Frontiers in Immunology最新文献

Psoriasis is a chronic immune-mediated inflammatory disease whose pathogenesis is a triad of genetic predisposition, immune dysregulation, and environmental triggers. This review provides a novel, in-depth synthesis arguing that microbial dysbiosis is not merely an associative phenomenon but a central regulatory node within this triad, actively shaping immune responses and clinical phenotypes. We move beyond cataloging microbial shifts to construct a detailed mechanistic framework of the gut-skin axis. Gut dysbiosis; characterized by reduced diversity, a diminished Bacteroidetes/Firmicutes ratio, and depleted SCFA producers, compromises intestinal barrier integrity, reduces systemic immunoregulatory tone via diminished SCFA signaling, and promotes Th17 polarization. This systemic inflammation is directly communicated to the skin. Concurrently, cutaneous dysbiosis, featuring Staphylococcus aureus dominance and fungal alterations, disrupts the local barrier, provides chronic antigenic stimulation, and amplifies IL-17-driven inflammation, creating a self-sustaining loop. Crucially, we analyze how specific infections (HCV, H. pylori, Streptococcus) act as environmental triggers by sharing or activating these very pathways. The bidirectional relationship with therapy is dissected: while biologics induce drug-specific microbiome shifts that often correlate with clinical normalization, they also carry infection risks that must be strategically managed. Emerging microbiome-targeted interventions like specific probiotics show promise but are hampered by methodological inconsistencies. This review uniquely highlights the causality gap and proposes that future breakthroughs require a shift from correlation to mechanism. We conclude that the microbiome is a dynamic interface between genes and environment in psoriasis; its successful integration into diagnostic and therapeutic paradigms demands standardized multi-omics approaches, functional validation, and personalized medicine strategies that target this critical axis.

Introduction: It is becoming increasingly evident that SARS-CoV-2 infection is here to stay. Therefore, understanding whether genetic variants may impact the response to the virus or vaccination is crucial. Studies on the genetic determinants of immune responses to SARS-CoV-2 have been limited by the scarcity of genetically homogenous populations and longitudinal designs that assess responses to both infection and vaccination in relation to individual genetic variation.

Methods: Here we performed genotyping and whole-genome sequencing in a well-annotated and intensively followed population from the municipality of Vo', which has previously provided critical insights into SARS-CoV-2 transmission, infection dynamics and COVID-19 clinical manifestations.

Results: We identified 99 variants within the major histocompatibility complex (MHC) associated with altered T cell response dynamics following infection. These variants clustered into two semi-independent linkage disequilibrium (LD) blocks, respectively tagged by the HLA-A*01:01 allele and by SNP rs1611581. Additionally, when examining the response to vaccination, we identified 617 MHC genetic variants clustering into 27 semi-independent LD blocks that correlated with either increased or decreased TCR responses. We constructed a polygenic risk score (PRS) that comprehensively captures this genetic variation. Finally, structural modelling of selected variants affecting HLA proteins identified specific amino acid residuals most likely to influence interactions with SARS-CoV-2 epitopes, including arginine at position 114, isoleucine at position 97, and alanine at position 152 of the HLA-A molecule.

Conclusion: Together, these findings provide robust evidence that genetic profiles modulate the immune response to SARS-CoV-2 in a longitudinal setting, offering insights that may inform further public health interventions.

Introduction: Endometrial receptivity is essential for implantation in both natural and ART cycles, yet the cellular and molecular environment of the endometrium during this window remains poorly characterized. While cytokines affecting implantation have been studied, data on immune cell subtypes in the endometrium are limited. The objective of this study was to determine the association between endometrial immune cell profile at the time of transfer and live birth in patients undergoing frozen embryo transfer (FET) using the index cycle.

Methods: This exploratory prospective observational cohort study (IRB#20190139) included 48 patients undergoing a hormone replacement FET cycle between May 2022 and May 2024. After ultrasound-guided FET, the catheter tip was rinsed in IMDM + 10% FBS, centrifuged, and stained for CD45, CD3, CD19, CD4, CD8, γδ TCR, CD25, CD127, CD66b, CD14, CD16, and CD56. The primary outcome was live birth. Secondary outcomes included miscarriage, biochemical pregnancy, and ectopic pregnancy.

Results: Elective single embryo transfer was performed for all the patients. There were 24 live births (50%), four miscarriages (8.3%), and three biochemical pregnancies (6.3%). There was no significant difference in demographics of patients that had a live birth compared to those who did not achieve implantation. There was an increased percentage of γδ T cells in the group of live birth compared to non-pregnant group (p=0.019). In contrast, an increased percentage of neutrophils (CD66b⁺) was noted in patients that did not achieve implantation (p<0.003). Importantly, we found receiver operating characteristic (ROC) curve area under the curve (AUC) of 0.72 with 95% confidence interval (CI) 0.5504 to 0.8989 for γδ T cells and AUC is 0.75 (95% CI 0.5681 to 0.9319) for CD66b⁺ cells, confirming the overall ability of these two tests to discriminate between patients who will achieve a live birth vs. ones who will have failed implantation.

Discussion: Our findings suggest that the uterine immune environment during FET may be associated with implantation outcomes. Characterization of endometrial immune cell profiles could provide insights into biological factors linked to implantation and live birth, although their clinical utility remains to be determined. To our knowledge, this study is among the first to describe associations between immune cell profiles assessed during the index FET cycle and subsequent IVF outcomes, supporting a potential role for endometrial immune composition in pregnancy success.

Ileostomy is extensively utilized as a preventive method to avert anastomotic leakage and other severe complications in colorectal surgery, serving as a valuable model for both study and clinical applications. The ileostoma, as a window, allows for the observation of a range of pathophysiological changes of complications in the mucosal layer of the defunctioned ileum, as well as in the defunctioned colon. It is precisely the changes in the intestinal microecology caused by ileostomy that may affect the efficacy of anti-tumor immunotherapy. Various interventions exist to flush the defunctioned intestine via the window, aiming to mitigate both short-term and long-term complications. These interventions include the use of normal saline, short-chain fatty acids, autologous intestinal fluid, and probiotics. Furthermore, there is a growing perspective advocating for the early closure (EC) of the ileostomy as a potentially superior management strategy. Moving forward, continued exploration of the window promises to yield further benefits for patients.

Background: Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection and remains a major global cause of mortality. Persistent immunosuppression contributes to secondary infections and adverse outcomes, yet the mechanisms underlying late-phase T-cell dysfunction remain incompletely understood.

Methods: We integrated publicly available human peripheral blood mononuclear cell single-cell RNA sequencing with a clinically relevant cecal ligation and puncture (CLP) mouse model to characterize CD8⁺ T-cell states during sepsis. Key computational findings were supported by flow cytometry and RNA fluorescence in situ hybridization (RNA FISH). The immunophenotypic effects of LAG3 blockade were evaluated in septic mice.

Results: Single-cell analysis identified a GZMB⁺CD8⁺ T-cell population with an exhaustion-like transcriptional program in sepsis, characterized by increased expression of inhibitory receptors including LAG3 and elevated ZNF683. ZNF683 expression tracked with exhaustion-associated features within the CD8⁺GZMB⁺ compartment. In CLP mice, anti-LAG3 treatment partially improved frequency of GZMB⁺CD8⁺ T cells by flow cytometry. RNA FISH further showed reduced ZNF683 signals in the lungs and liver of septic mice following LAG3 blockade.

Conclusion: ZNF683 is associated with an exhaustion-like GZMB⁺CD8⁺ T cell state in sepsis and may contribute to persistent T-cell dysfunction. Further mechanistic studies directly perturbing ZNF683 are needed to determine its causal role and therapeutic potential.

Background: Treponema pallidum subspecies pallidum causes systemic syphilis, exclusively infects humans in nature and can persist for decades in the absence of treatment despite generating robust adaptive immune responses. The T. pallidum repeat (Tpr) family of outer membrane proteins are immunogenic and are implicated in immune evasion, indicating them to be virulence factors displayed on the spirochete surface. Long-term survival of T. pallidum is largely attributed to sparse surface-exposed outer membrane proteins and antigenic variation in the major surface protein TprK through phase variation. This mechanism has been studied for decades; however, the functions of Tprs of this extracellular pathogen are not yet experimentally determined.

Methods: In this study, the localization and functional roles of TprD and TprK were investigated using a heterologous spirochete expression system and a gain-of-function approach by employing a non-infectious, non-adherent Borrelia burgdorferi B314 strain. Opsonophagocytosis of engineered B. burgdorferi as well as of T. pallidum Nichols and SS14 strains was evaluated using J774A.1 macrophages and mouse antibodies raised against predicted surface-exposed loops of TprD and TprK using IncuCyte system.

Results: Both TprD and TprK were found to be surface exposed in engineered B. burgdorferi and infectious T. pallidum strains. Expression of these proteins conferred adherence to several mammalian cell lines in vitro. In addition, antibodies we generated recognized TprD and TprK on the surface of spirochetes and significantly enhanced macrophage-mediated opsonophagocytosis.

Conclusion: Our findings here demonstrate that TprD and TprK function as T. pallidum adhesins that are also targets of opsonic antibodies. These Tprs likely facilitate tissue colonization during infection, while also rendering the pathogen susceptible to immune clearance. Our findings support inclusion of TprD and TprK as components of a multivalent vaccine against syphilis.

Recent studies, including reports of rare monogenic Toll-Like Receptor 7 (TLR7) gain-of-function mutations, have established TLR7 as a causal driver in a subset of human systemic lupus erythematosus (SLE) cases. Consequently, TLR7 and its downstream mediators have emerged as promising therapeutic targets. Beyond its role in B cells, TLR7 is also critical within the renal tissue of patients with lupus nephritis (LN), where single strand RNA (ssRNA) drives aberrant TLR7 activation in macrophages. This activation promotes robust inflammatory cytokines production, exacerbating autoantigen generation and inflammatory tissue damage in a self-reinforcing feedback loop that accelerates LN progression. This review explores the role of TLR7 in LN pathogenesis through the lens of macrophage biology, with the goal of identifying novel therapeutic strategies that modulate the TLR7 signaling pathway.

Background: Arctigenin (AG), a natural lignan compound, has been reported to reveal its anti-inflammatory effects in glucose, lipid metabolism and type 2 diabetes mellitus. An increasing number of studies suggest that microglia activation evoked neuroinflammation is known to contribute to the development and progression of neuropathic pain. This study aims to investigate the role and mechanism of AG in ameliorating spared nerve injury (SNI)-induced neuropathic pain.

Materials and methods: SNI model was defined as suffering severe hyperalgesia and allodynia and established in C57BL/6 male mice. The effects of AG on SNI mice and its underlying mechanisms were examined by behavioral tests, qPCR, western blotting, ELISA, immunofluorescence (IF), ROS test, transmission electron microscopy and mitochondrial test.

Results: We found that intraperitoneal administration of AG produced pronounced dose-dependent antinociceptive effects in SNI mice. Moreover, AG treatment significantly inhibited ERK, JNK and p38 phosphorylation in the lumbar spinal cord of SNI mice, but not AMPK, PGC-α and mTOR pathway. Meanwhile, we found that pretreatment with the U0126 or SB203580 or SP600125, 30 min prior to AG administration, blocked the analgesic effects of AG in SNI mice. Furthermore, mechanistic studies indicated that at the spinal cord level, AG produced pain relief through restoring mitochondrial biogenesis, inhibiting oxidative damage, suppressing microglia and astrocyte activation and decreasing the production of pro-inflammatory factors, which direct contributed to neuronal modulation. pretreating with minocycline reduced but did not completely block the analgesic effect of AG, indicating that the activation of spinal cord microglia is not necessary for the antiallodynic effect of AG. In addition to neuropathic pain, AG exhibits significant analgesic effects across diverse models, indicating its broad-spectrum analgesic properties. Concurrently, studies on short-term toxic side effects revealed that prolonged AG injection had no impact on hepatic or renal functions and produced none of the typical analgesic side effects, including tolerance, addiction, or constipation, indicating limited antinociceptive side effect.

Conclusions: The present study is the first to provide evidences that AG may represent a novel therapeutic target with high analgesic activity and low side effects for the treatment of neuropathic pain.

Uric acid has complex bidirectional effects on human physiology and disease, influenced by its antioxidant capacity, metabolic regulatory roles, and pro-inflammatory properties, all of which are highly context-dependent. In this review, we synthesize recent advancements related to the continuum from soluble uric acid (SUA) to amorphous monosodium urate (AMSU) and, ultimately, to crystalline monosodium urate (MSU). We propose that AMSU may act as a transitional intermediate that connects the soluble and crystalline states. Notably, AMSU may serve as a buffering stage between crystallization and inflammatory activation, providing a conceptual bridge between urate phase transitions and immune-metabolic signaling. Building on this idea, we establish a framework that links urate state dynamics with immune-metabolic pathways and disease progression. We systematically summarize the physiological roles of SUA in maintaining redox homeostasis and regulating metabolism, and we examine how sustained hyperuricemia contributes to chronic organ damage through impaired autophagy and metabolic inflammation. Additionally, we outline how the formation of MSU crystals triggers acute inflammatory responses via the TLR-NLRP3 two-signal model. Subsequent processes, such as neutrophil extracellular traps formation and macrophage polarization, drive chronic tissue remodeling and progressive pathology. Finally, we connect these mechanistic insights to both established and emerging therapeutic strategies, emphasizing the potential value of stage-specific and mechanism-oriented interventions. By conceptualizing uric acid biology as a dynamic, multi-state process, this review offers an integrated perspective on hyperuricemia-associated diseases and suggests directions for future targeted therapeutic research.