Fcγ receptor IIB (FcγRIIB) maintains humoral tolerance in the human immune system in vivo

Maintenance of immunological tolerance is crucial to prevent development of autoimmune disease. The production of autoantibodies is a hallmark of many autoimmune diseases and studies in mouse model systems suggest that inhibitory signaling molecules may be important checkpoints of humoral tolerance. By generating humanized mice with normal and functionally impaired Fcγ receptor IIB (FcγRIIB) variants, we show that the inhibitory Fcγ-receptor is a checkpoint of humoral tolerance in the human immune system in vivo. Impaired human FcγRIIB function resulted in the generation of higher levels of serum immunoglobulins, the production of different autoantibody specificities, and a higher proportion of human plasmablasts and plasma cells in vivo. Our results suggest that the inhibitory FcγRIIB may be an important checkpoint of humoral tolerance in the human immune system.     

Variation in platelet expression of FcγRIIa after myocardial infarction

Journal of Thrombosis and Thrombolysis - FcγRIIa amplifies platelet activation and greater platelet expression of FcγRIIa identifies patients at greater risk of subsequent cardiovascular...     

Expression of Fc Fragment Receptors of Immunoglobulin G (FcγRs) in Rat Hepatic Stellate Cells

Hepatic stellate cells (HSCs) are now considered the major cell type in the liver mediating the development of liver fibrosis. Recently it was demonstrated that HSCs express membrane proteins involved in antigen presentation. We further evaluate immunological properties of HSCs by examining the expression and function of the Fc fragment of immunoglobulin G (IgG) in HSCs. In this study, we document the presence of mRNAs for three FcRs in HSCs. Ligand binding assay indicated the existence of FcRs with different binding affinities on membranes of HSCs. We also documented that the abundance of the three Fc R mRNAs increased upon activation of HSCs in vitro. Moreover, an examination of the biological activities of IgG revealed that exposure to IgG significantly stimulated HSC differentiation and proliferation. Furthermore, we studied the intracellular signaling protein, LcK, in HSCs and regulation of Lck expression and phosphorylation by IgG. Although IgG did not regulate Lck abundance and phosphorylation in HSCs, highly phosphorylated Lck was present in these cells. In conclusion, we provided evidence that HSCs expresses receptors for the Fc fragment of IgG, and IgG regulates HSC differentiation and proliferation. Therefore, immunoglobulin G may play a role in HSC activation.     

Detection of higher levels of dengue viremia using FcγR-expressing BHK-21 cells than FcγR-negative cells in secondary infection but not in primary infection

It has been reported that levels of viremia reflect the severity of illness in dengue virus infection. We assessed the levels of viremia in patients with primary and secondary infections, using 2 cell lines: FcγR-expressing BHK cells and FcγR-negative cells. In primary infection, virus titers were at similar levels between FcγR-expressing and FcγR-negative cells. In secondary infection, however, virus titers were ～10 times higher in FcγR-expressing cells on days 1-6 when compared with FcγR-negative cells, indicating discrepancy in viremia titers between FcγR-expressing and FcγR-negative cells. The results suggest that dengue virus-antibody complexes with infectious capacity exist in patients with secondary infection, and these immune complexes can be detected by using FcγR-expressing cells. As it has been reported that principal target cells of dengue virus infection are FcγR-positive, monocyte/macrophage lineage cells, virus titers determined using FcγR-expressing cells may better reflect the actual viremic conditions in vivo.     

Structure of FcγRI in complex with Fc reveals the importance of glycan recognition for high-affinity IgG binding

Fc gamma receptor I (FcγRI) contributes to protective immunity against bacterial infections, but exacerbates certain autoimmune diseases. The sole high-affinity IgG receptor, FcγRI plays a significant role in immunotherapy. To elucidate the molecular mechanism of its high-affinity IgG binding, we determined the crystal structure of the extracellular domains of human FcγRI in complex with the Fc domain of human IgG₁. FcγRI binds to the Fc in a similar mode as the low-affinity FcγRII and FcγRIII receptors. In addition to many conserved contacts, FcγRI forms additional hydrogen bonds and salt bridges with the lower hinge region of Fc. Unique to the high-affinity receptor-Fc complex, however, is the conformation of the receptor D2 domain FG loop, which enables a charged KHR motif to interact with proximal carbohydrate units of the Fc glycans. Both the length and the charge of the FcγRI FG loop are well conserved among mammalian species. Ala and Glu mutations of the FG loop KHR residues showed significant contributions of His-174 and Arg-175 to antibody binding, and the loss of the FG loop–glycan interaction resulted in an ∼20- to 30-fold decrease in FcγRI affinity to all three subclasses of IgGs. Furthermore, deglycosylation of IgG₁ resulted in a 40-fold loss in FcγRI binding, demonstrating involvement of the receptor FG loop in glycan recognition. These results highlight a unique glycan recognition in FcγRI function and open potential therapeutic avenues based on antibody glycan engineering or small molecular glycan mimics to target FcγRI for certain autoimmune diseases.IgGs and pentraxins are circulating immune components that directly recognize pathogens. On formation of immune complexes or opsonization, they activate cellular response through Fc receptors (FcRs) (1, 2). The FcRs for IgGs include FcγRI (CD64); FcγRII (CD32) with A, B, and C isoforms; and FcγRIII (CD16) with two isoforms (3). Most of these are activating receptors either containing an intracellular immunoreceptor tyrosine-based activation motif or associated with an FcR common γ chain (4). FcγRIIB is an inhibitory receptor that contains an intracellular immunoreceptor tyrosine-based inhibitory motif. FcγRIIIB does not have a cytosolic domain and is anchored to the plasma membrane through glycosylphosphatidylinositol linkage. The binding affinity to IgG ranges from 10⁻⁸ M for FcγRI to 10⁻⁵–10⁻⁷ M for FcγRII and III (3).FcγRI plays an important role in the protection against bacterial infections, but also exacerbates certain autoimmune diseases (5). Owing to its high-affinity antibody binding, FcγRI is important in antibody therapy as well (6, 7). To date, the structure of the ligand-bound high-affinity receptor has not been determined, however. Consequently, the mechanism of its high-affinity antibody recognition remains to be elucidated. The role of glycan in antibody function has been a subject of intense study. Differential glycosylation of Fc, notably fucosylated Fc, is known to affect Fc receptor binding (8, 9). Furthermore, sialylated IgGs have been shown to be anti-inflammatory components of intravenous immunoglobulin (10, 11), and glycosylation affects their binding to the low-affinity FcγRIIB and FcγRIII (11–13). Structural evidence suggests that the conserved glycosylation at Asn-297 of the constant region of IgG₁ is important to maintain the conformation of Fc for receptor binding (12, 14). Whether Fc receptors make significant glycan contacts for their IgG affinity is not clear, however.Structures of the low-affinity Fcγ receptors have been determined with bound IgG-Fc (15–18). Unlike the other two-domain FcγRs, FcγRI contains three extracellular Ig-like domains, designated D1, D2, and D3. Earlier mutational analysis suggests that D2 and D3 domains are important to confer high-affinity antibody binding (19). Recently, the structure of human FcγRI showed a close packing of the FcγRI D1 and D2 domains resembling that of FcεRI, and mutations in the FG loop of the FcγRI D2 domain reduced its IgG binding affinity (20). The mechanism of the high-affinity FcγRI ligand recognition remains unresolved. To provide further insight into the high-affinity antibody recognition by FcγRI, and to facilitate the development of FcγRI-mediated immunotherapy, we determined the structure of the extracellular domains of human FcγRIA in complex with the Fc domain of human IgG₁. Our study identifies a structural mechanism for high-affinity IgG binding by the receptor.     

Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo

Agonistic anti-TNF receptor (TNFR) superfamily member antibodies are a class of promising antitumor therapies in active clinical investigation. An unexpected requirement for inhibitory Fcγ receptor FcγRIIB coengagement has recently been described for their in vivo antitumor activities. Although these findings have informed the design of more potent antitumor agonistic, anti-TNFR therapies, the underlying mechanism has remained obscure. Through detailed genetic analysis of strains conditionally deleted for FcγRIIB on defined cellular populations or mutated in specific signaling components, we now demonstrate that different agonistic anti-TNFR antibodies have specific requirements for FcγRIIB expression on defined cellular populations and function in trans in the absence of FcγRIIB signaling components, thus supporting a general mechanism of FcγRIIB cross-linking in vivo for the activities of these antibodies.Both mouse and human express several activating and one inhibitory Fcgamma receptors (FcγRs). These FcγRs are expressed broadly on lymphoid and myeloid cells such as B cells, dendritic cells, macrophages, neutrophils, and mast cells, where they regulate and mediate immune responses triggered by immune complexes. Whereas binding of immune complexes to activating FcγRs on dendritic cells and myeloid effector cells leads to cell activation, their binding to the coexpressed inhibitory FcγRIIB inhibits cell activation (1–4). In addition, FcγRIIB expression on B cells inhibits B-cell activation when coligated with B-cell antigen receptors. The opposing effects of activating and inhibitory FcγRs result from their different downstream signaling pathways (5). Typical activating human and mouse FcγRs either contain an immunoreceptor tyrosine-based activation motif (ITAM) or are associated with an ITAM-containing adaptor protein such as Fc receptor common γ-chain. Cross-linking of activating FcγRs by immune complexes results in ITAM phosphorylation, subsequent activation of phosphoinositide 3-kinase and generation of phosphatidylinositol-3,4,5-trisphosphate (PIP₃), calcium mobilization, and further downstream signaling events that lead to cell activation. In contrast, FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM), and its phosphorylation leads to the recruitment of SH2 domain-containing inositol 5-phosphatase (SHIP), which interferes with activating signaling pathways by hydrolyzing PIP₃.Activating FcγRs are essential mediators of antibody effector functions including cytotoxicity and phagocytosis by myeloid effector cells (5). It has been shown in both preclinical and clinical studies that interactions between the Fc domains of tumor antigen-specific effector antibodies and activating FcγRs are essential for their antitumor activities (6–9). Recently, αCTLA-4 antibodies that target a key negative immune checkpoint have also been demonstrated to mediate their antitumor activities through activating FcγR-dependent depletion of tumor-associated T regulatory cells that express high levels of CTLA-4 (10, 11). In addition, our previous studies have shown that the ratio of an Fc’s binding affinity to activating FcγRs relative to its binding affinity to the inhibitory FcγRIIB correlates with its ability to mediate antibody effector functions and antitumor responses (12). These findings highlight the importance of interactions between Fc and activating FcγRs in the activity of therapeutic effector antibodies, and have provided the basis for optimizing their antitumor activities by activating FcγR-targeted Fc engineering.Agonistic antibodies represent another class of antitumor antibodies designed to mimic the activity of endogenous ligands, thereby activating the downstream signaling pathways of targeted molecules. Many tumor necrosis factor receptor (TNFR) superfamily members such as CD40 and DR5 control key signaling pathways involved in immune and antitumor responses, and agonistic antibodies targeting these molecules have shown promising antitumor activities in preclinical studies (13). We and others have recently found that both agonistic αCD40 and αDR5 antibodies require Fc–FcγR interactions for their in vivo activities and, in contrast to cytotoxic effector antitumor antibodies, these agonistic antibodies require no activating FcγRs, but inhibitory FcγRIIB (14–16). These studies, together with previous and other recent studies (17, 18), have established a general requirement of FcγRIIB for the in vivo activities of agonistic anti-TNFR antibodies (19). In addition, we have also demonstrated that Fcs that preferentially bind to inhibitory FcγRIIB are more potent for agonistic anti-TNFR antibodies, and that the potency of agonistic anti-TNFR antibodies can be enhanced through FcγRIIB-targeted Fc engineering (14, 15). Although these studies have provided a logical approach to designing potent agonistic anti-TNFR antibodies, the in vivo mechanism underlying this general FcγRIIB requirement remains to be determined. We now demonstrate through the use of genetically defined deletions of FcγRIIB on specific immune cell populations and targeted mutations in FcγRIIB signaling domains the mechanistic basis for this general requirement.     

Expression of inhibitory Fc receptor (FcγRIIB) is a marker of poor response to rituximab monotherapy in follicular lymphoma

BackgroundFcγRIIB promotes rituximab internalisation on various B-cell targets, including in follicular lymphoma, which may lead to reduced efficacy. We analysed diagnostic tumour samples from the SAKK 35/98 trial, which has follow-up data of nearly 10 years to determine the relation of FcγRIIB expression with responses and clinical outcomes after rituximab monotherapy in follicular lymphoma.MethodsAvailable archived tissue samples were stained with an anti-human FcγRIIB antibody. Positive samples were graded into negative/low intensity staining (n=116) or medium/high staining (n=13) by a histopathologist masked to clinical outcomes. Failure-free survival (FFS) was defined as time from first rituximab infusion until failure to achieve complete/partial response at week 12, progression, relapse, a second cancer, or death from any cause. Objective response rate (ORR) was associated with intensity staining levels with Fisher's exact test. All time-to-event endpoints were evaluated with the Kaplan-Meier method; groups were compared with the log-rank test. Hazard ratio (HR) was assessed with Cox proportional hazards models.FindingsPatients expressing medium/high levels of FcγRIIB were less likely to respond to rituximab than were those with negative/low levels (ORR 23·1% [95% CI 7·5–50·9] vs 58·6% [49·5–67·2], p=0·02). FFS was higher in the negative/low staining group than in the medium/high staining group (median 8·3 months [95% CI 2·8–13·4, IQR 2·76–28·5] vs 2·8 [not calculable, 2·76–2·76], p=0·002; HR 0·43 [95% CI 0·23–0·78]). There was a non-significant trend towards better overall survival in the low/negative group compared with the medium/high group (median 140·0 months vs 50·0, p=0·13; HR 0·56 [95% CI 0·26–1·20]).InterpretationElevated FcγRIIB expression level is associated with poor response to rituximab in patients with follicular lymphoma. This group may show better results with non-internalising type II antibodies, a hypothesis for validation in future prospective clinical trials.FundingCancer Research UK.     

Fcγ Receptor Signaling in Phagocytes

Fcgamma receptors are among the best-studied phagocytic receptors. The key features of Fcgamma receptor-mediated phagocytosis include phagocytic cup formation by extensive actin cytoskeletal rearrangements, particle engulfment, and the release of proinflammatory mediators such as cytokines and reactive oxygen species. These events are elegantly regulated by the simultaneous engagement of activating and inhibitory Fcgamma receptors and by intracellular signaling molecules. Extensive studies in the past several years have defined the molecular mechanisms of the phagocytic process. The purpose of this review is to revisit some of the well-established signaling pathways as well as to summarize the new findings in this field.     

Human FcγRIIA induces anaphylactic and allergic reactions

IgE and IgE receptors (FcεRI) are well-known inducers of allergy. We recently found in mice that active systemic anaphylaxis depends on IgG and IgG receptors (FcγRIIIA and FcγRIV) expressed by neutrophils, rather than on IgE and FcεRI expressed by mast cells and basophils. In humans, neutrophils, mast cells, basophils, and eosinophils do not express FcγRIIIA or FcγRIV, but FcγRIIA. We therefore investigated the possible role of FcγRIIA in allergy by generating novel FcγRIIA-transgenic mice, in which various models of allergic reactions induced by IgG could be studied. In mice, FcγRIIA was sufficient to trigger active and passive anaphylaxis, and airway inflammation in vivo. Blocking FcγRIIA in vivo abolished these reactions. We identified mast cells to be responsible for FcγRIIA-dependent passive cutaneous anaphylaxis, and monocytes/macrophages and neutrophils to be responsible for FcγRIIA-dependent passive systemic anaphylaxis. Supporting these findings, human mast cells, monocytes and neutrophils produced anaphylactogenic mediators after FcγRIIA engagement. IgG and FcγRIIA may therefore contribute to allergic and anaphylactic reactions in humans.     

Expression of CD64 (FcγRI) in skin of patients with acute GVHD

GVHD remains a major problem in allo-SCT. We explored the presence of APC in skin biopsies of GVHD patients, using the IgG receptor CD64 expression as a hallmark for activated APC. By immunohistochemistry we demonstrated CD64 to be upregulated on host APC in skin biopsies of patients with acute GVHD and, less prominently, in chronic GVHD. Double staining for CD32 polymorphism revealed CD64-positive cells to be mainly of host origin. The majority of CD64-positive cells coexpressed CD68, indicating a macrophage phenotype. Given its very restricted cellular distribution, CD64 may represent an excellent target for APC-directed therapies in GVHD.     

The NA"null" phenotype of a young man is caused by an FcγRIIIB gene deficiency while the products of the neighboring FcγRIIA and FcγRIIIA genes are present

 A 27-year-old man with an allergy to house dust mites was found to lack the FcγRIIIb on his neutrophils. Cell surface marker and PCR techniques were used to investigate possible reasons for this deficiency. Agglutination and immunofluorescence assays using the man's neutrophils together with NA1- and NA2-specific antibodies were negative, and there was no reaction with the FcγRIII-specific mAb 3G8. Indirect immunofluorescence demonstrated the presence of the CD24 molecule, which, like the FcγRIIIb, is anchored to the cell membrane by glycosylphosphatidylinositol. Thus a lack of the FcγRIIIb cell membrane anchor was excluded. PCR analysis confirmed the absence of the NA1 and NA2 alleles. The individual was therefore typed as NA"null". The products of those genes located together with the FcγRIIIB gene within a complex on chromosome 1 (q23–24) were examined. FcγRII was demonstrated on monocytes and B cells with the use of FcγRII-specific monoclonal antibodies. About 5% of the individual's peripheral blood monocytes were positive with the 3G8 antibody, indicating the presence of FcγRIIIa. From these data we concluded that the FcγRIIIb deficiency on the neutrophil cell surface of this individual is due to a lack of the FcγRIIIB gene while excluding a lack of the FcγRIIA and the FcγRIIIA genes. Received: January 9, 1998 Accepted: March 5, 1998     

FcγRⅡb与自身免疫病的研究进展

FcγRⅡb(CD32b)是能与免疫球蛋白G(IgG)Fc段低亲和力结合的抑制性受体.胞内段具有免疫受体酪氨酸抑制基序( ITIM),介导免疫抑制作用.FcγRⅡb作为外周免疫耐受检查点能维持体液免疫耐受,FcγRⅡb表达下调或功能异常,与自身免疫病的发生发展密切相关[1].现就FcγRⅡb的表达、分型、功能及在自身免疫病中的作用综述如下.     

类风湿关节炎患者FcγR Ⅲ A多态性研究

目的 通过国人类风湿关节炎(RA)患者和对照组中FcγRⅢA-158F／V多态性的比较，确定其多态性与RA是否存在联系。方法 收集就诊192例汉族RA患者[符合1987年美国风湿病学会(ACR)所修订的RA诊断标准]的临床资料，利用等位基因特异性巢式聚合酶链反应(PCR)确定FcγRⅢA的多态性，以健康体检者作为对照。结果 RA患者中FcγRⅢA-158V／V纯合子基因型显著增高（X^2=11．85，P＜O．01)。FcγyRⅢA-158V／V纯合子患者发病较158F／F纯合子早(P＜0．05)。FcγRⅢA-158V／V纯合子类风湿因子(RF)的阳性率低于其他两组(P值分别为0．030和0．041)。结论 FcγRⅢA-158V／V纯合子与RA相关，FcγRⅢA多态性是RA发病的影响因素。     

Olanzapine-induced neutropenia in a patient with systemiclupus erythematosus: a role of FcγRIIIb polymorphism?

In this study, we report the case of a Chinese patient with systemic lupus erythematosus (SLE) who developed neutropenia after treatment by olanzapine for the SLE-related psychiatric symptoms. The relationship between agranulocytosis, SLE and olanzapine is still unknown. Fcγ receptor IIIb (FcγRIIIb) is a low-affinity receptor, constitutively expressed only by neutrophils; NA1 and NA2 have been identified as representing polymorphisms of FcγRIIIb. NA1 is associated with the incidence of autoimmune neutropenia and is particularly frequent in Asiatic ethnic groups. The Chinese patient resulted to be homozygous for NA1. We suggest that the presence of NA1 allele may be a predisposing factor to olanzapine-induced agranulocytosis in patients with SLE. Hence, the analysis of FcγRIIIb polymorphism should be investigated in other cases of antipsychotic-induced agranulocytosis.     

Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcγR signaling

Neutrophil recruitment into the joint is a hallmark of inflammatory arthritides, including rheumatoid arthritis (RA). In a mouse model of autoantibody-induced inflammatory arthritis, neutrophils infiltrate the joint via multiple chemoattractant receptors, including the leukotriene B₄ (LTB₄) receptor BLT1 and the chemokine receptors CCR1 and CXCR2. Once in the joint, neutrophils perpetuate their own recruitment by releasing LTB₄ and IL-1β, presumably after activation by immune complexes deposited on joint structures. Two pathways by which immune complexes may activate neutrophils include complement fixation, resulting in the generation of C5a, and direct engagement of Fcγ receptors (FcγRs). Previous investigations showed that this model of autoantibody-induced arthritis requires the C5a receptor C5aR and FcγRs, but the simultaneous necessity for both pathways was not understood. Here we show that C5aR and FcγRs work in sequence to initiate and sustain neutrophil recruitment in vivo. Specifically, C5aR activation of neutrophils is required for LTB₄ release and early neutrophil recruitment into the joint, whereas FcγR engagement upon neutrophils induces IL-1β release and subsequent neutrophil-active chemokine production, ensuring continued inflammation. These findings support the concept that immune complex-mediated leukocyte activation is not composed of overlapping and redundant pathways, but that each element serves a distinct and critical function in vivo, culminating in tissue inflammation.Sequential cascades of chemoattractants are a hallmark of immune cell recruitment in sterile inflammation (1, 2). We have recently shown that a lipid–cytokine–chemokine cascade, consisting of leukotriene B₄ (LTB₄)–IL-1β–neutrophil-active CCR1 and CXCR2 chemokine ligands drives neutrophil [polymorphonuclear leukocyte (PMN)] recruitment into the joint in a model of autoantibody-induced arthritis (3, 4). These mediators act in a nonredundant, sequential manner to regulate the recruitment of PMNs into the joint. Surprisingly, PMNs themselves are the predominant source of LTB₄ and IL-1β in this model, suggesting that PMNs can be central choreographers of inflammation, rather than pure effector cells (3, 5). Orchestration of PMN recruitment requires highly organized temporal and spatial patterns of chemoattractant expression (3, 6–8). The molecular mechanisms that achieve this sophisticated organization, however, are unknown and presumably differ depending on the individual pathologic stimulus and the specific tissue site. In this model of autoantibody-induced arthritis, despite progress in identifying the chemoattractants driving PMN recruitment, the specific stimuli inducing the sequential release of LTB₄ and IL-1β have not been defined.Arthritis is induced in this model by the transfer of serum from K/BxN mice into recipient mice and is therefore often referred to as the “K/BxN serum transfer model.” This model of autoantibody-induced arthritis is a prototypical model for immune complex (IC)-induced PMN-driven inflammation. K/BxN serum contains autoantibodies against glucose 6-phosphate isomerase (GPI), which form ICs on the cartilage surface (9–11). Notably, the classical pathway of complement activation does not play a role in this model, which, however, requires the complement factors C3 and C5 (9). C3 and IgG depositions colocalize in arthritic joints, implying that C3b-IgG complexes are formed on the cartilage surface, which activate complement via the alternative pathway finally cleaving C5a from C5 (9).In the K/BxN serum transfer model, adaptive immunity is bypassed and arthritis is independent of T and B lymphocytes and is instead dependent on innate immune cells and PMNs in particular (12–14). Several effector mechanisms are critically involved in the generation of arthritis in this model. In addition to LTB₄ and IL-1β, the C5a receptor (C5aR) and Fcγ receptors (FcγRs) are both also required for the development of arthritis. However, how these cell surface receptors and soluble mediators interact at the cellular level to initiate arthritis is not known.C5aR and FcγRs are central mediators of innate immunity and key for the execution of the effector phase of immune responses triggered by immune complexes (15, 16). One emerging paradigm suggests that the functions of C5aR and FcγR are intertwined and that a main function of C5aR is to lower the threshold for FcγR activation, which in turn executes the actual effector response (16–21). The relevance of this cross-regulation in vivo has been shown for autoimmune hemolytic anemia and IC-induced lung inflammation, where C5aR regulation of FcγR function occurs in Kupffer cells and alveolar macrophages, respectively (18, 19). In the latter model, this regulation enables alveolar macrophages to more efficiently direct PMN recruitment into the lung (18). However, it is not known whether this paradigm also holds true for immune responses that are not coordinated by tissue resident immune cells, and it is not known which effector mechanisms downstream of C5aR and FcγRs are required for disease induction and progression.Although it has been a matter of debate, most recent data suggest that tissue mast cells are not required for autoantibody-induced arthritis (22). The role of macrophages in this model is still debated, as macrophage-deficient op/op mice are fully susceptible to arthritis (23), whereas clodronate depletion of macrophages protects against arthritis (24). Natural killer (NK) cells and dendritic cells (DCs) are also not required for arthritis in this model (25), but compelling data suggest that PMNs are indispensable (12–14), and that C5aR and FcγR function in PMNs is required to initiate arthritis (13). However, the precise roles of C5aR and FcγR and the downstream effects of their activation on PMNs critical for the development of arthritis in this model have not been defined.In this study, we set out to identify the inducers of LTB₄ and IL-1β release from PMNs required for the pathogenesis of autoantibody-induced arthritis in this model. We hypothesized that the requirement of C5aR and FcγRs may be directly connected to the release of LTB₄ and IL-1β from PMNs. Here, we demonstrate that C5aR and FcγRs on PMNs each separately contributes to the initiation of arthritis by inducing the release of LTB₄ and IL-1β from PMNs in vivo, respectively. These findings support the concept that immune complex-mediated leukocyte activation is not composed of seemingly overlapping and redundant pathways, but that each element serves a distinct and critical function in vivo in a sequential, nonredundant manner culminating in tissue inflammation. Additionally, these results highlight how highly organized temporal and spatial patterns of chemoattractant expression can be achieved in vivo to orchestrate PMN recruitment and exemplify how PMNs can choreograph their own recruitment and inflammation.     

天平的两端:活化性和抑制性Fcγ受体

体内多种细胞表达不同类或亚类Ig的Fc受体,它们在促进和调节免疫方面起着重要作用,FcγRⅡB是体内唯一的抑制性Fcγ受体,越来越多的研究表明,FcγRⅡB在自身免疫性疾病的发病中起着重要作用,如系统性红斑狼疮、类风湿关节炎。多项研究表明,细胞表面活化性与抑制性Fcγ受体比例的失调也将导致多种疾病的发生,FcγRⅡB能下调活化性Fcγ受体介导的吞噬、免疫复合物诱导的炎症和相关细胞炎性因子的释放。因此,阐明其与疾病间的联系,将有助于为自身免疫性疾病提供新的治疗策略。     

树突状细胞及Fcγ受体在类风湿关节炎中的研究进展

类风湿关节炎是常见的慢性炎症性自身免疫性疾病。树突状细胞能调节免疫反应和免疫耐受间的平衡。近来研究发现其表面Fcγ受体在类风湿关节炎的发病机制中起重要作用,其中抑制型受体FcγRⅡb具有抑制树突状细胞,下调免疫反应,引起免疫耐受的功能,因此通过FcγRⅡb制备致耐受树突状细胞可能成为类风湿关节炎治疗的新途径。     

类风湿关节炎患者外周血B细胞FcγR Ⅱb表达

目的探讨类风湿关节炎(rheumatoid arthritis,RA)患者外周血B细胞亚群FcγRⅡb的表达及其临床意义。方法流式细胞仪检测20例初治RA患者及年龄性别匹配的15名健康对照者外周血B细胞FcγRⅡb的表达;评估其与RA病情指标的相关性。统计学分析采用独立样本t检验及Pearson相关分析。结果 RA患者记忆性B细胞亚群百分率[(18.30±8.94)%]低于健康对照组[(32.31±13.67)%],差异有统计学意义(t=3.665,P=0.001);初始B细胞亚群百分率[(78.11±9.00)%]高于健康对照组[(64.24±13.23)%],差异有统计学意义(t=-3.691,P=0.001);RA患者外周血CD19+CD27+记忆性B细胞表面FcγR IIb平均荧光强度(mean fluorescence intensity,MFI)[(7 571.95±4 494.53)%]显著低于健康对照组[(13 304.87±6 568.19)%],差异有统计学意义(t=3.068,P=0.004);RA患者外周血记忆性B细胞表面FcγRⅡb的MFI与RA患者的Ig G水平呈负相关(r=-0.732,P=0.007)。结论 RA患者外周血记忆性B细胞FcγR IIb表达低于健康对照,并与RA患者的Ig G水平呈负相关,FcγRⅡb表达异常可能在RA免疫发病机制中起重要作用。