into the cells inhibited the transcriptional activity of an NF-kappaB dependent reporter plasmid. Thus the constitutive expression of NF-kappaB in Hodgkin cells is a direct consequence of the abnormal expression of IkappaBalpha rather than changes in NF-kappaB that render it refractory to inhibition by IkappaB proteins. These changes could, at least in part, account for the characteristic activated phenotype of Hodgkin cells and their pattern of cytokine secretion, which determine the pathological appearance and clinical manifestations of Hodgkin's disease.
Common variable immunodeficiency (CVID) comprises a heterogeneous group of patients with as yet undefined genetic defects. Patients with CVID have in common a decrease in the levels of one or more serum immunoglobulin isotypes and a severe defect in the production of specific antibodies. Typically, the patients suffer from recurrent infections of the upper and lower respiratory tract or the gastrointestinal tract. In consequence of these infections patients may develop severe organ damage, such as chronic pulmonary disease with bronchiectases, leading to pulmonary failure. Early diagnosis of CVID is important, as antibody deficiency can efficiently be treated by regular intravenous IgG (IVIG) substitution therapy. IVIG therapy prevents the occurrence of further acute infectious episodes and the development of long-term complications. The basic immunological defect(s) in patients with CVID are still unknown. There is currently no convincing evidence for an intrinsic B-cell defect in patients with CVID. A defect in T-cell activation due to impaired signal transduction upon T-cell receptor triggering has been described in a large subgroup of patients with CVID. Defective T-cell activation may lead to an impairment in cognate T-B-cell interaction due to impaired expression of CD40 ligand and/or abnormalities in the production T-cell-derived cytokines required for fully functional B-cell activation, proliferation and/or differentiation which could indeed explain the impairment in antibody production present in CVID patients.