Immune checkpoint inhibitors combined with chemotherapy have improved outcomes for advanced gastric cancer, yet only a subset of patients derive benefit, and the contribution of the gut microbiome remains incompletely defined. To identify microbial signatures associated with chemoimmunotherapy response, we performed 16S rRNA gene sequencing on 90 fecal samples collected from 30 patients at baseline, one month after treatment initiation, and at the end of therapy. Patients were stratified by RECIST1.1 criteria into partial response (PR), stable disease (SD), and progressive disease (PD). While overall microbial composition and alpha diversity remained stable over time, immunotherapy enriched Lachnospiraceae and Bacteroidaceae. Notably, baseline microbiota differed significantly among response groups: Senegalimassilia and Lactobacillus were overrepresented in PR patients, whereas Parvimonas, Intestinibacter, and Catenibacterium characterized the SD and PD groups. By integrating public databases, we constructed microbe-metabolite-target and microbe-host interaction networks, indicating that response-associated genera may modulate host genes such as IFNG, IL12B, CXCL6, and DUOX2, thereby influencing CD8[+] T cell infiltration. These findings identify gut microbial signatures as predictive biomarkers and provide mechanistic insight into microbiome-mediated chemoimmunotherapy efficacy in gastric cancer.

Trypsin is commonly used as an adjunctive therapeutic agent for chronic inflammatory and autoimmune diseases. This study investigated the impact of trypsinogen (PRSS1) variants on type 2 immune responses mediated by M2 macrophage polarization in immunoglobulin G4-related disease (IgG4-RD). Whole-exome sequencing of affected tissue samples from patients with IgG4-RD, including two cases of IgG4-related autoimmune pancreatitis and one case of Mikulicz disease, identified novel PRSS1 variants, namely p.Lys70Asn and p.Phe73Leu. Activation of M2 macrophages was observed in these affected tissues. By integrating single-cell RNA sequencing datasets with spatial transcriptomic analysis of pancreatic tissues from mutation-positive cases, we found that molecules produced by M2 macrophages, including TGF-β, may promote type 2 immune responses. In conclusion, novel PRSS1 variants may contribute to the pathogenesis of IgG4-RD by activating type 2 immune responses.

Antibodies are the principal effector proteins of humoral immunity. Dysregulated antibody production is a feature of a number of heritable immune-mediated diseases, such as the antibody deficiencies and IgA nephropathy. To characterize the common-variant architecture of serum antibody levels in the general population, we conducted the largest GWAS meta-analyses to date of serum IgA, IgM and IgG, attaining sample sizes of 85,204, 55,368 and 58,777, respectively. We identified 82 novel associations across three isotypes, including 38 novel IgA associations (of a total of 77), 36 novel IgM associations (of a total of 82) and 8 novel IgG associations (of a total of 14). We found that isotype-specific genetic architecture was largely disjoint, with few signals colocalising across isotypes in spite of their overall positive genetic correlation. We identified a large number of colocalisations between antibody phenotypes and immune-mediated diseases and 16 between antibody phenotypes and a lymphocyte count phenotype. We report a greatly expanded catalogue of serum antibody-associated variants and characterise these in terms of their pathway context and relation to immune pathology.

Peripheral lymphoid organs in mammals are highly organized, complex tissues that support adaptive immune responses. In terms of comparative developmental biology, the mobile leukocytes of shared hematopoietic lineages in the spleen, lymph nodes, and mucosal lymphoid tissues perform similar functions during antigen recognition and intercellular communication, indicating them as largely homologous. However, the sessile stromal elements within these tissues that create preferential lodging domains for leukocytes differ considerably in their developmental features and structural organization, appearing analogous rather than homologous. Recent studies of splenic stromal architecture have identified region-specific transcription factors, chemokine signatures, and cell surface molecules that guide the specialization of the red pulp and marginal zone, two compartments unique to the spleen. This review-with particular emphasis on Nkx family members as key morphogens regulating spleen development and function-summarizes the roles of critical transcription factors in stromal differentiation pathways, architectural features, and immunological processes under both physiological and pathological conditions.

Despite advances in cancer treatment, the prognosis of clear cell renal cell carcinoma (ccRCC) remains poor. The role of CAFs in ccRCC remains unclear. The single-cell sequencing (scRNA-seq) data for ccRCC were downloaded from the GEO database, with the SERPINH1[+] fibroblast subpopulation identified. Cancer-associated fibroblasts (CAFs) were determined. In vitro assays analyzed SERPINH1 expression and its impact on ccRCC tumor progression. In vivo animal experiments validated SERPINH1 function. The scRNA-seq data analysis demonstrated that ccRCC cells showed remarkable intratumoral heterogeneity. CAFs were an important source of SERPINH1 in ccRCC, which was further verified in CAFs isolated from tumor tissue. In cell experiments, SERPINH1 from CAFs promoted the up-regulation of TGF-β to induce EMT in ccRCC cells, and TGF-β from tumor cells reinforced the secretion of SERPINH1 from CAFs to form a feedback loop. In vivo experiments elucidated the effects of blocking SERPINH1 function on ccRCC malignant progression. CAFs, as the communication center of TME in ccRCC, secrete SERPINH1 to elevate TGF-β level in tumor cells, and influence epithelial-mesenchymal transition (EMT) and malignant progression of ccRCC. The research helps to elucidate the tumor-promoting mechanism of CAFs and provides a new therapeutic strategy for repressing CAF activation.

Interleukin-33 (IL-33) is a central regulator of immune responses and inflammation, and genetic variation in IL33 and its receptor IL1RL1 (ST2) is strongly linked to disease susceptibility, notably asthma. Emerging evidence suggests that IL-33 also influences hematopoietic processes and platelet biology, indicating functions beyond canonical immunity. We investigated two missense variants identified in a patient with unexplained thrombocytopenia: a rare novel IL33 variant, c.385T>C (p.Tyr129His) and the common IL1RL1 variant c.1501_1502CA>AG (p.Gln501Arg), previously associated with reduced IL-33 signaling. Structural modeling revealed that IL-33 Y129H disrupts a conserved hydrogen bond within the IL-33/ST2/IL-1RAcP ternary complex, destabilizing receptor engagement. Functional assays confirmed markedly reduced binding affinity and biological activity, establishing Y129H as a loss-of-function variant. The IL1RL1 Q501R variant affects the Toll/IL-1 receptor (TIR) domain, critical for recruiting adapter proteins such as MyD88. Modeling revealed pronounced perturbation in a peripheral helix of the TIR domain, potentially impacting adapter recruitment and downstream signaling, providing a mechanistic basis for its protective association with asthma. Together, these findings provide structural and functional insights into clinically relevant IL33 and IL1RL1 variants. Their simultaneous occurrence in a patient with thrombocytopenia further supports a potential role for this pathway in platelet homeostasis and stress-responsive hematopoiesis.

Breast cancer is the most common malignancy among women worldwide, causing >650,000 deaths annually. Despite advances in personalized therapies, many patients fail to obtain durable benefits from treatments tailored to their disease subtype. For instance, only some patients with PD-L1[+] triple-negative breast cancer (TNBC) respond to chemotherapy plus immune checkpoint inhibitors. Moreover, while tumor-infiltrating lymphocyte levels correlate with improved survival in TNBC and HER2[+] breast cancer, this is not true for HR[+]HER2[-] disease. Thus, other immunobiological features of the breast cancer microenvironment may hold clinically relevant prognostic or predictive value, especially in HR[+]HER2[-] tumors. Here, we investigated transcriptional signatures of immune cell infiltration across three public transcriptomic datasets from patients with breast cancer. The relative abundance and activation status of tumor-infiltrating mast cells were consistently associated with shifts in survival indicators amongst patients with HR[+]HER2[-] breast cancer. Specifically, infiltration by resting (but not activated) mast cells was associated with prolonged survival, correlating inversely with tumor infiltration by immune cells and proliferation markers in cancer cells, but positively with stromal richness. While based on retrospective transcriptional analyses, these findings suggest that interactions between mast cells and non-malignant components of the breast cancer microenvironment, particularly fibroblasts, may shape disease progression and treatment sensitivity.

Tumor-infiltrating lymphocytes (TILs) shape melanoma behavior and response to immunotherapy, but the links between immune regulation, TIL patterning, and outcomes remain unclear. We retrospectively studied 32 primary melanoma samples from patients treated with anti-PD-1 therapy. Histopathologic TILs were classified as brisk or non-brisk, and primary tumors underwent targeted immune transcriptomic profiling (NanoString nCounter Human Immunology panel). External validation was performed with 96 TCGA-SKCM primary tumors. Brisk tumors displayed broad upregulation of immune transcripts, with enrichment of adhesion pathways (directed global significance scores - DGSS = 2.15) and MHC class II antigen presentation (DGSS = 2.128). Cross-cohort comparison identified 22 shared differentially expressed genes, with ZAP70 remaining significant in both datasets. Brisk tumors also showed higher total TIL (p = 0.036), cytotoxic-cell (p = 0.0095), and Th1 (p = 0.027) scores. Response-associated genes differed by TIL pattern, and subgroup-specific gene scores predicted anti-PD-1 benefit in brisk (4-gene, Area under curve - AUC = 1.000) and non-brisk (3-gene, AUC = 0.852) tumors; the non-brisk score remained independently associated with response (p = 0.029). Higher scores were also associated with prolonged survival. Integrating histopathological TIL patterning with immune transcriptomics may refine prognostication and support immunotherapy stratification in melanoma.

The contribution of human genetics in shaping the abundance of gut microbiota is small, about 5%; however, it can inform about disease etiopathogenesis, including multiple sclerosis (MS). Searching for MS-gut microbiota cross-comparison of reported genome-wide association studies (GWAS), we identified a coincident association of the disease with a commensal - Akkermansia massiliensis-in the selective Fc receptor of secretory IgA gene (FcRL3). Those two signals colocalized, supporting that lower abundance of A.massiliensis may contribute to MS predisposition. In cis, the FcRL3-MS predisposing signal downregulates the FcRL3 protein production and modulates the dynamic intron usage between naïve and mature B-cells, which we believe to be the primary molecular mechanism associated with MS risk in this region. The signal also increases the expression of the FcRL5 gene. In trans, it reduces the expression of neuropeptide B/W receptor 1 (NPBWR1) and azurocidin (AZU1), whereas it increases the expression of the tumor necrosis factor receptor superfamily, member 13B (TACI). Our view of MS etiopathogenesis suggests that low levels of FcRL3 and A. massiliensis may predispose to MS by causing impaired self-tolerance to commensal microbiota, dysregulation of B-cell function, and immune system effects on the neuroendocrine signaling by AZU1 and NPBWR1 proteins, which may be further investigated as targets for MS.

Brain-Derived Neurotrophic Factor (BDNF), highly enriched in platelets, contributes to vascular integrity and thrombotic responses. The rs11030119 variant, located in a BDNF intronic enhancer, has been linked to stroke recovery, but its influence on peripheral BDNF dynamics and hemostasis remains unexplored. In this study, we aimed to understand the impact of rs11030119 on circulating levels of BDNF, and its subsequent effects on thrombus formation. Twenty-six healthy individuals homozygous for either the GG or AA genotype of rs11030119 were matched for age and sex. BDNF and proBDNF levels were quantified in serum, plasma, and platelets. Platelet aggregation, ATP secretion, thrombin generation, and clot firmness were assessed. Washed platelets were also tested with recombinant BDNF. AA carriers displayed significantly lower plasma and serum BDNF levels and diminished BDNF release upon activation, despite comparable platelet BDNF content. The expression of its receptor, TrkB, on the platelet surface was also reduced in AA carriers. However, platelet reactivity, thrombin generation, and viscoelastic clot properties were preserved across genotypes. In conclusion, rs11030119 modulates circulating and platelet-releasable BDNF without impairing hemostatic function, suggesting that BDNF bioavailability may not directly correlate with thrombotic potential. These findings uncover a novel genetic mechanism controlling platelet-derived neurotrophin output.

Cyclic neutropenia (CyN) is a rare haematological disorder most often caused by mutations in the neutrophil elastase gene (ELANE). We describe three novel ELANE mutations in CyN patients and link them to impaired neutrophil extracellular trap (NET) formation. ELANE sequencing was performed using the Sanger method, and AlphaFold2 was used to visualize the impact of mutations on the structure of neutrophil elastase (NE). NET formation was assessed by colocalization of MPO, NE, and DNA using fluorescence microscopy, and free DNA was quantified fluorometrically. We identified two missense substitutions (M66K, V133G) and one deletion (G192-G196del). These mutations did not significantly alter the overall NE structure but exhibited functional effects: M66K may disrupt substrate binding, V133G increases protein mobility, and the Deletion of G192-G196 may limit the opening of the catalytic pocket. NETosis was impaired in CyN patients compared with controls. Their NETs appeared less expanded, and DNA release into supernatants was reduced, reaching the lowest levels during neutropenia, even in patients with normal neutrophil counts. These abnormalities were accompanied by reduced NE activity. In sum, novel ELANE variants may contribute to altered NE function and defective NET formation in CyN, suggesting that impaired NETosis is partly independent of cyclic changes in neutrophil numbers.

Psoriasis is an autoimmune disorder, and about 125 million people worldwide suffer from this chronic skin disease. It is a multifactorial disorder influenced by the combined action of many genetic factors and their interactions with environmental factors. Recently, significant advances in research have provided greater insight into the pathophysiologic mechanisms, highlighting the roles of genetic susceptibility loci such as HLA-C*06:02, IL12B, and TNIP1, as well as immune pathways involving IL-17, IL-23, and TNF-α. These discoveries not only provided a better understanding of psoriasis but also played a vital role in developing treatment strategies. This review highlights immunological and genetic insights of psoriasis, emphasising their translational relevance. The review also covers how genetic variations modulate the immune response, leading to disease occurrence and chronicity. Moreover, the article explores how these findings are shaping personalised diagnosis and treatment strategies. This strategy holds the promise of enhancing the treatment of individuals with psoriasis by transitioning from the traditional care paradigm to patient-centred care in dermatology.

Patients with Down Syndrome (DS) are characterized by dysfunction of several organs, including the liver, brain, heart defects, gastrointestinal anomalies, and lethal immune hypersensitivity. A person with DS is also susceptible to various inflammatory diseases, including hepatic autoimmune diseases. The Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is known to trigger the stimulator of interferon genes (STING) and downstream proinflammatory factors. In this work, we hypothesized that oxidative stress-associated DNA damage triggers activation of the cGAS-STING signaling pathway and promotes liver inflammation in DS. Here, we investigated the role of reactive oxygen species (ROS) associated DNA damage and the cGAS-STING signaling pathway in the pathogenesis of hepatic inflammation in the DS model. Our results showed that DS cells harbor excessive ROS and DNA damage in DS fibroblasts and DS mouse liver. Further, DS cells accumulate micronuclei that likely serve as a source of cytoplasmic DNA to stimulate cGAS-STING activation. In addition, RNA-seq analysis results showed enhanced expression of key type I interferon factors in cGAS-STING pathways in DS liver and inflammatory responses and elevated liver enzymes such as alanine transaminase (ALT) that indicate a hepatocellular liver injury in DS. The results of this study opened the opportunity to connect endogenous DNA damage triggers innate immune response, which may contribute to the upregulation of the cGAS-STING signaling to exacerbate hepatic inflammation in DS.

NRF2 modulates tumor immune microenvironment in several cancers. NRF2 is activated in about 50% of high-grade serous ovarian cancer (HGSOC), the most aggressive type of ovarian cancer. Through analyzing data from scRNA-seq (n = 7), bulk RNA-seq (n = 365), and tumor microarray (TMA) of human HGSOC (n = 240) samples, we demonstrated that NRF2 expression correlated with tumor immune microenvironment in HGSOC. Functional pathway enrichment analysis and transcription factors (TFs) prediction showed the functional relevance of NRF2 expression in shaping the immune phenotype of HGSOC. Pathways such as hedgehog and ROS signaling, and TFs including EGR1, ESRRA, SMAD proteins, and SP-family proteins, are implicated in the immune suppressive microenvironment of NRF2[High] tumors. Immune differentiation analysis showed patients with NRF2[High] tumors enriched with CD68 have lower survival (p = 0.038) than those with CD68[Low] tumors, whereas NRF2[Low] tumors enriched with immune-activated markers such as CD3E and CD80 exhibit a better prognosis. This study is the first that shows classification of HGSOC based on NRF2 levels, highlights new biomarkers, and suggests IHC-labeling and genomic evaluation of NRF2 and immune markers for better prognosis.

Complexity of the microenvironment of lung adenocarcinoma (LUAD) poses significant challenges in its clinical management. Systematic bioinformatic analysis of the Ras-association domain family (RASSF) identified RASSF2 as a potential tumour suppressor in LUAD. This study aims to investigate its clinical significance and functional mechanisms in LUAD. CCK-8, EdU, and colony formation assays were performed to investigate the impact of RASSF2 overexpression on the proliferative capacity of LUAD cells. Transwell and wound healing assays were performed to explore the significance of RASSF2 on LUAD cell migration and invasion. RNA sequencing analysis was conducted on three methylation-positive and three methylation-negative LUAD tissue samples to establish the underlying mechanism of RASSF2 methylation in LUAD. Functional studies indicated that RASSF2 overexpression significantly inhibited the proliferation, migration, and invasion of LUAD cells. Patients with RASSF2 promoter hypermethylation exhibited a significantly shorter overall survival than those without. RNA-seq of three pairs of LUAD tissue samples further demonstrated that RASSF2 methylation is associated with upregulation of the NF-κB signalling pathway and dysregulation of T-cell activation pathways. This study confirmed the tumour-suppressive role of RASSF2 in LUAD and suggests its potential as an immunotherapeutic target, thus providing new insights into LUAD treatment strategies.