Genes and immunity最新文献

Chagas disease is a zoonotic disease caused by Trypanosoma cruzi parasites. Tc24 and TSA1 parasite antigens are leading candidates for a therapeutic vaccine to treat infected patients to stop/delay the progression of chronic cardiomyopathy. As these antigens are nearing clinical trials, we aimed to assess their epitope recognition profile by antibodies from Chagas disease patients to better understand their immunogenicity in humans. Peptide microarrays covering Tc24-C4 and TSA1-C4 vaccine antigens were incubated with IgG from 27 T. cruzi-infected patients from Argentina, Honduras and Mexico. Most patients (20/27, 74%) had a highly similar recognition profile of both vaccine antigens, with the same immunodominant epitopes (three epitopes for Tc24-C4 and four for TSA1-C4). Remaining patients had limited reactivity against these antigens, targeting epitopes that varied among patients. All immunodominant epitopes were well conserved among T. cruzi strains and DTUs, and most were accessible on the surface of the proteins. The immunodominant epitope recognition profile was observed independently of patient HLA profile, diagnostic test reactivity or T. cruzi parasite burden. Patients were infected with mixtures of TcI, TcII, TcIV, TcV and TcVI parasites. These results present an important baseline for assessing potential changes in epitope profiles following therapeutic vaccination in future clinical trials.

Eukaryotic cells regulate gene expression through multiple checkpoints, including post-transcriptional mechanisms mediated by microRNAs (miRNAs). These small non-coding RNAs inhibit translation by binding to target mRNAs, often within a complex regulatory network involving other RNA species such as circular RNAs and long non-coding RNAs. miRNAs are now recognised as central players in the pathogenesis, immune modulation, and progression of infectious diseases. In this review, we thoroughly examine studies published over the past five years, focusing on miRNAs involved in immune regulation during four major viral infections: severe acute respiratory syndrome coronavirus 2, hepatitis B virus, human immunodeficiency virus, and herpes simplex virus. Our analysis centres on the core signalling pathways most frequently targeted by miRNAs: NF-κB, MAPK, JAK-STAT, TGF-β/Smad, and pattern-recognition receptor-associated cascades. Among the miRNAs most prominently implicated are miR-21, miR-146a, miR-150, and miR-155. These miRNAs modulate key signalling pathways, thereby influencing macrophage polarisation, T- and natural killer cell activity, antigen presentation, and inflammatory cytokine production. In addition, virus-encoded miRNAs and ceRNA or extracellular vesicle-mediated interactions are discussed where mechanistically validated, illustrating virus-specific regulatory layers. Collectively, this integrative synthesis underscores the pivotal roles of miRNAs in orchestrating antiviral immunity and highlights their potential as biomarkers and therapeutic targets in viral infections. A better understanding of miRNA-mediated immunoregulation may pave the way for precision interventions aimed at improving immune control and patient outcomes.

Colorectal cancer (CRC) is one of the three leading causes of tumor-related mortality worldwide. The recruitment of bone marrow-derived suppressor cells (MDSCs) is a key mechanism by which tumors evade immune surveillance, as these cells inhibit T cell activity and accelerate CRC progression. STAMBP, a member of the Jab1/MPN metalloenzyme family of deubiquitinases (DUBs), cleaves K63-linked polyubiquitin chains from protein substrates and participates in diverse physiological and pathological processes. Nevertheless, its role in CRC and the mechanisms through which it contributes to disease progression have not been clearly defined. In the present study, we observed that both STAMBP and MDSCs were significantly upregulated in CRC tissues and cell lines. Functional assays revealed that STAMBP promotes CRC cell proliferation while simultaneously enhancing MDSC recruitment. Mechanistic analysis demonstrated that STAMBP regulates the deubiquitination of CXCR4, which stabilizes its protein expression. Silencing of CXCR4 not only suppressed CRC cell growth but also diminished MDSC infiltration. In conclusion, these findings indicate that STAMBP facilitates CRC progression through CXCR4 stabilization and MDSCs recruitment, highlighting a potential target for therapeutic intervention.

N6-methyladenosine (m6A) RNA modifications and reovirus infections have recently been implicated in the development of celiac disease. While viral infections are known to alter the RNA modification machinery of the host, their interplay in autoimmune tissue damage remains unexplored. In this study we employed an in vitro model combining a viral mimic with gliadin peptides to simulate celiac disease conditions, alongside the analysis of serum and intestinal biopsies from controls and patients to investigate the link between m6A methylation and viral infections in inducing autoimmune inflammation. We found elevated anti-reovirus reactivity in patients, increased antiviral gene expression and enhanced m6A levels. Notably, the expression of IRF7 was synergistically induced by the combined exposure to the viral mimic and gliadin peptides, and this is mediated through m6A methylation in its coding region and interaction with the reader protein YTHDC2. Furthermore, the reduction of m6A through METTL3 silencing or simvastatin treatment reduced IRF7 mRNA methylation and downstream proinflammatory gene expression both in vitro and ex vivo. These findings highlight m6A methylation as a modulator of antiviral responses and a potential therapeutic target in autoimmune disorders.

Acute lung injury (ALI) is a common serious complication following deep hypothermic circulatory arrest (DHCA). Monocytes and macrophages play crucial roles in producing inflammatory mediators and regulating innate and adaptive immunity. In our specific rat model of DHCA-induced ALI, we previously showed that autophagy actually has a detrimental effect on lung injury rather than a protective effect. Recently, we reported that monocytes serve an important role in this model. Here, single-cell RNA sequencing was performed on lung tissue cells collected from healthy rats and rats after DHCA. Notably, there was a selective and dramatic increase in the subpopulation of CD43^low monocytes in the DHCA group, which expressed high levels of CCR5 and exhibited a proinflammatory phenotype. Allosteric CCR5 drug blockade not only reduced CCR5 expression and alleviated lung injury but also, interestingly, inhibited autophagy. These results suggest that the recruitment of CCR5⁺ inflammatory monocytes into pulmonary tissue contributes to ALI after DHCA and that blocking CCR5 is a plausible intervention for DHCA-induced lung injury by modulating autophagy.

Combination of radiotherapy (RT) and anti-PD-1 immunotherapy (IO) has shown significant efficacy in treating hepatocellular carcinoma (HCC). Nevertheless, yet the underlying mechanisms remain incompletely understood. A Hepa1-6 mouse HCC model was established to explore the anti-tumor mechanism of combination therapy in HCC. Notably, combination therapy effectively inhibited tumor growth in mice bearing Hepa1-6 tumors. Through MeRIP-sequencing, we indicated that combination therapy increased m6A modification and reduced mRNA expression of Hspb1, a negative regulator of ferroptosis, in tumors from mice. Both combination therapy and Hspb1 downregulation significantly induced Hepa1-6 cell ferroptosis. Metabolomics analysis revealed that Hspb1 downregulation further promoted abnormal lipid metabolism in Hepa1-6 tumor-bearing mice, enhancing pro-ferroptosis effects of combination therapy. Meanwhile, Hspb1 downregulation further enhanced RT and IO-induced anti-tumor immune response in tumor-bearing mice, as evidenced by significantly elevated numbers of cytotoxic CD8 + T cells. Additionally, combination therapy also significantly downregulated RNA demethylase Alkbh5 in tumor-bearing mice. Overexpression of Alkbh5 increased Hspb1 expression and inhibited ferroptosis, indicating that Alkbh5 regulates ferroptosis through targeting Hspb1. Targeting Alkbh5/Hspb1/ferroptosis axis may enhance anti-tumor effects in combination therapy, highlighting a potential therapeutic approach for HCC.

The extraordinary prevalence of helminths is attributable to secretion of molecules that manipulate the host immune system, facilitating their survival. Among the secretory products of the murine intestinal helminth Heligmosomoides polygyrus are 10 mimic proteins with functional resemblance to the mammalian immunosuppressive cytokine, TGF-β, but structurally distinct with five Complement Control Protein (CCP) domains, designated TGM-1 to -10. Here we dissect the structure and function of the mimic TGM-2 and its domains. We generated eight protein truncations lacking N- or C-terminal domains, for testing through pulldowns, mass spectrometric analysis and isothermal titration calorimetry, confirming affinity for TGFBR1 (ALK5), TGFBR2, and the co-receptor CD44. We observed that domains 1-3 bind TGFBR1 and TGFBR2, while domains 4 and 5 exhibit stronger binding to the CD44 co-receptor than TGM-1. Additionally, full-length TGM-2 activates the pSMAD pathway in the MFB-F11 fibroblast cell line at concentrations as low as 1 ng/mL and induces the in vitro conversion of naïve murine CD4⁺ T cells into Foxp3⁺ Tregs. Both stimulatory activities diminish significantly in the absence of domains 4 and 5 that interact with CD44. In vivo, both full-length TGM-2 and truncated Domains 1-3 construct potently alleviate allergic airway inflammation in mice exposed to Alternaria alternata allergen.

Actin-Related Protein Complex 1B (ARPC1B) is a subunit of the ARP2/3 complex that is predominately expressed in hematopoietic cells and is involved in the regulation of actin polymerization. ARPC1B deficiency leads to combined immunodeficiency (CID) with symptoms of eczema, allergies, inflammation, recurrent infection, and thrombocytopenia. We characterize the disease-causing variant c.899_944del (p.E300Gfs*7) on the ARPC1B gene that originated from a founder effect in an indigenous American population. We showed that this variant impairs protein expression leading to a complete deficiency of ARPC1B. Additionally, we used mass cytometry to thoroughly analyze the effects of this mutation on the frequencies of immune populations. Our findings suggest that ARPC1B is critical for class switching since our ARPC1B-deficient patient had reduced frequencies of class-switched memory B cells. Furthermore, the frequencies of total CD4⁺, CD8⁺, and γδ T cells were reduced, consistent with an essential function of ARPC1B in T cell development. Overall, this study advances the knowledge of the c.899_944del ARPC1B mutation and the understanding of the role of ARPC1B in the immune system.

Acute kidney injury (AKI) is a common and critical clinical condition with complex pathogenesis and limited early intervention options. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, plays a pivotal role in AKI development. This study aimed to investigate ferroptosis-related gene expression, spatial distribution, and immune interactions in AKI to identify potential therapeutic targets. We analyzed gene expression changes in a mouse model of ischemia-reperfusion-induced AKI and constructed a machine learning-based diagnostic model. This model identified five ferroptosis-related genes (TFRC, TXNRD1, SLC39A14, GCLM, and HMOX1) closely associated with immune cell infiltration. Integration of single-cell and spatial transcriptomics revealed that these genes were predominantly expressed in proximal tubule cells. Notably, TFRC exhibited distinct spatial proximity to infiltrating macrophages. In vivo, administration of the ferroptosis inhibitor NSC306711 significantly reduced macrophage infiltration and renal injury, as confirmed by immunofluorescence. In vitro, co-culture experiments showed that TfR1 degradation alleviated hypoxia-reoxygenation injury in tubular cells and attenuated immune cell activation. This study highlights the central role of ferroptosis in AKI pathogenesis and its interaction with immune components in the renal microenvironment. Targeting ferroptosis, particularly TFRC, may offer a promising strategy to mitigate kidney injury and immune activation in AKI.