International immunology最新文献

Lipids play fundamental roles in life. In essence, "phospholipase A2" (PLA2) indicates a group of enzymes that release fatty acids and lysophospholipids by hydrolyzing the sn-2 position of glycerophospholipids. To date, more than 50 enzymes that possess PLA2 or related lipid-metabolizing activities have been identified in mammals and are subdivided into several families in terms of their structures, catalytic mechanisms, tissue/cellular localizations, and evolutionary relationships. Among the PLA2 superfamily, the secreted PLA2 (sPLA2) family contains 11 isoforms in mammals, each of which has unique substrate specificity and tissue/cellular distributions. Recent studies using gene-manipulated (knockout and/or transgenic) mice for a full set of sPLA2s have revealed their diverse roles in immunity, metabolism, and other biological events. Application of mass spectrometric lipidomics to these mice has allowed the identification of target substrates and products of individual sPLA2s in tissue microenvironments. In principle, sPLA2s hydrolyze extracellular phospholipids such as those in extracellular vesicles, microbes, lipoproteins, surfactants, and ingested foods, as well as phospholipids in the plasma membrane of activated or damaged cells, thereby exacerbating or ameliorating various diseases. The actions of sPLA2s are dependent on, or independent of, the generation of free fatty acids, lysophospholipids, or their metabolites (lipid mediators) according to pathophysiological contexts. In this review, I will make an overview of recent understanding of the unexplored immunoregulatory roles of sPLA2s and their underlying lipid pathways, especially focusing on their unique actions on extracellular vesicles, activated/damaged cells, and gut microbiota.

Autoimmune rheumatic diseases (AIRDs) encompass a spectrum of disorders with a partially understood pathogenesis. A role for polyomaviruses in AIRDs occurrence has been reported. However, the involvement of Merkel cell polyomavirus (MCPyV), the main causative factor of Merkel cell carcinoma (MCC), an aggressive skin neoplasm related to immunosuppression, in AIRDs is unknown. The prevalence/serological profiles of immunoglobulin G (IgG) antibodies to MCPyV large and small T (LT/sT) oncoproteins and viral capsid proteins 1 and 2 (VP1/2) were investigated herein in 540 immunosuppressive treatment-naive AIRD patients, encompassing 447 rheumatoid arthritis (RA) and 93 ankylosing spondylitis (AS) patients by seven MCPyV-specific immunoassays. Control sera from 500 healthy subjects (HS) and 128 MCC patients were included. MCPyV DNA and LT/VP1 mRNAs were evaluated in peripheral blood mononuclear cells (PBMCs) from 75 randomly selected AIRD patients. AIRD patients exhibited higher prevalence and levels (optical densities) of serum anti-oncoprotein IgGs (12%-13%, 0.2-0.6) compared to HS (2%-7%, 0.1-0.4), but lower than MCC patients (70%-83%, 0.2-0.7) (P < .05), with the increase being more pronounced in AS (24%-29%, 0.3-0.8) than in RA (9%-11%, 0.2-0.8) (P < .05). Conversely, similar rates and levels of serum anti-capsid proteins IgGs were determined in most cases between study and control groups (60%-73%, 0.1-0.3) (P > .05). Moreover, receiver operating characteristic (ROC) curves indicated that the MCPyV serology can discriminate AIRD patients from HS (P < .0001). A fraction (11%) of AIRD PBMCs tested MCPyV DNA (7.4 ± 2.6 [copy/104 cells]) and mRNA-positive (0.5-0.1 [1/ΔCt]), while matched sera showed high rates and levels of anti-oncoproteins IgGs (38%-75%, 0.2-2). Our study provides the first evidence that AIRD patients are immunologically responsive to MCPyV oncoproteins, with a fraction of these patients presenting an increased presentation of MCPyV LT and sT antigens, possibly due to viral LT/sT oncogene expression in their PBMCs. These data suggest an association between MCPyV infection and AIRDs pathogenesis.

The COVID-19 pandemic accelerated vaccinology progress, driving rapid vaccine development for infectious and non-infectious diseases. However, challenges persist: malaria, HIV, and dengue lack fully effective vaccines, whereas influenza and tuberculosis face waning efficacy. Emerging pathogens and drug-resistant strains further highlight the need for improved vaccines, particularly those offering rapid deployment, broad immunogenicity, and durable protection against variants. Adjuvants can play a dual role in this context: as new stand-alone tools for an early response to a pandemic -aiming at the 100-days mission objective- and for prevention of anti-microbial resistance (AMR); and as traditional components enhancing the efficacy and breadth of vaccines. The understanding of their mechanisms of action and novel usage could address critical gaps in pandemic preparedness, especially for vulnerable populations like children and the elderly.

Particulate antigens (Ags) such as viruses can often induce strong B cell responses in vivo very effectively, but the molecular determinants of this complex process remain incompletely understood. In this review, we focus on recent mechanistic insights into the earliest steps in the initiation of primary B cell responses to viruses, gained by exploiting a new generation of model particulate Ag, synthetic virus-like structures (SVLS). We also review the characteristics of the resulting short- and long-term antibody (Ab) responses in mice. These studies reveal that a repeating pattern of epitope display on a virus-sized scaffold is a fundamental biophysical feature of viruses that triggers a qualitatively distinct mode of B cell Ag receptor (BCR) signal transduction relative to soluble Ag display, and consequently serves as a stand-alone danger signal for Ag-specific B cell activation. Quantitative variation in epitope density (ED) on such scaffolds modulates the degree and quality of B cell activation both in vitro and in vivo. The presence of internal nucleic acid (iNA) in the interior of these virus-like structures can profoundly influence the resulting Ab responses for the lifespan of immunized animals. We conclude that the ED of viral surface Ags and the iNA genomes provide two essential signals that together are sufficient for B cell activation and Ab production during antiviral responses. We place these findings in context of the literature, discuss implications for rational vaccine design, and highlight unanswered questions to guide future research directions.

Themis is a T-cell-specific protein that is critically required for positive selection in the thymus. However, its function in T-cell receptor (TCR) responses during allergic skin inflammation remains unclear. To investigate the function of Themis in peripheral T cells, we generated tamoxifen-induced Themis conditional knockout (cKO) mice. The deletion of Themis by tamoxifen treatment significantly reduced ear swelling and CD8 T cell infiltration induced by hapten 2,4-dinitrofluorobenzene (DNFB) challenge, which activates CD8 T cells. The CD8 T cells in the inflamed skin from Themis cKO mice showed decreased interferon gamma (IFNγ) production and T-bet and Eomes expression. Furthermore, the transgenic overexpression of Themis enhanced DNFB-induced allergic skin responses. However, Themis cKO mice showed unaltered skin inflammation induced by fluorescein isothiocyanate/dibutyl phthalate, which activates CD4 T cells. The TCR-stimulated proliferation and IFNγ production of Themis cKO naïve CD8 T cells were significantly decreased in vitro, whereas the proliferation and cytokine production of CD4 T cells were not altered. As expected, the administration of the SHP-1/2 inhibitor restored the reduced IFNγ production in Themis cKO CD8 T cells in vitro. Mice harboring mutant Themis lacking the Grb2-binding site showed a similar phenotype to Themis cKO mice, indicating that the function of Themis in peripheral CD8 T cells is dependent on Grb2 binding. Collectively, these results suggest that Themis regulates the threshold of TCR signaling in peripheral CD8 T cells, but not in CD4 T cells.

Immunity to viral infections is generally studied in isolation by measuring immune responses towards a single virus. However, concurrent or sequential viral co-infections can occur in a single host. Viral co-infections can impact anti-viral immunity by altering protective responses and driving immunopathology. Understanding immune mechanisms towards co-infections with unrelated viruses is highly relevant to treatment and prevention. There is, however, a paucity of data on immune responses towards viral co-infections, especially with unrelated viruses. Most commonly studied viral co-infections include chronic viruses, such as hepatitis B, hepatitis C, and human immunodeficiency virus, as well as viruses infecting the same tissues, including respiratory viral co-infections. However, the immunological consequences of co-infections with unrelated acute viruses are less understood, especially for viruses affecting different anatomical sites. As co-infecting viruses can have a more pronounced impact on human health compared to infection with a single virus, understanding immune responses and, especially, the impact of timing, sequence, and location of viral co-infections is of key importance. This review provides an overview of the current knowledge on acute viral co-infections with unrelated viruses, underpinning immune mechanisms, and implications for vaccination regimens.

Chronic rhinosinusitis (CRS) is an inflammatory disease of the upper respiratory tract. Although previously classified based on the presence or absence of nasal polyps, it is now commonly classified by endotype. Eosinophilic CRS (ECRS) is based on type 2 inflammation and the formation of intractable nasal polyps with eosinophil infiltration. Endoscopic surgery is the preferred treatment modality; however, recurrent cases are common. The central compartment of the nasal cavity has been implicated in these recurrences. Notably, the middle turbinate is considered crucial, but discussions have primarily focused on its anatomical significance. To date, there lacks a biochemical perspective on the role of the middle turbinate in recurrence. In this study, we evaluated the role of the middle turbinate as a source of inflammation in ECRS. Differences in gene expression between ECRS and non-ECRS (NECRS) middle turbinates were evaluated using RNA sequencing. Gene changes induced by MMP-9 stimulation of human nasal epithelial cells were also evaluated by RNA sequencing. Comprehensive analysis showed an enhanced IL-4 signaling pathway in the ECRS middle turbinate. Additionally, gene expression of matrix metalloproteinase-9 (MMP-9) was higher in the middle turbinates of patients with ECRS than in those with NECRS (P = .002). Furthermore, MMP-9 has been found to act on human nasal epithelial cells to enhance pathways such as IL-17, IL-6, and S100 family signaling. MMP-9 in the central compartment of the nasal cavity exacerbates ECRS by induction mixed-type 2 inflammation and airway remodeling.

Cancer progression can be understood as a process of diversification and selection (the evolutionary theory of cancer). The immune system also plays a critical role in this process of diversification and selection. The cancer immunoediting hypothesis provides a partial explanation of this evolutionary process; immune-evading cancer clones with genomic and/or epigenomic alterations are selected under the pressure of immune surveillance and immunosuppressive mechanisms are equipped, leading to the development of clinically apparent cancers. Indeed, inflammatory cancers equip immunosuppressive mechanisms in response to the pressure of the immune system. However, recent studies focusing on human cancers have revealed that certain non-inflammatory cancers, which often harbor a single-driver oncogenic mutation, are equipped with immunosuppressive machinery sufficient to evade immune surveillance at the time of malignant transformation. The sequential model of the cancer immunoediting hypothesis is inadequate to explain the development of these non-inflammatory cancers, highlighting the need for a novel concept that can explain their co-evolutionary processes. Moreover, inhibition of oncogenic signaling by specific driver oncogenes has been shown not only to kill cancer cells but also to augment antitumor immunity, suggesting the potential for the advent of molecularly targeted reagents with a variety of immunomodulatory functions from the perspective of personalized therapies. Here, we discuss the processes by which cancer cells and the immune system co-evolve to establish clinically apparent cancers, thereby introducing a new concept of 'immunogenomic cancer evolution', that provides a rationale for the potential of 'immunogenomic cancer precision medicine'.

Two major macrophage populations in the steady-state liver, resident Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs), contribute crucially to the unique physiological functions of the organ. Much remains to be learned, however, about how the differentiation and functions of these cell populations are regulated. We found here that Ly6C-MHCII+ MoMFs were severely reduced in mice lacking interferon (IFN) regulatory factor-2 (IRF-2) (Irf2-/- mice) but restored to the normal frequencies by introducing type I IFN receptor deficiency, indicating that IRF-2 supports MoMF differentiation through attenuating excess type I IFN signals. On the other hand, Irf2-/- KCs developed normally but lacked MHC class II (MHCII) expression. Similar MHCII deficiency in KCs in Il15-/- and Ifng-/- but not Rag1-/- mice pointed to the role for NK cell-derived IFN-γ. Indeed, MHCII expression on resident KCs in Ifng-/- mice was recovered via wild-type NK cells that circulated upon parabiosis as well as by administration of IFN-γ. In contrast, parabiotic restoration of NK cell deficiency in Irf2-/- mice failed to elevate MHCII expression on KCs. Furthermore, Irf2-/- KCs required several times higher amounts of IFN-γ to upregulate MHCII expression than Ifng-/- KCs. Thus, IRF-2 maintains steady-state MHCII expression on KCs by potentiating IFN-γ responses of KCs. Collectively, our current study revealed that IRF-2 plays critical roles in the establishment of the steady state hepatic macrophage system through negative and positive regulation of type I IFN and IFN-γ signaling, respectively.

Invariant natural killer T (iNKT) cells differentiate into at least three distinct subsets within the thymus, with each subset's frequency varying considerably among mouse strains; however, the molecular mechanisms involved remain unclear. We herein report that iNKT cell lineage diversity results from the significant expansion of iNKT2 cells with limited T cell receptor (TCR) diversity in BALB/c mice and the selection of iNKT1 cells with significantly diverse TCRs in B6 mice. Furthermore, signaling lymphocytic-activation molecule family 6 (SLAMF6) expression on immature thymocytes significantly differs among mouse strains, with the low expression of SLAMF6 on BALB/c immature thymocytes resulting in high "basal TCR signaling" in preselected DP thymocytes, associated with iNKT cell expansion. Our data suggest that the expression level of SLAMF6 on immature thymocytes affects basal TCR signaling in preselected DP thymocytes, which may influence thymocyte development in a T-cell subset.