Showing papers on "Fc receptor published in 2007"
TL;DR: There is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody.
Abstract: Many effective vaccines act by inducing neutralizing antibodies, and this approach is a top priority in work on HIV vaccines. But a new study suggests that anti-HIV antibodies are most effective when they act in two ways: through neutralization — killing the virus outright and blocking its entry into T cells — and by killing infected cells. The use of engineered versions of a neutralizing human antibody that protects against HIV in a monkey model shows that protection is dependent not only the antibody's neutralizing activity, but also on its interaction with Fc receptors on effector cells, which may act to reduce virus yield from infected cells. This work suggests that the best results might be achieved with vaccines that recruit both neutralizing antibodies and cell-mediated immunity via agents such as macrophages and cytokinins, rather than antibodies. Passively administered neutralizing antibodies have been shown to protect macaques against challenge by the HIV/SIV chimeric SHIV. The antiviral effects of the monoclonal antibody b12 are crucially dependent on antibody effector mechanisms. Most successful vaccines elicit neutralizing antibodies and this property is a high priority when developing an HIV vaccine1,2. Indeed, passively administered neutralizing antibodies have been shown to protect against HIV challenge in some of the best available animal models. For example, antibodies given intravenously can protect macaques against intravenous or mucosal SHIV (an HIV/SIV chimaera) challenge and topically applied antibodies can protect macaques against vaginal SHIV challenge3,4. However, the mechanism(s) by which neutralizing antibodies afford protection against HIV is not understood and, in particular, the role of antibody Fc-mediated effector functions is unclear. Here we report that there is a dramatic decrease in the ability of a broadly neutralizing antibody to protect macaques against SHIV challenge when Fc receptor and complement-binding activities are engineered out of the antibody. No loss of antibody protective activity is associated with the elimination of complement binding alone. Our in vivo results are consistent with in vitro assays indicating that interaction of Fc-receptor-bearing effector cells with antibody-complexed infected cells is important in reducing virus yield from infected cells. Overall, the data suggest the potential importance of activity against both infected cells and free virus for effective protection against HIV.
938 citations
TL;DR: In a xenograft murine model of B-cell malignancy, the greatest enhancement of an Fc-optimized anti-human B- cell mAb was accounted for by improved binding to FcgammaRIV, a unique mouse activating FcGammaR that is expressed by monocytes and macrophages but not natural killer cells.
Abstract: Monoclonal antibodies (mAb) are widely used in the treatment of non-Hodgkin's lymphoma and autoimmune diseases. Although the mechanism of action in vivo is not always known, the therapeutic activity of several approved mAbs depends on the binding of the Fcgamma regions to low-affinity Fcgamma receptors (FcgammaR) expressed on effector cells. We did functional genetic screens to identify IgG1 Fc domains with improved binding to the low-affinity activating Fc receptor CD16A (FcgammaRIIIA) and reduced binding to the low-affinity inhibitory Fc receptor, CD32B (FcgammaRIIB). Identification of new amino acid residues important for FcgammaR binding guided the construction of an Fc domain that showed a dramatically enhanced CD16A binding and greater than a 100-fold improvement in antibody-dependent cell-mediated cytotoxicity. In a xenograft murine model of B-cell malignancy, the greatest enhancement of an Fc-optimized anti-human B-cell mAb was accounted for by improved binding to FcgammaRIV, a unique mouse activating FcgammaR that is expressed by monocytes and macrophages but not natural killer (NK) cells, consistent with experimental and clinical data suggesting that mononuclear phagocytes, effector cells expressing both activating and inhibitory FcgammaR, are critical mediators of B-cell depletion in vivo. By using mice transgenic for human CD16A, enhanced survival was observed due to expression of CD16A-158(phe) on monocytes and macrophages as well as on NK cells in these mice. The design of new generations of improved antibodies for immunotherapy should aim at Fc optimization to increase the engagement of activating FcgammaR present on the surface of tumor-infiltrating effector cell populations.
383 citations
TL;DR: In contrast to the conventional FCR, FCRL molecules possess diverse extracellular frameworks, autonomous or dual signaling properties, and preferential B lineage expression, but there is no strong evidence thus far to support a role for them as Ig-binding receptors.
Abstract: Discovery of a large family of Fc receptor-like (FCRL) molecules, homologous to the well-known receptors for the Fc portion of immunoglobulin (FCR), has uncovered an impressive abundance of immunoglobulin superfamily (IgSF) genes in the human 1q21–23 chromosomal region and revealed significant diversity for these genes between humans and mice. The observation that FCRL representatives are members of an ancient multigene family that share a common ancestor with the classical FCR is underscored by their linked genomic locations, gene structure, shared extracellular domain composition, and utilization of common cytoplasmic tyrosine-based signaling elements. In contrast to the conventional FCR, however, FCRL molecules possess diverse extracellular frameworks, autonomous or dual signaling properties, and preferential B lineage expression. Most importantly, there is no strong evidence thus far to support a role for them as Ig-binding receptors. These characteristics, in addition to their identification ...
201 citations
TL;DR: Results reveal an unexpected inhibitory role for the activating FcgammaRIII in mediating suppression of IFN-gamma signaling and suggest that inhibition of macrophage responses to IFN -gamma contributes to the anti-inflammatory properties of IVIG.
163 citations
TL;DR: Evidence is presented that skin- but not lung-associated primary mast cells as well as in vitro-differentiated bone marrow-derived mast cells (BMMC) express granzyme (gzm) B, but not gzmA or perforin (perf), suggesting that activated mast cells contribute, via secreted gzmB, to cell death, increased vascular permeability, leukocyte extravasation and subsequent inflammatory processes in affected tissues.
Abstract: Mast cells respond to pathogens and allergens by secreting a vast array of preformed and newly synthesized mediators, including enzymes, vasoactive amines, lipid mediators, cytokines and chemokines, thereby affecting innate and adaptive immune responses and pathogenesis. Here, we present evidence that skin-, but not lung-associated primary mast cells as well as in vitro-differentiated bone marrow-derived mast cells (BMMC) express granzyme (gzm) B, but not gzmA or perforin (perf). GzmB is associated with cytoplasmic granules of BMMC and secreted after Fcepsilon-receptor-mediated activation. BMMC from wild type but not gzmB-deficient mice cause cell death in susceptible adherent target cells, indicating that the perf-independent cytotoxicity of BMMC is executed by gzmB. Furthermore, gzmB induces a disorganization of endothelial cell-cell contacts. The data suggest that activated mast cells contribute, via secreted gzmB, to cell death, increased vascular permeability, leukocyte extravasation and subsequent inflammatory processes in affected tissues.
136 citations
Journal Article•
TL;DR: The concept that abatacept therapeutic activity is primarily due to the binding to CD80/86 through the CTLA4 extracellular domain and not through activities mediated by the modified Fc domain is supported.
Abstract: OBJECTIVE: To assess the ability of abatacept to mediate complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC) of antigen-presenting cells, and to characterize the binding of abatacept to the 3 Fc receptor classes. METHODS: CDC was measured in vitro using rabbit, baby rabbit, guinea pig, or human complement with human B cell line PM-LCL as the target. ADCC was also measured with PM-LCL target cells, but with human peripheral blood mononuclear cells from 12 healthy blood donors as effectors. Fc receptor binding was analyzed in vitro by flow cytometry and surface plasmon resonance (SPR). RESULTS: In contrast to unmodified CTLA4-Ig, abatacept did not mediate CDC or ADCC of target B cells. While abatacept was found to bind its target receptor, CD80/86, it did not appreciably bind the low-affinity Fc receptors CD16 and CD32 as measured by flow cytometry and SPR. Abatacept was found to minimally bind the high-affinity Fc receptor CD69 as measured by flow cytometry and SPR with a Kd of 3 X 10-7 M as measured by SPR. CONCLUSION: Abatacept does not mediate CDC or ADCC of target B cells in vitro and has limited Fc receptor binding. These data support the concept that abatacept therapeutic activity is primarily due to the binding to CD80/86 through the CTLA4 extracellular domain and not through activities mediated by the modified Fc domain.
118 citations
TL;DR: SSL11 is a staphylococcal protein that targets myeloid cells by binding sialyllactosamine‐containing glycoproteins and a single amino acid mutation in the carbohydrate binding site abolished all SSL11 binding.
Abstract: Staphylococcus aureus is a major pathogen that produces a family of 14 staphylococcal superantigen-like (SSL) proteins, which are structurally similar to superantigens but do not stimulate T cells. SSL11 is one member of the family that is found in all staphylococcal strains. Recombinant SSL11 bound to granulocytes and monocytes through a sialic acid-dependent mechanism and was rapidly internalized. SSL11 also bound to sialic acid-containing glycoproteins, such as the Fc receptor for IgA (FcalphaRI) and P-selectin glycoprotein ligand-1 (PSGL-1), and inhibited neutrophil attachment to a P-selectin-coated surface. Biosensor analysis of two SSL11 alleles binding to sialyl Lewis X [sLe(x)- Neu5Acalpha2-3Galbeta1-4(Fuc1-3)GlcNAc] coupled to bovine serum albumin gave dissociation constants of 0.7 and 7 mum respectively. Binding of SSL11 to a glycan array revealed specificity for glycans containing the trisaccharide sialyllactosamine (sLacNac - Neu5Acalpha2-3Galbeta1-4GlcNAc). A 1.6 A resolution crystal structure of SSL11 complexed with sLe(x) revealed a discrete binding site in the C-terminal beta-grasp domain, with predominant interactions with the sialic acid and galactose residues. A single amino acid mutation in the carbohydrate binding site abolished all SSL11 binding. Thus, SSL11 is a staphylococcal protein that targets myeloid cells by binding sialyllactosamine-containing glycoproteins.
106 citations
TL;DR: A nonmammalian Fcγ receptor, CHIR-AB1, a member of the leukocyte receptor complex, that binds IgY with high affinity with its single Ig domain is described, representing a primordial Fc receptor that combines features of different mammalian counterparts.
Abstract: Fc receptors are key players of the immune system that link the fine specificity of immunoglobulins and innate effector responses. Here, we describe a nonmammalian Fcγ receptor, CHIR-AB1, a member of the leukocyte receptor complex, that binds IgY with high affinity with its single Ig domain. It is expressed on immature and mature B lymphocytes, monocytes, macrophages, and natural killer cells and harbors motifs of activating and inhibitory Fc receptors. In the absence of FceRIγ, CHIR-AB1 can be expressed on B cells but cross-linking does not induce intracellular calcium release. In contrast, cells expressing CHIR-AB1 and FceRIγ are triggered to release intracellular calcium upon stimulation with heat-aggregated IgY. CHIR-AB1 thus represents a primordial Fc receptor that combines features of different mammalian counterparts.
102 citations
TL;DR: It is concluded that FCRL5 has the functional potential to serve as an inhibitory coreceptor on mature B cells in humans.
Abstract: The Fc receptor-like protein 5 (FCRL5) on B cells has both an immunoreceptor tyrosine-based activation motif (ITAM)-like sequence and two consensus immunoreceptor tyrosine-based inhibitory motifs (ITIM) in its cytoplasmic region. To evaluate its signaling potential, we expressed constructs for chimeric molecules composed of the cytoplasmic region of FCRL5 and the extracellular and transmembrane regions of the IgG Fc receptor FcγRIIB in a B cell line lacking an endogenous Fc receptor. Coligation of this fusion protein with the B cell receptor (BCR) inhibited BCR-mediated calcium mobilization, intracellular tyrosine phosphorylation, and Erk kinase activation. Our mutational analysis indicated that, whereas tyrosines in both the inhibitory and activation motifs are phosphorylated after ligation, only those in ITIMs influence BCR-mediated signaling. This FCRL5 inhibitory effect was mediated through dual ITIM recruitment of the SH2-containing protein tyrosine phosphatase, SHP-1, which in turn dephosphorylates the ITAM-based tyrosines in BCR Igα/Igβ heterodimers. An FCRL5 inhibitory effect on BCR signaling was likewise demonstrable for primary B cells. Although its ligand is presently unknown, we conclude that FCRL5 has the functional potential to serve as an inhibitory coreceptor on mature B cells in humans.
100 citations
TL;DR: Staining with HLA tetramers provides a means for identifying, quantifying, and isolating HLA-specific B cells.
Abstract: Background. The development of highly sensitive and specific assays for detecting and characterizing HLA-specific antibodies has contributed to an appreciation of the extensive involvement of those antibodies in graft injury and dysfunction. However, understanding the regulatory processes of the humoral response to transplantation and the mechanisms underlying therapeutic agents and protocols for preventing and treating sensitization requires a way to study HLA-specific B cells. Methods. Lymphocyte preparations enriched for B cells were stained with one or more of three different HLA tetramers. Tetramer-positive (tet+) B cells were enumerated and evaluated for an association of their frequencies with known sensitization. In some cases, tet+ B cells were isolated and placed in culture with supplements known to activate B cells in a nonspecific fashion. Results. For all tetramers used, the frequencies of tet+ B cells were significantly higher (4.1%-5.5%) among sensitized patients than among nonsensitized patients (1.6%-3.2%, P<0.001). Binding of the tetramers occurred by the surface immunoglobulin antigen receptor with little or no binding to antibody captured in the Fc receptor. Cultured tet+ B cells produced antibodies specific for epitopes of the tetramer antigen. There appeared to be a certain amount of crossreactivity in the binding of tetramers. The frequency of CD27+ cells among tet+ B cells was higher, on average (34.4%-38.8%) than among all B cells (26.2%) whereas the frequencies of CD38 were comparable in the two groups. Conclusions. Staining with HLA tetramers provides a means for identifying, quantifying, and isolating HLA-specific B cells.
74 citations
TL;DR: The objective is to determine whether a functional single-nucleotide polymorphism in the gene encoding Fc receptor type IIIA (FcRIIIA) correlates with the response to treatment with tumor necrosis factor (TNF) during the first trimester of cancer treatment.
Abstract: Objective: To determine whether a functional single-nucleotide polymorphism in the gene encoding Fc receptor type IIIA (FcRIIIA) correlates with the response to treatment with tumor necrosis factor ...
TL;DR: It is strongly suggested that in vivo activation of TNFalpha-primed neutrophils by atypical ANCAs of IVIg may contribute to the side effects ofIVIg therapy and for the first time demonstrate that the activation of neutrophil granulocytes by IVIG occurs in an Fc receptor (FcR)-independent, hence antigen-dependent, way.
TL;DR: Using IgM and IgA ligands and newly generated Fcα/μR specific monoclonal antibodies the authors have defined biochemical features and cellular distribution of the human Fcβ-μR, which may function in antigen presentation and B cell selection in the germinal center response.
Abstract: The Fc receptor for IgA and IgM (Fcalpha/muR) is of particular interest because it can bind antibodies of both IgM and IgA isotypes and thus may play a pivotal role in systemic and mucosal immunity. Using IgM and IgA ligands and newly generated Fcalpha/muR specific monoclonal antibodies we have defined biochemical features and cellular distribution of the human Fcalpha/muR. Both recombinant and native forms of human Fcalpha/muR are expressed on the cell surface as remarkably stable homodimeric transmembrane glycoproteins that can bind specifically polymeric IgM or IgA. The only human B cells to express Fcalpha/muR, albeit at very low levels, are found in the pre-germinal center subpopulation defined by the IgD+/CD38+ phenotype. Hence the expression pattern differs from that of the mouse wherein Fcalpha/muR is expressed by both circulating and resident B cell populations. Significantly, the predominant cell type expressing the Fcalpha/muR in humans is the follicular dendritic cell of germinal centers. The Fcalpha/muR may thus function in antigen presentation and B cell selection in the germinal center response.
TL;DR: Results suggest that the innate immune system is at least in part regulated by the qualitative and quantitative balance of the paired receptors LMIR3 and LMIR4.
TL;DR: A reduction in RBC CD47 expression just below 50% of that in normal RBCs can significantly accelerate RBC clearance by macrophages in the presence of RBC autoantibodies.
TL;DR: IgG Fc receptors limit the neutralization of gamma-herpesviruses such as MHV-68, which appeared to be predominantly latent in macrophages regardless of whether Fc receptor+ cells were engaged.
Abstract: Background. Herpesviruses can be neutralized in vitro but remain infectious immune hosts. One difference betweeh these settings is the availability of immunoglobulin Fc receptors. The question therefore arises whether a herpesvirus exposed to apparently neutralizing antibody can still infect Fc receptor+ cells. Principal Findings. Immune sera blocked murine gamma herpesvirus-68 (MHV-68) infection of fibroblasts, but failed to block and even enhanced its infection of macrophages and dendritic cells. Viral glycoprotein-specific monoclonal antibodies also enhanced infection. MHV-68 appeared to be predominantly latent in macrophages regardless of whether Fc receptors were engaged: but the infection was not abortive and new virus production soon overwhelmed infected cultures, Lyticaily infected macrophages down-related MHC class 1-restricted antigen presentation, endocytosis and their response to LPS. Conclusions. IgG Fc receptors limit the neutralization of gamma-herpesviruses such as MHV-68. Copyright
TL;DR: In an effort to understand developmental aspects of immune receptor function, the partially annotated zebrafish genome is accessed to identify six different adaptor molecules that are homologous to those effecting immune function in mammals.
TL;DR: Expansion of FcRL6-positive lymphocytes is indicative of the dysregulated expansion of terminally differentiated effector lymphocyte populations in response to chronic HIV-1 infection and may serve as an important marker for chronic immune activation and for tracking the generation of effector cells following immune stimulation.
TL;DR: Results demonstrate that expression of FcRγ, most likely FcγRI, on APCs is important during the sensitization phase for the development of allergic airway inflammation and AHR.
Abstract: The FcR common γ-chain (FcRγ) is an essential component of the receptors FceRI, FcγRI, and FcγRIII, which are expressed on many inflammatory cell types. The role of these receptors in the initiation or maintenance of allergic inflammation has not been well defined. FcRγ-deficient (FcRγ−/−) and control (wild-type (WT)) mice were sensitized and subsequently challenged with OVA. Following sensitization and challenge to OVA, FcRγ-deficient (FcRγ−/−) mice developed comparable levels of IgE and IgG1 as WT mice. However, numbers of eosinophils, levels of IL-5, IL-13, and eotaxin in bronchoalveolar lavage fluid, and mononuclear cell (MNC) proliferative responses to OVA were significantly reduced, as was airway hyperresponsiveness (AHR) to inhaled methacholine. Reconstitution of FcRγ−/− mice with whole spleen MNC from WT mice before sensitization restored development of AHR and the numbers of eosinophils in bronchoalveolar lavage fluid; reconstitution after sensitization but before OVA challenge only partially restored these responses. These responses were also restored when FcRγ−/− mice received T cell-depleted MNC, T and B cell-depleted MNC, or bone marrow-derived dendritic cells before sensitization from FcR+/+ or FcγRIII-deficient but not FcRγ−/− mice. The expression levels of FcγRIV on bone marrow-derived dendritic cells from FcR+/+ mice were found to be low. These results demonstrate that expression of FcRγ, most likely FcγRI, on APCs is important during the sensitization phase for the development of allergic airway inflammation and AHR.
TL;DR: The ability of the model to predict the antibody dose dependence of the macrophage phagocytic efficacy for C. neoformans strongly suggest that the major variables that determine the efficacy of this process have been identified.
Abstract: Macrophages ingest the fungus Cryptococcus neoformans only in the presence of opsonins, and this provides a remarkably clean system for the detailed analysis of phagocytosis. This system is also unusual in that antibody-mediated phagocytosis involves ingestion through both Fc and complement receptors in the absence of complement. Mathematical modeling was used to analyze and explain the experimental data that the macrophage phagocytic index increased with increasing doses of antibody despite saturating concentrations and declined at high concentrations. A model was developed that explains the increase in phagocytic index with increasing antibody doses, differentiates among the contributions from Fc and complement receptors, and provides a tool for estimating antibody concentrations that optimize efficacy of phagocytosis. Experimental results and model calculations revealed that blocking of Fc receptors by excess antibody caused a reduction in phagocytic index but increased phagocytosis through complement receptors rapidly compensated for this effect. At high antibody concentrations, a further reduction in phagocytic index was caused by interference with complement receptor ingestion as a consequence of saturation of the fungal capsule. The ability of our model to predict the antibody dose dependence of the macrophage phagocytic efficacy for C. neoformans strongly suggest that the major variables that determine the efficacy of this process have been identified. The model predicts that the affinity constant of the opsonic antibody for the Fc receptor and the association-dissociation constant of antibody from the microbial antigen are critical parameters determining the efficacy of phagocytosis.
TL;DR: The study demonstrates a link between Toll-like and Fc receptor signaling and thyroid gland function, uncovering a role of mast cells in murine NTI.
Abstract: Bacterial infections and other pathologic conditions induce complex dysfunctions of the hypothalamic-pituitary-thyroid axis, collectively known as nonthyroidal illness (NTI). To explore the pathogenesis of bacterial NTI, we injected Mycobacterium tuberculosis extracts or Escherichia coli LPS in mice lacking key components of the Toll-like receptor or crystallizable fragment (Fc) receptor pathways. In wild-type mice, the bacterial components induced a hypothyroidism characterized by elements of both hypothalamic and thyroidal dysfunction. This NTI hypothyroidism did not develop in mice lacking the MyD88 adaptor or in those with a reduced number of mast cells. The hypothyroid responsiveness to LPS, however, was restored upon reconstitution with mast cells derived from the bone marrow of wild-type donors. In addition to bacterial components, whole immunoglobulins induced NTI hypothyroidism in wild-type mice, but not in those lacking activating Fc receptors or mast cells. The study demonstrates a link between Toll-like and Fc receptor signaling and thyroid gland function, uncovering a role of mast cells in murine NTI.
Patent•
13 Apr 2007
TL;DR: In this paper, the binding proteins comprising one or more immunoglobulin Fc region hinge, CH2 and/or CH3 domain are modified to alter the binding protein's binding affinity and specificity for a cognate receptor.
Abstract: Provided herein are binding proteins comprising one or more immunoglobulin Fc region hinge, CH2, and/or CH3 domain wherein one or more hinge and/or constant region CH2 and/or CH3 domain is modified to alter the binding protein's binding affinity and/or specificity for a cognate receptor (eg, an Fc receptor) and/or to impart one or more new binding specificity(ies) to the hinge and/or constant region that the corresponding unmodified immunoglobulin does not possess (eg, affinity for distinct class of cognate receptor distinct from the class of cognate receptor to which the unmodified binding protein specifically binds) Binding proteins according to the present invention include, for example, modified antibodies, antibody fragments, recombinant binding proteins, and molecularly engineered binding domain-immuno globulin fusion proteins, including small modular immunopharmaceutical products (SMIP™ products)
TL;DR: The main signal transduction pathways that are initiated by Fc receptors and integrins in phagocytic leukocytes are described, with emphasis on the activation ofphagocytosis and gene expression.
Abstract: Specific receptors for antibodies, named Fc receptors, and for extracellular matrix proteins, named integrins, contribute to phagocyte activation. Because phagocyte activation is the mechanism whereby most of the potential pathogens are ultimately destroyed, there is a lot of interest to elucidate the biochemical signals that Fc receptors and integrins induce to activate phagocyte functions. This review describes the main signal transduction pathways that are initiated by Fc receptors and integrins in phagocytic leukocytes, with emphasis on the activation of phagocytosis and gene expression. New findings on the common signaling pathways used by Fc receptors and integrins are also discussed.
TL;DR: In this article, a full-length chicken monocyte transcript was cloned and expressed that encodes an avian homologue of the mammalian FcR family, chFcR/L, which is a transmembrane protein with four extracellular Ig-like domains and a short cytoplasmic tail.
Abstract: Homologues of almost all mammalian Ig-like immunoregulatory receptor families have been found in the chicken, except the Fc receptor (FcR) family. In addition to classical FcRs that specifically bind antibodies and mediate their effector functions, this family includes “Fc receptor-like” (FCRL) proteins for which ligands have yet to be identified. We have cloned and expressed a full-length chicken monocyte transcript that encodes an avian homologue of the mammalian FcR family. We have termed it chFcR/L as it possesses characteristics of both mammalian FcR and FCRL, but is phylogenetically distinct from either. chFcR/L is a transmembrane protein with four extracellular Ig-like domains and a short cytoplasmic tail. It can be expressed on the cell surface only in the presence of an accessory molecule, chFcRγ, through which it acquires signalling potential.
TL;DR: This chapter discusses the biology of spleen tyrosine kinase (Syk), its inhibitors and therapeutic applications, and R112 is the first small molecule inhibitor of Syk kinase that has advanced to Phase 2 clinical trials.
Abstract: Publisher Summary This chapter discusses the biology of spleen tyrosine kinase (Syk), its inhibitors and therapeutic applications The most understood function of Syk kinase activity is in ITAM-dependent activation of immunoreceptors, including Fc receptor complexes (FcR) that bind the invariable Fc portion of the different immunoglobulin isotypes and the immunoglobulin B-cell-antigen receptor (BCR) complex Allergic disorders are characterized by hypersensitive type I immune responses, mediated by immunoglobulin isotype E (IgE), to foreign antigens Only a handful of pertinent Syk kinase inhibitors have been reported One such example has been a family of pyrimidine-5-carboxamides R112 is the first small molecule inhibitor of Syk kinase that has advanced to Phase 2 clinical trials Compound R112 inhibited Syk kinase with Ki = 0096 mM, selectively inhibited tryptase release from human mast cells induced by anti-IgE cross-linking, histamine from basophils, and dust mite allergen induced histamine release from human basophils with EC50S = 0353, 028 and 049 mM, respectively One advantage of compound 8 was its rapid onset of action since rapidly effective treatment is highly desirable during an allergic attack
TL;DR: It is suggested that CR3 and FcR play a critical role in production of MMP-9 and may be regulated by intracellular signal transduction, including that by phosphoinositide 3-kinase (PI3K) and tyrosine kinase (TK).
Abstract: Complement receptor type 3 (CR3)- and Fc receptor (FcR)-mediated metalloproteinase-9 (MMP-9) secretion and their intracellular signalling of bovine neutrophils were evaluated. Relative density of MMP-9 secreted by neutrophils stimulated with opsonized zymosan (OPZ, stimulant for CR3) was significantly (p < 0.05) increased when the OPZ concentration was increased from 0 to 0.4 mg/ml. Similar results were obtained for neutrophils stimulated with heat-aggregated IgG (Agg-IgG, stimulant for Fc receptor) at concentrations from 0 to 0.40 mg/ml. Preincubation of neutrophils with 1-30 nmol/L wortmannin (phosphoinositide 3-kinase inhibitor) resulted in inhibition of MMP-9 secretion induced by stimulation with OPZ and Agg-IgG in a concentration-dependent manner, 30 nmol/L wortmannin causing complete inhibition. Similarly, preincubation of neutrophils with 0-100 mumol/L genistein (tyrosine kinase inhibitor) also resulted in inhibition of OPZ- and Agg-IgG-induced MMP-9 secretion in a concentration-dependent manner, with 100 micromol/L genistein causing complete inhibition. Significant (p < 0.05) positive correlations were found between MMP-9 and luminal-dependent chemiluminescent response (LDCL) in the case of stimulation with OPZ (r = 0.754) and in the case of stimulation with Agg-IgG (r = 0.728). Our findings suggested that CR3 and FcR play a critical role in production of MMP-9 and may be regulated by intracellular signal transduction, including that by phosphoinositide 3-kinase (PI3K) and tyrosine kinase (TK).
[...]
TL;DR: This data indicates that TGF-β is a major determinant of Drosophila myeloid differentiation primary response gene 88 disease and Treg cell – regulatory T cell is a potential source of infection.
Abstract: Abbreviations CMC – chronic mucocutaneous candidiasis; CMI – cell-mediated immunity; CR – complement receptor; CR3 – complement receptor 3; DC – dendritic cell; FcR – Fc receptor; IDO – indoleamine 2,3-dioxygenase; IL – interleukin; MBL – mannose-binding lectin; MR – mannose receptor; MyD88 – Drosophila myeloid differentiation primary response gene 88; PRR – pattern recognition receptor; TGF-β – transforming growth factor-β; Th, helper T cell; TLR – Toll-like receptor; Treg cell – regulatory T cell
TL;DR: The concept that FcγRIIa genotype may affect IL‐1β production, possibly leading to interindividual differences in periodontitis risk is supported.
Abstract: The functional bi-allelic polymorphism of immunoglobulin G (IgG) Fc receptor (FcgammaR) IIa influences the efficiency of human IgG2 binding. Our previous study showed that the high affinity FcgammaRIIa genotype (-H/H131) was associated with periodontitis risk. As interleukin-1 (IL-1) is one of the major causes of periodontal tissue destruction, it is hypothesized that the FcgammaRIIa-H/H131cross-linking could induce an increased IL-1 release by mononuclear cells. In this study, we evaluated the intracellular expressions of IL-1beta in CD14 positive cells upon stimulation with human IgG2 by flow cytometry. FcgammaRIIa-H/H131 subjects exhibited a higher percentage of IL-1beta-producing cells than FcgammaRIIa-R/H131 and -R/R131 subjects (P < 0.05). These results support the concept that FcgammaRIIa genotype may affect IL-1beta production, possibly leading to interindividual differences in periodontitis risk.
Patent•
20 Dec 2007TL;DR: In this article, the present invention relates to amino acid sequences that are directed a gainst (as defined herein) receptors for proteins with an immunoglobulin fol d (Fc receptors), as well as compounds or constructs, and in particular p roteins and polypeptides, that comprise or essentially consist of one or mor e such amino acids sequences.
Abstract: The present invention relates to amino acid sequences that are directed a gainst (as defined herein) receptors for proteins with an immunoglobulin fol d (Fc receptors), as well as to compounds or constructs, and in particular p roteins and polypeptides, that comprise or essentially consist of one or mor e such amino acid sequences. The invention also relates to nucleic acids enc oding such amino acid sequences and polypeptides; to methods for preparing s uch amino acid sequences and polypeptides; to host cells expressing or capab le of expressing such amino acid sequences or polypeptides; to compositions, and in particular to pharmaceutical compositions, that comprise such amino acid sequences, polypeptides, nucleic acids and/or host cells; and to uses o f such amino acid sequences or polypeptides, nucleic acids, host cells and/or compositions, in particular for prophylactic, therapeutic or diagnostic pu iposes, such as the prophylactic, therapeutic or diagnostic purposes mention ed herein.