Background
The poliovirus receptor (CD155) is expressed ubiquitously at low levels on both hematopoietic and nonhematopoietic cells, but its expression is upregulated in various tumor cells. An ...activating receptor DNAM-1 expressed on cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells binds to CD155 and mediates the cytotoxic activity of CTLs and NK cells against tumors. Unlike mouse tissues, human tissues express a soluble form of CD155 (sCD155), which is a splicing isoform of CD155 lacking the transmembrane region. We previously reported that the serum levels of sCD155 were higher in lung, gastrointestinal, breast, and gynecologic cancer patients than in healthy donors. Here, we focus on breast cancer patients.
Methods
To analyze the association between serum level of sCD155 and clinicopathological parameters of breast cancer, we quantified sCD155 in the sera of 153 breast cancer patients by sandwich ELISA.
Results
sCD155 levels in the sera of breast cancer patients were positively correlated with patient age, disease stage, and invasive tumor size. Moreover, they were higher in patients with estrogen receptor (ER)-negative cancers than in those with ER-positive tumors, and higher in those with Ki-67-high cancers than in those with Ki-67-low cancers.
Conclusions
The serum level of sCD155 is correlated with high risk factors in breast cancer.
► CD300a is a new phosphatidylserine receptor expressed on myeloid cells. ► Phosphatidylserine delivers a signal for recruitment of SHP-1 by CD300a in mast cells. ► The CD300a/phosphatidylserine ...interaction is blocked by MFG-E8 or anti-CD300a antibody.
CD300a is a member of CD300 family molecules consisting of seven genes on human chromosome 17 and nine genes in mouse chromosome 11. CD300a has a long cytoplasmic region containing the consensus immunoreceptor tyrosine-based inhibitory motif (ITIM) sequence. Upon crosslinking with antibodies against CD300a, CD300a mediates an inhibitory signal in myeloid cells. However, the ligand for CD300a has not been identified and the physiological role of CD300a remained unclear. Here, we demonstrate that the chimeric fusion protein of CD300a extracellular domain with the Fc portion of human IgG specifically bound phosphatidylserine (PS), which is exposed on the outer leaflet of the plasma membrane of apoptotic cells. PS binding to CD300a induced SHP-1 recruitment by CD300a in mast cells in response to LPS. These results indicated that CD300a is a new PS receptor.
Invariant NKT (iNKT) cells play an important role in a variety of antimicrobial immune responses due to their ability to produce high levels of immune‐modulating cytokines. Here, we investigated the ...role of iNKT cells in host defense against candidiasis using Jα18‐deficient mice (Jα18−/−), which lack iNKT cells. Jα18−/− mice were more resistant to the development of lethal candidiasis than wild‐type (WT) mice. In contrast, treatment of WT mice with the iNKT cell activating ligand α‐galactosylceramide markedly enhanced their mortality after infection with Candida albicans. Serum IL‐10 levels were significantly elevated in WT mice in response to infection with C. albicans. Futhermore, IL‐10 production increased after in vitro coculture of peritoneal macrophages with iNKT cells and C. albicans. The numbers of peritoneal macrophages, the production of IL‐1β and IL‐18, and caspase‐1 activity were also significantly elevated in Jα18−/− mice after infection with C. albicans. The adoptive transfer of iNKT cells or exogenous administration of IL‐10 into Jα18−/− reversed susceptibility to candidiasis to the level of WT mice. These results suggest that activation of iNKT cells increases the initial severity of C. albicans infection, most likely mediated by IL‐10 induced modulation of macrophage antifungal activity.
The putative mechanisms for increase in susceptibility to Candidia infections by iNKT cells. Macrophages stimulated with C. albicans might activate iNKT cells by producing IL‐12 and IL‐18; then activated iNKT cells might negatively regulate the anticandidal activities of macrophages and neutrophils by mediating IL‐10.
Recruitment of circulating monocytes and neutrophils to infection sites is essential for host defense against infections. Here, we identified a previously unannotated gene that encodes an ...immunoglobulin-like receptor, designated CD300H, which is located in the CD300 gene cluster. CD300H has a short cytoplasmic tail and associates with the signaling adaptor proteins, DAP12 and DAP10. CD300H is expressed on CD16+ monocytes and myeloid dendritic cells. Ligation of CD300H on CD16+ monocytes and myeloid dendritic cells with anti-CD300H monoclonal antibody induced the production of neutrophil chemoattractants. Interestingly, CD300H expression varied among healthy subjects, who could be classified into two groups according to “positive” and “negative” expression. Genomic sequence analysis revealed a single-nucleotide substitution (rs905709 (G→A)) at a splice donor site on intron 1 on either one or both alleles. The International HapMap Project database has demonstrated that homozygosity for the A allele of single nucleotide polymorphism (SNP) rs905709 (“negative” expression) is highly frequent in Han Chinese in Beijing, Japanese in Tokyo, and Europeans (A/A genotype frequencies 0.349, 0.167, and 0.138, respectively) but extremely rare in Sub-Saharan African populations. Together, these results suggest that CD300H may play an important role in innate immunity, at least in populations that carry the G/G or G/A genotype of CD300H.
Background: CD300 family molecules regulate innate immune responses.
Results: We identified and characterized a novel immunoreceptor, CD300H.
Conclusion: CD300H mediates neutrophil chemoattractant production.
Significance: CD300H may play an important role in innate immunity.
DNA demethylation plays a critical role in transcriptional regulation in differentiated somatic cells. However, there is no experimental evidence that CpG methylation in a small region of a genome ...restricts gene expression. Here, we show that the anti‐CD3ε/CD28 antibody stimulation of human CD4+ T cells induces IL2 expression following epigenetic changes, including active demethylation of a specific CpG site, recruitment of Oct‐1, and changes in histone modifications. When the stimulatory signal is withdrawn, Oct‐1 remains on the enhancer region as a stable marker of the stimulation, causing the second induction to be faster and stronger. Our observations indicate that Oct‐1‐binding followed by CpG demethylation are key events in the epigenetic regulation of IL2 expression and may act as a memory of the regulatory event.
Tumor recognition by immune effector cells is mediated by antigen receptors and a variety of adhesion and costimulatory molecules. The evidence accumulated since the identification of CD155 and CD112 ...as ligands for DNAM-1 in humans and mice has suggested that the interactions between DNAM-1 and its ligands play an important role in T cell- and natural killer (NK) cell-mediated recognition and lysis of tumor cells. We have previously demonstrated that methylcholanthrane (MCA) accelerates tumor development in DNAM-1-deficient mice, and the Cd155 level on MCA-induced tumors is significantly higher in DNAM-1-deficient mice than in wild-type (WT) mice. By contrast, Cd112 expression on the tumors is similar in WT and DNAM-1-deficient mice, suggesting that CD155 plays a major role as a DNAM-1 ligand in activation of T cells and NK cells for tumor immune surveillance. To address this hypothesis, we examined MCA-induced tumor development in CD155-deficient mice. Unexpectedly, we observed no significant difference in tumor development between WT and CD155-deficient mice. Instead, we found that Cd112 expression was significantly higher in the MCA-induced tumors of CD155-deficient mice than in those of WT mice. We also observed higher expression of DNAM-1 and lower expression of an inhibitory receptor, TIGIT, on CD8+ T cells in CD155-deficient mice. These results suggest that modulation of the expression of receptors and CD112 compensates for CD155 deficiency in immune surveillance against MCA-induced tumors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
DNAM-1 (CD226) is an activating immunoreceptor expressed on lymphocytes and myeloid cells. CD155 and CD112 are the ligands for DNAM-1. DNAM-1 plays an important role in tumor immunity mediated by CD8
...T cells and NK cells. Moreover, the interaction of DNAM-1 with the ligands contributed to the development of acute graft versus host disease (GVHD) and treatment with anti-DNAM-1 monoclonal antibodies (mAb) dramatically improved acute GVHD in a mouse model, suggesting that DNAM-1 may be a good molecular target for therapy to acute GVHD in human. In this study, we generated and characterized five novel clones of anti-human DNAM-1 mAbs, named TX94, TX95, TX96, TX107, and TX108. Among these mAbs, TX94 is a unique neutralizing mAb that most efficiently blocked the interaction between DNAM-1 and CD155. Furthermore, TX94 inhibited NK cell-mediated cytotoxicity against a tumor cell line and suppressed CD8
T cell proliferation mediated by allogeneic mixed lymphocyte reaction. Thus, TX94 may be useful for molecular therapy targeting DNAM-1.
Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because diagnosis of aGVHD is exclusively based on clinical symptoms ...and pathological findings, reliable and noninvasive laboratory tests for accurate diagnosis are required. An activating immunoreceptor, DNAM-1 (CD226), is expressed on T cells and natural killer cells and is involved in the development of aGVHD. Here, we identified a soluble form of DNAM-1 (sDNAM-1) in human sera. In retrospective univariate and multivariate analyses of allo-HSCT patients (n = 71) at a single center, cumulative incidences of all grade (grade I-IV) and sgrade II-IV aGVHD in patients with high maximal serum levels of sDNAM-1 (≥30 pM) in the 7 days before allo-HSCT were significantly higher than those in patients with low maximal serum levels of sDNAM-1 (<30 pM) in the same period. However, sDNAM-1 was not associated with other known allo-HSCT complications. Our data suggest that sDNAM-1 is potentially a unique candidate as a predictive biomarker for the development of aGVHD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Natural immunoglobulin M (IgM) is reactive to autoantigens and is believed to be important for autoimmunity. Blood pentameric IgM loaded with antigens forms a large immune complex (IC) that contains ...various elements, including apoptosis inhibitor of macrophage (AIM). Here we demonstrate that this IgM-AIM association contributes to autoantibody production under obese conditions. In mice fed a high-fat diet, natural IgM increased through B cell TLR4 stimulation. AIM associated with IgM and protected AIM from renal excretion, increasing blood AIM levels along with the obesity-induced IgM augmentation. Meanwhile, the AIM association inhibited IgM binding to the Fcα/μ receptor on splenic follicular dendritic cells, thereby protecting the IgM IC from Fcα/μ receptor-mediated internalization. This supported IgM-dependent autoantigen presentation to B cells, stimulating IgG autoantibody production. Accordingly, in obese AIM-deficient (AIM−/−) mice, the increase of multiple IgG autoantibodies observed in obese wild-type mice was abrogated. Thus, the AIM-IgM association plays a critical role in the obesity-associated autoimmune process.
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► AIM is protected from renal excretion via binding to IgM pentamers in blood ► Association with AIM interferes with Fcα/μ receptor-mediated internalization of IgM ► IgM-dependent autoantigen presentation on FDCs is preserved by AIM ► Absence of AIM tempers obesity-associated multiple IgG autoantibody production
In addition to inducing metabolic and cardiovascular diseases, obesity also increases blood immunoglobulin M (IgM) levels, followed by multiple autoantibody expansion leading to autoimmune disease. Here, Arai, Miyazaki, and colleagues show that apoptosis inhibitor of macrophage (AIM) associates with IgM and abrogates IgM internalization through the Fcα/μ receptor. This response supports IgM-dependent autoantigen presentation to B cells on splenic follicular dendritic cells, thereby enhancing the development of high-affinity IgG autoantibody-producing plasma cells. Thus, AIM suppression may be a promising candidate for the next generation of therapy for preventing obesity-associated autoimmune diseases.
Inflammatory monocytes play an important role in host defense against infections. However, the regulatory mechanisms of transmigration into infected tissue are not yet completely understood. Here we ...show that mice deficient in MAIR-II (also called CLM-4 or LMIR2) are more susceptible to caecal ligation and puncture (CLP)-induced peritonitis than wild-type (WT) mice. Adoptive transfer of inflammatory monocytes from WT mice, but not from MAIR-II, TLR4 or MyD88-deficient mice, significantly improves survival of MAIR-II-deficient mice after CLP. Migration of inflammatory monocytes into the peritoneal cavity after CLP, which is dependent on VLA-4, is impaired in above mutant and FcRγ chain-deficient mice. Lipopolysaccharide stimulation induces association of MAIR-II with FcRγ chain and Syk, leading to enhancement of VLA-4-mediated adhesion to VCAM-1. These results indicate that activation of MAIR-II/FcRγ chain by TLR4/MyD88-mediated signalling is essential for the transmigration of inflammatory monocytes from the blood to sites of infection mediated by VLA-4.
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