Immunology最新文献

Down syndrome (DS) is characterised by delayed brain development and intellectual disabilities. Brain macrophages originate from primitive macrophages that arise from mesodermal cells in the yolk sac and play a role in brain development. Previously, we showed a reduced number of brain macrophages in Ts1Cje foetuses, a murine model of DS. However, the mechanism underlying this reduction in Ts1Cje embryos remains unknown. First, in this study, we identified that the reduced brain macrophages in Ts1Cje foetuses were microglia. This study further reports the low production of primitive macrophages from Ts1Cje mouse embryonic stem cells (Ts1Cje-mESCs). Gene expression profiling in Ts1Cje-mESC-derived cells indicated the persistence of pluripotency, preference for endodermal differentiation, and suppression of mesodermal differentiation. Consistently, Ts1Cje-mESC-derived cells showed the disturbed expression of cytokine receptors and apoptosis, and a decreased number of primitive macrophages was confirmed in the Ts1Cje yolk sac. A human induced pluripotent stem cell line established from an individual with DS also showed lower primitive macrophage production relative to diploidized controls. Thus, our data indicate resistance to mesodermal differentiation and impaired production of primitive macrophages in DS, providing valuable insights into abnormalities in brain development associated with DS.

Sickle cell disease (SCD) is caused by a mutation in the β-globin gene, resulting in abnormal haemoglobin S (HbS). Beyond genetic mutation, dysregulation of immune-related genes such as those regulating NF-κB signalling, inflammasome activation and type I interferon responses exacerbates the inflammatory milieu and drives many of the complications observed in SCD. Chronic inflammation, linked to disease severity, highlights the crucial role of the immune system in SCD pathophysiology. Immune dysregulation in SCD leads to chronic inflammation, heightened infection risk and possible autoimmune reactions. Immune dysregulation is driven by splenic damage and pro-inflammatory cytokines from sickled red blood cells. While progress has been made studying innate immune cell roles, the adaptive immune system's contributions remain poorly understood. T-cell abnormalities in SCD highlight the complexity of adaptive immune responses. Alterations in T-cell counts, shifts in Th1/Th2 responses and changes in regulatory T-cell behaviour reflect immune dysregulation, further contributing to chronic inflammation and disease progression. While studies have focused on polyclonal T-cell phenotyping, antigen-specific T-cells, crucial for immune activation, remain underexplored. Focusing on antigen-specific T-cell responses will deepen our understanding of adaptive immune dysfunction in SCD and aid in developing targeted therapies to manage the disease. Furthermore, there is significant impairment in the B cell compartment in SCD, including reduced B cell proliferation, fewer memory B cells and abnormalities in class-switching memory B cells. These defects weaken antigen-specific immune responses, mainly by lowering IgM-secreting memory B cells, essential for early defence against infections. The loss of these cells also diminishes vaccine effectiveness, leaving patients more vulnerable to infections. Additionally, impaired memory B cell differentiation and class switching contribute to an increased risk of infections and autoimmune complications, highlighting the need for targeted immune therapies in the management of SCD. This review highlights the need to explore dysregulation in innate and adaptive immune mechanisms in SCD. Investigating T and B cell dysfunctions, especially antigen-specific immune activation, is crucial for developing immune-targeted therapies and improving vaccine responses, ultimately advancing treatments and enhancing the quality of life and survival for SCD patients.

Ficolin-1 (FCN1, M-FCN), the key pattern recognition molecule of the innate immune system, possesses a collagen-like domain and a fibrinogen-like domain, exhibiting bidirectional immunomodulatory functions that influence immune homeostasis and disease progression. Recent studies reveal that beyond its well-established roles in pathogen recognition and complement activation, FCN1 orchestrates the balance between pro-inflammatory and anti-inflammatory responses, facilitating crosstalk between innate and adaptive immunity. This review synthesises cutting-edge research to systematically elucidate the multifaceted roles of FCN1 in human diseases, including autoimmune disorders, infectious diseases, tumour, cardiovascular and cerebrovascular disease. We highlight how FCN1 exerts its regulatory effects through diverse mechanisms ranging from pathogen binding and clearance to cytokine secretion modulation and immune cell fate determination, ultimately shaping disease susceptibility, progression and prognosis. By compiling these groundbreaking findings, we propose FCN1 as a pivotal orchestrator of immune responses, providing a theoretical foundation for its translation into diagnostic biomarkers and novel therapeutic targets in precision medicine. This review advocates for the establishment of standardised FCN1 assays and large-scale clinical validation to accelerate its transformation from bench to bedside.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge due to the pathogen's ability to evade host immune responses and persist within macrophages. We investigated the metabolic changes in mouse bone marrow-derived macrophages (BMDMs) upon Mtb infection and identified significant alterations in gene expression related to key metabolic pathways through RNA sequencing analyses. Among them, glycolysis-related genes, including hypoxia-inducible factor 1α as a key regulator of glycolysis, are upregulated in Mtb-infected BMDMs. To investigate whether glycolysis plays a critical role in reducing intracellular Mtb growth, we cultured Mtb-infected BMDMs under high- or low-glucose conditions. We found that high-glucose conditions increased glycolytic enzyme levels, inducible nitric oxide synthase expression and proinflammatory cytokine production, reducing Mtb's intracellular survival. HIF1α agonist treatment increased glycolysis, reactive oxygen species levels and proinflammatory cytokine production, enhancing bactericidal activity against Mtb. In contrast, inhibition of HIF1α by a specific inhibitor FM19G11 leads to decreased glycolysis, reduced proinflammatory cytokine production and increased Mtb survival. Since succinate has been known to increase the stabilisation and activation of HIF1α, we added succinate to Mtb-infected BMDMs to evaluate the function of succinate related to HIF1α activation. As expected, succinate treatment enhanced glycolysis through HIF1α stabilisation and shifted BMDMs to proinflammatory M1-like phenotype. Our findings indicate that Mtb-induced glycolysis plays a central role in the reduction of intracellular Mtb in BMDMs. Succinate is a key factor for HIF1α-mediated glycolysis in Mtb-infected BMDMs.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne orthonairovirus associated with severe hemorrhagic fever and high mortality in humans. The genome is comprised of three segments of single-stranded, negative-sense RNA. The nucleocapsid (NP) protein, which is the focus of our study, encoded by the smallest (S) segment, plays a central role in viral RNA encapsidation and is known to be highly immunogenic, eliciting innate, humoral and cellular immune responses. This study aimed to identify the immunodominant regions of the NP that trigger T cell-mediated immune responses. To this end, three truncated variants of the NP from the CCHFV Kelkit'06 strain [NPdelN(1-135 aa), NPdelM(136-295 aa) and NPdelC(296-482 aa)] as well as the full-length NP(1-482 aa) were tested. Following mice immunisations, local lymph node cells were used as the source of lymphocytes and these cells were assessed to gauge the T cell responses. Stimulated splenocytes were analysed for lymphoproliferative responses and cytokine mRNA expression to evaluate T cell polarisation. Based on the data obtained, it appears that the amino-terminal region (1-135 amino acids) of NP is significantly more immunogenic than the other regions. In contrast, the carboxy-terminal region (296-482 aa) appears to play a suppressive role in cellular immune activation. Additionally, the middle region (136-295 aa) of the NP is identified as being responsible for inducing Th17-type cellular immune responses. In conclusion, this study points out to the specific regions of the CCHFV NP that are involved in shaping the cellular immune responses, representing a crucial step toward refining the structural elements contributing anti-viral immunity and providing a sound ground for modulation efforts.

Zika virus (ZIKV) is an emerging arbovirus belonging to the Flaviviridae family and Orthoflavivirus genus, with a pronounced tropism for the central nervous system (CNS), where it induces neuroinflammation and neuronal death. ZIKV is known to exploit host cellular mechanisms, including the activation of survival pathways such as the PI3K/AKT signalling cascade, to evade apoptosis and enhance its replication. However, the role of the PI3Kγ isoform in ZIKV-induced neuroinflammation has not been previously explored, and this study aimed to investigate PI3Kγ in ZIKV pathogenesis. Primary neuronal cultures from PI3Kγ-deficient mice (PI3Kγ^kd/kd) and human neuroblastoma SH-SY5Y cells treated with the PI3Kγ inhibitor AS605240 were infected with ZIKV to assess the impact of PI3Kγ signalling on viral replication and neuronal survival. Additionally, interferon α/β receptor knockout (A129) mice were treated with AS605240 either before or after ZIKV infection to evaluate the pathway's role in neuroinflammation. In vitro, both genetic ablation and pharmacological inhibition of PI3Kγ suppressed ZIKV replication (~3% and ~17%, respectively) and prevented neuronal death (~16%). In vivo, mice treated with the PI3Kγ inhibitor exhibited enhanced protection against ZIKV infection, characterised by reduced viral load (~12%) and diminished brain and optic nerve damage. This neuroprotective effect correlated with reduced TNF production (about ~67%) by microglia. Furthermore, inhibition of PI3Kγ curtailed the recruitment and activation of CD8+ T cells and decreased the production of pro-inflammatory mediators, including IFN-γ and IL-17, in the brains of ZIKV-infected mice. These findings suggest that PI3Kγ activation facilitates ZIKV infection and exacerbates neuroinflammation. Pharmacological inhibition of the PI3Kγ pathway may offer therapeutic benefits by limiting viral replication and alleviating neuroinflammatory responses during ZIKV infection.

The intracellular, tick-borne bacterium Neoehrlichia (N.) mikurensis can cause neoehrlichiosis in patients with compromised B-cell defences, while immunocompetent individuals are frequently healthy carriers of the infection. We hypothesised that N. mikurensis induces latent infections that reactivate when B-cell immunity is compromised. We tested this hypothesis by determining the incidence of N. mikurensis reactivation in 97 patients with B-cell lymphomas who were treated with anti-CD20 antibody therapy (rituximab) and evaluating the presence of N. mikurensis-specific T cells in latently infected individuals. Four patients (4%) reactivated N. mikurensis infection and four patients (4%) had asymptomatic infection before the initiation of B-cell suppression. All eight patients who were infected with N. mikurensis had N. mikurensis-specific, perforin-expressing Th1 and CD8+ T-cell populations with up-regulation of CXCL10 and IFN-γ, in contrast to the noninfected lymphoma patients who lacked these T-cell subsets. The infected lymphoma patients also had expanded γδ T-cell populations. This study supports the notion of latent, reactivatable N. mikurensis infections.

Non-small cell lung cancer (NSCLC) is an aggressive malignancy necessitating innovative therapeutic approaches to augment antitumour immunity. Our study examined the function of the STAT2 protein in CD4⁺ T helper cells, which are essential for the immune response to cancer. We utilised CRISPR/Cas9 to ablate STAT2 in CD4⁺ T cells from stage I NSCLC patients (n = 30), assessing its impact on cellular function and diverse epigenetic pathways. Our findings indicate that the depletion of STAT2 markedly enhances the anti-cancer efficacy of T lymphocytes. Deletion of STAT2 diminished oxidative stress, enhanced the synthesis of advantageous TH1 cytokines. STAT2 depletion reduced DNA methylation and R-loop formation. T cells deficient in STAT2 showed enhanced efficacy in activating cytotoxic T lymphocytes to eliminate cancer cells. These findings identify STAT2 as a crucial regulator of immune function in the lung cancer microenvironment. Targeted STAT2 inhibition in tumour-reactive T cells may reinstate anti-tumour immunity, although systemic inhibition requires further research on targeted intervention strategies.

Despite recent approvals of belimumab and anifrolumab, durable, steroid-sparing remission in systemic lupus erythematosus (SLE) remains uncommon, underscoring ongoing therapeutic needs. The BXSB.Yaa mouse model, harbouring Y-linked Tlr7 duplication on a polygenic susceptibility background, has been instrumental in elucidating the TLR7-type I interferon (IFN1) axis central to SLE. This review positions BXSB.Yaa as a comparative model system and advances a mechanism-aligned framework that maps murine models to human SLE endotypes (e.g., IFN1-high vs. IFN-γ-dominant; germinal center- vs. extrafollicular-biased B-cell responses) and links those endotypes to targeted interventions. We highlight the fidelity of BXSB.Yaa to IFN1-high patient biology, and its contributions of polygenic susceptibility in driving immune cell dysregulation, cytokine imbalance, and therapeutic responsiveness to BAFF and IFN1 blockade. Notably, this model also recapitulates pathogenic pDC activation, highlighting its relevance for emerging pDC-targeted strategies. By contrasting BXSB.Yaa with other prominent lupus-prone strains (e.g., MRL/lpr, NZBWF1, NZM2410, B6.SLE1/2/3, BXD2, and Kika), we benchmark its predictive value for clinical heterogeneity and treatment response. We synthesise insights from BXSB.Yaa studies, including those that informed FDA-approved biologics, and discuss implications for next-generation precision therapies. Collectively, we advocate for BXSB.Yaa as an essential pre-clinical platform among complementary models to accelerate mechanism-based drug development and enable stratified translation in SLE research.

This schematic illustrates the role of endoplasmic reticulum (ER) stress and PERK inhibition in modulating pancreatic cancer cell fate. ER stress activates the PERK pathway, which contributes to tumor cell survival. Pharmacologic inhibition of PERK, as depicted, leads to two downstream effects: decreased cellular proliferation and increased apoptosis. The diagram highlights the therapeutic potential of PERK-targeting strategies in disrupting cancer cell growth and promoting programmed cell death.