Frontiers in Immunology最新文献

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease characterized by hyperkeratotic follicular papules, palmoplantar hyperkeratosis, and associated normal "islands of unaffected skin". Its pathogenesis has not been fully elucidated, and treatment poses significant challenges. Conventional therapies include oral retinoids and topical emollients. In recent years, although biological agents have been used in treatment, they are associated with side effects such as an increased risk of infection, and some patients show no response to treatment, thus necessitating the exploration of new therapeutic approaches.This case represents the first reported use of a TYK2 inhibitor (deucravacitinib) for the treatment of PRP. The patient was a 39-year-old male who developed extensive erythema in December 2024. The erythema gradually increased and progressed to red punctate eruptions accompanied by mild desquamation, slight pruritus with a stinging sensation, and "islands of unaffected skin". Initial treatment with topical dinoprostone and mometasone furoate cream was ineffective. In March 2025, the patient received deucravacitinib (6 mg daily) in combination with topical halometasone cream. At the 1-month follow-up, significant improvements were observed in erythema, desquamation, and pruritus. At the final 6-month follow-up, the skin lesions almost resolved, leaving only mild erythema and a small amount of desquamation. Both the disease severity and the patient's quality of life were significantly improved. This case suggests that deucravacitinib exhibits favorable efficacy and safety in the treatment of PRP. However, due to the low incidence of PRP, which makes large-scale controlled trials difficult, and the lack of recognized treatment guidelines, more clinical studies are needed in the future to further verify the potential of deucravacitinib in the treatment of PRP.

Background: Mepolizumab blocks IL-5, targeting eosinophilic type-2 inflammation. Due to existing phenotype driven patient selection, evidence of its effectiveness in primary diffuse CRS and CRS without nasal polyps (CRSsNP) and in real-world populations is limited. Our objective was to evaluate the real-world effectiveness of mepolizumab in patients with primary diffuse CRS, regardless of nasal polyp status, and to assess outcomes across CRS phenotypes and prior surgical history.

Methods: Adults with primary diffuse CRS treated with mepolizumab for ≥6 months were identified. Pre- and post-therapy outcomes included serum eosinophil counts, Lund-Mackay CT scores, Lund-Kennedy endoscopic scores, and SNOT-22 symptom scores. Subgroup analyses were performed by CRS phenotype (CRSwNP vs. CRSsNP) and prior endoscopic sinus surgery (ESS). Biologic switching and discontinuation were recorded.

Results: Among 277 patients (mean age 60.8 ± 14.7 years; 54.9% female), 93.5% had type-2 comorbidities, 29.6% had CRSsNP, and 27.8% were ESS-naïve. The median duration of mepolizumab therapy was 31 months. Mepolizumab therapy significantly reduced serum eosinophils (median 0.57 to 0.07 ×10⁹/L, p<0.001) and Lund-Mackay scores (median 14 to 10, p<0.001), which was consistent across all subgroups. Improvements in SNOT-22 and endoscopic scores were modest and not consistently significant. CRSwNP patients were more likely to undergo ESS during therapy, but time to first post-therapy ESS was longer than in CRSsNP. There were no differences in likelihood of undergoing ESS during therapy, time to subsequent ESS, or oral corticosteroid use between prior ESS and ESS-naïve patients. Biologic switching occurred in 24.9%, and discontinuation in 16.6%, primarily due to disease recalcitrance.

Conclusion: Mepolizumab effectively reduced systemic eosinophilia and radiographic disease burden in primary diffuse CRS, independent of phenotype or prior ESS. Symptom improvement was variable, highlighting the heterogeneity of clinical response. These findings support an endotype-driven approach to biologic therapy and suggest that IL-5 blockade may benefit selected CRSsNP patients.

B cells play a crucial role in immunity against various infectious diseases. However, their role in tuberculosis (TB) has been largely understudied. Emerging evidence suggests that B cells actively shape immune responses in TB. Beyond their classical functions, B cells contribute to the formation of inducible bronchus-associated lymphoid tissue (iBALT), a tertiary lymphoid structure (TLS) that enhances localized immune responses in the lungs. As iBALT is a site for B-T cell interactions and the generation of high-affinity antibodies, recent studies suggest that sex differences in iBALT formation influence TB immunity. This review synthesizes evidence from both TB and non-TB models to highlight the expanding role of B cells and iBALT, underscoring their potential implications for vaccine development and immunotherapy.

Kidney transplantation remains the most effective treatment for end-stage renal disease (ESRD). However, long-term graft survival is still limited by chronic allograft dysfunction (CAD), which is primarily characterized by renal interstitial fibrosis (RIF). The development of RIF is an actively regulated and progressive process involving both immune and non-immune mechanisms. Within the renal microenvironment, multiple cell populations interact to form a self-reinforcing profibrotic network that ultimately drives irreversible fibrotic remodeling. Despite increasing mechanistic insights, the precise modes of multicellular crosstalk remain incompletely understood, and effective targeted therapies are still lacking in clinical practice. In this review, we systematically summarize the dynamic interactions among immune cells, renal epithelial cells, and stromal cells during renal allograft interstitial fibrosis. By integrating recent advances at the cellular and molecular levels, we identify key regulatory nodes within this multicellular network and discuss emerging therapeutic targets and precision intervention strategies aimed at inhibiting profibrotic signaling, alleviating pathological tissue remodeling, and improving long-term graft function and survival.

Introduction: Post-allogeneic stem cell transplantation (alloSCT) can be complicated by poor graft function (PGF), a life-threatening condition characterized by complete donor chimerism alongside persistent multilineage cytopenias. PGF significantly increases the risk of bleeding, infection, and transfusion dependence. The cellular changes during hematopoiesis post-alloSCT, particularly in PGF, remain poorly defined.

Methods: To evaluate the immune and hematopoietic reconstitution and dysfunction post-alloSCT, with a focus on PGF, we applied a comprehensive suite of histological, immunological, and molecular biological techniques to bone marrow (BM) and peripheral blood samples from patients with PGF, good graft function (GGF), and healthy donors (HDs).

Results: By approximately 100 days post-alloSCT, patients demonstrated T cell oligoclonality, activation, and exhaustion compared to HDs. BM nucleated cells, particularly monocytes, exhibited increased activation and IFN-g response post-alloSCT compared to those of HDs. Moreover, cell-cell interactions between immune cells and hematopoietic stem and progenitor cells were notably enhanced post-alloSCT. While most inflammatory changes were present in both PGF and GGF, they were more pronounced in PGF.

Discussion: Our results demonstrate a hyper-inflamed post-alloSCT environment involving both innate (monocytes) and adaptive (T cells) immune responses and their active interactions, more in PGF, highlighting that immune modulation may serve as an alternative or adjunctive therapeutic approach for PGF.

Background: Pseudorabies virus (PRV) is a major swine pathogen that causes substantial economic losses. The dynamic remodeling of host cell chromatin plays a pivotal role during viral infections. However, the epigenetic mechanisms underlying PRV-host interactions remain unclear.

Methods: This study integrates ATAC-seq and RNA-seq to investigate the dynamic changes in host chromatin accessibility and gene transcription during PRV infection. The accessible chromatin regions were analyzed for enrichment in genomic features and transcription factor binding motifs. RNA-seq data were used to identify differentially expressed genes and dysregulated pathways. The two datasets were integrated to examine correlations between chromatin accessibility and gene expression.

Results: PRV infection induces a genome-wide elevation in host chromatin accessibility, which progressively intensifies throughout the course of infection. These accessible chromatin regions are predominantly enriched in promoters and binding motifs for bZIP family transcription factors, such as BATF, ATF3, and AP-1, suggesting these transcription factors may play an important role in PRV infection. RNA-seq analysis reveals that PRV infection significantly dysregulates genes involved in metabolic and immune response pathways, with extensive transcriptional suppression observed in the late stages. Integration of ATAC-seq and RNA-seq data demonstrates that chromatin accessibility is positively correlated with gene expression for the majority of differentially expressed genes. However, certain genes exhibit discordant regulation, implying the existence of more complex regulatory mechanisms.

Conclusion: This study provides valuable epigenetic insights into the PRV-host interaction and establishes a theoretical framework for developing novel antiviral strategies.

Objective: To develop a mechanistic physiologically-based model describing CD4⁺ T-lymphocyte homeostasis across the human lifespan, incorporating maturation, differentiation, migration aspects and the impact of age on distinct cell subpopulations.

Methods: A stepwise modeling approach was implemented by integrating published quantitative data on CD4⁺ T-cell concentration in blood and various tissues for narrowly defined age ranges, together with experimental kinetic parameters. The homeostatic CD4⁺ T-lymphocyte kinetics model was represented as a system of ordinary differential equations for four thymocyte subpopulations and six CD4⁺ T-lymphocyte subpopulations, incorporating five physiological compartments: the thymus, blood, lymphoid tissue, the gastro-intestinal tract, and lung tissue. A series of empirical functions was sequentially tested to describe age-related changes in homeostasis. Reciprocal cellular feedback functions were assessed for incorporation in the model, as an alternative to age-dependent functions. An extensive set of model evaluations was performed, including model validation on total and memory CD4⁺ T-cell concentrations, simulations of homeostasis perturbations following thymectomy, and global sensitivity analysis, to determine the processes most influential in shaping CD4⁺ T-cell homeostasis.

Results: Age-related shifts in proliferation of naïve and activated cells, differentiation of memory subsets, survival of recent thymic emigrants (RTE) and migration aspects of CD4⁺ T-cells - together with reduced thymic output - were identified as key determinants of immune homeostasis. Sensitivity analyses showed that thymocyte and naïve cell homeostasis drives early differentiation stages, whereas clonal expansion dominates memory and effector cell maintenance, with the influence of all processes declining with age. Although increased naïve T-cell proliferation and reduced RTE death may partially compensate for thymic loss, these mechanisms are insufficient to restore long-term CD4⁺ T-cell counts after thymectomy.

Conclusion: By unifying diverse clinical and experimental observations within a multiscale mechanistic quantitative framework, the proposed model offers a robust tool for predicting CD4⁺ T-cell dynamics and assessing the impact of physiological changes or interventions on immune homeostasis.

Post-transplant anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) recurrence on the allograft is rare and, to our knowledge, has never been described in the situation of a previous double-positive vasculitis with both ANCA and anti-glomerular basement membrane (GBM) antibodies. We report an unusual case of anti-myeloperoxydase (MPO) antibody-associated vasculitis recurrence occurring 14 years after kidney transplantation following a double-positive anti-GBM and anti-MPO glomerulonephritis. The transplant induction regimen consisted of anti-thymocyte globulin, and initial maintenance therapy associated tacrolimus, mycophenolate mofetil, and corticosteroids. Mycophenolate mofetil was discontinued 4 months after transplantation due to persistent leukopenia, and tacrolimus was maintained along with corticosteroids. At 14 years post-transplantation, the patient presented with diffuse alveolar hemorrhage, acute kidney injury stage 1 of Kidney Disease Improving Global Outcomes, proteinuria, microhematuria, serous otitis media and anti-MPO antibodies resurgence, without detectable anti-GBM antibodies. A kidney allograft biopsy was performed and showed rare active crescents with severe chronic injuries. This pulmonary and renal involvement was attributed to an anti-MPO antibody-associated vasculitis recurrence. The induction treatment of the relapse consisted of methylprednisolone at 5 mg/kg and rituximab at 375 mg/m² per week for 4 weeks. Renal function remained stable, urinary protein to creatinine ratio decreased from 0.9 g/g to 0.3 and 0.2 g/g at 6 and 12 months, respectively. Microhematuria resolved at 6 months and remained absent subsequently. Maintenance treatment was continued with rituximab every 6 months. According to the literature, post-transplant isolated AAV recurrence on the allograft remains exceptional, ranging between 0.003 and 0.076 per patient per year. To our knowledge, there are no reported cases of post-transplant anti-MPO-associated vasculitis recurrence in a patient with former anti-MPO and anti-GBM antibody-associated vasculitis. This case underlines the fact that AAV can recur late after transplantation in previously double-positive vasculitis patients. Thus, close monitoring of clinical and biological signs of recurrence is necessary in these patients. Because the pathophysiology of this atypical entity remains unclear, further trials are still necessary to highlight the underlying mechanisms of this particular auto-immune association and, more specifically, of isolated post-transplant AAV recurrence in double-positive patients to improve prevention and to elaborate more efficient immunosuppressive strategies.

Neoantigens have emerged as promising targets for personalized cancer immunotherapy. However, accurate identification of immunogenic neoantigens remains a challenge due to limitations in existing predictive models. Here, we present CNNeo, a novel deep learning-based neoantigen prediction model, and CNNeoPP, an integrated computational pipeline for neoantigen discovery. CNNeo employs large language model-derived sequence representations and multi-modal feature integration, demonstrating superior predictive performance compared to existing tools. CNNeoPP was rigorously validated using independent datasets, including the TESLA dataset, and experimental validation via ELISpot T-cell assays. Additionally, we conducted a proof-of-concept study utilizing plasma cell-free DNA to explore the feasibility of non-invasive neoantigen prediction. We found that increased sequencing depth enhances neoantigen detectability, further amplified by the prioritization strategy of CNNeoPP. CNNeoDB, a publicly accessible database was developed compiling neoantigen data from multiple sources. This study establishes robust tools for neoantigen prediction, with implications for optimizing cancer immunotherapy and liquid biopsy-based tumor monitoring. CNNeoPP is available at https://github.com/AaronChen007/neoantigen.

Immunotherapy has transformed the treatment landscape of several malignancies, yet solid tumors such as pancreatic ductal adenocarcinoma (PDAC), glioblastoma multiforme (GBM), and triple-negative breast cancer (TNBC) remain largely resistant due to poor immune infiltration, immunosuppressive tumor microenvironments (TMEs) and, the limited success of T cell-centric strategies. The lymphotoxin-beta receptor (LTβR), a member of the tumor necrosis factor (TNF) receptor superfamily, is broadly expressed on stromal, endothelial, and myeloid cells within the TME and signals through both canonical and non-canonical NF-κB pathways. Depending on context and activation mode, LTβR can drive either tumor progression or anti-tumor immunity. While persistent LTβR signaling supports immunosuppressive macrophage phenotypes and promotes tumor growth in hepatocellular carcinoma, preclinical models of colorectal and cervical cancer have demonstrated that LTβR activation induces tertiary lymphoid structures (TLSs), high endothelial venules (HEVs), and immune infiltration, thereby improving responsiveness to immune checkpoint blockade (ICB). This perspective examines in depth the functional duality of LTβR and its emerging therapeutic potential in solid tumors. LTβR agonism has been shown to promote TLS formation and immune activation, whereas antagonistic strategies such as ligand traps may suppress tumor-supportive LTβR signaling in immunosuppressive compartments. Strategically localized LTβR stimulation presents a promising avenue to induce targeted immune reprogramming within the TME. We further explore LTβR's interactions with key immune subsets-myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and tumor-associated macrophages (TAMs)-and its synergy with ICB and CAR T cell therapies. Selective LTβR modulation may reprogram the TME, overcome immunotherapy resistance, and broaden durable responses in refractory solid tumors.