Frontiers in Immunology最新文献

Periodontitis, a chronic inflammatory disease, often causes alveolar bone loss. Neisseria bacilliformis is a Gram-negative bacterium that has been identified in periodontal patients, but its role in periodontitis remains unclear. In the present study, we examined whether N. bacilliformis exacerbates periodontitis in a mouse ligature-induced periodontitis (LIP) model and investigated its underlying molecular mechanism. Topical treatment with N. bacilliformis on maxillary second molar exacerbated alveolar bone loss and worsened epithelial and periodontal ligament damage. Histological analyses showed that N. bacilliformis increases tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and inducible nitric oxide synthase (iNOS) levels in the gingival tissue. Treatment with N. bacilliformis induced nitric oxide (NO) production in RAW 264.7 cells, which was inhibited by polymyxin B, implying that N. bacilliformis lipooligosaccharide (LOS) is a major etiologic agent in the inflammatory response. Indeed, LOS purified from N. bacilliformis enhanced NO production and iNOS expression, primarily with activating Toll-like receptor (TLR) 4 and partially activating TLR2. LOS administration into the disto-palatal papilla near the molar further aggravated periodontitis in the LIP mouse model. These results suggest that N. bacilliformis is a periodontal pathogen that exacerbates inflammation and alveolar bone loss, with its LOS acting as an important virulence factor via TLR2/4 activation, leading to the production of the inflammatory mediator NO.

Introduction: The manipulation of the gut microbiota of disease vectors has emerged as a new approach to use in the integrated control of vector-borne diseases. For this purpose, a deep knowledge of their gut microbial communities is essential. To our knowledge, to date, no study has documented the gut microbiome dynamics of Phlebotomus duboscqi sand flies over the entire time-period required for the maturation of a Leishmania infection. Here, we address this limitation.

Methods: P. duboscqi midguts were dissected both before and at different days after L. major infection and subjected to genomic DNA extraction followed by amplification of the V3-V4 hypervariable regions of the 16S rRNA, sequencing, and metagenomics analysis.

Results: We observed a decrease in the number of Amplicon Sequence Variants (ASVs) early after infection, at D2, and late after infection, at D12. More so Sphingomonas, Ochrobactrum, and Serratia emerged as the most prevalent genera in relative terms, before, early after, and late after infection, respectively. These results translated into a separation between the 3 groups in the context of a beta diversity analysis, with statistical relevance. Importantly, we were able to establish Corynebacterium spp. and Enterococcus spp. as potential markers of non-infected and infected sand flies, respectively, as well as Streptococcus spp., Sphingomonas spp., Ralstonia spp., and Abiotrophia spp. as potential specific markers of late infections (ANCOM-BC analysis).

Discussion: Overall, we show that the composition of the gut microbiota of P. duboscqi sand flies changes significantly over the course of an infection with L. major parasites.

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system often associated with aquaporin-4-immunoglobulin-G (AQP4-IgG), which activate the complement system, and it can lead to progressive neurological disability. Complement inhibitors have been shown to be effective in preventing relapses. While there exist rare case reports on the early initiation of eculizumab in the acute exacerbation phase, no data are available for early treatment with ravulizumab.

Case: A 59-year-old patient was diagnosed with AQP4-IgG seropositive NMOSD upon presentation with paraplegia, and MRI-confirmed longitudinally extensive transverse myelitis from C2 to T5 in November 2023. Treatment included high-dose methylprednisolone, followed by immunoadsorption (IA) and complement-inhibition therapy with ravulizumab initiated 13 days after attack onset alongside with IA. The patient additionally developed an interstitial pneumonia complicating the case, likely attributable to complement-mediated autoimmune processes. Over time, there was significant improvement in neurological and respiratory conditions, as evidenced by reduced spinal cord edema and partial resolution of pulmonary infiltrates on follow-up imaging in January 2024. By January 2025, the patient exhibited further neurological improvement and regained the ability to stand upright with external support. Ravulizumab therapy was well tolerated, and the patient will continue with eight-weekly infusions.

Conclusion: Overall, this case highlights that early targeted immunotherapy with ravulizumab within two weeks of attack onset, supported by IA, can be an effective choice for controlling NMOSD disease activity and improving patient outcomes. NMOSD-related interstitial pneumonitis, though rare, underscores the need for vigilance in recognizing atypical manifestations of the disease.

Pemphigus vegetans (PVeg) is a rare variant of pemphigus vulgaris characterized by pustules and/or vegetating plaques, preferentially affecting the flexural areas. The diagnosis of PVeg depends on clinical grounds, histopathology, and direct immunofluorescence. Systemic corticosteroid is the first-line therapy for PVeg, and immunosuppressive treatments such as azathioprine, mycophenolate mofetil, and intravenous immunoglobulins can be used to improve remission rates. Also, there have been a few reports on the use of rituximab for treating PVeg. Here, we present a rare case of PVeg successfully treated by rituximab and provide the first brief review of the application of rituximab in PVeg. Additionally, this patient experienced muscle weakness after treatment but gradually improved with tapering prednisone, which increased our understanding of steroid myopathy.

This review provides a comprehensive synthesis of the link between inflammatory bowel disease (IBD) and male erectile dysfunction (ED), with a distinct emphasis on underlying mechanisms and novel perspectives. We critically evaluate the evidence and then systematically elucidate the "gut-penis axis" detailing how gut-derived signals orchestrate a systemic inflammatory response that culminates in penile vascular dysfunction. A novel aspect of our work is the integration of psychological factors into a cohesive psychoneuroimmunological framework, linking stress, the cholinergic anti-inflammatory pathway, and direct pro-inflammatory neural circuits to ED pathogenesis. Beyond mechanistic insight, we examine the clinical implications of this connection, discussing the potential of anti-inflammatory therapies and the necessity of integrated management strategies that address both intestinal and sexual health. Our work aims to bridge knowledge gaps and stimulate targeted interventions to improve the quality of life for men living with IBD.

Background: Precise regulation of Toll-like receptor (TLR) signaling via myeloid differentiation factor 88 (MyD88) is critical for balancing immune defense and inflammation. While ubiquitination represents a dominant mechanism controlling MyD88 stability, the full spectrum of E3 ligases that regulate MyD88 stability remains undefined.

Methods: In the present study, we investigated the regulatory role of Cbl in MyD88 signaling in macrophage.

Results: We identified Cbl as a direct negative regulator of MyD88 in macrophages. Cbl is upregulated during inflammatory responses, and myeloid-specific Cbl deficiency exacerbates cytokine production and MyD88-dependent signaling in macrophages. Mechanistically, Cbl could interact with MyD88. The overexpression of Cbl promoted the ubiquitination and proteasomal degradation of MyD88, whereas Cbl deficiency abrogated its ubiquitination. Moreover, we found that Cbl activation required intracellular calcium and phosphorylation. Calcium chelation and inhibited phosphorylation of Cbl abrogated Cbl-mediated MyD88 downregulation.

Conclusion: findings establish Cbl as a novel suppressor of inflammation and direct-interacting E3 ligase of MyD88 in macrophages. Our study expands the knowledge of intrinsic immunoregulatory networks of TLR- MyD88 signaling and the regulatory mechanism of Cbl, suggesting new therapeutic strategies for inflammatory disorders.

[This corrects the article DOI: 10.3389/fimmu.2025.1585421.].

Introduction: Gastric cancer is one of the most diagnosed cancers and a major contributor to cancer-related death in China. Recent studies have demonstrated the failure of tumor mutational burden (TMB) in predictive accuracy. Here, we aimed to evaluate the prognostic value of tumor neoantigen burden (TNB) to predict the clinical outcome among patients undergoing gastric cancer resection.

Methods: This study performs whole exome and transcriptome sequencing of tumor tissues of 85 gastric cancer patients who underwent resection surgery. The prognostic value of TMB and TNB in Chinese gastric cancer patients were evaluated, respectively.

Results: In contrast to TMB, TNB achieved significance in predicting overall survival at both early (a median follow-up period of 23.5 month) and late (a median follow-up period of 35.5 month) timepoints (p-value<0.05), particularly with expanding 2-year and 3-year restricted mean survival time (RMST). According to the comparative enrichment and protein-protein interaction analysis of TNB- and TMB-associated genes, we found the upregulated TNB-associated genes were significantly enriched in hormone and nutrient sensing cascades, whereas their counterparts were predominantly linked to cytoskeletal development. In addition, we also noticed an increased infiltration of neutrophils in TNB-High group (p-value=0.04).

Discussion: In summary, this study indicated that the prognosis of TNB-High patients was significantly better than their counterparts, which might be associated with impaired energy metabolism.

Atherosclerosis, a chronic vascular disease characterized by lipid-driven inflammation and arterial wall remodeling, remains the leading cause of cardiovascular morbidity and mortality. This review aims to systematically summarize recent advances in our understanding of its multidimensional pathogenesis and the corresponding evolution of therapeutic strategies. We focus on the intricate crosstalk between endothelial dysfunction, dyslipidemia, and immune-inflammatory activation, which collectively drive disease progression. Key mechanisms discussed include metabolic reprogramming of immune cells, phenotypic switching of vascular smooth muscle cells, and novel modes of programmed cell death. Beyond conventional lipid-lowering approaches, we highlight emerging therapeutic avenues such as immunomodulatory vaccines, RNA-based therapeutics, and biodegradable stents with inherent anti-ferroptotic properties. Furthermore, we explore the potential of modernized traditional Chinese medicine formulations that target multiple pathways. Looking forward, we conclude that integrating multi-omics data, single-cell technologies, and artificial intelligence is pivotal for advancing precision medicine. This integration will enable the development of individualized risk prediction models and targeted interventions, ultimately bridging the gap between molecular mechanisms and effective clinical management to overcome current bottlenecks in atherosclerosis prevention and treatment.

Introduction: Selective IgA deficiency (sIgAD) is the most common primary antibody deficiency in Western populations and is associated with increased risks of respiratory infections, atopy, and autoimmunity. However, the serologic and B-cell-intrinsic pathways underlying this immune dysregulation remain poorly defined. We sought to characterize a population-based adult sIgAD cohort clinically and immunologically and to identify soluble and transcriptional signatures that link cytokine milieu to B-cell dysfunction.

Methods: We studied 61 adults with sIgAD and 73 age- and sex-matched healthy controls from the Icelandic sIgAD cohort. Participants completed standardized questionnaires on infections, atopy, and autoimmune disease. Serum immunoglobulins and autoantibodies (ANA, ENA, RF, CCP) were quantified, and a 65-plex Luminex cytokine/chemokine panel was measured in a subset of sIgAD individuals without active inflammatory disease and healthy controls. Purified CD19⁺ B cells from adults with sIgAD and controls were profiled by bulk RNA-seq at baseline and after 48 h TLR9 stimulation with CpG ODN 2006. Unsupervised analyses, differential expression, and correlation networks integrated clinical, serologic, and transcriptional data.

Results: Clinically, adults with sIgAD had an airway-predominant infectious burden (notably increased sinusitis and pneumonia), a skin-skewed atopic pattern (eczema and urticaria), and frequent ANA/ENA positivity despite normal IgG and IgM. Immunoglobulin measurements showed very low IgA, increased total IgG and IgG1, and selectively reduced IgG4. Serum profiling revealed a coherent five-analyte signature, IL-18, sCD40L, TSLP, CCL3, and TWEAK, elevated in sIgAD and associated with higher IgG, lower residual IgA, and ANA/ENA positivity. This pattern was not reproduced in CpG-stimulated B-cell supernatants, indicating a non-B-cell origin. RNA-seq of purified B cells demonstrated diagnosis-dependent transcriptional programs at baseline and after CpG, with prominently reduced expression of IL-18 receptor components in sIgAD B cells.

Discussion: Adult sIgAD is characterized by a blood-measurable endotype in which a systemic IL-18-centered soluble signature coexists with reduced IL-18 receptor expression and altered signaling programs in B cells. This IL-18-IL-18R axis aligns with ANA/ENA-associated immune dysregulation and an IgG-skewed class-switch profile, nominating IL-18-related mediators and B-cell IL-18R expression as candidate biomarkers and mechanistic targets in a subset of adults with sIgAD.