Bone Marrow-derived Antigen-presenting Cells Research Articles

Ferruginous components of particulate matters in subway environments, α-Fe2O3 or Fe3O4, exacerbates allergies

The respiratory effects of particulate matter (PM) in subway station platforms or tunnels have attracted considerable research attention. However, no studies have characterized the effects of subway PM on allergic immune responses. In this study, iron oxide (α-Fe2O3 and Fe3O4) particles—the main components of subway PM—were intratracheally administered to BALB/c mice where ovalbumin (OVA) induced allergic pulmonary inflammation. Iron oxide particles enhanced OVA-induced eosinophil recruitment around the bronchi and mucus production from airway epithelium. The concentrations of type 2 cytokines, namely, interleukin (IL)-5 and IL-13, in bronchial alveolar lavage fluids were increased by iron oxide particles. Iron oxide particles also increased the number of type 2 innate lymphoid cells and CD86+ cells in the lung. Moreover, phagocytosis of particles in lung cells was confirmed by Raman spectroscopy. In a subsequent in vitro study, bone marrow-derived antigen-presenting cells (APCs) isolated from NC/Nga mice were exposed to iron oxide particles and OVA. They were also exposed to outdoor ambient PM: Vehicle Exhaust Particulates (VEP) and Urban Aerosols (UA) as references. Iron oxide particles promoted the release of lactate dehydrogenase, C-X-C motif chemokine ligand 1 and IL-1α from APCs, which tended to be stronger than those of VEP. These results suggest that iron oxide particles enhance antigen presentation in the lungs, promoting allergic immune response in mice; iron oxide particles-induced death and inflammatory response of APCs can contribute to allergy exacerbation. Although iron oxide particles do not contain various compounds like VEP, iron oxide alone may have sufficient influence.

Corneal dendritic cells in diabetes mellitus: A narrative review.

Diabetes mellitus is a global public health problem with both macrovascular and microvascular complications, such as diabetic corneal neuropathy (DCN). Using in-vivo confocal microscopy, corneal nerve changes in DCN patients can be examined. Additionally, changes in the morphology and quantity of corneal dendritic cells (DCs) in diabetic corneas have also been observed. DCs are bone marrow-derived antigen-presenting cells that serve both immunological and non-immunological roles in human corneas. However, the role and pathogenesis of corneal DC in diabetic corneas have not been well understood. In this article, we provide a comprehensive review of both animal and clinical studies that report changes in DCs, including the DC density, maturation stages, as well as relationships between the corneal DCs, corneal nerves, and corneal epithelium, in diabetic corneas. We have also discussed the associations between the changes in corneal DCs and various clinical or imaging parameters, including age, corneal nerve status, and blood metabolic parameters. Such information would provide valuable insight into the development of diagnostic, preventive, and therapeutic strategies for DM-associated ocular surface complications.

Helminth-derived peptide GK-1 induces Myd88-dependent pro-inflammatory signaling events in bone marrow-derived antigen-presenting cells

GK-1 is an immunomodulatory, 18-aa-long peptide that has been proved to promote the activation of mouse peritoneal macrophages and LPS-pulsed mouse bone marrow-derived dendritic cells (BM-DCs). This study is aimed to explore the mechanisms underlying the activation of these antigen-presenting cells (APCs) by GK-1. In our study, GK-1 up-regulated in vitro the expression of CD86 and CD40, and it increased the secretion of NO in bone marrow-derived macrophages (BMDMs). In BM-DCs, GK-1 upregulated the expression of MHC class II and CD86. Additionally, GK-1 was found to be involved in the phosphorylation of MAPK p38, JNK and ERK 1/2 and in Myd88-dependent activation of NF-κB in both antigen-presenting cell types. In vivo, GK-1 increased the secretion of IL-15, CCL2, and IL-6 through a Myd88-dependent mechanism. This study demonstrated that GK-1 promotes the activation and effector activity of APCs through a mechanism dependent on Myd88, probably involving a Toll-like receptor as a target.

Indirect presentation in the thymus limits naive and regulatory T-cell differentiation by promoting deletion of self-reactive thymocytes.

Acquisition of T-cell central tolerance involves distinct pathways of self-antigen presentation to thymocytes. One pathway termed indirect presentation requires a self-antigen transfer step from thymic epithelial cells (TECs) to bone marrow-derived cells before the self-antigen is presented to thymocytes. The role of indirect presentation in central tolerance is context-dependent, potentially due to variation in self-antigen expression, processing and presentation in the thymus. Here, we report experiments in mice in which TECs expressed a membrane-bound transgenic self-antigen, hen egg lysozyme (HEL), from either the insulin (insHEL) or thyroglobulin (thyroHEL) promoter. Intrathymic HEL expression was less abundant and more confined to the medulla in insHEL mice compared with thyroHEL mice. When indirect presentation was impaired by generating mice lacking MHC class II expression in bone marrow-derived antigen-presenting cells, insHEL-mediated thymocyte deletion was abolished, whereas thyroHEL-mediated deletion occurred at a later stage of thymocyte development and Foxp3+ regulatory T-cell differentiation increased. Indirect presentation increased the strength of T-cell receptor signalling that both self-antigens induced in thymocytes, as assessed by Helios expression. Hence, indirect presentation limits the differentiation of naive and regulatory T cells by promoting deletion of self-reactive thymocytes.

Aqueous and organic extract of PM2.5 collected in different seasons and cities of Japan differently affect respiratory and immune systems.

Particulate matter with diameters <2.5μm (i.e., PM2.5) has multiple natural and anthropological sources. The association between PM2.5 and the exacerbation of respiratory allergy and asthma has been well studied, but the components of PM2.5 that are responsible for allergies have not yet been determined. Here, we elucidated the effects of aqueous and organic extract of PM2.5 collected during four seasons in November 2014-December 2015 in two cities (Kawasaki, an industrial area and Fukuoka, an urban area affected by transboundary pollution matter) of Japan on respiratory health. Ambient PM2.5 was collected by high-volume air samplers and extracted into water soluble and lipid soluble components. Human airway epithelial cells, murine bone marrow-derived antigen-presenting cells (APC) and splenocytes were exposed to PM2.5 extracts. We measured the cell viability and release of interleukin (IL)-6 and IL-8 from airway epithelial cells, the DEC205 and CD86 expressions on APCs and cell proliferation, and TCR and CD19 expression on splenocytes. The water-soluble or aqueous extracts, especially those from Kawasaki in fall, had a greater cytotoxic effect than the lipid-soluble or organic extracts in airway epithelial cells, but they caused almost no pro-inflammatory response. Extract of fall, especially the aqueous extract from Fukuoka, increased the DEC205 and CD86 expressions on APC. Moreover, aqueous extracts of fall, summer, and spring from Fukuoka significantly increased proliferation of splenocytes. Organic extract of spring and summer from Kawasaki significantly elevated the TCR expression, and organic extract of summer from Kawasaki decreased the CD19 expression. These results suggest that PM2.5 extract samples are responsible for cytotoxicity in airway epithelial cells and for activating APCs and T-cells, which can contribute to the exacerbation of respiratory diseases such as asthma. These effects can differ by PM2.5 components, collection areas and seasons.

Synergistic effect of carbon nuclei and polyaromatic hydrocarbons on respiratory and immune responses.

Particulate matter with aerodynamic diameter ≤2.5 μm (PM2.5 ) is generally composed of carbon nuclei associated with various organic carbons, metals, ions and biological materials. Among these components, polyaromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BaP) and quinones have detrimental effects on airway epithelial cells and immunodisrupting effects, which leads to the exacerbation of respiratory allergies. The effects of PAHs and the carbon nuclei, separately as well as in combination, remain to be established. We investigated the effects of BaP, 9,10-phenanthroquinone (9,10-PQ), and 1,2-napthoquinone (1,2-NQ) and their combined effects with heated diesel exhaust particle (H-DEP) as carbon nuclei of typical PM2.5 . We exposed human airway epithelial cells (BEAS-2B), murine bone marrow-derived antigen-presenting cells (APCs), and murine splenocytes to BaP, 9,10-PQ, or 1,2-NQ in the presence and absence of H-DEP. Several important inflammatory cytokines and cell surface molecules were measured. PAHs alone did not have apparent cytotoxic effects on BEAS-2B, whereas combined exposure with H-DEP induced noticeable detrimental effects which mainly reflected the action of H-DEP itself. BaP increased CD86 expression as an APC surface molecule regardless of the presence or absence of H-DEP. None of the BaP, 9,10-PQ, or 1,2-NQ exposure alone or their combined exposure with H-DEP resulted in any significant activation of splenocytes. These results suggest that PAHs and carbon nuclei show additive effects, and that BaP with the carbon nuclei may contribute to exacerbations of allergic respiratory diseases including asthma by PM2.5 , especially via antigen-presenting cell activation.

Effects of Components of PM2.5 Collected in Japan on the Respiratory and Immune Systems.

Epidemiologic studies have reported that particulate matter with aerodynamic diameters ≤2.5 μm (PM2.5) affect respiratory diseases, including asthma. The components and/or factors of PM2.5 that contribute to the exacerbation of asthma have not been identified. We investigated the effects of extracts of PM2.5 collected in Japan on the respiratory and immune systems. PM2.5 was collected from an industrial area and an urban area in December 2013. Airway epithelial cells and immune cells were exposed to aqueous or organic extracts of PM2.5. Exposure to extracts from both areas, especially to organic extracts rather than aqueous extracts, caused a pro-inflammatory response via interleukin (IL) 6 production from airway epithelial cells, and it induced the maturation/activation of bone marrow-derived antigen-presenting cells via dendritic and epithelial cell (DEC) 205 and cluster of differentiation (CD) 86 expression and proportional changes in the constitution of the splenocytes. The extracts collected from the industrial area tended to show greater effects than those from the urban area. These results suggest that organic components of PM2.5 affect the respiratory and immune systems. These effects can differ by the collection areas. In addition, IL-6, DEC205, and CD86 can be predictive biomarkers for the respiratory and immune effects of ambient PM2.5.

Coagulation factor XII induces pro-inflammatory cytokine responses in macrophages and promotes atherosclerosis in mice.

Atherosclerosis is considered a chronic inflammatory disease of the vessel wall. Coagulation pathways and immune responses contribute to disease development. The role of coagulation factor XII (FXII) in vascular inflammation, however, remains controversial. We here investigated the function of FXII in atherosclerosis using apolipoprotein E and FXII-deficient (F12-/-Apoe-/-) mice. Compared to F12+/+Apoe-/- controls, atherosclerotic lesion formation was reduced in F12-/-Apoe-/- mice. This was associated with a decrease in serum interleukin (IL)-1β and IL-12 levels and reduced expression of pro-inflammatory cytokines in the aorta in atherosclerotic F12-/-Apoe-/- mice, as well as diminished Th1-cell differentiation in the aorta, blood, and lymphoid organs. No changes in circulating bradykinin, thrombin-antithrombin-complexes or plasminogen were observed. Mechanistically, activated FXII (FXIIa) was revealed to directly induce bone marrow-derived macrophages to secrete pro-inflammatory cytokines, including tumour necrosis factor-α, IL-1β, IL-12, and IL-6. Exposure of bone marrow-derived antigen presenting cells to FXIIa similarly induced pro-inflammatory cytokines, and an enhanced capacity to trigger antigen-specific interferon γ-production in CD4+ T cells. Notably, bone-marrow derived macrophages were capable of directly activating FXII. Moreover, the induction of cytokine expression by FXIIa in macrophages occurred independently of FXII protease enzymatic activity and was decreased upon phospholipase C treatment, suggesting urokinase-type plasminogen activator receptor (uPAR) to confer FXIIa-induced cell signalling. These data reveal FXII to play an important role in atherosclerotic lesion formation by functioning as a strong inducer of pro-inflammatory cytokines in antigen-presenting cells. Targeting of FXII may thus be a promising approach for treating cardiovascular disease.

Biological factor related to Asian sand dust particles contributes to the exacerbation of asthma.

Epidemiologic studies have revealed that Asian sand dust particles (ASDs) can affect respiratory and immune health represented by asthma. Factors responsible for the exacerbation of asthma remain unclear. The fungus Bjerkandera adusta (B.ad) and polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP) have been identified in ASDs collected from the atmosphere when an ASD event occurred. We investigated the effects of B.ad and BaP related to ASDs on respiratory and immune systems. Bone marrow-derived antigen-presenting cells (APCs) and splenocytes from atopic prone NC/Nga mice and human airway epithelial cells were exposed to the B.ad or to BaP in the presence and absence of heated-ASDs (H-ASDs). B.ad and BaP in both the presence and absence of H-ASDs increased the expression of cell surface molecules on APCs. H-ASDs alone slightly activated APCs. The expressions induced by B.ad were higher than those induced by BaP in the presence and absence of H-ASDs. There were no remarkable effects on the activation of splenocytes or the proinflammatory responses in airway epithelial cells. These results suggest that B.ad rather than BaP contributes to the exacerbation of asthma regardless of the presence or absence of sand particles, particularly by the activation of the immune system via APCs. Copyright © 2016 John Wiley & Sons, Ltd.

Continuous Acquisition of MHC:Peptide Complexes by Recipient Cells Contributes to the Generation of Anti-Graft CD8+ T Cell Immunity.

Understanding the evolution of the direct and indirect pathways of allorecognition following tissue transplantation is essential in the design of tolerance‐promoting protocols. On the basis that donor bone marrow–derived antigen‐presenting cells are eliminated within days of transplantation, it has been argued that the indirect response represents the major threat to long‐term transplant survival, and is consequently the key target for regulation. However, the detection of MHC transfer between cells, and particularly the capture of MHC:peptide complexes by dendritic cells (DCs), led us to propose a third, semidirect, pathway of MHC allorecognition. Persistence of this pathway would lead to sustained activation of direct‐pathway T cells, arguably persisting for the life of the transplant. In this study, we focused on the contribution of acquired MHC‐class I on recipient DCs during the life span of a skin graft. We observed that MHC‐class I acquisition by recipient DCs occurs for at least 1 month following transplantation and may be the main source of alloantigen that drives CD8+ cytotoxic T cell responses. In addition, acquired MHC‐class I:peptide complexes stimulate T cell responses in vivo, further emphasizing the need to regulate both pathways to induce indefinite survival of the graft.

Extracellular Mg concentration and Ca blockers modulate the initial steps of the response of Th2 lymphocytes in co-culture with macrophages and dendritic cells

Magnesium is highly involved in the metabolic network such that even subtle disturbances in its homeostasis affect many cellular functions, including calcium homeostasis, signal transduction, energy metabolism, membrane stability and cell proliferation. Recently, magnesium level has been proposed to modulate the priming and activity of immune cells. We studied the behavior of antigen-presenting cells (APCs) and T lymphocytes after altering the magnesium/calcium balance. We used two different populations of primary APCs, i.e. bone marrow-derived dendritic cells and bone marrow-derived macrophages, while D10.G4.1 cells served as a model of responding Th2 cells. Our principal findings are the following: (i) the extracellular magnesium concentration had no significant impact on endocytosis by bone marrow-derived APCs, (ii) high concentrations of extracellular magnesium, with or without calcium antagonists, significantly decreased IL-4 and IL-10 secretion by Th2 cells in a co-culture system of APCs and Th2 lymphocytes, (iii) proliferation of Th2 cells in co-culture systems was significantly inhibited by calcium antagonists independently from extracellular magnesium concentrations. Our results suggest that alterations of magnesium and calcium homeostasis impact on some crucial steps of the immune response.

Immunobiology of radiotherapy: new paradigms.

It has been well demonstrated that irradiated dying cancer cells release tumor antigens. The extracellular antigens and dying tumor cells are engulfed by circulating bone marrow-derived antigen-presenting cells (APCs). After antigen uptake, APCs migrate to lymph nodes, where they engage with helper T cells for post-stimulation and APC activation. Induction of Th1 response and the activation of APCs further stimulate the induction of tumor specific cytotoxic T lymphocytes (CTLs) that could potentially clear tumor cells both at primary and metastatic sites (Fig. 1). FIG. 1 Schematic representation of the envisioned mechanism of radiation-primed immunotherapy of advanced cancer. Radiation-induced immune modulation happens in two important phases. First, radiation induces damage-associated molecular pattern (DAMP) molecules. In this event, radiation normalizes tumor vasculature, modulates tumor cell phenotype and increases immune recognition of the tumor cell. Radiation treatment can cause: a. upregulation of chemokines and adhesion molecules, providing signals for T cells to be attracted to the tumor; and b. upregulation of MHC molecules and tumor-associated antigens, making it easier for endogenous or immunotherapy-induced T cells to recognize and kill tumor (immunogenic modulation). Second, amplification by abrogating immune checkpoint factors with simultaneous costimulation of effector factors can ultimately lead to the induction of multiple unique T-cell populations (antigen cascade) that can kill antigen disparate tumor cells at metastatic sites (systemic effect) (Fig. 2). FIG. 2 Model for radiation-induced immunogenic modulation.

Experimentally-induced early recruitment of CD14+ monocytes in human allergic rhinitis

Background Allergic rhinitis (AR) is a complex inflammatory disorder where antigen presenting cells (APCs) are believed to activate allergen-specific CD4+ T cells at the site of allergen exposure. By sorting cells from the nasal mucosa in an experimental model of AR we have found, at the transcriptome level, that the total population of CD45+ HLA-DR+ cells showed signs of activation concomitant with an activated Th2 signature in purified CD4+ T cells. Bone marrow-derived APCs consists of many distinct subsets including dendritic cells (DC) and monocytes/ macrophages. The aim of this work was to study the trafficking of various APC subsets during the allergic inflammation.

T-cell migration to vascularized organ allografts

To review the classical paradigm of leukocyte migration and present new evidence that cognate antigen, and not signaling via Gαi-coupled chemokine receptors, drives the migration of effector and memory T cells into vascularized organ transplants. Blocking Gαi function does not hinder integrin-dependent T-cell migration to heart and kidney allografts or significantly delay acute rejection. T-cell firm adhesion and transmigration is instead mediated by engagement of the T cell receptor for antigen (TCR) on antigen-specific (antidonor) T cells by cognate antigen presented by either graft endothelial cells or bone marrow-derived antigen-presenting cells that reach into the vascular lumen. Influx of bystander T cells is Gαi-dependent but occurs only if antigen-specific T cells are present. Antigen-driven migration of effector and memory T cells sheds new light on the pathogenesis of transplant rejection and predicts that interrupting the TCR-triggered 'inside-out' signaling pathway, rather than that initiated by Gαi-coupled chemokine receptors, is a key approach to preventing rejection.

Intestinal Epithelial Cells Modulate Antigen-Presenting Cell Responses to Bacterial DNA

Intestinal epithelial cells and antigen-presenting cells orchestrate mucosal innate immunity. This study investigated the role of bacterial DNA in modulating epithelial and bone marrow-derived antigen-presenting cells (BM-APCs) and subsequent T-lymphocyte responses. Murine MODE-K epithelial cells and BM-APCs were treated with DNA from either Bifidobacterium breve or Salmonella enterica serovar Dublin directly and under coculture conditions with CD4(+) T cells. Apical stimulation of MODE-K cells with S. Dublin DNA enhanced secretion of cytokines from underlying BM-APCs and induced interleukin-17 (IL-17) and gamma interferon (IFN-γ) secretion from CD4(+) T cells. Bacterial DNA isolated from either strain induced maturation and increased cytokine secretion from BM-APCs. Conditioned medium from S. Dublin-treated MODE-K cells elicited an increase in cytokine secretion similar to that seen for S. Dublin DNA. Treatment of conditioned medium from MODE-K cells with RNase and protease prevented the S. Dublin-induced increased cytokine secretion. Oral feeding of mice with B. breve DNA resulted in enhanced levels of colonic IL-10 and transforming growth factor β (TGFβ) compared with what was seen for mice treated with S. Dublin DNA. In contrast, feeding mice with S. Dublin DNA increased levels of colonic IL-17 and IL-12p70. T cells from S. Dublin DNA-treated mice secreted high levels of IL-12 and IFN-γ compared to controls and B. breve DNA-treated mice. These results demonstrate that intestinal epithelial cells are able to modulate subsequent antigen-presenting and T-cell responses to bacterial DNA with pathogenic but not commensal bacterial DNA inducing effector CD4(+) T lymphocytes.

Role of MHC class II in Treg-mediated tolerance to allogeneic transplants (126.26)

Abstract Transfer of donor MHC class II genes (MHCII) in the bone marrow of recipients of allografts induced tolerance spreading to all alloantigens. Tolerance was donor MHCII-specific, transferable only via host CD4 Tregs and selectively induced by MHCII gene therapy. Studies on the fate of transgenic MHCII molecules revealed that both the α and β chains provided peptides presented on the MHCII of bone marrow-derived antigen-presenting cells (APCs). Transgene-matched graft MHCII was critical for survival as donor MHCII-treated recipients promptly rejected MHCII-deficient transplants. Next, the role of thymic transgenic MHCII peptides on Treg development was studied in a model recapitulating MHCII peptide presentation: the IEα 52-68 peptide/IAb complexes recognized by the YA-e mAb and TEa transgenic TCR. With this model we showed that 1) the highly conserved IEα sequence was dominantly exposed on all dendritic cells located in the thymic medulla, the birthplace of Tregs, and 2) transfer of the IEα peptide into IEneg mice via bone marrow transplantation, converted host IEα-specific CD4 T cells into CD4+ CD25+ Foxp3+ Tregs. These data are consistent with a dominant role of MHCII peptides in shaping Treg TCR specificity and differentiation. They also propose a mechanism for MHCII-tolerance: MHCII-specific Tregs require activation by cognate MHCII peptide provided by MHCII-matched transplants prior to suppressing alloreactive T cells of different TCR specificity.

Mechanisms of tolerance

Mechanisms of tolerance

Human Dendritic Cells and Transplant Outcome

Early interest in dendritic cells (DC) in transplantation centered on the role of graft interstitial DC in the instigation of rejection. Much information has subsequently accumulated concerning the phenotypic and functional diversity of these rare, migratory, bone marrow-derived antigen-presenting cells, and their role in the induction and regulation of immunity. Detailed insights have emerged from studies of freshly isolated or in vitro-propagated DC, and from analyses of their function in experimental animal models. The functional plasticity of these uniquely well-equipped antigen-presenting cells is reflected in their ability not only to induce alloimmune responses, but also to serve as potential targets and therapeutic agents for the long-term improvement of transplant outcome. Notably, however, a great deal remains to be understood about the immunobiology of DC populations in relation to human transplant outcome. Herein, we briefly review aspects of human DC biology in organ and bone marrow transplantation, the potential of these cells for monitoring outcome, and the role of DC in development of vaccines to protect against infectious disease or to promote allograft tolerance.

129: Immunomodulation by Photopheresis Involves Regulatory T Cells

was confirmed by histopathological examination. Results: Expression of IA in transduced antigen-presenting cells (APCs) from CBA mice, promoted operational tolerance to B6 hearts which showed no sign of cardiac allograft vasculopathy. Control third party transplants as well as B6 hearts implanted in GFP-treated CBA mice were rejected with a mean survival time 20 days. In contrast, genetic matching for IA between B10.A(5R) donor and B6 recipient mice treated with anti-CD8, led to delayed acute rejection of heart grafts (84 31.9 days). Conclusions: Results indicate that contrary to genetic MHC II matching, somatic MHC II matching via IA gene transfer in bone marrow, leads to immune tolerance. Given that: 1) it is known that thymic medulla includes bone marrow-derived APCs and 2) we previously demonstrated that IA gene transfer induced IA-specific regulatory T cells (T-regs), we suggest that selective IA expression in thymic medulla favors T-reg differentiation/activation in this model.

Bone marrow-derived cells present MHC class I-restricted tumour antigens in priming of antitumour immune responses.

Many tumours express tumour-specific antigens capable of being presented to CD8+ T cells by major histocompatibility complex (MHC) class I molecules. Current models of antigen presentation predict that the tumour cell itself should present its own MHC class I-restricted antigens to T cells. Earlier cross-priming experiments have demonstrated that at least some MHC class I-restricted antigens may also be presented by bystander cells. There is no detectable presentation of MHC class I-restricted tumour antigens by the tumour itself during priming of tumour-specific responses. The tumour antigens are presented exclusively by host bone marrow-derived cells. These results imply that an efficient mechanism exists in vivo for transfer of MHC I-restricted antigens to bone marrow-derived antigen presenting cells. They also suggest that HLA matching may not be critical in the clinical application of allogeneic tumour vaccines.