Immunology最新文献

Variation in microbiome composition is linked to differences in intestinal immune phenotypes and can be leveraged to identify microbiome-driven contributions to phenotypes of interest. Furthermore, such variation has been associated with differing inter-individual susceptibility to the development of inflammatory bowel disease (IBD), a chronic inflammatory disease of the gastrointestinal tract that is driven by dysfunctional immune-microbiome interactions. Here, we identified that differences in microbiome composition in C57BL/6 mice from two commonly used commercial vendors, Charles River (CR) and Jackson (JAX) Laboratories, were associated with variation in the intestinal immune phenotype, with CR mice having greater Th17 levels and faecal IgA. In turn, CR mice demonstrated enhanced susceptibility to the dextran sulfate sodium (DSS)-induced model of colitis compared to JAX mice. Co-housing studies revealed that CR mice could transmit enhanced susceptibility to colitis to JAX mice, implicating differences in microbiome composition as drivers of disease susceptibility. Faecal metabolomics studies using targeted mass spectrometry revealed several metabolites differentially enriched in colitis-susceptible and colitis-resistant mice. Correlation analysis uncovered metabolites that were both negatively and positively associated with colitis severity. Taken together, our study leveraged natural microbiome variation to identify gut microbial metabolites with the potential to predict the severity of IBD. Importantly, we further establish susceptible and non-susceptible murine microbial communities that represent a tractable system in which to further uncover microbiome contributions to IBD in the DSS-colitis model.

A fully mass-standardised quantitative comparative analysis of the differential antibody binding to spike variant proteins to SARS-CoV-2 has been performed for the variants: Wuhan, Alpha, Beta, Gamma, Delta and the Omicron variants BA.1, BA.2.12.1, BA.2.75, BA.4 and BA.5. Evolution of immunity through five patient cohorts (n = 148 in total) was studied including pre-pandemic, first infection, first vaccine, second vaccine and triple-vaccinated cohorts. A population of immunity endotypes has been observed and is classified against a recovery antibody threshold, with concentrations below this threshold being regarded as a 'dropout': U(+) showing protection to all variants; U(±) with single, double, triple and further dropout endotypes; and U(-) with all variant concentrations being under the threshold. The U(+) incidence rises significantly following multiple rounds of vaccination reaching an (n = 41) incidence of 54% (95% CI 39%-68%) suggesting between half and three-quarters of the population have universal variant vaccine antibody protection. The U(+) epitopes are targeted preferentially to the S1 region. U(±), with at least one dropout, has an incidence of 42% (95% CI 28%-57%), an immunity gap. Further, a U(-) sub-cohort of the population up to 13% does not make antibodies above the threshold and may not have a sterilising serum leading to persistent virus and a risk of Long COVID.

Transplant rejection, primarily caused by the immune system's recognition of allografts, continues to pose a significant challenge to graft survival. Drawing inspiration from the function of interferon regulatory factor 2 (IRF2) in tumour immune evasion, we explored its potential role in the context of transplantation. We quantified the expression of MHC-I, PD-L1 and associated molecules in cardiac tissues of IRF2 KO mice through RNA and protein analyses. Subsequently, we established a murine heterotopic cardiac transplantation model using IRF2-KO donors to evaluate the role of IRF2 in post-transplant survival. Immunofluorescence and immunohistochemical staining revealed IRF2-dependent regulation of MHC-I and PD-L1 in grafts, accompanied by altered CD4⁺/CD8⁺T-cell infiltration patterns. Further, in vitro experiments employing RNA interference (RNAi) in cardiomyocytes demonstrated IRF2-mediated control of MHC-I/PD-L1 expression and its functional impact on T-cell proliferation and apoptosis in co-culture systems. In mice heart tissues, as revealed by the transcriptome sequencing, IRF2 knockdown downregulated immune-related pathways (MHC, inflammation) and upregulated apoptosis-linked pathways. IRF2 deficiency enhances PD-L1 and suppresses TAP2/ERAP1-MHC-I axis at RNA and protein levels. After transplantation, IRF2 deficiency in allografts prolongs survival by attenuating CD4⁺/CD8⁺T-cell infiltration via PD-L1 upregulation and MHC-I downregulation, thereby mitigating inflammatory injury. In vitro, IRF2 knockdown in HL-1 murine cardiomyocytes via siRNA upregulated PD-L1 expression, suppressed TAP2/ERAP1 levels and attenuated T-cell proliferation while promoting apoptosis in co-culture systems. We elucidate the principal mechanism underlying IRF2-mediated allograft immune evasion, thereby identifying its targeted modulation as an innovative therapeutic approach to prevent early acute rejection and diminish long-term reliance on immunosuppressive therapy in transplantation.

The cause of rheumatic diseases is poorly understood; many appear to have a dominant inheritance with low, incomplete penetrance. A recent theory poses that all DNA is continuously damaged at a constant rate, causing a constant rate of mutations. Here, the hypothesis is tested that a constant, low rate of somatic mutations explains the low, incomplete penetrance of autoimmune rheumatic diseases and the increased penetrance of monogenic inflammatory rheumatic disease driven by multiple DNA loci prone to somatic mutation. Monogenic rheumatic diseases are proposed to require two mutations according to the two-hit hypothesis by Knudson: a germline mutation on one allele, and a somatic mutation initiating rheumatic disease on the wild-type allele. Two approaches are taken. The first one investigates whether the epidemiology of autoimmune rheumatic diseases adheres to two expected characteristics: a linear prevalence of disease and a tapering distribution of multiple disease events in individuals at risk. The second approach analyses at-risk DNA for evidence of hypermutable loci: somatic hypermutation (SHM) hotspots. Autoimmune and monogenic inflammatory rheumatic diseases provide an opportunity to determine whether more than one similar SHM hotspot leads to earlier onset of disease and a higher degree of disease penetrance. Results show that examples of rheumatic diseases, such as rheumatoid arthritis, systemic sclerosis, lupus and Sjogren's syndrome, show a linear prevalence and an exponential distribution of one or more additional autoimmune diseases. SHM hotspots in HLA and non-HLA genes in at-risk people are associated with the risk of rheumatic diseases, and the difference in the number of SHM hotspots, one in autoimmune and PLB1 arthritis and several in COPA syndrome, associated with autoimmune and monogenic non-HLA rheumatic diseases, explains the time of onset of disease and the degree of incomplete penetrance. This clarifies why autoimmune rheumatic diseases are inherited as true autosomal dominant traits with incomplete penetrance and non-HLA monogenic rheumatic diseases as pseudo-dominant traits with incomplete penetrance in accordance with the two-hit hypothesis. Therefore, epidemiology and genetics are compatible with a constant rate of DNA damage and associated somatic mutations as the cause of autoimmune and monogenic rheumatic diseases among at-risk people.

Allergic rhinitis (AR) is a prevalent immune disorder driven by Th2-polarised inflammation, with current therapies primarily providing symptomatic relief rather than addressing the underlying immune dysfunction. Allergen-specific immunotherapy (AIT) holds promise for inducing long-term tolerance but is limited by poor mucosal delivery, enzymatic degradation of antigens, and inconsistent efficacy. A liposomal formulation co-encapsulating SpaCBA (probiotic protein) and ovalbumin (OVA) was engineered. Characterisation included in vitro/in vivo evaluations of immune modulation and therapeutic efficacy in a murine AR model. The SpaCBA-OVA liposome exhibited stable characteristics (size: 100 ± 25 nm; zeta potential: -22 ± 3 mV; 85% entrapment efficiency) and enhanced proteolytic resistance (> 70% protein integrity after 48-h trypsin exposure vs. > 90% degradation of free proteins). Bone marrow-derived DCs (BMDCs) internalised the liposome 3-3.5× more efficiently via CD206/TLR2, adopting a semi-mature (CD86low/MHC-II^high) phenotype and secreting IL-10 (320 ± 30 pg/mL) and TGF-β (280 ± 25 pg/mL). RNA-seq identified 980 differentially expressed genes in T cells, with upregulation of Treg markers (FOXP3, IL-10) and downregulation of Th2 factors (GATA3, IL4). Epigenetic analysis confirmed 55% demethylation of the FOXP3 promoter. In AR mice, the liposome reduced sneezing and nasal rubbing by 60%-65% (p < 0.001), decreased nasal eosinophils by 55%, normalised ZO-1/occludin expression (90% of controls), and reduced epithelial permeability (FITC-dextran flux). The SpaCBA-OVA liposome enhances mucosal delivery and stability of antigens, reprograms DCs to induce Treg-mediated tolerance via metabolic and epigenetic mechanisms, and effectively ameliorates AR pathology in mice. This formulation represents a promising targeted therapy for AR, addressing key limitations of current AIT.

Cytotoxic T lymphocytes (CTLs), especially CD4⁺ CTLs, play a critical role in immune responses against infections and cancers. Nevertheless, the surface markers that define CD4⁺ CTLs remain incompletely characterised, which limits their diagnostic and therapeutic potential. In this study, we investigate CD319 (SLAMF7) and GPR56 as potential surface markers of CD4⁺ CTLs, with a focus on their cytotoxic functions and relevance in primary Sjögren's syndrome (pSS). Using single-cell RNA sequencing and flow cytometry, we detected strong co-expression of GPR56 with cytotoxic effector molecules such as granzyme B in CD4⁺ T cells. Notably, pSS patients showed an elevated frequency of CD4⁺GPR56⁺ T cells, which was associated with disease severity, indicating their potential contribution to pSS pathogenesis. Comparative transcriptomic analysis revealed distinct gene expression profiles between CD4⁺GPR56⁺ and CD4⁺GPR56^- T cells, with enriched pathways related to immune activation and cytotoxicity. Together, our results identify GPR56 as a novel and functionally significant surface marker for CD4⁺ CTLs, providing new insights into their role in autoimmune disorders and their potential for targeted therapeutic strategies.

Down syndrome (DS) is characterised by delayed brain development and intellectual disabilities. Brain macrophages originate from primitive macrophages that arise from mesodermal cells in the yolk sac and play a role in brain development. Previously, we showed a reduced number of brain macrophages in Ts1Cje foetuses, a murine model of DS. However, the mechanism underlying this reduction in Ts1Cje embryos remains unknown. First, in this study, we identified that the reduced brain macrophages in Ts1Cje foetuses were microglia. This study further reports the low production of primitive macrophages from Ts1Cje mouse embryonic stem cells (Ts1Cje-mESCs). Gene expression profiling in Ts1Cje-mESC-derived cells indicated the persistence of pluripotency, preference for endodermal differentiation, and suppression of mesodermal differentiation. Consistently, Ts1Cje-mESC-derived cells showed the disturbed expression of cytokine receptors and apoptosis, and a decreased number of primitive macrophages was confirmed in the Ts1Cje yolk sac. A human induced pluripotent stem cell line established from an individual with DS also showed lower primitive macrophage production relative to diploidized controls. Thus, our data indicate resistance to mesodermal differentiation and impaired production of primitive macrophages in DS, providing valuable insights into abnormalities in brain development associated with DS.

Chlamydia is a genus of intracellular parasitic microorganisms with a unique developmental cycle that is widely distributed and can cause various human and animal diseases. T helper 17 (Th17) cells are a distinct subpopulation of Th cells with a unique transcriptional profile (STAT3, RORγt and RORα), a pattern of cytokine production (IL-17 family, IL-21, IL-22) and specific cytokines required for differentiation (IL-6, TGF-β, IL-21 and IL-23). Results from mouse models of infection and human epidemiologic studies indicate that Th17 cells may be vital in modulating innate and adaptive immune responses for protective immunity against chlamydia and are associated with the progression of inflammatory diseases in various organs and tissues. This article reviews the differentiation of Th17 cells during Chlamydia infection, the host defence mechanisms involved, and their critical role in the pathogenesis of inflammation and autoimmune damage, with the aim of informing the development of safe and effective Th17 cell-based vaccines against Chlamydia.