Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02749 (beta2-glycoprotein I)
 836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoreactive CD4(+) T cells to beta2-glycoprotein I (beta2GPI) that promote antiphospholipid antibody production were recently identified in patients with antiphospholipid syndrome (APS). To further examine antigen recognition profiles and T-cell helper activity in beta2GPI-reactive T cells, 14 CD4(+) T-cell clones specific to beta2GPI were generated from 3 patients with APS by repeated stimulation of peripheral blood T cells with recombinant beta2GPI. At least 4 distinct T-cell epitopes were identified, but the majority of the beta2GPI-specific T-cell clones responded to a peptide encompassing amino acid residues 276 to 290 of beta2GPI (KVSFFCKNKEKKCSY; single-letter amino acid codes) that contains the major phospholipid-binding site in the context of the DRB4*0103 allele. Ten of 12 beta2GPI-specific T-cell clones were able to stimulate autologous peripheral blood B cells to promote anti-beta2GPI antibody production in the presence of recombinant beta2GPI. T-cell helper activity was exclusively found in T-cell clones capable of producing interleukin 6 (IL-6). In vitro anti-beta2GPI antibody production induced by T-cell clones was inhibited by anti-IL-6 or anti-CD40 ligand monoclonal antibody. In addition, exogenous IL-6 augmented anti-beta2GPI antibody production in cultures of the T-cell clone lacking IL-6 expression. These results indicate that beta2GPI-specific CD4(+) T cells in patients with APS preferentially recognize the antigenic peptide containing the major phospholipid-binding site and have the capacity to stimulate B cells to produce anti-beta2GPI antibodies through IL-6 expression and CD40-CD40 ligand engagement. These findings are potentially useful for clarifying the pathogenesis of APS and for developing therapeutic strategies that suppress pathogenic antiphospholipid antibody production in these patients.
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PMID:Autoreactive CD4(+) T-cell clones to beta2-glycoprotein I in patients with antiphospholipid syndrome: preferential recognition of the major phospholipid-binding site. 1153 26

There is increasing evidence showing that recurrent thrombosis and intrauterine fetal loss in antiphospholipid syndrome (APS) are attributable to antiphospholipid (aPL) antibodies. We have recently identified autoreactive CD4+ T cells to beta2-glycoprotein I (beta2GPI) that promote production of pathogenic antiphospholipid antibodies. beta2GPI-specific CD4+ T cells preferentially recognize the antigenic peptide containing the major phospholipid (PL)-binding site in the context of DR53. T-cell helper activity that stimulates B cells to produce IgG anti-beta2GPI antibodies is mediated through IL-6 and CD40-CD154 interaction. beta2GPI-specific T cells respond to reduced beta2GPI and recombinant beta2GPI fragments produced in a bacterial expression system but not to native beta2GPI, indicating that the epitopes recognized by beta2GPI-specific T cells are 'cryptic' determinants, which are generated at a subthreshold level by the processing of native beta2GPI under normal circumstances. Although beta2GPI-specific T cells are detected in both APS patients and healthy individuals, these autoreactive T cells are activated in vivo in APS patients but not in healthy individuals. These findings indicate activation of beta2GPI-specific T cells and subsequent production of pathogenic anti-beta2GPI antibodies can be induced by the exposure of such T cells to cryptic peptides of beta2GPI efficiently presented by functional antigen-presenting cells (APC). Delineating the mechanisms that induce the efficient processing and presentation of cryptic determinants of beta2GPI as a consequence of antigen processing would clarify the etiology that initiates the autoantibody response in APS.
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PMID:Beta2-glycoprotein I: antiphospholipid syndrome and T-cell reactivity. 1550 64

The human plasma protein beta2-glycoprotein I (beta2-GPI) is the most common target for antiphospholipid antibodies associated with thrombotic events in chronic disorders related to endothelial cell dysfunction. Crucial information is needed to clarify why this self-abundant protein is targeted by autoimmune responses. In this study, we investigated whether oxidative modification of beta2-GPI, either spontaneous in culture wells or induced by treatment with H2O2, renders this self-protein able to activate immature monocyte-derived dendritic cells (DCs) from healthy human donors. Oxidized beta2-GPI caused DCs to mature so that CD83 appeared and CD80, CD86, human leukocyte antigen-D region related (HLA-DR), and CD40 increased. The interaction between oxidized beta2-GPI and DCs specifically stimulated these cells to secrete interleukin 12 (IL-12), IL-1beta, IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha), and IL-10. Oxidized beta2-GPI-stimulated DCs had increased allostimulatory ability and primed naive T lymphocytes, thus inducing T helper 1 (Th1) polarization. The interaction between oxidized beta2-GPI and DCs involved interleukin-1 receptor associated kinase (IRAK) phosphorylation and nuclear factor kappaB (NFkappaB) activation. Pretreatment of beta2-GPI with the antioxidant alpha-tocopherol prevented DC maturation. These findings show that human oxidized beta2-GPI, probably by interacting with a member of the Toll-like receptor (TLR) family, causes DCs to mature. Because this key beta2-GPI function requires oxidative modification, in several chronic disorders related to endothelial cell dysfunction oxidative stress might trigger the "autoimmune spiral."
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PMID:Oxidized beta2-glycoprotein I induces human dendritic cell maturation and promotes a T helper type 1 response. 1609 86

Atherosclerosis (AT) is a metabolic, systemic inflammatory/immune disease characterized by lipoproteins metabolism alteration that leads to immune/inflammatory system activation with the consequent proliferation of smooth-muscle cells, narrowing arteries and atheroma formation. Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombophilic state and circulating antiphospholipid antibodies (aPL) including anti beta2-GPI. Experimental studies and human observations suggest that APS is associated with AT. In fact, innate and adaptive immune responses participate in the pathogenesis of both diseases. Anti-oxLDL, anti-aPL, anti beta2GPI, anti-HSP antibodies, among others, has been found in patients with APS and AT. Endothelial dysfunctions, oxidative stress, increase of cell adhesion molecules, active platelets, are common findings in both diseases. Macrophages, dendritic cells, T-cell activation, CD40-CD40 ligand interaction, are considered as pathogenic mechanism of AT and APS. Premature AT may be the first symptom of APS. Thrombophilia, aPL antibodies, and APS may be present in patients with premature AT. An association between AT and venous thrombosis (a clinical hallmark of APS) has been proposed in unselected patients with deep venous thrombosis of the legs without symptomatic AT. Asymptomatic AT, defined in terms of carotid intima media thickness and lumen diameter decrease, was observed in patients with APS. Premenopausal female patients with PAPS have a higher prevalence of cerebrovascular disease in comparison with male patients. Accelerated AT and hormones could be the explanation of these findings. High levels of aCLs, significantly predict the risk of future ischemic stroke in women but not in men. AT is one of the main features of systemic APS and offer opportunities for new treatment strategies.
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PMID:Systemic antiphospholipid syndrome and atherosclerosis. 1791 89

Although atherosclerosis was previously thought to be mainly a degenerative disease, it is now well ascertained that its pathogenesis is inflammatory. This review describes the history of a new atherogenetic concept, including the pivotal role of apoE-knockout mice in understanding the inflammatory background of atherosclerosis. There has been lack of unequivocal evidence of an important inflammatory component in atherogenesis. This evidence was delivered by a new technique--gene targeting, for the invention of which Mario R. Capecchi, Martin J. Evans and Oliver Smithies received in 2007 the Nobel Prize in Physiology or Medicine. The pivotal stage of atherogenesis is the antigen presentation by macrophages to T lymphocytes. This antigen could be a fragment of oxidized low-density lipoproteins "digested" by macrophage, heat shock protein 60, beta2-glycoprotein I or fragments of bacterial antigens. For interaction between the immunological cells a presence of CD40 receptor on macrophages and its ligand CD40L on the surface of T lymphocytes are necessary. During the interaction between these cells an immunological type T helper 1 (Th1--cellular) or T helper 2 (Th2--humoral) response arises. Th1 response and its mediators: interferon gamma, tumor necrosis factor alpha, interleukin-1, interleukin-12 and interleukin-18 enhance atherogenesis, whereas Th2 response and its mediators: interleukin-4, interleukin-5, interleukin-10 and interleukin-13 inhibit the development of atherosclerosis. Atherosclerosis is therefore a chronic inflammatory disease, in most cases initiated by hypercholesterolemia. Nowadays, hypercholesterolemia and inflammation are considered as "partners in crime". The concept of atherosclerosis as inflammatory disease is fairly new, however, it is already considered as an undisputable achievement of science which have particular therapeutic consequences.
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PMID:New insights into immunological aspects of atherosclerosis. 1847 59