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PubMed2001

Primary refractoriness to platelet transfusion caused by Nak(a) antibody alone.

BACKGROUND AND OBJECTIVES: Anti-Nak(a), a platelet-specific antibody, occasionally causes platelet-transfusion refractoriness (PTR) together with human leucocyte antigen (HLA) antibodies. Anti-Nak(a) usually appears after frequent platelet transfusions or pregnancy. We report the first case of PTR caused by anti-Nak(a) alone. MATERIALS AND METHODS: A 19-year-old male patient with testicular tumour showed PTR when receiving his first transfusion of platelets. Screening for platelet antigens and platelet antibodies revealed that he had type I CD36 (Nak(a)) deficiency and that anti-Nak(a), but not anti-HLA, was present before he received his first transfusion. RESULTS: The transfusion of Nak(a)-negative, but HLA non-selected, platelets was effective in raising the platelet count. CONCLUSION: Clinically significant Nak(a) antibody was present as naturally occurring antibody in a platelet glycoprotein IV (CD36)-negative non-transfused male patient.

Adult↗
PubMed1998

Significance of membrane glycoproteins in platelet interaction with oxidized low-density lipoprotein.

The significance of three platelet membrane glycoproteins, (CD62p, CD63, and CD36) was studied in platelet interaction with native and copper-oxidized plasma low-density lipoproteins (LDL). Native LDL acquired platelet-activating ability only after oxidation. Flow-cytometric studies showed that CD62P and CD63 were rapidly expressed on platelets at a low concentration of oxidized LDL, indicating that they are more sensitive markers than platelet aggregation for detection of platelet activation by oxidized LDL. CD36 was found to be contributing to the binding and activation of platelets with oxidized LDL, but not to the binding of platelets with native LDL. Although the presence of oxidized LDL in plasma is known, its effect on platelet function remains to be studied.

Antigens, CD↗
PubMed2003

Atopy patch test reactions show a rapid influx of inflammatory dendritic epidermal cells in patients with extrinsic atopic dermatitis and patients with intrinsic atopic dermatitis.

BACKGROUND: Normal human skin harbors a single epidermal dendritic cell (DC) population, the CD1a(+++)CD11b(-) Langerhans cells. In many chronic inflammatory skin diseases, the epidermal DC pool bears a second population, the CD1a(+)CD11b(+++) inflammatory dendritic epidermal cells (IDECs). Immunophenotypic, ultrastructural, and functional aspects of IDECs have been investigated in chronic untreated skin lesions of intrinsic and extrinsic atopic dermatitis (AD), contact dermatitis (CD), and psoriasis, but little is known about freshly induced early skin lesions. OBJECTIVE: We sought to characterize enumerative and immunophenotypic changes in the epidermal DC pool during the development of eczematous skin lesions. METHODS: The atopy patch test with aeroallergens and food-protein allergens and a conventional patch test with standard-series haptens were performed as models for early skin lesions of extrinsic and intrinsic AD and CD, respectively. After 72 hours, epidermal cell suspensions were prepared, analyzed in a standardized flow cytometric technique, and compared with the results obtained from chronic lesions. RESULTS: The migration of IDECs into the epidermis occurs within 72 hours and is thus an early event. It continues in chronic AD, but not in chronic CD, lesions. The specific upregulation of FcepsilonRI, especially on IDECs, occurs later during formation of extrinsic but not intrinsic AD lesions. LCs were negative for Cd36 in patch test lesions, whereas in chronic skin lesions, LCs expressed Cd36. CONCLUSION: The DC alteration during skin lesion formation can be subdivided into early and late events, with the influx of IDECs as an early event and the alteration of the DC phenotype as a late event.

Adolescent↗
PubMed2002

Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARgamma agonist.

Lysophosphatidic acid (LPA) is a pluripotent lipid mediator acting through plasma membrane-associated LPA(x) receptors that transduce many, but not all, of its effects. We identify peroxisome proliferator-activated receptor gamma (PPARgamma) as an intracellular receptor for LPA. The transcription factor PPARgamma is activated by several lipid ligands, but agonists derived from physiologic signaling pathways are unknown. We show that LPA, but not its precursor phosphatidic acid, displaces the drug rosiglitazone from the ligand-binding pocket of PPARgamma. LPA and novel LPA analogs we made stimulated expression of a PPAR-responsive element reporter and the endogenous PPARgamma-controlled gene CD36, and induced monocyte lipid accumulation from oxidized low-density lipoprotein via the CD36 scavenger receptor. The synthetic LPA analogs were effective PPARgamma agonists, but were poor ones for LPA(1), LPA(2), or LPA(3) receptor transfected cells. Transfection studies in yeast, which lack nuclear hormone and LPA(x) receptors, show that LPA directly activates PPARgamma. A major growth factor of serum is LPA generated by thrombin-activated platelets, and media from activated platelets stimulated PPARgamma function in transfected RAW264.7 macrophages. This function was suppressed by ectopic LPA-acyltransferase expression. LPA is a physiologic PPARgamma ligand, placing PPARgamma in a signaling pathway, and PPARgamma is the first intracellular receptor identified for LPA. Moreover, LPA produced by stimulated plasma platelets activates PPARgamma in nucleated cells.

Animals↗
PubMed1996

Variant antigens and endothelial receptor adhesion in Plasmodium falciparum.

Parasite-derived proteins expressed on the surface of erythrocytes infected with Plasmodium falciparum are important virulence factors, since they mediate binding of infected cells to diverse receptors on vascular endothelium and are targets of a protective immune response. They are difficult to study because they undergo rapid clonal antigenic variation in vitro, which precludes the derivation of phenotypically homogeneous cultures. Here we have utilized sequence-specific proteases to dissect the role of defined antigenic variants in binding to particular receptors. By selection of protease-resistant subpopulations of parasites on defined receptors we (i) confirm the high rate of antigenic variation in vitro; (ii) demonstrate that a single infected erythrocyte can bind to intercellular adhesion molecule 1, CD36, and thrombospondin; (iii) show that binding to intercellular adhesion molecule 1 and CD36 are functions of the variant antigen; and (iv) suggest that binding to thrombospondin may be mediated by other components of the infected erythrocyte surface.

Animals↗
PubMed2001

Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria.

Sequestration of malaria-infected erythrocytes in the peripheral circulation has been associated with the virulence of Plasmodium falciparum. Defining the adhesive phenotypes of infected erythrocytes may therefore help us to understand how severe disease is caused and how to prevent or treat it. We have previously shown that malaria-infected erythrocytes may form apparent autoagglutinates of infected erythrocytes. Here we show that such autoagglutination of a laboratory line of P. falciparum is mediated by platelets and that the formation of clumps of infected erythrocytes and platelets requires expression of the platelet surface glycoprotein CD36. Platelet-dependent clumping is a distinct adhesive phenotype, expressed by some but not all CD36-binding parasite lines, and is common in field isolates of P. falciparum. Finally, we have established that platelet-mediated clumping is strongly associated with severe malaria. Precise definition of the molecular basis of this intriguing adhesive phenotype may help to elucidate the complex pathophysiology of malaria.

Agglutination Tests↗
PubMed1996

Mechanism of uptake of copper-oxidized low density lipoprotein in macrophages is dependent on its extent of oxidation.

Several investigators have reported nonreciprocal cross-competition between unlabeled acetyl low density lipoprotein (LDL) and oxidized LDL for the degradation of the corresponding labeled LDLs. The failure of acetyl LDL to compete fully for the degradation of oxidized LDL has been interpreted as evidence for additional receptor(s) specific for oxidized LDL. In the present study, it is demonstrated that the ability of oxidized LDL to compete for the degradation of acetyl LDL is determined largely by its extent of oxidation. Extensively oxidized LDL competed for 90% of acetyl LDL degradation in murine macrophages, and hence there appears to be no pathway in these cells that is specific for acetyl LDL but not oxidized LDL. The reciprocal situation (competition by acetyl LDL for uptake and degradation of oxidized LDL) proved to be more complicated. Oxidized LDL is known to be susceptible to aggregation, and less than half of the aggregates found in the present experiments were large enough to be removed by filtration or centrifugation at 10,000 x g. When oxidized LDL was prepared under conditions that resulted in minimal aggregation, acetyl LDL competed for greater than 80% of oxidized LDL degradation. With more extensive oxidation and aggregation of LDL, acetyl LDL only competed for about 45% of oxidized LDL degradation, while polyinosinic acid remained an effective competitor. Individual preparations of oxidized LDL that differed in degree of oxidation were separated into aggregated and nonaggregated fractions, and it was shown that both fractions were competed to a similar degree by acetyl LDL in mouse peritoneal macrophages and in Chinese hamster ovary cells transfected with human scavenger receptor type I cDNA. Hence, aggregation by itself did not alter the apparent rate of uptake by the scavenger receptor pathway. These results indicate that the extent of oxidation of LDL affects its mechanism of uptake and that about half of the uptake of very extensively oxidized LDL appears to be via a pathway distinct from the scavenger receptor type I/II. The uptake of very extensively oxidized LDL was not affected by cytochalasin D, an inhibitor of phagocytosis. As well, it was not affected by an antibody to CD36 in human monocyte-derived macrophages or in THP-1 cells, suggesting that this alternate pathway does not involve CD36.

Animals↗
PubMed2006

Reduction in ABCG1 in Type 2 diabetic mice increases macrophage foam cell formation.

Atherosclerosis development is accelerated severalfold in patients with Type 2 diabetes. In the initial stages of disease, monocytes transmigrate into the subendothelial space and differentiate into foam cells. Scavenger receptors and ATP binding cassette (ABC) Transporters play an important role in foam cell formation as they regulate the influx and efflux of oxidized lipids. Here, we show that peritoneal macrophages isolated from Type 2 diabetic db/db mice have decreased expression of the ABC transporter ABCG1 and increased expression of the scavenger receptor CD36. We found a 2-fold increase in accumulation of esterified cholesterol in diabetic db/db macrophages compared with wild-type control macrophages. Diabetic db/db macrophages also had impaired cholesterol efflux to high density lipoprotein but not to lipid-free apo A-I, suggesting that the increased esterified cholesterol in diabetic db/db macrophages was due to a selective loss of ABCG1-mediated efflux to high density lipoprotein. Additionally, we were able to confirm down-regulation of ABCG1 using C57BL/6J peritoneal macrophages cultured in elevated glucose in vitro (25 mM glucose for 7 days), suggesting that ABCG1 expression in diabetic macrophages is regulated by chronic exposure to elevated glucose. Diabetic KK(ay) mice were also studied and were found to have decreased ABCG1 expression without an increase in CD36. These observations demonstrate that ABCG1 plays a major role in macrophage cholesterol efflux and that decreased ABCG1 function can facilitate foam cell formation in Type 2 diabetic mice.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2006

MARCO mediates silica uptake and toxicity in alveolar macrophages from C57BL/6 mice.

Scavenger receptors (SR), on the surface of the macrophage, appear to be responsible for silica uptake and cell death signaling in the macrophage. The purpose of this study was to isolate which SRs (macrophage receptor with collagenous structure (MARCO), CD204, or CD36) were involved using a variety of SR single and double null mice. The findings indicated that MARCO was the critical SR involved in silica uptake and cytotoxicity in the primary alveolar macrophages (AM) from C57BL/6 mice, as there was no particle uptake or cell death in the absence of this SR. The level of MARCO expression on AM changed significantly with the absence of other SR, and silica uptake was proportional to cell surface MARCO expression. In addition, silica uptake and cytotoxicity were completely blocked by an anti-mouse MARCO antibody. Transfection of Chinese hamster ovary cells with human MARCO supported these conclusions, as silica particles bound to and initiated apoptosis in the MARCO-transfected cells. Strain differences with regard to SR distribution were also examined. There was a differential expression of these SR on AM from each strain, with MARCO dominant for C57BL/6, CD36 dominant on BALB/c, and all three SR expressed on 129/SvJ mice. Similar to the results with C57BL/6 AM, MARCO was involved with silica-induced cell death in the 129/SvJ strain. In contrast, BALB/c AM used an unidentified mechanism for silica uptake because the SR antibodies failed to block particle internalization. Taken together, these results indicate MARCO is the primary AM receptor interacting with silica, depending on mouse strain and level of constitutive expression.

Animals↗
PubMed1999

Plasmacytoid monocytes appear in the bronchoalveolar lavage: differences between smokers and nonsmokers.

The primary purpose of this study was to describe the expression pattern of the surface antigens CD68, CD36, 27E10, G16/1, and RM3/1 on bronchoalveolar lavage (BAL) cells of smokers and nonsmokers. We found a cell type, morphologically similar to lymphocytes, which showed a strong expression of the monocyte markers CD68 and CD36. We therefore recognized these cells as plasmacytoid monocytes (PM). Hereby we report the appearance of PM in the BAL and its dependency of smoking. The study was conducted in 40 patients with various lung diseases and normal subjects. Sixteen patients and normal subjects were smokers and 24 were nonsmokers. There was a significant increase of PM in the BAL of smokers compared to nonsmokers. However we could not find a disease-related increase of PM in the BAL. This is the first report demonstrating the occurrence of PM in the BAL. Our data support the monocytic origin of PM and suggest an involvement in T cell-mediated responses of the lung.

Antibody Specificity↗
PubMed2004

HIV protease inhibitors-induced atherosclerosis: prevention by alpha-tocopherol.

Prolonged treatments with inhibitors of human immunodeficiency(HIV)-encoded protease (ARPI) have been reported to induce early atherosclerotic events. Our in vitro study indicates that alpha-tocopherol may prevent drug-induced premature atherosclerosis since it interferes with CD36 scavenger receptor over-expression induced by ritonavir in monocytes. The mechanism of CD36 upregulation by ritonavir involves inhibition of the ubiquitin-proteasome system and alpha-tocopherol is able to normalize proteasome activity. These findings suggest that ARPI combined with early alpha-tocopherol supplementation may decrease the drug-induced atherosclerotic risk.

Arteriosclerosis↗
PubMed2003

Insulin mediated hemodynamic responses in spontaneous hypertensive rats (SHRs): effect of chromosome 4 gene transfer.

The spontaneous hypertensive rat (SHR) is a widely studied model of essential hypertension and has been reported to exhibit alterations in carbohydrate and lipid metabolism. Genetic linkage studies implicated that SHR carries deletion variant of Cd36 gene of chromosome 4, the gene that encodes fatty acid transporter. Thus it could be possible that primary genetic defect in SHR is compromised tissue utilization of fatty acid that would form the basis for the pathogenesis of hyperinsulinemia, insulin resistance and insulin-mediated responses. We measured both the hemodynamic and metabolic responses to insulin in SHR in comparison with the chromosome congenic spontaneous hypertensive rats (cSHRs) (rats in which piece of chromosome 4 containing wild type Cd36 was integrated into the SHR genome). A bolus infusion of insulin increased iliac conductance and decreased blood pressure in Wistar Kyoto (WKY) rats. However, in SHR insulin did not reduce blood pressure as in WKY but after about 15 min it significantly enhanced blood pressure and reduced iliac conductance. Whereas in cSHR insulin did not reduce blood pressure as in WKY rats. However, pressor responses to insulin were eliminated by chromosome 4 gene transfer. Glucose clearance was significantly slower in both SHR and cSHR. Glucose tolerance test revealed that SHR are hyperinsulinemic and insulin resistant. These findings indicate that transfer of segment of chromosome 4 from Brown Norway rats onto spontaneous hypertensive background eliminates hyperinsulinemia and pressor effects of insulin.

Animals↗
PubMedDate not supplied

Binding of [99mTc]chondroitin sulfate to scavenger receptors on human chondrocytes as compared to binding of oxidized [125I]LDL on human macrophages.

Chondroitin sulfate (CS) used for treatment of osteoarthritis exerts distinct effects on human articular chondrocytes in vitro. We performed a binding analysis with 99mTc-labeled CS (Condrosulf, a commercial CS preparation containing calcium stearate) and cultured human chondrocytes in order to evaluate the presence of specific receptors. Saturation binding at 37 degrees C for 2 h revealed the presence of high-affinity binding sites for CS with a Kd of 2.3 x 10(-9) mol/L and a Bmax of 5.0 x 10(8). Extensive dialysis of Chondrosulf led to a decrease of the binding affinity by 52.5 +/- 19.5% and of the number of CS binding sites/cell by 62.0 +/- 14.0%, demonstrating that the additive present in the Condrosulf preparation enhances CS binding. The nature of the binding site is not yet known but evidence exists in the literature that the scavenger receptor CD36, thoroughly investigated on macrophages, is also found on chondrocytes and might be involved in CS binding. Therefore, we undertook a comparative binding study with human monocytes and labelled LDL and oxidized LDL, the latter being a postulated atherogenic agent in atherosclerosis. For [125I]-LDL binding we found a Kd of 0.45 x 10(-8) mol/L and a Bmax of 0.14 x 10(6) on quiescent monocytes and for [125I]-(ox)LDL binding a Kd of 1.8 x 10(-8) mol/L and a Bmax of 1.3 x 10(6) using LPS-activated monocytes. These data are comparable to the binding affinity found for lipoprotein-proteoglycan-complexes and hence are an indication but not a proof that CD36 is involved in CS binding to human chondrocytes.

Adult↗
PubMed2006

Placental chondroitin sulfate A-binding malarial isolates evade innate phagocytic clearance.

Pregnancy-associated malaria is characterized by the accumulation of parasitized erythrocytes (PEs) and monocytes in the placenta, and they are believed to directly contribute to adverse birth outcomes. Although most parasite isolates adhere to CD36, placental isolates express novel variant surface antigens (VSAs) and bind to chondroitin sulfate A (CSA). CSA-binding PEs are rarely observed outside of pregnancy, and most primigravid women lack immunity and must rely on innate immune mechanisms to clear these placental parasite variants. We hypothesized that differences in VSA expression and adhesive phenotype between pregnancy-associated (CSA-binding) and non-pregnancy-associated (CD36-binding) isolates may have direct implications for the failure of primigravid women to control the placental parasite burden through innate phagocytic pathways. We demonstrate here, both in vitro and in vivo, that there is a nonopsonic phagocytic defect for CSA-binding PEs. The ability of CSA-binding PEs to evade innate clearance pathways may contribute to the parasite accumulation and recruitment of monocytes that characterize placental malaria.

Animals↗
PubMed1999

Mechanism of minimally modified LDL-mediated induction of serum amyloid A gene in monocyte/macrophage cells.

Minimally modified low-density lipoprotein (MM-LDL) is regarded as a major risk factor for the development of atherosclerosis. In this report, we show that this lipoprotein complex can induce expression of an inflammatory protein, serum amyloid A (SAA), in monocyte/macrophage cells, a key cell type implicated in the pathogenesis of atherosclerosis. By promoter function analysis and site-directed mutagenesis, we have located promoter regions responsive to MM-LDL action. Using electrophoretic mobility shift, antibody ablation/supershift, and Western blot assays, we showed that induction of SAA by MM-LDL is mediated via activation of SAS binding factor (SAF) and C/EBP transcription factors. We further show that tamoxifen, a downregulator of CD36, one of the major scavenger receptors which binds MM-LDL, can inhibit MM-LDL-mediated SAA induction in THP-1 cells. This finding suggests that CD36 participates in the manifestation of the inflammatory effects of MM-LDL. Our experiments provide the first evidence for transcription factor activation by MM-LDL.

Blotting, Northern↗
PubMed1995

Cellular requirements for cytokine production in response to the immunomodulators imiquimod and S-27609.

Imiquimod (R-837) and its analog, S-27609, belong to a class of imidazoquinolinamines that have potent antitumor and antiviral effects in animals. Much of their biologic activity is a result of the induction of cytokines, including interferon-alpha (IFN-alpha), tumor necrosis factor alpha (TNF), and others. In this study, the cells responsible for S-27609- and imiquimod-induced cytokine production were characterized. E rosette+ T cells were not the major cell population responsible for IFN-alpha and TNF in response to S-27609 or imiquimod. In contrast, E rosette- cells and unseparated PBMC produced similar concentrations of IFN-alpha and TNF in response to S-27609 and imiquimod. Elimination of monocytes by treatment with the lysosomotropic agent L-leucine methyl ester (LME) or depletion using antibody to CD14 and immunomagnetic beads abrogated IFN-alpha and TNF production induced by S-27609, imiquimod, or LPS but not poly(I)/(C). LME treatment also abolished interleukin (IL)-1 alpha, IL-beta, IL-6, and IL-8 production stimulated by S-27609 and imiquimod. Removal of HLA-DR+ or CD36+ monocytes also caused a significant reduction in S-27609- and imiquimod-induced IFN-alpha and TNF. Elimination of B cells, NK cells, and dendritic cells did not significantly reduce cytokine induction in response to S-27609. Thus, the cell population responsible for the majority of cytokine release in human PBMC in response to S-27609 and imiquimod is a E rosette-, CD14+, CD36+, HLA-DR+ monocyte.

Adjuvants, Immunologic↗
PubMed2000

Cell contact-dependent activation of alpha3beta1 integrin modulates endothelial cell responses to thrombospondin-1.

Thrombospondin-1 (TSP1) can inhibit angiogenesis by interacting with endothelial cell CD36 or proteoglycan receptors. We have now identified alpha3beta1 integrin as an additional receptor for TSP1 that modulates angiogenesis and the in vitro behavior of endothelial cells. Recognition of TSP1 and an alpha3beta1 integrin-binding peptide from TSP1 by normal endothelial cells is induced after loss of cell-cell contact or ligation of CD98. Although confluent endothelial cells do not spread on a TSP1 substrate, alpha3beta1 integrin mediates efficient spreading on TSP1 substrates of endothelial cells deprived of cell-cell contact or vascular endothelial cadherin signaling. Activation of this integrin is independent of proliferation, but ligation of the alpha3beta1 integrin modulates endothelial cell proliferation. In solution, both intact TSP1 and the alpha3beta1 integrin-binding peptide from TSP1 inhibit proliferation of sparse endothelial cell cultures independent of their CD36 expression. However, TSP1 or the same peptide immobilized on the substratum promotes their proliferation. The TSP1 peptide, when added in solution, specifically inhibits endothelial cell migration and inhibits angiogenesis in the chick chorioallantoic membrane, whereas a fragment of TSP1 containing this sequence stimulates angiogenesis. Therefore, recognition of immobilized TSP1 by alpha3beta1 integrin may stimulate endothelial cell proliferation and angiogenesis. Peptides that inhibit this interaction are a novel class of angiogenesis inhibitors.

Allantois↗
PubMed2006

Thrombospondin orchestrates the tolerance-promoting properties of TGFbeta-treated antigen-presenting cells.

Eye-derived antigen-presenting cells (APCs) are known to contribute to the immune privilege status of the eye by inducing a form of peripheral tolerance that deviates T(h)1 type of pro-inflammatory immune responses. Similar systemic tolerance can also be induced by non-ocular APCs exposed to transforming growth factor beta (TGFbeta) in vitro. Such APCs were found to express enhanced levels of thrombospondin (TSP)-1, an extracellular matrix (ECM) protein. In this report, we analyzed the significance of TSP-1 in conferring tolerance-inducing properties on APCs. While TSP-treated APCs matched TGFbeta-treated APCs in their functional ability to induce systemic tolerance, a deficiency of TSP-1 or its receptor CD36 prevented APCs from becoming tolerogenic in response to TGFbeta. Exogenous TSP-1 restored tolerogenic ability of TGFbeta-treated TSP-1 null APCs. Both TGFbeta-treated TSP-1 null and CD36 knockout APCs failed to inhibit IL-12 secretion. Furthermore, TGFbeta-treated TSP-1 null APCs, unlike similarly treated wild-type APCs, failed to increase secretion of active TGFbeta. Similar to TGFbeta, TSP could also up-regulate expression of MIP-2, TGFbeta2 and tumor necrosis factor alpha-all of which are required for tolerance induced by TGFbeta-treated APCs. We conclude that TSP-1, an ECM protein induced by TGFbeta treatment, orchestrates the changes in APC functional programs that equip these cells to promote tolerance of the eye-derived type.

Animals↗