共查询到20条相似文献,搜索用时 15 毫秒
1.
Otten MA van der Bij GJ Verbeek SJ Nimmerjahn F Ravetch JV Beelen RH van de Winkel JG van Egmond M 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(10):6829-6836
Many patients with colorectal cancer will develop liver metastases, even after successful surgical removal of the primary tumor at a time at which no visible metastases are present. We previously demonstrated that surgery--although mandatory--paradoxically enhances the risk of developing liver metastases. Because Ab therapy has been acknowledged as a successful strategy to treat malignancies, we studied the potential of postoperative adjuvant Ab therapy to prevent outgrowth of liver metastases. Treatment with murine anti-gp75 (TA99) mAb completely prevented outgrowth of B16F10 liver metastases in over 90% of mice. Therapeutic efficacy was maintained in either C1q- or complement receptor 3-deficient mice but was completely abrogated in FcR gamma-chain knockout mice. This indicates that the classical complement pathway was not essential, but interaction with activatory Fc gammaR was necessary for successful therapy. TA99-treatment was still effective in Fc gammaRI(-/-), Fc gammaRIII(-/-), Fc gammaRI/III(-/-), and Fc gammaRI/II/III(-/-) mice, suggesting an important role for Fc gammaRIV. However, wild-type mice that were treated with TA99 Abs and an Fc gammaRIV blocking Ab (mAb 9E9) were protected against development of liver metastases as well. Only when both Fc gammaRI and Fc gammaRIV functions were simultaneously inhibited, TA99-mediated curative Ab treatment was abrogated, indicating functional redundancy between both IgG receptors in the liver. Furthermore, depletion of liver macrophages (Kupffer cells) reduced the efficacy of Ab therapy, supporting that Kupffer cells are involved as effector cells. Importantly, since Ab treatment almost completely prevented development of liver metastases, postoperative adjuvant Ab therapy may help to improve patient prognosis. 相似文献
2.
Peptides targeting the human neonatal Fc receptor (FcRn) were conjugated to poly(ethylene glycol) (PEG) polymers to study their effect on inhibition of the IgG:FcRn protein-protein interaction both in vitro and in mice. Both linear (5-40kDa) and branched (20, 40kDa) PEG aldehydes were conjugated to an amine-containing linker of a homodimeric anti-FcRn peptide using reductive alkylation chemistry. It was found that conjugation of PEG to the peptide compromised the in vitro activity, with larger and branched PEGs causing the most dramatic losses in activity. The conjugates were evaluated in transgenic mice for their ability to accelerate the catabolism of human IgG. Optimal pharmacodynamic properties were observed with PEG-peptide conjugates that contained 20-40kDa linear PEGs and a 20kDa branched PEG. The optimal PEG-peptide conjugates were more effective in vivo than the unconjugated peptide control on a mole:mole and mg/kg basis, and represent potential new longer-acting peptide therapeutics for the treatment of humorally-mediated autoimmune disease. 相似文献
3.
Stefano Menegatti Mahmud Hussain Amith D. Naik Ruben G. Carbonell Balaji M. Rao 《Biotechnology and bioengineering》2013,110(3):857-870
Cyclic peptides are attractive candidates for synthetic affinity ligands due to their favorable properties, such as resistance to proteolysis, and higher affinity and specificity relative to linear peptides. Here we describe the discovery, synthesis and characterization of novel cyclic peptide affinity ligands that bind the Fc portion of human Immunoglobulin G (IgG; hFc). We generated an mRNA display library of cyclic pentapeptides wherein peptide cyclization was achieved with high yield and selectivity, using a solid‐phase crosslinking reaction between two primary amine groups, mediated by a homobifunctional linker. Subsequently, a pool of cyclic peptide binders to hFc was isolated from this library and chromatographic resins incorporating the selected cyclic peptides were prepared by on‐resin solid‐phase peptide synthesis and cyclization. Significantly, this approach results in resins that are resistant to harsh basic conditions of column cleaning and regeneration. Further studies identified a specific cyclic peptide—cyclo[Link‐M‐WFRHY‐K]—as a robust affinity ligand for purification of IgG from complex mixtures. The cyclo[Link‐M‐WFRHY‐K] resin bound selectively to the Fc fragment of IgG, with no binding to the Fab fragment, and also bound immunoglobulins from a variety of mammalian species. Notably, while the recovery of IgG using the cyclo[Link‐M‐WFRHY‐K] resin was comparable to a Protein A resin, elution of IgG could be achieved under milder conditions (pH 4 vs. pH 2.5). Thus, cyclo[Link‐M‐WFRHY‐K] is an attractive candidate for developing a cost‐effective and robust chromatographic resin to purify monoclonal antibodies (mAbs). Finally, our approach can be extended to efficiently generate and evaluate cyclic peptide affinity ligands for other targets of interest. Biotechnol. Bioeng. 2013; 110: 857–870. © 2012 Wiley Periodicals, Inc. 相似文献
4.
Zhang G Guo J Zhou J Wang X Li Q Yang Y Shen H Zhao D Zhang H Xi J Wang L Qiao S Jin X 《FEBS letters》2006,580(5):1383-1390
To identify the linear epitope for Fc-binding on the bovine IgG2 Fc receptor (boFcgamma2R), peptides derived from the membrane-distal extracellular domain (EC1) of boFcgamma2R corresponding to the homologous region of human FcalphaRI were synthesized. Binding of bovine IgG2 to the different peptides was tested by Dot-blot assay, and the peptide showing maximal binding was further modified by truncation and mutation. The minimum effective peptide 82FIGV85 located in the putative F-G loop of the EC1 domain was found to bind bovine IgG2 specifically and inhibit the binding of bovine IgG2 to the receptor. The Phe82, Ile83 and Val85 residues within the linear epitope were shown to be critical for IgG2-binding. Such functional epitope peptide should be very useful for understanding the IgG-Fcgamma interaction and development of FcR-targeting drugs. 相似文献
5.
Neutrophils are effectors of the innate immune response to adenovirus vectors. Following the systemic administration of Cy2-labeled AdLuc in mice, flow cytometry and PCR analysis of liver leukocytes revealed that 25% of recruited neutrophils interacted with adenovirus vectors. In vitro, flow cytometry of human neutrophils incubated with Cy2-labeled AdLuc also demonstrated a significant interaction with adenovirus vectors. Fluorescence and electron microscopy confirmed vector internalization by neutrophils. The AdLuc-neutrophil interaction reduced vector transduction efficiency by more than 50% in coincubation assays in epithelium-derived cells. Adenovirus vector uptake by neutrophils occurred independently of coxsackievirus adenovirus receptor (CAR) and capsid RGD motifs, since neutrophils do not express CAR and uptake of the RGD-deleted vector AdL.PB* was similar to that of AdLuc. Furthermore, both AdLuc and AdL.PB* activated neutrophils and induced similar degrees of L-selectin shedding. Neutrophil uptake of AdLuc was dependent on the presence of complement and antibodies, since the interaction between AdLuc and neutrophils was significantly reduced when they were incubated in immunoglobulin G-depleted or heat-inactivated human serum. Blocking of complement receptor 1 (CD35) but not complement receptor 3 (CD11b/CD18) significantly reduced neutrophil uptake of AdLuc. Blocking of Fc gammaRI (CD64), Fc gammaRII (CD32), and Fc gammaRIII (CD16) individually or together also reduced neutrophil uptake of AdLuc, although less than blocking of CD35 alone. Combined CR1 and Fc receptor blockade synergistically inhibited neutrophil-AdLuc interactions close to baseline. These results demonstrate opsonin-dependent adenovirus vector interactions with neutrophils and their corresponding receptors. 相似文献
6.
TPO模拟肽与人IgG1 Fc片段的融合表达及其生物学特性研究 总被引:7,自引:0,他引:7
依据本室获得的人TPO模拟肽序列,合成了该模拟肽的DNA序列,分别连接至4种不同长度的人IgG1 Fc基因片段的5′端,并克隆至质粒表达载体pET28a( ),转化大肠杆菌BL21(DE3),筛选获得了4种重组工程菌,其中3种分别高效表达了3种不同长度的融合蛋白,而第4种工程菌未表达,表达的3种融合蛋白的分子量分别约为28kD,12kD和12kD。表达量约占菌体蛋白总量的30%左右,纯化获得了3种TPO模拟肽融合蛋白,3种融合蛋白均有较好的体外活性,维持TPO依赖细胞Ba/F3-mp1生长的EC50分别为:13,10,10nmol/L,用血小板减少症小鼠动物模型,测定了它们的体内活性,3种融合蛋白均有升高血小板和缩短血小板恢复时间的功能,分别比TPO模拟肽活性提高了18,8,8倍,而对白细胞及红细胞无显著影响,分别用3种融合蛋白免疫BALB/c小鼠,均未刺激小鼠产生抗TPO模拟肽抗体,并显示了较好的应用潜力。 相似文献
7.
报道编码牛 Ig G高亲和力受体 ( bovine Ig G Fc receptor I,bo FcγR )的全长序列 .从牛肺巨噬细胞 c DNA文库中克隆的该片段全长 1 .4kb,其中的 ORF为 1 0 50 bp,共编码包括信号肽、胞外域、穿膜区和胞内区在内的 349个氨基酸 ,含有 5个潜在的 N-连接糖基化位点 .与人和鼠的 Ig G高亲和力受体 ( hu FcγR 和 mo FcγR )相比 ,其核苷酸同源性分别为 80 %和 69% ,氨基酸同源性分别为 66%和 55% .研究表明 ,人、牛和鼠的 3种 Ig G高亲和力受体的单体 Ig G结合域高度保守 相似文献
8.
J. W. Prahl 《The Biochemical journal》1967,104(2):647-655
The digestion of the Fc fragment of rabbit immunoglobulin IgG by several proteolytic enzymes was investigated by using gel filtration and starch-gel electrophoresis in 8m-urea-formate as criteria of the extent of degradation. Though fragment Fc and mildly reduced fragment Fc proved resistant to tryptic hydrolysis, papain and pepsin cleaved the fragment at acidic pH values and appeared to give rise to a similar spectrum of products. A (limit) peptide comprising the C-terminal 113 residues of the heavy chain was isolated and identified from the pepsin-digest products of fragment Fc. The products of proteolytic digestion of fragment Fc were no longer able to inhibit passive cutaneous anaphylaxis by rabbit anti-(bovine serum albumin) or demonstrate reversed passive cutaneous anaphylaxis in the guinea pig. Nor were they able to inhibit the intestinal absorption of heterologous immunoglobulin IgG in the young mouse. These studies imply that the site or sites responsible for these biological properties of intact fragment Fc reside in the N-terminal 30-40% of the fragment. 相似文献
9.
Delisle Milton RC Milton SC Chamberlin AR 《International journal of peptide research and therapeutics》2011,17(4):337-342
The anti-inflammatory drug, PMX205, is an antagonist of the C5a complement receptor and has been shown to be effective in
rodent models of amyotrophic lateral sclerosis and Alzheimer’s disease. This cyclic hexapeptide (c[Arg-Trp-D-Cha-Pro-Orn]-Hca)
has been reported to produce relatively low yields for both the linear peptide assembly and the cyclization reaction in solution
and solid phase syntheses. During attempts to reproduce the solid phase methodology, a catastrophic loss of substitution was
encountered which could be avoided or reduced by the use of 2-chlorotrityl resin. Likewise, the cyclization reaction could
be significantly improved by the use of FDPP (pentafluorophenyl diphenylphosphinate) at high dilution (up to 80% purified
yield). Both improvements are accomplished with commercially available products. 相似文献
10.
Matthias J. Feige Susanne Nath Silvia R. Catharino Daniel Weinfurtner Stefan Steinbacher Johannes Buchner 《Journal of molecular biology》2009,391(3):599-40613
A prototypic IgG antibody can be divided into two major structural units: the antigen-binding fragment (Fab) and the Fc fragment that mediates effector functions. The IgG Fc fragment is a homodimer of the two C-terminal domains (CH2 and CH3) of the heavy chains. Characteristic of the Fc part is the presence of a sugar moiety at the inner face of the CH2 domains. The structure of this complex branched oligosaccharide is generally resolved in crystal structures of Fc fragments due to numerous well-defined sugar-protein interactions and a small number of sugar-sugar interactions. This suggested that sugars play an important role in the structure of the Fc fragment. To address this question directly, we determined the crystal structure of the unglycosylated Fc fragment of the murine IgG1 MAK33. The structures of the CH3 domains of the unglycosylated Fc fragment superimpose perfectly with the structure of the isolated MAK33 CH3 domain. The unglycosylated CH2 domains, in contrast, approach each other much more closely compared to known structures of partly deglycosylated Fc fragments with rigid-body motions between 10 and 14 Å, leading to a strongly “closed” conformation of the unglycosylated Fc fragment. The glycosylation sites in the C′E loop and the BC and FG loops are well defined in the unglycosylated CH2 domain, however, with increased mobility and with a significant displacement of about 4.9 Å for the unglycosylated Asn residue compared to the glycosylated structure. Thus, glycosylation both stabilizes the C′E-loop conformation within the CH2 domain and also helps to ensure an “open” conformation, as seen upon Fc receptor binding. These structural data provide a rationale for the observation that deglycosylation of antibodies often compromises their ability to bind and activate Fcγ receptors. 相似文献
11.
Aglycosylation of human IgG1 and IgG3 monoclonal antibodies can eliminate recognition by human cells expressing Fc gamma RI and/or Fc gamma RII receptors. 总被引:5,自引:1,他引:4
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Aglycosylated human IgG1 and IgG3 monoclonal anti-D (Rh) and human IgG1 and IgG3 chimaeric anti-5-iodo-4-hydroxy-3-nitrophenacetyl (anti-NIP) monoclonal antibodies produced in the presence of tunicamycin have been compared with the native glycosylated proteins with respect to recognition by human Fc gamma RI and/or Fc gamma RII receptors on U937, Daudi or K562 cells. Human red cells sensitized with glycosylated IgG3 form rosettes via Fc gamma RI with 60% of U937 cells. Inhibition of rosette formation required greater than 35-fold concentrated more aglycosylated than glycosylated human monoclonal anti-D (Rh) antibody. Unlabelled polyclonal human IgG and glycosylated monoclonal IgG1 and anti-D (Rh) antibody inhibited the binding of 125I-labelled monomeric human IgG binding by U937 Fc gamma RI at concentrations greater than 50-fold lower than the aglycosylated monoclonal IgG1 anti-D (Rh) (K50 approximately 3 x 10(-9) M and approximately 6 x 10(-7) M respectively). Similar results were obtained using glycosylated and aglycosylated monoclonal human IgG1 or IgG3 chimaeric anti-NIP antibody-sensitized red cells rosetting with Fc gamma RI-/Fc gamma RII+ Daudi and K562 cells. Rosette formation could be inhibited by the glycosylated form (at greater than 10(-6) M) but not by the aglycosylated form. Haemagglutination analysis using a panel of murine monoclonal antibodies specific for epitopes located on C gamma 2, C gamma 3 or C gamma 2/C gamma 3 interface regions did not demonstrate differences in Fc conformation between the glycosylated or aglycosylated human monoclonal antibodies. These data suggest that the Fc gamma RI and Fc gamma RII sites on human IgG are highly conformation-dependent and that the carbohydrate moiety serves to stabilize the Fc structure rather than interacting directly with Fc receptors. 相似文献
12.
A family of head-to-tail cyclic peptide models of the antigenic site A (G-H loop of viral protein 1) of foot-and-mouth disease virus has been designed on the basis of the three-dimensional structure adopted by the linear peptide YTASARGDLAHLTTT upon binding to neutralizing monoclonal antibodies. Three different methods of cyclization have been examined to access the peptides. Solution cyclization of a minimally protected linear precursor provided the expected products but required several purification steps that lowered the yields to approximately 10%. The two other approaches relied on side-chain anchoring of the peptide through the Asp residue and cyclization on the solid phase. A synthetic scheme combining Fmoc, tBu and OAI protections was practicable but inefficient when scaled-up. The combination of Boc, Bzl and OFm protections was more promising, but suffered from high epimerization during the initial esterification of Boc-Asp-OFm to benzyl alcohol-type resins. This problem was solved by performing the esterification via the cesium salt of Boc-Asp-OFm. With this improvement, the Boc/Bzl/OFm has become the method of choice for the preparation of cyclic head-to-tail peptides in satisfactory yields and with minimal purification. 相似文献
13.
Prolonged papain digestion of rat IgG2a has recently been shown to yield two species of Fc fragments, termed Fc(I) AND Fc(II). The results of structural studies indicated that Fc(II) fragment was 15 to 20% smaller than Fc(I), probably secondary to loss of a carboxy-terminal peptide. The effects of these structural laterations on the catabolism and biologic properties of the Fc fragments were determined. The results of catabolic experiments indicated that after injection into normal rats Fc(I) fragments were retained in the circulation and slowly catabolized whereas Fc(II) fragments rapidly underwent filtration in the kidneys. In nephrectomized rats, however, both Fc(I) and Fc(II) fragments possessed identical slow rates of catabolism, as determined by serum disappearance and whole body catabolic experiments. Fragment pFc, corresponding to Cgamma3 domain, was different from either of the Fc fragments in exhibiting rapid rates of catabolism in both normal and nephrectomized rats. Fc(I) was more active in complement fixation and in adherence to the Fc receptor on monocytes in comparison with Fc(II). These results support the conclusion that catabolism of Fc and maintenance in circulation are separate processes influenced by different structures in the Fc fragment. The catabolism of Fc is controlled by structures in the Cgamma2 domain. This process probably is not related either to complement fixation or to adherence to the Fc receptor on monocytes. Some correlations between the structure and biologic properties of these Fc fragments are discussed. 相似文献
14.
Ligand-sensitive binding of actin-binding protein to immunoglobulin G Fc receptor I (Fc gamma RI). 总被引:7,自引:0,他引:7
The high affinity receptor that binds the Fc domain of immunoglobulin G (IgG) subclasses 1 and 3 (Fc gamma RI) mediates important immune defense functions by inducing cell surface changes on human leukocytes. In this article, we document direct high affinity binding of Fc gamma RI to the actin filament cross-linking protein, actin-binding protein (ABP). In the absence of IgG, all Fc gamma RI molecules in undifferentiated cells of myeloid line U937 bound to ABP over a 9-fold range of Fc gamma RI expression induced by human IFN-gamma. Binding of IgG to U937 cells constitutively expressing Fc gamma RI or to COS cells genetically transfected to express Fc gamma RI rapidly decreased the avidity of Fc gamma RI for ABP. This finding suggests the existence of a pathway communicating a signal between a functional IgG receptor and intracellular components involved in the effector responses to Fc gamma RI-ligand interaction. 相似文献
15.
N-Glycans at Asn(297) in the Fc domain of IgG molecules are required for Fc receptor-mediated effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In this study we have specifically remodeled the Fc N-glycans of intact recombinant IgG(1) therapeutic monoclonal antibody (Mab) products, Rituxan and Herceptin, with a soluble recombinant rat beta-1,4-N-acetylglucosaminyltransferase III (rGnTIII) produced by baculovirus-infected insect cells. N-Glycan remodeling in vitro permitted a controlled and selective transfer of a bisecting beta1,4-linked GlcNAc to the core beta-linked mannose of degalactosylated Mab N-glycans to yield Mabs varying in bisecting GlcNAc content from 31% to 85%. This was confirmed by analysis of N-glycans by both normal phase HPLC and MALDI-MS, the latter yielding the expected mass increase of 203.2 Da with no other oligosaccharide modifications evident. ADCC of remodeled Rituxan and Herceptin Mabs was determined using peripheral blood mononuclear cells as effectors and either CD20(+) (SKW6.4 and SU-DHL-4) or Her2(+) (SKBR-3) target cells, respectively. A conserved 10-fold increase in ADCC was observed for both remodeled therapeutic Mabs with high (>80%) bisecting GlcNAc content. In contrast, although the presence of a bisecting GlcNAc had minimal effect on CDC, degalactosylation of Rituxan reduced CDC by approximately half, relative to unmodified (variably galactosylated) control Mab. In summary, our data suggests that in vitro remodeling of therapeutic Mab Fc N-glycans may be utilized to control the therapeutic efficacy of Mabs in vivo and to offer a more "humanized" glycoform profile for recombinant Mab products. 相似文献
16.
The erythroleukemic cell line K562 bears a 40-kDa Fc receptor (Fc gamma RII) serologically related to and with a similar molecular weight as the Fc gamma R present on a broad range of leukocytes. The human IgG subclass specificity of the Fc gamma R on K562 was investigated using IgG aggregates of defined size, obtained from purified human myeloma proteins. The monoclonal antibody IV.3, which reacts with the Fc gamma RII present on various cell types, totally prevented binding of 125I-IgG2 trimers to K562. Experiments with radiolabeled IgG2 trimers showed that K562 cells bound a mean of 156,764 +/- 9895 molecules per cell with an association constant (Ka) of 1.8 +/- 0.7 X 10(8) M-1. Similar results were obtained with IgG3 oligomers. IgG3 and IgG2 trimers were about two- to threefold more effective in inhibiting binding of 125I-IgG2 trimers to K562 than IgG1 and IgG4 trimers. These results were confirmed by inhibition experiments using IgG monomers. The subclass specificity of the Fc gamma RII on K562 (i.e., IgG2 = IgG3 greater than IgG1 = IgG4) is quite distinct from the one reported for the Fc gamma RI and III of human cells (i.e., IgG1 = IgG3 greater than IgG4 and IgG2). 相似文献
17.
Baudino L Shinohara Y Nimmerjahn F Furukawa J Nakata M Martínez-Soria E Petry F Ravetch JV Nishimura S Izui S 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(9):6664-6669
Replacement of aspartic acid by alanine at position 265 (D265A) in mouse IgG1 results in a complete loss of interaction between this isotype and low-affinity IgG Fc receptors (Fc gammaRIIB and Fc gammaRIII). However, it has not yet been defined whether the D265A substitution could exhibit similar effects on the interaction with two other Fc gammaR (Fc gammaRI and Fc gammaRIV) and on the activation of complement. To address this question, 34-3C anti-RBC IgG2a and IgG2b switch variants bearing the D265A mutation were generated, and their effector functions and in vivo pathogenicity were compared with those of the respective wild-type Abs. The introduction of the D265A mutation almost completely abolished the binding of 34-3C IgG2a and IgG2b to all four classes of Fc gammaR and the activation of complement. Consequently, these mutants were hardly pathogenic. Although oligosaccharide side chains of these mutants were found to contain higher levels of sialic acids than those of wild-type Abs, the analysis of enzymatically desialylated D265A variants ruled out the possibility that very poor Fc-associated effector functions of the D265A mutants were due to an increased level of the mutant Fc sialylation. Thus, our results demonstrate that aspartic acid at position 265 is a residue critically implicated in triggering the Fc-associated effector functions of IgG, probably by defining a crucial three-dimensional structure of the Fc region. 相似文献
18.
Maturation-related changes in the expression of Fc gamma RII and Fc gamma RIII on mouse mast cells derived in vitro and in vivo. 总被引:2,自引:0,他引:2
H R Katz J P Arm A C Benson K F Austen 《Journal of immunology (Baltimore, Md. : 1950)》1990,145(10):3412-3417
The expression and function of Fc gamma RII and Fc gamma RIII on three mouse mast cell populations that differ in maturity as assessed by secretory granule constituents were analyzed by cellular and immunochemical approaches. As quantified by flow cytometric analysis of the binding of the rat 2.4G2 anti-Fc gamma RII/III mAb, mouse serosal mast cells (SMC) purified from the peritoneal cavity expressed more receptors per cell than did mouse IL-3-dependent, bone marrow culture-derived mast cells (BMMC), which are progenitors of SMC. Coculture of BMMC with mouse 3T3 fibroblasts for 2 wk, which alters the secretory granule composition toward that of SMC, also increased receptor epitope expression to a level equivalent to that of SMC. As assessed by rosette assays with mouse mAb to SRBC, all three mast cell populations bound IgG1, IgG2a, and IgG2b, essentially all binding was inhibited by 2.4G2 antibody, and greater quantities of the antibody were required to block immune adherence by cocultured mast cells and SMC as compared with BMMC. Immunoprecipitation and SDS-PAGE analysis of Fc gamma RII and Fc gamma RIII from BMMC, cocultured mast cells, and SMC that were surface radiolabeled with Na125I revealed predominant native forms of 62, 57, and 56 kDa, respectively, and an additional surface form of 43 kDa in SMC. Removal of N-linked carbohydrate from immunoprecipitates demonstrated that BMMC expressed peptide cores of 38 kDa (Fc gamma RII-1 gene product) and 31 kDa (Fc gamma RII-2 gene product), and barely detectable amounts of a 28-kDa (Fc gamma RIII gene product) core. The expression of all three was increased by coculture with 3T3 fibroblasts, consistent with the increased expression of their common epitope by cytofluorographic analysis. SMC expressed primarily the Fc gamma RII-1 and some Fc gamma RIII gene product. Thus, the three populations of mast cells express different amounts and ratios of the Fc gamma RII and Fc gamma RIII gene products, and maturation of BMMC during coculture with fibroblasts in vitro and in the peritoneal cavity in vivo augments cell-surface expression of the receptors and immune adherence function. 相似文献
19.
Human Fc gamma RI and Fc gamma RII interact with distinct but overlapping sites on human IgG. 总被引:5,自引:0,他引:5
J Lund G Winter P T Jones J D Pound T Tanaka M R Walker P J Artymiuk Y Arata D R Burton R Jefferis 《Journal of immunology (Baltimore, Md. : 1950)》1991,147(8):2657-2662
Cellular receptors for IgG (Fc gamma R) mediate important protective functions. By using site-specific mutants of a chimeric antibody (mouse V H domain and L chain; human IgG3 C H domains), we have demonstrated that human Fc gamma RI interacts with a site in the lower hinge of human IgG (residues 234 to 237) and that this interaction dictates Fc gamma RI-mediated superoxide generation. Mutations at position 235 resulted in the most profound reductions in Fc gamma RI recognition. We have also mapped an interaction site for Fc gamma RII to the same region; however, mutations at position 234 and 237 resulted in the greatest reductions in Fc gamma RII recognition. The two receptors appear to recognize overlapping but nonidentical sites on the lower hinge of IgG. Deviations from the optimal motif 234-Leu-Leu-Gly-Gly-237 may then explain the human IgG subclass specificity profile for human Fc gamma RI and Fc gamma RII. 相似文献
20.
Role of FcRs in animal model of autoimmune bullous pemphigoid 总被引:2,自引:0,他引:2
Zhao M Trimbeger ME Li N Diaz LA Shapiro SD Liu Z 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(5):3398-3405
Bullous pemphigoid (BP) is a bullous dermatosis associated with autoantibodies directed against the hemidesmosomal Ags BP180 and BP230. Lesional skin is characterized by detachment of the epidermis from the dermis with an intense inflammatory cell infiltrate in the upper dermis. In experimental BP, subepidermal blistering is triggered by rabbit anti-murine BP180 (mBP180) IgG and depends upon complement activation, mast cell degranulation, and neutrophil infiltration. In this study, we determined the role of Fc gammaRs on neutrophils in experimental BP. Mice deficient in Fc gammaRIII (Fc gammaRIII-/-) and those deficient in both Fc gammaRI and Fc gammaRIII (Fc gammaRI&III-/-) but not in Fc gammaRII (Fc gammaRII-/-) were resistant to BP. Pathogenic IgG activated wild-type neutrophils, but not Fc gammaRIII-deficient neutrophils, to secrete proteolytic enzymes. The function of anti-mBP180 IgG depended entirely on its Fc domain; F(ab')2 of IgG had no pathogenic activities. In wild-type mice injected with pathogenic IgG, an Fc gammaR blocker abolished the BP phenotype and inhibited activation of wild-type neutrophils stimulated by pathogenic IgG. Results from this study establish that Fc gammaRIII plays a critical role in the activation of infiltrating neutrophils and the subsequent blistering in experimental BP. 相似文献