Effective Innate Response Research Articles

Immunopathogenesis of Behçet's disease

Behçet's disease (BD) is a multi-system inflammatory disorder with vasculitic features. It does not suit any of the current pathogenesis-driven disease classifications well, a unifying concept of its pathogenesis is not unanimously conceivable at present, and its etiology is obscure.Still, evidence from immunogenetic and other studies supports the notion of a complex-polygenic disease with robust innate effector responses, reconstitution of regulatory T cells upon successful treatment, and first clues to the role of an, as of yet, underexplored adaptive immune system and its antigen recognition receptors.Without an attempt to be comprehensive, this review aims to collect and organize impactful parts of this evidence in a way that allows the reader to appreciate the work done and define the efforts needed now. The focus is on literature and notions that drove the field into new directions, whether recent or more remote.

Why Does the Severity of COVID-19 Differ With Age?: Understanding the Mechanisms Underlying the Age Gradient in Outcome Following SARS-CoV-2 Infection.

Although there are many hypotheses for the age-related difference in the severity of COVID-19, differences in innate, adaptive and heterologous immunity, together with differences in endothelial and clotting function, are the most likely mechanisms underlying the marked age gradient. Children have a faster and stronger innate immune response to SARS-CoV-2, especially in the nasal mucosa, which rapidly controls the virus. In contrast, adults can have an overactive, dysregulated and less effective innate response that leads to uncontrolled pro-inflammatory cytokine production and tissue injury. More recent exposure to other viruses and routine vaccines in children might be associated with protective cross-reactive antibodies and T cells against SARS-CoV-2.There is less evidence to support other mechanisms that have been proposed to explain the age-related difference in outcome following SARS-CoV-2 infection, including pre-existing immunity from exposure to common circulating coronaviruses, differences in the distribution and expression of the entry receptors ACE2 and TMPRSS2, and difference in viral load.

Eicosanoid pathway on host resistance and inflammation during Mycobacterium tuberculosis infection is comprised by LTB4 reduction but not PGE2 increment

The functions of eicosanoids, a family of potent biologically active lipid mediators, are not restricted to inflammatory responses and they also act as mediators of the pathogenesis process. However, the role of eicosanoids in tuberculosis remains controversial. To investigate the specific role of LTB4 in Mycobacterium tuberculosis (Mtb) infection, we used 5-lipoxygenase-deficient (5-LO−/−) mice and WT (sv129) mice inoculated intranasally with LTB4 (encapsulated in PLGA microspheres). We showed that deficiency of the 5-LO pathway was related to resistance to Mtb infection. LTB4 inoculation increased susceptibility to Mtb in 5-LO−/− mice but not in WT mice, resulting in worsening of lung inflammation and tissue damage. In infected WT mice, most supplementary LTB4 was metabolized to the inactive form 12-oxo-LTB4 in the lung. A high amount of PGE2 was detected during Mtb infection, and pharmacological inhibition of COX-2 induced a significant reduction of bacterial load and an improved innate immune response in the lungs, independently of baseline LTB4 levels. COX-2 inhibition with celecoxib significantly reduced PGE2 levels, enhanced IFN-γ production and NO release, and increased macrophage phagocytosis of Mtb. The results suggest that a balance between PGE2/LTB4 is essential in the pathogenesis process of tuberculosis to prevent severe inflammation. Moreover, optimal levels of PGE2 are required to induce an effective innate response in the early phase of Mtb infection. Thus, pharmacological modulation of eicosanoid production may provide an important host-directed therapy in tuberculosis.

Apicidin Attenuates MRSA Virulence through Quorum-Sensing Inhibition and Enhanced Host Defense

Recurrent epidemics of drug-resistant Staphylococcus aureus illustrate the rapid lapse of antibiotic efficacy following clinical implementation. Over the last decade, community-associated methicillin-resistant S.aureus (MRSA) has emerged as a dominant cause of infections, and this problem is amplified by the hyper-virulent nature of these isolates. Herein, we report the discovery of a fungal metabolite, apicidin, as an innovative means to counter both resistance and virulence. Owing to its breadth and specificity as a quorum-sensing inhibitor, apicidin antagonizes all MRSA agr systems in a non-biocidal manner. In skin challenge experiments, the apicidin-mediated abatement of MRSA pathogenesis corresponds with quorum-sensing inhibition at invivo sites of infection. Additionally, we show thatapicidin attenuates MRSA-induced disease by potentiating innate effector responses, particularly through enhanced neutrophil accumulation and function at cutaneous challenge sites. Together, these results indicate that apicidin treatment represents a strategy to limit MRSA virulence and promote host defense.

Eosinophils in fungal diseases: An overview.

Eosinophils are the prominent cells in asthma, allergic bronchopulmonary mycosis (ABPMs), and fungal-sensitization-associated asthma, but their roles in the immunopathology of these disorders are not well understood. Moreover, the immunological mechanisms underlying the molecular direct effector interactions between fungi and eosinophils are rare and not fully known. Here, we provide an overview of eosinophil contributions to allergic asthma and ABPMs. We also revise the major general mechanisms of fungal recognition by eosinophils and consider past and recent advances in our understanding of the molecular mechanisms associated with eosinophil innate effector responses to different fungal species relevant to ABPMs (Alternaria alternata, Candida albicans, and Aspergillus fumigatus). We further examine and speculate about the therapeutic relevance of these findings in fungus-associated allergic pulmonary diseases.

Role of lipid mediators and control of lymphocyte responses in type 2 immunopathology

Type 2 immunopathology is a cardinal feature of allergic diseases and involves cooperation between adaptive immunity and innate effector responses. Virtually all cell types relevant to this pathology generate leukotriene and/or prostaglandin mediators that derive from arachidonic acid, express receptors for such mediators, or both. Recent studies highlight prominent functions for these mediators in communication between the innate and adaptive immune systems, as well as amplification or suppression of type 2 effector responses. This review focuses on recent advances and insights, and highlights existing and potential therapeutic applications of drugs that target these mediators or their receptors, with a special emphasis on their regulation of the innate and adaptive lymphocytes relevant to type 2 immunopathology.

Live attenuated Leishmania donovani Centrin knock out parasites generate non-inferior protective immune response in aged mice against Visceral Leishmaniasis

Abstract Visceral Leishmaniasis (VL) causes significant mortality. Age appears to be critical in determining the clinical outcome of VL and there is no effective vaccine available against VL for any age group. Previously, we showed that gene deleted live attenuated L. donovani parasites (LdCen−/−) induced a strong protective immune response in young mice. In this study we analyzed LdCen−/− mediated modulation of immune response in aged mice (18 months) and compared to young (2 months) mice. Analysis of innate response in dendritic cells (DCs) from both young and aged mice upon infection with LdCen−/− parasites, showed significant enhancement of innate effector responses, which consequently augmented CD4+ Th1 cell effector function compared to LdWT infected DCs in vitro. Similarly, parasitized splenic DCs from LdCen−/− infected young and aged mice revealed induction of proinflammatory cytokines and down regulation of anti-inflammatory cytokine genes compared to LdWT infected mice. Furthermore, immunization with LdCen−/− induced higher IgG2a antibodies, lymphoproliferative response and stimulated splenocytes for heightened leishmanicidal activity in young and aged mice. Additionally, upon virulent L. donovani challenge, LdCen−/− immunized mice from both age groups displayed multifunctional Th1-type CD4 and cytotoxic CD8 T cells leading to significantly reduced parasite burden in the spleen and liver compared to naïve mice. Although, there was no difference in the LdCen−/− induced innate response in DCs between aged and young, the adaptive response in terms of T cell and B cell activation in aged was reduced, which correlated with LdCen−/− induced significant but diminished protective response in aged compared to young mice against VL.

Distinct Characteristics of Endometrial and Decidual Macrophages and Regulation of Their Permissivity to HIV-1 Infection by SAMHD1

In order to develop strategies to prevent HIV-1 (human immunodeficiency virus type 1) transmission, it is crucial to better characterize HIV-1 target cells in the female reproductive tract (FRT) mucosae and to identify effective innate responses. Control of HIV-1 infection in the decidua (the uterine mucosa during pregnancy) can serve as a model to study natural mucosal protection. Macrophages are the main HIV-1 target cells in the decidua. Here we report that in vitro, macrophages and T cells are the main HIV-1 targets in the endometrium in nonpregnant women. As reported for decidual macrophages (dM), endometrial macrophages (eM) were found to have an M2-like phenotype (CD68+ CD163+ CD206+ IL-10high). However, eM and dM may belong to different subpopulations, as they differently express certain markers and secrete different amounts of proinflammatory and anti-inflammatory cytokines. We observed strong expression of the SAMHD1 restriction factor and weak expression of its inactive form (pSAMHD1, phosphorylated at residue Thr592) in both eM and dM. Infection of macrophages from both tissues was enhanced in the presence of the viral protein Vpx, suggesting a role for SAMHD1 in the restriction of HIV-1 infection. This study and further comparisons of the decidua with FRT mucosae in nonpregnant women should help to identify mechanisms of mucosal protection against HIV-1 infection. The female reproductive tract mucosae are major portals of HIV-1 entry into the body. The decidua (uterine mucosa during pregnancy) can serve as a model for studying natural mucosal protection against HIV-1 transmission. A comparison of target cells and innate responses in the decidua versus the endometrium in nonpregnant women could help to identify protective mechanisms. Here, we report for the first time that macrophages are one of the main HIV-1 target cells in the endometrium and that infection of macrophages from both the endometrium and the decidua is restricted by SAMHD1. These findings might have implications for the development of vaccines to prevent HIV-1 mucosal transmission.

The adaptor CARD9 is required for adaptive but not innate immunity to oral mucosal Candida albicans infections (MPF3P.805)

Abstract Oropharyngeal candidiasis (OPC, thrush) is an opportunistic infection caused by the commensal fungus Candida albicans. OPC is common in individuals with HIV/AIDS, infants, and individuals with congenital immune defects. Immunity to OPC is dependent on the IL-23/IL-17R axis, as mice and humans with defects in IL-17R signaling (IL17F, ACT1, IL-17RA) or in genes that direct Th17 differentiation (STAT3, STAT1, CARD9) are prone to mucocutaneous candidiasis. Conventional Th17 cells are induced in response to C. albicans via signals from C-type lectin receptors, which signal through the adaptor CARD9 leading to production of Th17-inducing cytokines such as IL-6, IL-1 and IL-23. Recent data indicates that IL-17 can also be made by numerous innate cell subsets. These innate ‘Type 17’ cells resemble conventional Th17 cells, but they can be activated without need for prior antigen exposure. Because C. albicans is not a commensal organism in rodents and thus mice are naïve to this fungus, we had the opportunity to assess the role of CARD9 in innate versus adaptive responses using an OPC infection model. As expected, CARD9-/- mice failed to mount an adaptive Th17 response following oral Candida infection. Surprisingly, however, CARD9-/- mice had preserved innate IL-17-dependent responses and were almost fully resistant to OPC. Thus, CARD9 is important primarily for adaptive immunity to C. albicans, whereas alternate recognition systems appear to be needed for effective innate responses.

Circulating neutrophil counts and mortality in septic shock

Polynuclear neutrophils can play dual roles in sepsis: on the one hand they mediate major antimicrobial activities and on the other hand they can contribute to the development of multiple organ failure [1]. Nonetheless, in spite of the importance of these cells in sepsis, the influence of the circulating neutrophil count (CNC) on the prognosis of septic patients with this pathology has not been properly evaluated. We analyzed the association between CNC and outcome in two cohorts of patients with diagnostic criteria of septic shock (SS) [2]: the first was recruited in the context of a single center study (EXPRESS study, discovery cohort, n = 195; Table 1), and the second in the context of a multi-centric study (GRECIA study, validation cohort, n = 194; Table 2). Written informed consent was obtained from each patient or their legal representative. The two studies were approved by the Research Ethics Committee of the Hospital Clinico Universitario, Valladolid, Spain (for the EXPRESS study) and Hospital Universitario Rio Hortega, Valladolid, Spain (coordinating center for the GRECIA study). Table 1 Clinical characteristics of the patients in the discovery study in survivors and non-survivors at 28 days Table 2 Clinical characteristics of the patients in the validation study in survivors and non-survivors at 28 days When patients of the discovery cohort were split based on deciles for CNC at SS diagnosis, those with CNC <7,226 cells/mm3 (decile 2) died earlier than the other non-survivors (Figure 1). Multivariate Cox regression analysis showed that patients with CNC below this cutoff value had an almost two-fold risk of death (Figure 1). The cutoff value was evaluated again in the validation cohort, with similar results (Figure 1). Counts of other leukocyte subtypes had no significant association with outcome. Figure 1 Impact of circulating neutrophil count on mortality: Kaplan-Meier survival curves. Groups were compared by the log-rank test (Mantel- Haenzel). Bottom: multivariate Cox regression analysis for mortality risk. Circulating neutrophil count (CNC) was adjusted ... Although normal reference values in blood vary depending on sex, race and age, available literature supports that 7,226 cells/mm3 is at the upper limit of normal CNC values [3]. Patients with insufficient numbers of circulating neutrophils during the early stages of SS could have difficulties mounting effective innate responses against the invading microbe(s). Increased neutrophil adhesion to the vascular endothelium in sepsis could contribute to lower CNC. Neutrophils adhered to the blood vessel wall seem to induce endothelial damage [4], forming leukocyte aggregates that could lead to microvascular thrombosis [1,5]. Host immunity compromise and/or increased endothelial damage could both impair outcome in these patients. CNC at diagnosis is a major prognostic factor in SS. Our work provides a CNC cutoff that is potentially useful as a prognostic indicator.

The Adaptor CARD9 Is Required for Adaptive but Not Innate Immunity to Oral Mucosal Candida albicans Infections

Oropharyngeal candidiasis (OPC [thrush]) is an opportunistic infection caused by the commensal fungus Candida albicans. OPC is common in individuals with HIV/AIDS, infants, patients on chemotherapy, and individuals with congenital immune defects. Immunity to OPC is strongly dependent on the interleukin-23 (IL-23)/IL-17R axis, as mice and humans with defects in IL-17R signaling (IL17F, ACT1, IL-17RA) or in genes that direct Th17 differentiation (STAT3, STAT1, CARD9) are prone to mucocutaneous candidiasis. Conventional Th17 cells are induced in response to C. albicans infection via signals from C-type lectin receptors, which signal through the adaptor CARD9, leading to production of Th17-inducing cytokines such as IL-6, IL-1β, and IL-23. Recent data indicate that IL-17 can also be made by numerous innate cell subsets. These innate "type 17" cells resemble conventional Th17 cells, but they can be activated without need for prior antigen exposure. Because C. albicans is not a commensal organism in rodents and mice are thus naive to this fungus, we had the opportunity to assess the role of CARD9 in innate versus adaptive responses using an OPC infection model. As expected, CARD9(-/-) mice failed to mount an adaptive Th17 response following oral Candida infection. Surprisingly, however, CARD9(-/-) mice had preserved innate IL-17-dependent responses to Candida and were almost fully resistant to OPC. Thus, CARD9 is important primarily for adaptive immunity to C. albicans, whereas alternate recognition systems appear to be needed for effective innate responses.

N-Linked Glycan Structures of the Human Fcγ Receptors Produced in NS0 Cells

Immune recognition of nonself is coordinated through complex mechanisms involving both innate and adaptive responses. Circulating antibodies communicate with effector cells of the innate immune system through surface receptors known as Fcγ receptors (FcγRs). The FcγRs are single-pass transmembrane glycoproteins responsible for regulating innate effector responses toward antigenic material. Although immunoglobulin G (IgG) antibodies bind to a range of receptors, including complement receptors and C-type lectins, we have focused on the Fcγ receptors. A total of five functional FcγRs are broadly classified into three families (FcγRI, FcγRII, and FcγRIII) and together aid in controlling both inflammatory and anti-inflammatory responses of the innate immune system. Due to the continued success of monoclonal antibodies in treating cancer and autoimmune disorders, research is typically directed toward improving the interaction of antibodies with the FcγRs through manipulation of IgG properties such as N-linked glycosylation. Biochemical studies using recombinant forms of the FcγRs are often used to quantitate changes in binding affinity, a key indicator of a likely biological outcome. However, analysis of the FcγRs themselves is imperative as recombinant FcγRs differ greatly from those observed in humans. In particular, the N-linked glycan composition is significantly important due to its function in the IgG-FcγR interaction. Here, we present data for the N-linked glycans present on FcγRs produced in NS0 cells, namely, FcγRIa, FcγRIIa, FcγRIIB, FcγRIIIa, and FcγRIIIb. Importantly, these FcγRs demonstrate typical murine glycosylation in the form of α-galactose epitopes, N-glycolylneuraminic acid, and other key glycan properties that are generally expressed in murine cell lines and therefore are not typically observed in humans.

Neutrophils Usher Monocytes Into Sites of Inflammation

One of the key processes of inflammation is the transmigration of circulating leukocytes across the endothelium. Among the leukocytes, neutrophils and monocytes are large phagocytes that can respond quickly to infection or injury. On sensing danger, neutrophils and monocytes adhere to the endothelium and transmigrate to the adjacent tissue via the coordinated activities of adhesion molecules, integrins, cytokines, and chemokines.1 Once they accumulate, these myeloid cells participate in a myriad of immune inflammatory activities. The importance of this event cannot be understated, especially because the accumulation of leukocytes in tissue is a double-edged sword. On the one hand, coordinated leukocyte accumulation in injured or infected sites is required for effective pathogen elimination and tissue healing. On the other hand, uncontrolled accumulation is a defining feature of chronic diseases, such as atherosclerosis.2 Understanding leukocyte migration is essential to understanding the immune system. Article, see p 792 Neutrophils and monocytes do not accumulate all at once. In a typical acute inflammatory response, there is a well-defined sequence: neutrophils accumulate first; monocytes accumulate second. Among the monocytes, of which ≥2 subsets circulate in the mouse and human, there is yet another …

Massively Parallel Amplicon Sequencing Reveals Isotype-Specific Variability of Antimicrobial Peptide Transcripts in Mytilus galloprovincialis

BackgroundEffective innate responses against potential pathogens are essential in the living world and possibly contributed to the evolutionary success of invertebrates. Taken together, antimicrobial peptide (AMP) precursors of defensin, mytilin, myticin and mytimycin can represent about 40% of the hemocyte transcriptome in mussels injected with viral-like and bacterial preparations, and unique profiles of myticin C variants are expressed in single mussels. Based on amplicon pyrosequencing, we have ascertained and compared the natural and Vibrio-induced diversity of AMP transcripts in mussel hemocytes from three European regions.Methodology/Principal FindingsHemolymph was collected from mussels farmed in the coastal regions of Palavas (France), Vigo (Spain) and Venice (Italy). To represent the AMP families known in M. galloprovincialis, nine transcript sequences have been selected, amplified from hemocyte RNA and subjected to pyrosequencing. Hemolymph from farmed (offshore) and wild (lagoon) Venice mussels, both injected with 107 Vibrio cells, were similarly processed. Amplicon pyrosequencing emphasized the AMP transcript diversity, with Single Nucleotide Changes (SNC) minimal for mytilin B/C and maximal for arthropod-like defensin and myticin C. Ratio of non-synonymous vs. synonymous changes also greatly differed between AMP isotypes. Overall, each amplicon revealed similar levels of nucleotidic variation across geographical regions, with two main sequence patterns confirmed for mytimycin and no substantial changes after immunostimulation.Conclusions/SignificanceBarcoding and bidirectional pyrosequencing allowed us to map and compare the transcript diversity of known mussel AMPs. Though most of the genuine cds variation was common to the analyzed samples we could estimate from 9 to 106 peptide variants in hemolymph pools representing 100 mussels, depending on the AMP isoform and sampling site. In this study, no prevailing SNC patterns related to geographical origin or Vibrio injection emerged. Whether or not the contact with potential pathogens can increase the amount of AMP transcript variants in mussels requires additional study.

Deletion of the murine scavenger receptor CD68

Scavenger receptors (ScRs) are a structurally unrelated family of receptors with the ability to bind modified low density lipoprotein (LDL) as well as a broad range of polyanionic ligands. CD68, whose expression is restricted to mononuclear phagocytes, is a unique ScR family member, owing to its lysosome associated membrane protein (LAMP)-like domain and predominant endosomal distribution. Knockout (ko) mice were generated to directly evaluate the role murine CD68 may play in oxidized LDL (Ox-LDL) uptake. However, CD68⁻/⁻ macrophages took up Ox-LDL robustly. Likewise, no defects were observed in the ability of CD68⁻/⁻ mononuclear phagocytes to take up or mount an effective innate response against a number of microbes. Curiously, CD68⁻/⁻ mononuclear phagocytes exhibited a trend toward enhanced antigen presentation to CD4⁺ T-cells, raising the possibility that CD68 may function either to negatively regulate antigen uptake, loading, or major histocompatibility complex class II (MHC-II) trafficking.

Interferons Direct an Effective Innate Response to Legionella pneumophila Infection

Legionella pneumophila remains an important opportunistic pathogen of human macrophages. Its more limited ability to replicate in murine macrophages has been attributed to redundant innate sensor systems that detect and effectively respond to this infection. The current studies evaluate the role of one of these innate response systems, the type I interferon (IFN-I) autocrine loop. The ability of L. pneumophila to induce IFN-I expression was found to be dependent on IRF-3, but not NF-kappaB. Secreted IFN-Is then in turn suppress the intracellular replication of L. pneumophila. Surprisingly, this suppression is mediated by a pathway that is independent of Stat1, Stat2, Stat3, but correlates with the polarization of macrophages toward the M1 or classically activated phenotype.

Natural killer cells in infection and inflammation of the lung

The lungs are a major site of entry of pathogens into the body and thus require rapid and effective innate responses to prevent pathogens establishing infection and to limit their spread. Additionally, the immune response in the lung must be tightly regulated such that pathogens are cleared, but immunopathology and chronic inflammation are prevented. In this review, I consider the role of natural killer (NK) cells in pulmonary infection and inflammation, specifically their contributions to influenza, tuberculosis, asthma and chronic obstructive pulmonary disease (COPD), which are major causes of morbidity and mortality world-wide. Despite evidence of the importance of NK cells in these diseases, there are still major gaps in our understanding of how their function is regulated in this unique tissue environment. Understanding how different beneficial and detrimental effector functions of NK cells are triggered will be crucial if NK cells are to be exploited therapeutically in respiratory disease.

The turkey, compared to the chicken, fails to mount an effective early immune response to Histomonas meleagridis in the gut

Histomonosis is a disease of poultry caused by Histomonas meleagridis. Chickens usually recover while the mortality rate in turkeys is high. The immunological response of both species towards H. meleagridis was investigated. Parasites migrated in greater numbers to the turkey liver compared with that of chicken. Chicken mounted an effective caecal innate response, with increased expression of IL-1beta, CXCLi2 and IL-6 mRNA, resulting in control of parasite numbers. The turkey failed to mount such an effective innate response in the caecal tonsil, allowing greater numbers to migrate to the liver, where a sustained, uncontrolled immune response was mounted, evidenced by the upregulation of mRNA for IL-1beta, CXCLi2, IFN-gamma, IL-13, IL-4 and IL-10. Expression levels of mRNA of the chicken and turkey beta-defensin AvBD2 suggest that this response was not limited to the cytokines. There was an influx of CD4+, CD8alpha+, CD28+ and CD44+ cells into the livers of both species, coinciding with parasite movement. These influxes were more pronounced in the turkey, correlating with a decrease in numbers of the same cells in the spleen, which was not observed in the chicken. Antibody levels in the chicken increased more than those in the turkey, supporting evidence of an adaptive response.

Selective expression of inhibitory Fcγ receptor by metastatic melanoma impairs tumor susceptibility to IgG‐dependent cellular response

During melanoma progression, patients develop anti-tumor immunity including the production of anti-tumor antibodies. Although the strategies developed by malignant cells to escape anti-tumor cellular immunity have been extensively investigated, little is known about tumor resistance to humoral immunity. The main effect of IgG antibodies is to activate the immune response by binding to host Fc gamma receptors (FcgammaR) expressed by immune cells. We previously reported in a limited study that some human metastatic melanoma cells ectopically express the FcgammaRIIB1, an inhibitory isoform of FcgammaR. By analyzing a large panel of different types of human primary and metastatic solid tumors, we report herein that expression of FcgammaRIIB is restricted to melanoma and is acquired during tumor progression. We show that FcgammaRIIB expression prevents the lysis of human metastatic melanoma cells by NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) in vitro, independently of the intracytoplasmic region of FcgammaRIIB. Using experimental mouse models, we demonstrate that expression of FcgammaRIIB protects B16F0 melanoma tumors from the ADCC induced by monoclonal and polyclonal anti-tumor IgG in vivo. Thus, our results identify FcgammaRIIB as a marker of human metastatic melanoma that impairs the tumor susceptibility to FcgammaR-dependent innate effector responses.

The chicken leukocyte receptor complex encodes a primordial, activating, high-affinity IgY Fc receptor

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 Fcgamma 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 FcepsilonRIgamma, CHIR-AB1 can be expressed on B cells but cross-linking does not induce intracellular calcium release. In contrast, cells expressing CHIR-AB1 and FcepsilonRIgamma 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.