Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteoprotegerin (OPG) acts as a decoy receptor for receptor activator of nuclear factor-kappaB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG regulates bone remodeling and the immune response. The primary objective was to decipher, among human peripheral blood mononuclear leukocytes (PBML) that produce OPG, the subset(s) responsible for this synthesis and its regulation. To this end, normal human PBML and CD4-, 8-, 19-, 14-enriched subpopulations were studied in vitro for OPG synthesis. PBML were subjected to adherence and immunomagnetic separation, and OPG expression was analyzed by PCR, northern and western blotting, and ELISA. The antiapoptotic effects of OPG were studied on TRAIL-stimulated RPMI 8226 myeloma cells. OPG was time-dependently produced by primary CD4+ T lymphocytes exclusively. OPG secretion was upregulated by anti-CD3 antibody stimulation or incubation with interleukin (IL)-4, IL-1beta, TNF-alpha, GM-CSF, and vitamin D(3). In contrast, IL-10 inhibited the basal and IL-4-induced production of OPG by T cells. Conditioned media from activated T lymphocytes decreased TRAIL-induced apoptosis of RPMI 8226 cells. This effect was reversed by addition of RANKL to the T-cell conditioned media. As human immunodeficiency virus-1 (HIV-1) targets CD4+ T cells, we evaluated the effects of recombinant HIV-1 gp120 proteins on OPG synthesis. The gp120 from three different HIV-1 strains significantly reduced the basal output of OPG from T cells. Furthermore, all four protease inhibitors (PIs) used in highly active antiretroviral therapy decreased OPG synthesis by human blood T cells, nelfinavir being the most efficient PI. The simultaneous presence of an HIV-1 gp120 and a PI abrogated the basal output of OPG. In conclusion, these results highlight a new role for T lymphocytes involved in pathologies. Activated CD4+ T cells could, through OPG release, have a paracrine effect on adjacent cells and contribute to reduce the local process of bone remodeling and cellular apoptosis.
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PMID:Normal human primary CD4+ T lymphocytes synthesize and release functional osteoprotegerin in vitro. 1804 Feb 68

Historically, bone was thought to be immunologically inactive with the sole function of supporting locomotion and ensuring stromaness functions as a major lymphoid organ. However, a myriad of pathogens (bacteria such as staphylococcus as well as viruses including alphaviruses, HIV or HCV) can invade the bone. These pathogens can cause apoptosis, autophagy and necrosis of osteoblasts and lead to lymphopenia and immune paralysis. There are now several detailed studies on how osteoblasts contribute to innate immune and inflammatory responses; indeed, osteoblasts in concert with resident macrophages can engage an armory of defense mechanisms capable of detecting and controlling pathogen evasion mechanisms. Osteoblasts can express the so-called pattern recognition receptors such as TOLL-like receptors involved in the detection for example of lipids and unique sugars (polysaccharides and polyriboses) expressed by bacteria or viruses (e.g. LPS and RNA respectively). Activated osteoblasts can produce interferon type I, cytokines, chemokines and interferon-stimulated proteins through autocrine and paracrine mechanisms to control for viral replication and to promote phagocytosis or lysis of bacteria for example by defensins. Uncontrolled and sustained innate immune activation of infected osteoblasts will also lead to an imbalance in the production of osteoclastogenic factors such as RANKL and osteoprotegerin involved in bone repair.
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PMID:Bone responses in health and infectious diseases: A focus on osteoblasts. 2877 51