CD40 is a member of the growing tumor necrosis factor receptor (TNF-R) family of molecules, and has been shown to play important roles in T cell-mediated B lymphocyte activation. Ligation of B cell CD40 by CD154 expressed on activated T cells stimulates B cell proliferation, differentiation, isotype switching, upregulation of surface molecules contributing to antigen presentation, development of the germinal center, and the humoral memory response. The present review will summarize recent literature data on the various CD40 signalling pathways, which involve both the TNF-R associated factors (TRAFs) and additional signalling proteins, and lead to activation of kinases and transcription factors.
"Signalling of OX40 requires and is controlled by its ligand, OX40L (CD134L), which is constitutively expressed on APCs including B cells, macrophages, DC, and endothelial cells . While OX40 signalling enhances survival of T cells and their subsequent cytokine production and expansion of their memory cell pool, stimulation of OX40L enhances B-cell proliferation and differentiation . A recent study has found that OX40L stimulation inhibited the generation of IL-10-producing CD4+ Tregs cells from memory and naive T cells. "
[Show abstract][Hide abstract] ABSTRACT: System lupus erythematosus (SLE) is an immune-complex-mediated autoimmune condition with protean immunological and clinical manifestation. While SLE has classically been advocated as a B-cell or T-cell disease, it is unlikely that a particular cell type is more pathologically predominant than the others. Indeed, SLE is characterized by an orchestrated interplay amongst different types of immunopathologically important cells participating in both innate and adaptive immunity including the dendritic cells, macrophages, neutrophils and lymphocytes, as well as traditional nonimmune cells such as endothelial, epithelial, and renal tubular cells. Amongst the antigen-presenting cells and lymphocytes, and between lymphocytes, the costimulatory pathways which involve mutual exchange of information and signalling play an essential role in initiating, perpetuating, and, eventually, attenuating the proinflammatory immune response. In this review, advances in the knowledge of established costimulatory pathways such as CD28/CTLA-4-CD80/86, ICOS-B7RP1, CD70-CD27, OX40-OX40L, and CD137-CD137L as well as their potential roles involved in the pathophysiology of SLE will be discussed. Attempts to target these costimulatory pathways therapeutically will pave more potential treatment avenues for patients with SLE. Preliminary laboratory and clinical evidence of the potential therapeutic value of manipulating these costimulatory pathways in SLE will also be discussed in this review.
[Show abstract][Hide abstract] ABSTRACT: Infection with mouse adenovirus type 1 (MAV-1) results in acute encephalomyelitis that is fatal in susceptible mouse strains. In the brain, MAV-1 only infects endothelial cells. We investigated factors influencing MAV-1-induced encephalitis, including the role of natural killer (NK) cells, the inflammatory response, and viral effects on the blood brain barrier (BBB). MAV-1-infected mice depleted of NK cells had viral loads in the brain similar to those measured in mock-depleted control animals. Control and NK cell-depleted mice were able to clear MAV-1 infection to undetectable levels by 20 days post-infection. These results indicate that NK cells were not important for control of MAV-1 infection in the brain. Brains of MAV-1-infected C57BL/6 mice showed a significant increase in leukocytes, including CD8 T cells. MAV-1 infection of C57BL/6 mice caused a dose-dependent breakdown of the BBB, indicated by dye staining of brain tissues. Breakdown of the BBB correlated with brain viral load, and was primarily due to direct effects of virus infection, because brains were permeable to dye even in the absence of inflammation. Cytotoxic inflammatory cells were not necessary for breakdown of the BBB. A primary mouse brain endothelial cell (pMBEC) culture was used to measure direct effects of virus infection in the absence of an inflammatory response. MAV-1 infection caused a loss of transendothelial electrical resistance, which is necessary for maintaining the BBB. Tight junction proteins claudin-5 and occludin are required for the integrity of the BBB and transendothelial electrical resistance, and both proteins showed reduced cell surface expression on pMBECs following MAV-1 infection. Taken together, these results demonstrate that MAV-1 caused breakdown of the BBB and decreased barrier properties in infected endothelial cells, likely due to altered localization of tight junction proteins. MAV-1-induced inflammation is dependent on the presence of the E3 protein products, but MAV-1-induced breakdown of the BBB did not require E3. No functional role for E3 has yet been described for MAV-1 E3. We developed a tandem affinity purification system to identify cellular proteins that interact with the major E3 protein product, E3 gp11k. Mass spectrometry analysis identified several candidate E3 gp11k-interacting proteins. Ph.D. Microbiology & Immunology University of Michigan, Horace H. Rackham School of Graduate Studies http://deepblue.lib.umich.edu/bitstream/2027.42/61720/1/lgralins_2.pdf http://deepblue.lib.umich.edu/bitstream/2027.42/61720/2/lgralins_1.pdf
[Show abstract][Hide abstract] ABSTRACT: Lymph nodes (LNs) represent the principal site where antigen-specific memory T- and B-cell responses are primed and differentiated into memory and effector cells. During chronic viral infections such as HIV, these lymphoid tissues undergo substantial structural changes. These changes are mostly caused by an imbalanced cytokine milieu, hyper-immune activation and collagen deposition leading to fibrotic LNs. The structural integrity of the LNs is essential to prime and maintain memory responses. Because cellular signalling events both up- and down-stream of FOXO3a are critical to the generation and the maintenance of lymphocyte memory, this review will focus on the interplay between the deregulation of the immune system caused by the virus and its impact on FOXO3a.
Seminars in Immunology 07/2008; 20(3):196-203. DOI:10.1016/j.smim.2008.07.008 · 5.17 Impact Factor
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