Showing papers in "International Immunology in 2017"

Hyperferritinemia and inflammation

Abstract: Understanding of ferritin biology has traditionally centered on its role in iron storage and homeostasis, with low ferritin levels indicative of deficiency and high levels indicative of primary or secondary hemochromatosis. However, further work has shown that iron, redox biology and inflammation are inexorably linked. During infection, increased ferritin levels represent an important host defense mechanism that deprives bacterial growth of iron and protects immune cell function. It may also be protective, limiting the production of free radicals and mediating immunomodulation. Additionally, hyperferritinemia is a key acute-phase reactants, used by clinicians as an indication for therapeutic intervention, aimed at controlling inflammation in high-risk patients. One school of thought maintains that hyperferritinemia is an 'innocent bystander' biomarker of uncontrolled inflammation that can be used to gauge effectiveness of intervention. Other schools of thought maintain that ferritin induction could be a protective negative regulatory loop. Others maintain that ferritin is a key mediator of immune dysregulation, especially in extreme hyperferritinemia, via direct immune-suppressive and pro-inflammatory effects. There is a clear need for further investigation of the role of ferritin in uncontrolled inflammatory conditions both as a biomarker and mediator of disease because its occurrence identifies patients with high mortality risk and its resolution predicts their improved survival.

IVIG-mediated effector functions in autoimmune and inflammatory diseases

Abstract: Intravenous immunoglobulin (IVIG) is a pooled preparation of normal IgG obtained from several thousand healthy donors. It is widely used in the immunotherapy of a large number of autoimmune and inflammatory diseases. The mechanisms of action of IVIG are complex and, as discussed in this review, experimental and clinical data provide an indicator that the therapeutic benefit of IVIG therapy is due to several mutually non-exclusive mechanisms affecting soluble mediators as well as cellular components of the immune system. These mechanisms depend on Fc and/or F(ab')2 fragments. A better understanding of the effector functions of IVIG should help in identification of biomarkers of responses to IVIG in autoimmune patients.

Mechanisms governing inflammasome activation, assembly and pyroptosis induction

Abstract: Inflammasomes are multimeric protein complexes that regulate inflammatory responses and pyroptotic cell death to exert host defense against microbes Intracellular pattern-recognition receptors such as nucleotide-binding domain and leucine-rich repeat receptors (NLRs) and absent in melanoma 2 like receptors (ALRs) assemble the inflammasome complexes in response to pathogens and danger or altered-self signals in the cell Inflammasome sensors, in association with an adaptor protein-apoptosis-associated speck-like protein containing a caspase-activation and -recruitment domain (ASC)-activate inflammatory caspase-1 to enable the release of inflammatory cytokines and induce cell death, conferring host defense against pathogens Beyond infectious diseases, the importance of inflammasomes is implicated in a variety of clinical conditions such as auto-inflammatory diseases, neuro-degeneration and metabolic disorders and the development of cancers Understanding inflammasome activation and its molecular regulation can unveil therapeutic targets for controlling inflammasome-mediated disorders In this review, we describe recent advances in inflammasome biology and discuss its activation, structural insights into inflammasome assembly and mechanisms for the execution of pyroptosis

Neuro-immune interactions in allergic diseases: novel targets for therapeutics.

Abstract: Recent studies have highlighted an emerging role for neuro-immune interactions in mediating allergic diseases. Allergies are caused by an overactive immune response to a foreign antigen. The peripheral sensory and autonomic nervous system densely innervates mucosal barrier tissues including the skin, respiratory tract and gastrointestinal (GI) tract that are exposed to allergens. It is increasingly clear that neurons actively communicate with and regulate the function of mast cells, dendritic cells, eosinophils, Th2 cells and type 2 innate lymphoid cells in allergic inflammation. Several mechanisms of cross-talk between the two systems have been uncovered, with potential anatomical specificity. Immune cells release inflammatory mediators including histamine, cytokines or neurotrophins that directly activate sensory neurons to mediate itch in the skin, cough/sneezing and bronchoconstriction in the respiratory tract and motility in the GI tract. Upon activation, these peripheral neurons release neurotransmitters and neuropeptides that directly act on immune cells to modulate their function. Somatosensory and visceral afferent neurons release neuropeptides including calcitonin gene-related peptide, substance P and vasoactive intestinal peptide, which can act on type 2 immune cells to drive allergic inflammation. Autonomic neurons release neurotransmitters including acetylcholine and noradrenaline that signal to both innate and adaptive immune cells. Neuro-immune signaling may play a central role in the physiopathology of allergic diseases including atopic dermatitis, asthma and food allergies. Therefore, getting a better understanding of these cellular and molecular neuro-immune interactions could lead to novel therapeutic approaches to treat allergic diseases.

Diversification of IgG effector functions.

Abstract: IgG is the major immunoglobulin class produced during an immune response against foreign antigens and efficiently provides protection through its bifunctional nature. While the Fab domains confer highly specific recognition of the antigen, the Fc domain mediates a wide range of effector functions that modulate several aspects of innate and adaptive immunity. Engagement of the various types of Fcγ receptors (FcγRs) by an IgG Fc domain can activate distinct immunomodulatory pathways with pleiotropic functional consequences for several leukocyte types. Fc effector functions are not limited to phagocytosis and cytotoxicity of IgG-opsonized targets but exhibit remarkable diversity and include modulation of leukocyte activity and survival, cytokine and chemokine expression, maturation of antigen-presenting cells, antigen processing and presentation, B-cell selection and IgG affinity maturation, as well as regulation of IgG production. These functions are initiated upon specific interactions of the Fc domain with the various types of FcγRs-a process that is largely determined by the structural heterogeneity of the IgG Fc domain. Modulation of the Fc-associated glycan structure and composition along with differences in the primary amino acid sequence among the IgG subclasses represent the two main diversification mechanisms of the Fc domain that generate a spectrum of Fc domain phenotypes with distinct affinity for the various FcγR types and differential capacity to activate immunomodulatory pathways.

Mesenchymal stem cell-derived extracellular vesicles: a glimmer of hope in treating Alzheimer's disease.

Abstract: One of the pathological hallmarks of Alzheimer's disease (AD) is the presence of extracellular plaques resulting from the accumulation of beta-amyloid peptide (Aβ). To date, a definitive cure for this disease is still lacking as the currently approved drugs used are mainly symptomatic treatments. The revolutionary discovery of extracellular vesicles (EVs) has shed new light on the development of disease-modifying treatments for AD, owing to their potential in delivering the therapeutic agents to the brain. The feasibility of harnessing EVs for clinical applications is highly dependent on the donor cell, which determines the intrinsic properties of EVs. The merit of mesenchymal stem cells (MSCs) as therapeutic delivery vehicles, and the proven therapeutic effects of the EVs derived from these cells, make researchers esteem MSCs as ideal producers of EVs. Therefore, MSC-derived EVs (MSC-EVs) emerge to be an appealing therapeutic delivery approach for the treatment of AD. Here, we discuss perspectives on the therapeutic strategies using MSC-EVs to treat AD and the associated challenges in clinical application.

Mesenchymal stromal cells and autoimmunity.

Abstract: Mesenchymal stromal cells (MSCs) are committed progenitors of mesodermal origin that are found virtually in every organ and exhibit multilineage differentiation into osteocytes, adipocytes and chondrocytes. MSCs also mediate a wide spectrum of immunoregulatory activities that usually dampen innate and adaptive immune responses. These features have attracted interest in the perspective of developing novel cell therapies for autoimmune disease. However, depending on the microenvironmental conditions, MSCs may show a plastic behavior and switch to an immunostimulatory phenotype. After thorough characterization of the effects of MSCs on the immune system, MSC cell therapy has been tested in animal models of autoimmunity using different cell sources, protocols of in vitro expansion and routes and schedules of administration. The pre-clinical results have been encouraging in some models [e.g. Crohn's disease (CD), multiple sclerosis] and heterogeneous in others (e.g. graft-versus-host disease, systemic lupus erythematosus, rheumatoid arthritis). Clinical trials have been carried out and many are ongoing. As discussed, the results obtained are too preliminary to draw any conclusion, with the only exception of topical administration of MSCs in CD that has proven efficacious. The mechanism of action of infused MSCs is still under investigation, but the apparent paradox of a therapeutic effect achieved in spite of the very low number of cells reaching the target organ has been solved by the finding that MSC-derived extracellular vesicles (EVs) closely mimic the therapeutic activity of MSCs in pre-clinical models. These issues are critically discussed in view of the potential clinical use of MSC-derived EVs.

Improvement of Foxp3 stability through CNS2 demethylation by TET enzyme induction and activation.

Abstract: Since induced regulatory T cells (iTregs) can be produced in a large quantity in vitro, these cells are expected to be clinically useful to induce immunological tolerance in various immunological diseases. Foxp3 (Forkhead box P3) expression in iTregs is, however, unstable due to the lack of demethylation of the CpG island in the conserved non-coding sequence 2 (CNS2) of the Foxp3 locus. To facilitate the demethylation of CNS2, we over-expressed the catalytic domain (CD) of the ten-eleven translocation (TET) protein, which catalyzes the steps of the iterative demethylation of 5-methylcytosine. TET-CD over-expression in iTregs resulted in partial demethylation of CNS2 and stable Foxp3 expression. We also discovered that TET expression was enhanced under low oxygen (5%) culture conditions, which facilitated CNS2 DNA demethylation and stabilization of Foxp3 expression in a TET2- and TET3-dependent manner. In combination with vitamin C treatment, which has been reported to enhance TET catalytic activity, iTregs generated under low oxygen conditions retained more stable Foxp3 expression in vitro and in vivo and exhibited stronger suppression activity in a colitis model compared with untreated iTregs. Our data indicate that the induction and activation of TET enzymes in iTregs would be an effective method for Treg-mediated adoptive immunotherapy.

Glycosylation of IgG-Fc: a molecular perspective.

Abstract: Antibodies of the IgG class carry a pair of oligosaccharides (N-glycans) in the Fc region. The importance of the N-glycan is clearly demonstrated by its profound effect in the physicochemical and biological properties of antibodies. The term 'glycoengineering' has been coined to describe contemporary strategies to improve the performance of therapeutic monoclonal antibodies on the basis of modifications in the structure and composition of the N-glycan. These methodologies have resulted in the approval and commercialization of a new generation of antibodies with improved therapeutic efficacy. So far, these advances have been driven by herculean efforts in a process of trial-and-error. The collective work of researchers in this field is progressively revealing the molecular basis of N-glycans for the function of antibodies. This knowledge will ultimately be conducive to the application of rational approaches for the successful manipulation of antibodies using glycoengineering strategies. Herein, we review advances in our understanding of the role of the N-glycan in the structural and dynamic integrity, and biological activity, of antibodies. Since the N-glycan has a multifaceted effect in antibodies, in this review we have emphasized the importance of integrating various techniques that address this problem from multiple points of view. In particular, the combination of X-ray crystallography with nuclear magnetic resonance, molecular dynamics simulations and biophysical approaches based on thermodynamic principles, has emerged as a powerful combination that is deepened our understanding of this unique system with critical implications for human well-being.

Splicing in immune cells-mechanistic insights and emerging topics.

Abstract: Differential splicing of mRNAs not only enables regulation of gene expression levels, but also ensures a high degree of gene-product diversity. The extent to which splicing of mRNAs is utilized as a mechanism in immune cells has become evident within the last few years. Still, only a few of these mechanisms have been well studied. In this review, we discuss some of the best-understood mechanisms, for instance the differential splicing of CD45 in T cells, as well as immunoglobulin genes in B cells. Beyond that we provide general mechanistic insights on how, when and where this process takes place and discuss the current knowledge regarding these topics in immune cells. We also highlight some of the reported links to immune-related diseases, genome-wide sequencing studies that revealed thousands of differentially spliced transcripts, as well as splicing studies on immune cells that remain mechanistically not fully understood. We thereby display potential emerging topics for future studies centered on splicing mechanisms in immune cells.

Transcriptional control of monocyte and macrophage development.

Abstract: Monocytes and macrophages play critical roles in immune responses, tissue homeostasis and disease progression. There are a number of functionally and phenotypically distinct subpopulations throughout the body. However, the mechanisms by which macrophage and monocyte heterogeneity is established remain unclear. Recent studies have suggested that most tissue-resident macrophages originate from fetal progenitors but not from hematopoietic stem cells, whereas some subpopulations are derived from adult monocytes. In addition, transcription factors specifically required for the development of each subpopulation have been identified. Interestingly, local environmental factors such as heme, retinoic acid and RANKL induce the expression and/or activation of tissue-specific transcription factors, thereby controlling transcriptional programs specific for the subpopulations. Thus, distinct differentiation pathways and local microenvironments appear to contribute to the determination of macrophage transcriptional identities. In this review, we highlight recent advances in our knowledge of the transcriptional control of macrophage and monocyte development.

Role of scavenger receptors as damage-associated molecular pattern receptors in Toll-like receptor activation.

Abstract: Damage-associated molecular patterns (DAMPs) have been implicated in sterile inflammation in various tissue injuries. High-mobility group box 1 (HMGB1) is a representative DAMP, and has been shown to transmit signals through receptors for advanced glycation end products (RAGEs) and TLRs, including TLR2 and TLR4. HMGB1 does not, however, bind to TLRs with high affinity; therefore, the mechanism of HMGB1-mediated TLR activation remains unclear. In this study, we found that fluorescently labeled HMGB1 was efficiently internalized into macrophages through class A scavenger receptors. Although both M1- and M2-type macrophages internalized HMGB1, only M1-type macrophages secreted cytokines in response to HMGB1. The pan-class A scavenger receptor competitive inhibitor, maleylated bovine serum albumin (M-BSA), inhibited HMGB1 internalization and reduced cytokine production from macrophages in response to HMGB1 but not to LPS. The C-terminal acidic domain of HMGB1 is responsible for scavenger receptor-mediated internalization and cytokine production. HMGB1 and TLR4 co-localized in macrophages, and this interaction was disrupted by M-BSA, suggesting that class A scavenger receptors function as co-receptors of HMGB1 for TLR activation. M-BSA ameliorated LPS-induced sepsis and dextran sulfate sodium (DSS)-induced colitis models in which HMGB1 has been shown to play progressive roles. These data suggest that scavenger receptors function as co-receptors along with TLRs for HMGB1 in M1-type inflammatory macrophages.

Regulation of mRNA stability by CCCH-type zinc-finger proteins in immune cells.

Abstract: Current studies using knockout mice have revealed that some Cys-Cys-Cys-His (CCCH)-type zinc-finger proteins, namely tristetraprolin (TTP), Roquin and Regnase-1, play important roles in the immune system. These proteins are closely associated with the fate of their target RNAs in normal immune responses. However, the functions of many RNA-binding proteins have not been characterized precisely. To understand the molecular mechanisms of RNA metabolism in the immune system, investigation of TTP/Roquin/Regnase-1 might provide new knowledge. In this review, we will discuss the current understanding of these proteins in immune regulation and homeostasis and discuss RNA metabolism in the immune system.

Generation of allo-antigen-specific induced Treg stabilized by vitamin C treatment and its application for prevention of acute graft versus host disease model.

Abstract: Antigen-specific regulatory T cells (Tregs) possess the potential to reduce excess immune responses in autoimmune diseases, allergy, rejection after organ transplantation and graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. Although in vitro-expanded antigen-specific induced Tregs (iTregs) have been considered to be a promising therapeutic agent against such excessive immune reactions, the instability of iTregs after transfer is a fundamental problem in their clinical application. In this study, we searched for the optimal way to generate stable iTregs for the prevention of the murine GVHD model, in which conventional iTregs are reported to be inefficient. Allo-antigen-specific iTregs were generated by co-culturing naive T cells with allogenic dendritic cells in the presence of TGF-β and retinoic acid. By examining various agents and genes, we found that vitamin C stabilized Foxp3 expression most effectively in adoptively transferred iTregs under a GVHD environment. Vitamin C treatment caused active DNA demethylation specifically on the conserved non-coding sequence 2 (CNS2) enhancer of the Foxp3 gene locus in allo-antigen-specific iTregs and reduced iTreg conversion into pathogenic exFoxp3 cells. Vitamin C-treated iTregs suppressed GVHD symptoms more efficiently than untreated iTregs. Vitamin C also facilitated induction of a FOXP3high iTreg population from human naive T cells, which was very stable even in the presence of IL-6 in vitro. The treatment of vitamin C for iTreg promises innovative clinical application for adoptive Treg immunotherapy.

NALT M cells are important for immune induction for the common mucosal immune system.

Abstract: Nasopharynx-associated lymphoid tissue (NALT) is one of the major constituents of the mucosa-associated lymphoid tissue (MALT), and has the ability to induce antigen-specific immune responses. However, the molecular mechanisms responsible for antigen uptake from the nasal cavity into the NALT remain largely unknown. Immunohistochemical analysis showed that CCL9 and CCL20 were co-localized with glycoprotein 2 (GP2) in the epithelium covering NALT, suggesting the existence of M cells in NALT. In analogy with the reduced number of Peyer's patch M cells in CCR6-deficient mice, the number of NALT M cells was drastically decreased in CCR6-deficient mice compared with the wild-type mice. Translocation of nasally administered Salmonella enterica serovar Typhimurium into NALT via NALT M cells was impaired in CCR6-deficient mice, whereas S. Typhimurium demonstrated consistent co-localization with NALT M cells in wild-type mice. When wild-type mice were nasally administered with an attenuated vaccine strain of S. Typhimurium, the mice were protected from a subsequent challenge with wild-type S. Typhimurium. Antigen-specific fecal and nasal IgA was detected after nasal immunization with the attenuated vaccine strain of S. Typhimurium only in wild-type mice but not in CCR6-deficient mice. Taken together, these observations demonstrate that NALT M cells are important as a first line of defense against infection by enabling activation of the common mucosal immune system (CMIS).

The human NAIP-NLRC4-inflammasome senses the Pseudomonas aeruginosa T3SS inner-rod protein

Abstract: While NLRC4-dependent sensing of intracellular Gram-negative pathogens such as Salmonella enterica serovar typhimurium is a beneficial host response, NLRC4-dependent sensing of the Pseudomonas aeruginosa type 3 secretion system (T3SS) has been shown to be involved in pathogenicity. In mice, different pathogen-associated microbial patterns are sensed by the combination of the NLRC4-inflammasome with different neuronal apoptosis inhibitory proteins (NAIPs). NAIP2 is involved in sensing PscI, an inner-rod protein of the P. aeruginosa T3SS. Surprisingly, only a single human NAIP (hNAIP) has been found. Moreover, there is no description of hNAIP-NLRC4 inflammasome recognition of T3SS inner-rod proteins in humans. Here, we show that the P. aeruginosa T3SS inner-rod protein PscI and needle protein PscF are both sensed by the hNAIP-NLRC4 inflammasome in human macrophages and PBMCs from healthy donors, allowing caspase-1 and IL-1β maturation and resulting in a robust inflammatory response. TLR4 and TLR2 are involved in redundantly sensing these two T3SS components.

A transcriptional serenAID: the role of noncoding RNAs in class switch recombination

Abstract: During an immune response, activated B cells may undergo class switch recombination (CSR), a molecular rearrangement that allows B cells to switch from expressing IgM and IgD to a secondary antibody heavy chain isotype such as IgG, IgA or IgE. Secondary antibody isotypes provide the adaptive immune system with distinct effector functions to optimally combat various pathogens. CSR occurs between repetitive DNA elements within the immunoglobulin heavy chain (Igh) locus, termed switch (S) regions and requires the DNA-modifying enzyme activation-induced cytidine deaminase (AID). AID-mediated DNA deamination within S regions initiates the formation of DNA double-strand breaks, which serve as biochemical beacons for downstream DNA repair pathways that coordinate the ligation of DNA breaks. Myriad factors contribute to optimal AID targeting; however, many of these factors also localize to genomic regions outside of the Igh locus. Thus, a current challenge is to explain the specific targeting of AID to the Igh locus. Recent studies have implicated noncoding RNAs in CSR, suggesting a provocative mechanism that incorporates Igh-specific factors to enable precise AID targeting. Here, we chronologically recount the rich history of noncoding RNAs functioning in CSR to provide a comprehensive context for recent and future discoveries. We present a model for the RNA-guided targeting of AID that attempts to integrate historical and recent findings, and highlight potential caveats. Lastly, we discuss testable hypotheses ripe for current experimentation, and explore promising ideas for future investigations.

Commercial rodent diets differentially regulate autoimmune glomerulonephritis, epigenetics and microbiota in MRL/lpr mice.

Abstract: The course and severity of lupus in spontaneous murine lupus models varies among laboratories, which may be due to variations in diet, housing and/or local environmental conditions. In this study, we investigated the influence of common rodent diets while keeping other factors constant. Female lupus-prone MRL/lpr (MRL/MpJ-Faslpr/J) mice were subjected to the same housing conditions and given one of the three diets: Teklad 7013 containing isoflavone-rich soy and alfalfa, Harlan 2018 isoflavone-rich soy-based diet or Research Diets Inc. D11112226 (RD) purified-ingredients diet containing casein and no phytoestrogens. While the total caloric intake was similar among all three treatment groups, mice fed on the 2018 diet developed higher levels of proteinuria and mice fed on either 7013 or 2018 developed higher levels of glomerular immune complex deposition. Remarkably, mice fed the RD diet had markedly decreased proteinuria with diminished C3, total IgG, IgG1 and IgG3 immune complex deposition, along with reduced CD11b+ cellular infiltration into the glomeruli. The type of diet intake also influenced cytokine production, fecal microbiota (increased Lachnospiraceae in mice fed on 2018), altered microRNAs (miRNAs; higher levels of lupus-associated miR-148a and miR-183 in mice fed on 7013 and/or 2018) and altered DNA methylation. This is the first study to comprehensively compare the cellular, molecular and epigenetic effects of these commercial diets in murine lupus.

Rbm10 regulates inflammation development via alternative splicing of Dnmt3b.

Abstract: RNA-binding motif 10 (Rbm10) is an RNA-binding protein that regulates alternative splicing, but its role in inflammation is not well defined. Here, we show that Rbm10 controls appropriate splicing of DNA (cytosine-5)-methyltransferase 3b (Dnmt3b), a DNA methyltransferase, to regulate the activity of NF-κB-responsive promoters and consequently inflammation development. Rbm10 deficiency suppressed NF-κB-mediated responses in vivo and in vitro. Mechanistic analysis showed that Rbm10 deficiency decreased promoter recruitment of NF-κB, with increased DNA methylation of the promoter regions in NF-κB-responsive genes. Consistently, Rbm10 deficiency increased the expression level of Dnmt3b2, which has enzyme activity, while it decreased the splicing isoform Dnmt3b3, which does not. These two isoforms associated with NF-κB efficiently, and overexpression of enzymatically active Dnmt3b2 suppressed the expression of NF-κB targets, indicating that Rbm10-mediated Dnmt3b2 regulation is important for the induction of NF-κB-mediated transcription. Therefore, Rbm10-dependent Dnmt3b regulation is a possible therapeutic target for various inflammatory diseases.

Uromodulin-SlpA binding dictates Lactobacillus acidophilus uptake by intestinal epithelial M cells.

Abstract: Bacterial access to the gut immune system is a crucial process to promote host immune responses. The probiotic L-92 strain of Lactobacillus acidophilus exerts anti-allergic immunomodulatory effects upon oral administration in mice. Here, we show that microfold cells (M cells) are responsible for L-92 internalization for evoking L-92-mediated immune responses. L-92 specifically bound to uromodulin, a glycosylphosphatidylinositol-anchored protein expressed exclusively on M cells among intestinal epithelial cells. Internalization of L-92 into M cells was significantly reduced in uromodulin-deficient (Umod-/-) mice compared to Umod+/+ mice. Furthermore, the binding of L-92 to uromodulin was significantly decreased after removal of surface layer protein A (SlpA) from the bacteria. Our study thus revealed a crucial role of uromodulin on the M-cell surface for the uptake of SlpA-positive lactic acid bacteria into M cells, possibly leading to subsequent delivery of the bacteria to dendritic cells closely associated with M cells for immunomodulation. Our study also shed light on the possibility that SlpA and uromodulin could be used as vehicle and target, respectively, for efficient mucosal vaccine delivery.

Sweet SIGNs: IgG glycosylation leads the way in IVIG-mediated resolution of inflammation.

Abstract: A hallmark of many chronic inflammatory and autoimmune diseases is that there is an impaired resolution of inflammation and return to the steady state. The infusion of high doses of pooled serum IgG preparations from thousands of donors [intravenous immunoglobulin (IVIG) therapy] has been shown to induce resolution of inflammation in a variety of chronic inflammatory and autoimmune diseases, suggesting that IgG molecules can instruct the immune system to stop inflammatory processes and initiate the return to the steady state. The aim of this review is to discuss how insights into the mechanism of IVIG activity may help to understand the molecular and cellular pathways underlying resolution of inflammation. We will put a special emphasis on pathways dependent on the IgG FC domain and IgG sialylation, as several recent studies have provided new insights into how this glycosylation-dependent pathway modulates innate and adaptive immune responses through different sets of C-type or I-type lectins.

Polymorphisms of immunoglobulin receptors and the effects on clinical outcome in cancer immunotherapy and other immune diseases: a general review.

Abstract: Receptors for the Fc domain of immunoglobulins [Fc receptors (FcRs)] are essential for the maintenance of antibody-mediated immune responses. FcRs consist of activating- and inhibitory-type receptors that regulate adequate thresholds for various immune cells. In particular, polymorphisms and/or gene copy-number variations of FcRs for IgG (FcγRs) are closely associated with the development of inflammatory disorders, including autoimmune diseases. Recent evidence has implicated polymorphisms of FcRs in the efficacy of monoclonal antibody (mAb)-mediated therapy. This review provides an overview of genetic variations in human FcγRs and the clinical contribution of FcγR polymorphisms in mAb treatments for cancer, autoimmune diseases and allergies.

A clinical update on inflammasomopathies.

Abstract: Inflammasomes are important elements of the innate immune defense. The most common autoinflammatory syndromes, as well a number of rare ones, are due to hereditary defects in the inflammasomes, hence are called inflammasomopathies. The recent clinical advances in these diseases will be reviewed, with special emphasis on reflecting the international collaborative work in the field. Recent recommendations for familial Mediterranean fever, cryopyrin-associated periodic syndromes and hyper-IgD syndrome/mevalonate kinase deficiency will be presented and diagnostics tests, treatment alternatives and follow-up recommendations will be summarized. The other rare inflammasomopathies will be briefly discussed based on clinical features; these diseases are pyogenic arthritis, pyoderma gangrenosum and acne, NLRC4-related macrophage-activation syndrome of enterocolitis, mutations in NLRP12 that cause hereditary periodic fever syndromes (familial cold inflammatory syndrome 2) and NLRP1-associated autoinflammation with arthritis and dyskeratosis.

MicroRNA-mediated dynamic control of mucosal immunity.

Abstract: The gastrointestinal tract is a complex and important physiological and immunological organ embodying the first line of defense by which mucosal immunity regulates the immense number and diversity of naturally encountered antigens and commensal microflora. Effective microRNA (miRNA) control of transcription factors or mediators in mucosal immunity is essential to host defense and homeostasis in both physiologic and pathologic states. MiRNA biology has advanced our understanding of the immune regulatory system network at the level of post-transcriptional gene modification. Increasing knowledge on circulating miRNAs could potentially enhance diagnostic techniques in inflammatory bowel disease (IBD). Furthermore, recent findings on the dynamic role of exosomes vis-a-vis the intercellular transportation of miRNAs may provide insights on the use of miRNA as a target for treating IBD.

The spleen is the site where mast cells are induced in the development of food allergy.

Abstract: It has been reported that splenic immune responses play pivotal roles in the development of allergic diseases; however, the precise role of the spleen remains unclear. Herein, we demonstrated a novel role of the spleen in the pathogenesis of food allergy (FA). We found that mast cells (MCs) developed from progenitor cells present in spleen during an antigen-specific T-cell response in vitro. In a Th2 response-mediated FA model, significant expansion of MCs was also observed in spleen. The incidence of allergic diarrhea was profoundly reduced in splenectomized mice, whereas adoptive transfer of in vitro-induced splenic MCs into these mice restored allergic symptoms, suggesting that the splenic MCs functioned as the pathogenic cells in the development of FA. The in vitro-generated MCs required not only IL-3 but also IFN-γ, and treatment of FA-induced mice with anti-IFN-γ antibody suppressed expansion of MCs in spleen as well as diarrhea development, highlighting that IFN-γ in the spleen orchestrated the development of FA, which was followed by a Th2 response in the local lesion. Overall, we propose that the role of the spleen in the development of FA is to provide a unique site where antigen-specific T cells induce development of pathogenic MCs.

Identification of biomarker sets for predicting the efficacy of sublingual immunotherapy against pollen-induced allergic rhinitis.

Abstract: Sublingual immunotherapy (SLIT) is effective against allergic rhinitis, although a substantial proportion of individuals is refractory Herein, we describe a predictive modality to reliably identify SLIT non-responders (NRs) We conducted a 2-year clinical study in 193 adult patients with Japanese cedar pollinosis, with biweekly administration of 2000 Japanese allergy units of cedar pollen extract as the maintenance dose After identifying high-responder (HR) patients with improved severity scores and NR patients with unchanged or exacerbated symptoms, differences in 33 HR and 34 NR patients were evaluated in terms of peripheral blood cellular profiles by flow cytometry and serum factors by ELISA and cytokine bead array, both pre- and post-SLIT Improved clinical responses were seen in 72% of the treated patients Pre-therapy IL-12p70 and post-therapy IgG1 serum levels were significantly different between HR and NR patients, although these parameters alone failed to distinguish NR from HR patients However, the analysis of serum parameters in the pre-therapy samples with the Adaptive Boosting (AdaBoost) algorithm distinguished NR patients with high probability within the training data set Cluster analysis revealed a positive correlation between serum Th1/Th2 cytokines and other cytokines/chemokines in HR patients after SLIT Thus, processing of pre-therapy serum parameters with AdaBoost and cluster analysis can be reliably used to develop a prediction method for HR/NR patients

Lysosome biogenesis regulated by the amino-acid transporter SLC15A4 is critical for functional integrity of mast cells.

Abstract: Mast cells possess specialized lysosomes, so-called secretory granules, which play a key role not only in allergic responses but also in various immune disorders. The molecular mechanisms that control secretory-granule formation are not fully understood. Solute carrier family member 15A4 (SLC15A4) is a lysosome-resident amino-acid/oligopeptide transporter that is preferentially expressed in hematopoietic lineage cells. Here, we demonstrated that SLC15A4 is required for mast-cell secretory-granule homeostasis, and limits mast-cell functions and inflammatory responses by controlling the mTORC1-TFEB signaling axis. In mouse Slc15a4-/- mast cells, diminished mTORC1 activity increased the expression and nuclear translocation of TFEB, a transcription factor, which caused secretory granules to degranulate more potently. This alteration of TFEB function in mast cells strongly affected the FceRI-mediated responses and IL-33-triggered inflammatory responses both in vitro and in vivo. Our results reveal a close relationship between SLC15A4 and secretory-granule biogenesis that is critical for the functional integrity of mast cells.

Efficiency of antibody therapy in demyelinating diseases

Abstract: Monoclonal antibody therapy is a new treatment strategy for many types of diseases including cancers and autoimmune diseases, realizing a high efficacy and tolerability. In multiple sclerosis (MS) and neuromyelitis optica (NMO) spectrum disorders, several monoclonal antibodies have been suggested to decrease the incidence of clinical relapse and the disease activity. In MS, anti-α4 integrin (natalizumab), anti-CD52 (alemtuzumab), anti-CD25 (daclizumab) and anti-CD20 (ocrelizumab) have been shown to effectively reduce the relapses in randomized controlled trials and have been approved by the Food and Drug Administration. Specifically, ocrelizumab is the first drug that has shown significant suppression of brain volume loss and suppression of chronic disability progression. In NMO, though there have yet to be any approved monoclonal antibodies, rituximab, anti-complement C5 (eculizumab), anti-IL-6 receptor (tocilizumab), anti-CD19 (inebilizumab) and non-pathogenic anti-aquaporin 4 (aquaporumab) have been suggested to be effective, and some of these are now under clinical trials. Aquaporumab is a non-pathogenic recombinant human monoclonal antibody that competitively inhibits the binding of the pathogenic auto-antibody against aquaporin 4 in NMO patients; thus, it is expected to be highly disease specific with less non-specific adverse events. Some of these monoclonal antibodies in MS and NMO are known to cause several notable adverse events. Natalizumab and rituximab increase the risk of progressive multifocal leukoencephalopathy. Eculizumab increases the risk of meningococcal infection. Tocilizumab is known to cause intestinal diverticulitis that can cause intestinal perforation. In this review, we summarize the characteristics of, evidence for and notable adverse events of each monoclonal antibody in MS and NMO.

Antibody therapy for the management of severe asthma with eosinophilic inflammation.

Abstract: One of the characteristic features of asthma is chronic airway inflammation typically with eosinophil infiltration. Most asthmatics can be treated successfully with conventional treatment appropriate for their severity, but in some severe cases, asthma cannot be well controlled even with thorough treatment and this condition is known as 'refractory asthma'. To overcome severe refractory asthma, a new therapeutic strategy with biologics has been developed based on the knowledge of molecular mechanisms of airway inflammation in asthma, induced by the condition of high Th2-type responses and activation of eosinophils as well as allergic reactions. Humanized anti-human IgE antibody (anti-IgE; omalizumab) was the first biological preparation approved for treating asthma. Based on clinical evidence, treatment with anti-IgE (anti-IgE therapy) has been accepted as a new therapeutic approach for severe allergic asthma in adults since 2009 and in children since 2012 and has been shown to have ~60% efficacy. More recently, a humanized anti-IL-5 antibody (anti-IL-5; mepolizumab) was launched in June 2016 and has attracted great interest due to its potential effects. Several clinical studies are also ongoing to evaluate the biological preparations targeting IL-5 receptor α (IL-5Rα), IL-4 receptor α (IL-4Rα), which is shared by IL-4 and IL-13, thymic stromal lymphopoietin (TSLP) and IL-33. The new strategy with biologics targeting eosinophilic airway inflammation might open a new array for us to overcome severe refractory asthma in the future.

E3 ubiquitin ligases SIAH1/2 regulate hypoxia-inducible factor-1 (HIF-1)-mediated Th17 cell differentiation.

Abstract: IL-17 is known to be a cytokine mainly secreted from Th17 cells, which well associate with autoimmune inflammatory responses. In the generation of Th17 cells, RORc and RORa have pivotal roles in controlling the transcription of Il17. We speculated additional regulation in Il17a transcription and randomly screened a 6344 clone cDNA library to identify specific modulators for Il17a promoter activity. After the screen, the E3 ubiquitin ligases SIAH1 and SIAH2 were investigated further and confirmed to increase Il17a promoter activity in a T-cell line and to promote Th17 development ex vivo. This enhancement was a consequence of enhanced expression of hypoxia-inducible factor-1α (HIF-1α) protein, which is reported to directly regulate expression of Il17a and Rorgt at the transcriptional level. In the absence of HIF-1α, both ubiquitin ligases had little effect on Th17 cell differentiation. These results suggest that the SIAH1 and SIAH2 play a pivotal role to promote Th17 cell differentiation through maintaining the stability of HIF-1α protein.