Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042384 (vasculitis)
 20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutrophils from patients suffering from severe congenital neutropenia (SCN), who were receiving recombinant human granulocyte colony-stimulating factor (rhG-CSF), were investigated in order to analyze the previously described decrease in chemotaxis. This study demonstrated the decreased chemotaxis to five well-known chemoattractants, FMLP, C5a, IL-8, LTB4 and PAF. To further investigate this impairment of patients' neutrophils, receptors and receptor turnover for chemoattractants were examined using flow cytometry. We found 1) increased FMLP receptor and decreased C5a receptor expression, 2) a normal expression of intracellular FMLP receptors after incubation with PMA, 3) increased loss and decreased re-expression of FMLP receptors after incubation with this peptide, 4) normal expression of adhesion glycoproteins CR3 (CD11b/CD18) and LFA1 (CD11a/CD18), 5) further signs of in vivo preactivation: high expression of Fc gamma-RI (CD64) and Fc gamma-RII (CD32), decreased expression of Fc gamma-RIII (CD16), increased expression of CD14, and low expression of HLA-DR. These data demonstrate that the decrease of chemotaxis of neutrophils from SCN patients is not due: a) to a decrease in the number of intra- or extracellular FMLP receptors; b) to a decrease of adhesion molecules. However, the decreased chemotaxis could result from an altered FMLP receptor turnover. The relevance of the altered Fc gamma-receptor pattern for the in vivo occurrence of side-effects, e.g. the necrotic vasculitis, of G-CSF treatment is discussed.
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PMID:Altered function and surface marker expression of neutrophils induced by rhG-CSF treatment in severe congenital neutropenia. 137 Apr 19

Fc gamma receptors are a group of three different receptors with several subtypes. They are widely distributed on many cells of the immune system and contribute to the pathogenesis of immune complex- and autoantibody-mediated diseases such as vasculitis, rheumatoid arthritis, idiopathic thrombocytopenic purpura or autoimmune neutropenia. This review focuses on the structure, distribution and function in Fc gamma receptors and their subtypes.
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PMID:[Fc gamma receptors: structure, function, and clinical significance]. 138 31

Leukoclastic vasculitis is thought to be initiated by deposition of immune complexes (ICs) in the vascular wall. To study the neutrophil response in a related in vitro model, we primed human umbilical vein endothelial cell (HUVEC) monolayers with antibodies against human fibronectin. The resulting respiratory burst to the immobilized ICs depended on the antibody concentration used to prime the monolayers and included a marked release of primary and secondary granule constituents. On IC-bearing HUVEC monolayers, but not on ICs directly bound to tissue culture dishes, blocking monoclonal antibodies (mAbs) to crystallizable fragment-gamma receptor II (Fc gamma RII) and Fc gamma RIII markedly inhibited the respiratory burst and the release of elastase. However, on both surfaces the neutrophil response was strongly inhibited by mAbs against CD18. Regardless of whether we used neutrophils from a patient with severe paroxysmal nocturnal hemoglobinuria (PNH) lacking the Fc gamma RIII, or whether the Fc gamma RII-mediated signal transduction was blocked by pertussis toxin, the respiratory burst to the IC-bearing HUVECs was essentially unchanged. With PNH neutrophils, the respiratory burst was predominantly blocked by an anti-Fc gamma RII mAb. In contrast, the response of pertussis toxin treated neutrophils was strongly inhibited by a mAb against Fc gamma RIII. Together these data indicate that the answer of neutrophils to ICs immobilized at the endothelial barrier depends on the cooperative function of both low-affinity Fc gamma Rs.
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PMID:Neutrophil activation in response to immune complex-bearing endothelial cells depends on the functional cooperation of Fc gamma RII (CD32) and Fc gamma RIII (CD16). 749 May 18

Antineutrophil cytoplasmic autoantibodies (ANCA) have been described in sera of patients with several forms of systemic vasculitis, including Wegener's granulomatosis and microscopic polyarteritis. The two main targets of ANCA in vasculitis are proteinase 3 (PR3) and myeloperoxidase (MPO). ANCA are capable of activating neutrophils primed by tumor necrosis factor-alpha (TNF-alpha) in vitro, which may be relevant for the induction of the vascular inflammation observed in vivo. Recently, it has been suggested that engagement of Fc gamma receptor IIa (Fc gamma RIIa) on the neutrophils is involved in the activation by ANCA. In the present study, we show that activation of the neutrophil respiratory burst by anti-PR3 and anti-MPO is strongly enhanced after TNF priming and lost on removal of the Fc parts of the antibodies. Similar results were obtained when the neutrophils were activated with antibodies against known membrane antigens without major changes in the expression of the target antigens. The TNF-induced enhancement of the neutrophil activation was not observed when adherence of the cells was prevented by continuous stirring of the suspension or by the addition of CD18 antibodies before TNF exposure. Hence, our results indicate that engagement of both Fc gamma RIIa and beta 2 integrins is instrumental in neutrophil activation induced by ANCA.
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PMID:Effect of tumor necrosis factor-induced integrin activation on Fc gamma receptor II-mediated signal transduction: relevance for activation of neutrophils by anti-proteinase 3 or anti-myeloperoxidase antibodies. 757 14

Using two different kinds of monoclonal autoantibodies, anti-mouse RBC (MRBC) autoantibodies and IgG3 rheumatoid factor (RF) cryoglobulins, we have attempted to better define the molecular and cellular basis of the pathogenicity of autoantibodies. Among eight anti-MRBC monoclonal antibodies (mAbs) obtained from NZB mice, only five of them are able to cause anemia. The distinct differences in specificity between pathogenic and non-pathogenic anti-MRBC mAbs emphasize the importance of autoantibody specificity for the pathogenesis of autoimmune hemolytic anemia. Histological examination has revealed that Fc gamma receptor-mediated erythrophagocytosis and sequestration of agglutinated RBC in spleens and livers are the major pathogenic mechanisms of hemolytic anemia. This indicates that the affinity of autoantibodies for the Fc gamma receptors of phagocytes and/or the ability to cause hemagglutination, both of which vary among immunoglobulin isotypes, are additional factors determining the pathogenic activity of anti-MRBC autoantibodies. Studies on a panel of anti-IgG2a RF mAbs derived from MRL-lpr/lpr mice have demonstrated that only the IgG3 isotypes of RF mAb are able to generate cryoglobulins and to induce skin leukocytoclastic vasculitis and glomerulonephritis in normal mice. Although the cryoglobulin activity of RF mAb associated with the IgG3 isotype has been shown to be solely responsible for the generation of glomerular lesions (both RF and cryoglobulin activities are necessary for cutaneous vascular lesions), the absence of nephritogenic activity by some IgG3 monoclonal cryoglobulins supports the idea that qualitative features of cryoglobulins are critical to determine their pathogenic activities. Of interest, IgG3 autoantibodies lacking the cryoglobulin activity may not be harmful, but even protective against the development of IgG3 cryoglobulin-mediated tissue lesions, because they inhibit the cryoglobulin formation of pathogenic IgG3 autoantibodies as a result of their nonspecific IgG3 Fc-Fc interaction. Our results on monoclonal autoantibodies clearly indicate the importance of certain subpopulations of autoantibodies in the pathogenesis of autoantibody-mediated cellular and tissue injuries.
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PMID:Molecular and cellular basis for pathogenicity of autoantibodies. 780 5

The presence of anti-neutrophil cytoplasmic Abs (ANCA) in many patients with systemic vasculitis suggests that ANCA may play a role in disease pathogenesis. Neutrophils from patients with Wegener's granulomatosis often express ANCA target Ags (myeloperoxidase (MPO) and proteinase 3 (PR3)) on their surface, making these intracellular primary granule enzymes accessible to these autoantibodies. Similarly, normal neutrophils can be induced to translocate MPO and PR3 to the cell surface in vitro, and we demonstrate that murine mAb ANCA IgG, but not IgM, binds to the ANCA target and engages the Fc gamma RIIa ligand-binding site on the surface of human neutrophils. In contrast to ANCA IgM, ANCA IgG also induces an oxidative burst in neutrophils (oxidation of dihydrorhodamine = 91 +/- 15 fluorescence units with anti-PR3 IgG vs 17 +/- 2 with anti-PR3 IgM, p < 0.001). Blockade of the ligand-binding site of Fc gamma RIIa with an antibinding site mAb Fab significantly reduces this ANCA IgG-triggered production of reactive oxygen species (p < 0.01). Similarly, human ANCA bind the ANCA target, engage Fc gamma RIIa, and induce an oxidative burst in neutrophils. The allelic phenotype of Fc gamma RIIa strongly influences the Fc gamma receptor engagement by ligand, and Fc gamma RIIa homozygous donors differ by more than threefold in the quantitative production of reactive oxygen intermediates (ROI) (p < 0.01). Thus, engagement of Fc gamma RIIa by the Fc region of ANCA is one mechanism by which these autoantibodies activate receptor-mediated signal transduction systems in human neutrophils to initiate programs of inflammation and tissue injury. Fc gamma receptor alleles may represent heritable disease risk factors influencing the magnitude of such a process.
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PMID:Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa. 802 54

Immune complexes are thought to be the major cause of cutaneous necrotizing vasculitis, but the mechanism of immune complex targeting to specific vessels is largely unknown. In myelomonocytic cells, immune complex binding and receptor-mediated endocytosis are mediated by Fc gamma R. We asked whether dermal microvascular endothelial cells (DMEC) express Fc gamma Rs. In cryostat sections of normal human skin, mAb IV.3 or AT10, both recognizing CD32 (Fc gamma RII), localizes to the luminal surface of DMEC of the superficial but not of the deep vascular plexus. All DMEC do not express CD16 (Fc gamma RIII) or CD64 (Fc gamma RI) molecules. Adult skin-derived DMEC in culture express CD32 (Fc gamma RII) molecules, as measured by FACS, but are negative for CD16 or CD64. HUVEC, tested for comparison, do not express CD16, 32, or 64 proteins. By reverse-transcriptase PCR and subsequent Southern blot analysis, the isoform of the CD32 molecule expressed on DMEC is determined as Fc gamma RIIa. HUVEC do not contain Fc gamma RIIa or Fc gamma RIIb mRNA. In DMEC, Fc gamma RIIa cross-linking results in immediate intracellular free Ca2+ ([Ca2+]i) concentration fluxes and in rapid internalization of the occupied receptors. We conclude that DMEC are equipped with fully functional Fc gamma RIIa molecules.
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PMID:Dermal microvascular endothelial cells express CD32 receptors in vivo and in vitro. 856 59

Antibody-antigen complexes are central to the inflammatory response and are implicated in the development of such diverse diseases as systemic lupus erythematosis, rheumatoid arthritis, immune glomerulonephritis, and vasculitis. We recently demonstrated that experimental immune complex-mediated injury in mice, as modeled by the cutaneous Arthus reaction, requires receptors for the Fc portion of the antibody and is unaffected by deficiencies in complement components. However, the responsible cell type(s) and Fc receptor(s) were not known. We now demonstrate by differential reconstitution in vivo that Fc gamma RIII on mast cells is necessary for this inflammatory response. We propose a general model of antibody-mediated diseases as an immunopathologic spectrum whose specific manifestations are determined by the Fc receptor and cell type engaged.
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PMID:A dominant role for mast cell Fc receptors in the Arthus reaction. 888 71

Activation of polymorphonuclear leukocytes (PMN) plays an important role in vascular injury associated with systemic vasculitis and in models of autoantibody- and immune complex-mediated disease. The potential role of intravascular activation of PMN, however, is confounded by the observation that some stimuli injected i.v. (e.g., IL-8 and C5a) lead to L-selectin shedding by PMN, which inhibits attachment to endothelium and may be functionally anti-inflammatory. To explore the impact of Fc gamma receptor (Fc gamma R)-mediated activation on the PMN adhesive phenotype, Fc gamma RIIa (CD32) and Fc gamma RIIIb (Cd16) were targeted with receptor-specific reagents, and the expression of adhesion molecules-mediating rolling (L-selectin) and firm adhesion (CD11b/CD18) was measured. Engagement of either Fc gamma RIIa or Fc gamma RIIIb leads to activation, demonstrated by degranulation (upregulation of CD66b), and to increased expression of total CD11b/CD18 and functional CD11b/CD18 (I-domain). In contrast, L-selectin shedding induced by PMN Fc gamma R was divergent. Despite the 5- to 10-fold greater expression and engagement at saturation, activation via Fc gamma RIIIb led to little or no change in L-selectin expression. Stimulation of PMN with intact murine anti-receptor IgG1 showed a contribution of Fc gamma RIIa receptor polymorphisms, underscoring the direct influences of Fc gamma R allotypes on receptor function. These observations suggest that Fc gamma RIIIb-mediated activation of circulating PMN may lead to a proadhesive phenotype likely to promote systemic vascular damage. This Fc gamma R-mediated adhesive phenotype will vary with the receptors engaged and their allotypes, which, in turn, reflect properties of the immune complex and the genetics of the host.
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PMID:Cross-linking of Fc gamma receptor IIa and Fc gamma receptor IIIb induces different proadhesive phenotypes on human neutrophils. 937 82

The expression of CD14, CD18, and major histocompatibility complex II on unprimed monocytes from healthy donors after incubation with IgG from patients with antineutrophil cytoplasmic autoantibody (ANCA)-positive active Wegener's granulomatosis (n = 6) and microscopic polyangiitis (n = 6) in comparison with IgG from healthy controls (n = 6) was studied. Monocytes were incubated with IgG (100 microg/ml) at 37 degrees C, and expression of antigens was measured by fluorescence-activated cell sorter after 18 h. Cytoplasmic ANCA (C-ANCA) IgG and perinuclear ANCA (P-ANCA) IgG in comparison with control IgG increased the expression of CD14 (49.2% [SD: 37, P: < 0. 001], and 55.8% [SD: 41, P: < 0.05]) and CD18 (11.4% [SD: 18, P: < 0. 01] and 8% [SD: 26, P: < 0.05]) but did not change the major histocompatibility complex II expression. Upregulation of CD14 started after 6 h and reached a peak after 10 to 14 h of incubation and was not inhibited by polymyxin B. F(ab)(2) fragments of C- and P-ANCA IgG also increased expression of CD14 and CD18 as compared with control IgG F(ab)(2), but for CD14 less than with complete IgG. ANCA IgG depleted of antiproteinase 3 and antimyeloperoxidase antibodies by immunoadsorption failed to upregulate CD14. Monoclonal murine antibodies against proteinase 3 and myeloperoxidase yielded a strong upregulation of CD14 when compared with an isotype control or human control IgG. The data show that CD14 and CD18 are upregulated on monocytes by C- and P-ANCA IgG in vitro, as well as by monoclonal antibodies against proteinase 3 and myeloperoxidase and that this effect is not dependent on Fc gamma receptor crosslinking. Upregulation of CD14 and CD18 on monocytes by ANCA suggests a pathogenetic role of ANCA monocyte interactions in systemic vasculitis.
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PMID:Upregulation of CD14 and CD18 on monocytes In vitro by antineutrophil cytoplasmic autoantibodies. 1096 88


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