Crosstalk between the immune system and the microbiome is critical for maintaining immune homeostasis. Here, we examined this communication and the impact of immune-suppressive IL-10 signaling on pulmonary homeostasis. We found that IL-10 sensing by interstitial macrophages (IMs) is required to prevent spontaneous lung inflammation. Loss of IL-10 signaling in IMs initiated an inflammatory cascade through the activation of classical monocytes and CD4+ T cell subsets, leading to chronic lung inflammation with age. Analyses of antibiotic-treated and germ-free mice established that lung inflammation in the animals lacking IL-10 signaling was triggered by commensal bacteria. 16S rRNA sequencing revealed Delftia acidovorans and Rhodococcus erythropolis as potential drivers of lung inflammation. Intranasal administration of these bacteria or transplantation of human fecal microbiota elicited lung inflammation in gnotobiotic Il10-deficient mice. These findings highlight that IL-10 sensing by IMs contributes to pulmonary homeostasis by preventing lung inflammation caused by commensal dysbiosis.

Autophagy is a pro-survival process that regulates the degradation and renewal of cellular components, making it a crucial mechanism for cellular homeostasis. There are selective forms of autophagy that are specific to a number of substrates, such as pathogens (bacteria or viruses), protein aggregates or excess/damaged organelles. These processes involve as key players autophagy receptors, that link the cargo to be degraded to the autophagic machinery. Among them, NDP52 (also known as CALCOCO2) has been described to act as a "bridge" between the autophagy machinery and (1) damaged mitochondria in the mitophagy process; (2) pathogens during xenophagy or (3) proteins in the process of aggrephagy. The aim of this review is to summarize the major functions of NDP52, and to highlight the existence of two human NDP52 variants that have been described as risk or protective factors for Crohn's disease or Multiple Sclerosis and Alzheimer's disease patients, respectively. As these three diseases share common pathological features that lead to inflammation, such as mitochondria or gut microbiota dysfunctions, but also pathogenic infections, it seems clear that NDP52 could be a key player at the crossroad by acting indirectly on inflammation, and therefore a potential target for clinical applications and benefits.

BTB domain and CNC homolog 2 (BACH2) is a transcription repressor from the basic region leucine zipper (bZIP) family. Although BACH2 is predominantly expressed in lymphoid cells, it plays pivotal roles throughout hematological development and differentiation, ranging from the regulation of hematopoietic stem and progenitor cell (HSPC) lineage commitment to the development of both innate and adaptive immune cells. Given its extensive regulation of immunity, it is not surprising that BACH2 has been implicated in cancer, particularly in hematological malignancies. While multiple findings indicate that BACH2 acts primarily as a tumor suppressor, other findings suggest that BACH2, whether within tumor cells or their surrounding microenvironment, may contribute to tumorigenesis and progression, highlighting the complexity of its roles and the diverse networks involved in different contexts. In this review, we provide a comprehensive overview of the evolving roles of BACH2 across various stages of hematopoiesis, with a particular focus on its associations with cancer and its therapeutic potential in a wide range of cancer types.

Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, arise from various factors such as dietary, genetic, immunological, and microbiological influences. The gut microbiota plays a crucial role in the development and treatment of IBD, though the exact mechanisms remain uncertain. Current research has yet to definitively establish the beneficial effects of the microbiome on IBD. Bacteria and viruses (both prokaryotic and eukaryotic) are key components of the microbiome uniquely related to IBD. Numerous studies suggest that dysbiosis of the microbiota, including bacteria, viruses, and bacteriophages, contributes to IBD pathogenesis. Conversely, some research indicates that bacteria and bacteriophages may positively impact IBD outcomes. Additionally, plant metabolites play a crucial role in alleviating IBD due to their anti-inflammatory and microbiome-modulating properties. This systematic review discusses the role of the microbiome in IBD pathogenesis and evaluates the potential connection between plant metabolites and the microbiome in the context of IBD pathophysiology.

The regulation of pH homeostasis is crucial in many biological processes vital for survival, growth, and function of life. The pH-sensing G protein-coupled receptors (GPCRs), including GPR4, GPR65 and GPR68, play a pivotal role in detecting changes in extracellular proton concentrations, impacting both physiological and pathological states. However, comprehensive understanding of the proton sensing mechanism is still elusive. Here, we determined the cryo-electron microscopy structures of GPR4 and GPR65 in various activation states across different pH levels, coupled with Gs, Gq or G13 proteins, as well as a small molecule NE52-QQ57-bound inactive GPR4 structure. These structures reveal the dynamic nature of the extracellular loop 2 and its signature conformations in different receptor states, and disclose the proton sensing mechanism mediated by networks of extracellular histidine and carboxylic acid residues. Notably, we unexpectedly captured partially active intermediate states of both GPR4-Gs and GPR4-Gq complexes, and identified a unique allosteric binding site for NE52-QQ57 in GPR4. By integrating prior investigations with our structural analysis and mutagenesis data, we propose a detailed atomic model for stepwise proton sensation and GPCR activation. These insights may pave the way for the development of selective ligands and targeted therapeutic interventions for pH sensing-relevant diseases.

Rheumatoid arthritis (RA) has become a serious threat to human health and quality of life worldwide. Previous studies have demonstrated that genetic factors play a crucial role in the onset and progression of RA. Due to the rapid development of genome-wide association study (GWAS) and large-scale genetic analysis, GWAS research on RA has received widespread attention in recent years. Therefore, we conducted a comprehensive visualization and bibliometric analysis of publications to identify hotspots and future trends in GWAS research on RA.

Literature on RA and GWAS published between 2002 and 2024 was extracted from the Web of Science Core Collection database by strategic screening. Collected data were further analyzed by using VOSviewer, CiteSpace, and Excel. The collaborations networks of countries, authors, institutions, and the co-citation networks of publications were visualized. Finally, research hotspots and fronts were examined.

A total of 713 publications with 45,773 citations were identified. The number of publications and citations has had a significant surge since 2007. The United States contributed the most publications globally. Okada, Yukinori, was the most influential author. The most productive institution in this field was the University of Manchester. The analysis of keywords revealed that "mendelian randomization analysis", "association", "innate", "instruments", "bias", "pathogenesis", and "genome-wide association study" are likely to be the frontiers of research in this field.

This study can be used to predict future research advances in the fields of GWAS on RA and helps to promote academic collaboration among scholars.

Takayasu arteritis, a granulomatosis vasculitis with a pathogenesis that is poorly defined but known to be associated with HLA-B*52, shares many features with other MHC-I-opathies. In addition to the shared clinical features of inflammatory bowel diseases, cutaneous inflammation, and HLA-B*52, is shared association of an IL12B single- nucleotide polymorphism encoding the common IL-12 and IL-23 p40 subunit, which might affect not only type 17 cytokine responses, but also IFNγ and TNF production-the cardinal type 1 cytokines in granuloma formation. Considering the translational context of responses to TNF inhibition in Takayasu arteritis, in this Personal View we propose Takayasu arteritis as a type 1 MHC-I-opathy. Additionally, type 1 and type 17 T-cell immune responses show immune plasticity, which connects the overlapping features of Takayasu arteritis and spondyloarthritis spectrum disorders, providing a basis for shared anti-TNF responses, and points to p40 and IFNγ cytokine antagonism and potential selective CD8 T-cell repertoire ablation.

Inflammatory bowel disease (IBD) encompasses a spectrum of chronic, idiopathic, and progressive inflammatory conditions of the gastrointestinal tract, with Crohn's disease and ulcerative colitis comprising the majority. Both conditions have distinct pathophysiological and clinical characteristics but share common immune-mediated mechanisms. Specific facets of IBD and its management in the pediatric population differ from adult parallels. This article explores the surgical treatments of pediatric IBD, focusing on indications for surgery and perioperative considerations.

Inflammatory bowel diseases (IBDs) are relapsing, remitting inflammatory diseases of the intestinal tract. Familial aggregation and genome-wide association studies revealed susceptibility variants that point toward a combination of innate immune and adaptive immune dysregulation that in concert with environmental factors, such as our microbiome, can initiate and perpetuate inflammation. Innate immune perturbations include functional abnormalities in the intestinal barrier, endoplasmic reticulum stress, and abnormal recognition of microbes. Adaptive immune changes include dysregulation of cytokines, regulatory T cells, and leukocyte migration. IBD is linked with an abnormal wound-healing response leading to fibrosis. This article summarizes key pathogenic mechanisms in the pathogenesis of IBDs.

Hundreds of risk loci for immune mediated inflammatory and infectious diseases have been identified by genome-wide association studies (GWAS). Yet, what causal variants and genes in risk loci underpin the observed associations remains poorly understood for most. The identification of colocalized cis-expression Quantitative Trait Loci (cis-eQTLs) is a promising way to identify candidate causative genes. The catalogue of cis-eQTLs of the immune system is likely incomplete as many cis-eQTLs may be context-specific. We built a large cohort of 406 healthy individuals and expanded the immune cis-regulome through their whole blood transcriptome obtained after stimulation with specific toll-like receptor (TLR) agonists and T-cell receptor (TCR) antagonist. We report three mechanisms that may explain why an eQTL could only be revealed after immune stimulation. More than half of the cis-eQTLs detected in this study would have been overlooked without specific immune stimulations. We then mined this new catalogue of response (r)eQTLs, with public GWAS summary statistics of three diseases through a colocalization approach: inflammatory bowel diseases, rheumatoid arthritis and COVID-19 disease. We identified reQTL-specific colocalizations for risk loci for which no matching eQTL were reported before, revealing interesting new candidate causal genes.

Crohn's disease (CD), also known as cicatrizing enteritis, is an inflammatory bowel disease that occurs in the distal ileum and right colon of unknown cause and is also called inflammatory bowel disease (IBD) with ulcerative colitis (UC). In recent years, intestinal biota have been confirmed to play a significant role in various gastrointestinal diseases. Studies have found that intestinal microbiota disorders are closely associated with the onset and progression of Crohn's disease. Bacteroidetes, the second largest microbiota in the intestine, are crucial for equilibrium in the microbiota and intestinal environment. Certain Bacteroides can induce the development of Crohn's disease and aggravate intestinal inflammation directly or through their metabolites. Conversely, certain Bacteroides can reduce intestinal inflammation and symptoms of Crohn's disease. This article reviews the effect of several intestinal Bacteroides in the onset and progression of Crohn's disease and their impact on its treatment.

Genome wide association studies (GWAS) identify many risks for Crohn's disease (CD), including a site near the metabolism gene laccase domain containing 1 (LACC1). We previously found this site near LACC1 was associated with decreased LACC1 expression in T lymphocytes, yet the mechanism affecting gene expression and its links to T cell function and inflammatory disease were unknown. Here we identify variants in the promoter region that influence transcription of LACC1. Direct association of disease-risk variants with lower LACC1 pre-mRNA in human CD4+ T cells is confirmed by comparing transcripts from each allele from donors heterozygous for the LACC1 CD-risk allele. Using gene editing, we validate the function of this promoter region in LACC1 expression in T cells. Human CD4+ T cells with LACC1 gene knockdown show altered metabolism, including reduced oxygen consumption rate, and reduced in vitro regulatory T cell differentiation. Therefore, our study provides a mechanism linking these specific LACC1 variants to colitis by attributing promoter region variants to changes in T cell metabolism and function.

G protein-coupled receptors (GPRs), including pro-inflammatory GPR4 and ovarian cancer GPR1 (OGR1/GPR68), are involved in the pH sensing of the extracellular space and have been implicated in inflammatory bowel disease (IBD). Previous data show that a loss of GPR4 or OGR1 independently is associated with reduced intestinal inflammation in mouse models of experimental colitis. In the present manuscript, we investigated the impact of the simultaneous loss of GPR4 and OGR1 in animal models of IBD. To study the effects of combined loss of Gpr4 Ogr1 in IBD we used the well-established acute dextran sodium sulfate (DSS) and spontaneous Il10-/- murine colitis models. Disease severity was assessed using multiple clinical scores (e.g., body weight loss, disease activity score, murine endoscopic index of colitis severity (MEICS) and histological analyses). Real-time quantitative polymerase chain reaction (qPCR), Western blot, and flow cytometry were used to investigate changes in pro-inflammatory cytokines expression and immune cells infiltration. We found that a combined loss of GPR4 and OGR1 significantly reduces colon inflammation in IBD relative to single deficiencies as evidenced by reduced body weight loss, disease score, CD4/CD8 ratio, and Il1β, Il6, and Tnf in the colon. Similarly, in the II10 deficiency model, the inflammation was significantly ameliorated upon the simultaneous deletion of GPR4 and OGR1, evidenced by a reduction in the MEICS score, colon length, Tnf and Il1β measurements, and a decrease in the number of macrophages in the colon, as compared to single deletions. Importantly, hydroxyproline levels were decreased close to baseline in Il10-/- × Gpr4-/- × Ogr1-/- mice. Our findings demonstrate that the simultaneous loss of GRP4 and OGR1 functions exerts an additive effect on multiple parameters associated with colonic inflammation. These results further reinforce the hypothesis that chronic inflammatory acidosis is a driver of fibrosis and is dependent on GPR4 and OGR1 signaling. The inhibition of both GPR4 and OGR1 by pH-sensing receptor modulators may constitute as a potential therapeutic option for IBD, as both pH-sensing receptors appear to sustain inflammation by acting on complementary pro-inflammatory pathways.

SP140, a lymphocytic-restricted protein, is an epigenetic reader working as a corepressor of genes implicated in inflammation and orchestrating macrophage transcriptional programs to maintain cellular identity. Reduced SP140 expression is associated both to autoimmune diseases and blood cancers. However, the molecular mechanisms that link SP140 altered protein levels to detrimental effects on the immune response and cellular growth, as well as the interactors through which SP140 promotes gene silencing, remain elusive. In this work, we have applied a multi-omics approach (i.e. interactomics, ChIP-seq and proteomics) in two Burkitt lymphoma cell lines to identify both interactors and target genes of endogenous SP140. We found that SP140 interacts with the PRC2 and NuRD complexes, and we showed that these interactions are functional as SP140 directs H3K27me3 deposition and NuRD binding on a set of target genes implicated in cellular growth and leukemia progression.

Bach2 has been suggested to be a risk factor for allergic diseases in previous studies. Because type IV hypersensitivity reactions, including allergic contact dermatitis (ACD), develop through activated T cells, and because the expression of Bach2 is regulated in the development and functional differentiation of T cells, the expression of Bach2 in T cells may be involved in the onset of ACD. However, the role of Bach2 in T cells during ACD development has not yet been determined.

We investigated the role of the appropriate expression of Bach2 in T cells in the development and prolongation of ACD.

We induced ACD in mice by repeatedly applying a hapten and analyzed the expression of Bach2 in the T cells of lesional skin or skin-draining lymph nodes (sdLNs). We performed a phenotypic analysis of the skin and/or sdLNs by comparing mice with T cells overexpressing Bach2 or with Bach2 loss to the control mice.

We found that Bach2lo T cells accumulated in the skin and sdLNs as ACD developed. T-cell-specific Bach2-deficient mice showed more severe inflammatory responses to the hapten and had prolonged inflammation with T cells expressing higher levels of IL-13 in the skin and IFN-γ and IL-13 in the sdLNs. In contrast, the mice overexpressing Bach2 in T cells developed almost no symptoms of ACD.

The appropriate expression of Bach2 in T cells may be a key factor in the resolution of ACD.

Crohn's disease (CD) is a chronic inflammatory bowel disease with a multifactorial pathogenesis involving environmental and genetic factors. Since the late 20th century, the discovery of the first susceptibility gene (NOD2, previously referred to as CARD15) for CD has paved the way for further investigations into the correlations between clinical features and genetics, and its potential impact on clinical practice has fueled the research in the last 2 decades. Recent therapeutic advancements involving novel biologic drugs and small molecules have shifted inflammatory bowel disease management from a disease-centered to a patient-centric approach. To date, the role of NOD2 has not been fully understood yet. Recent data suggest that its clinical impact may be greater than currently recognized. This review overviews the most common NOD2 variants' role in real-life clinical practice. These genetic variants increase the risk of developing the disease and can aid in tailoring diagnosis and treatment. They are associated with the stricturing phenotype and ileal involvement and increase the risk of steroid refractoriness. In the meantime, limited and inconclusive evidence exists regarding their predictive role in response to azathioprine, biologic drugs, and small molecules. Eventually, their role in increasing the risk for surgery is evident, especially in those with the L1007fs variant. If further trials will support the initial evidence reported so far, NOD2 genetic variants will emerge as possible candidates for developing precision medicine in CD.

Type I interferons (IFN-Is) are essential for antiviral immunity but must be tightly regulated1-3. The conserved transcriptional repressor SP140 inhibits interferon beta (Ifnb1) expression via an unknown mechanism4,5. Here we report that SP140 does not directly repress Ifnb1 transcription. Instead, SP140 negatively regulates Ifnb1 mRNA stability by directly repressing the expression of a previously uncharacterized regulator we call RESIST (REgulated Stimulator of Interferon via Stabilization of Transcript, previously annotated as Annexin-2 Receptor). RESIST promotes Ifnb1 mRNA stability by counteracting Ifnb1 mRNA destabilization mediated by the Tristetraprolin (TTP) family of RNA-binding proteins and the CCR4-NOT deadenylase complex. SP140 localizes within nuclear bodies, punctate structures that play important roles in silencing DNA virus gene expression in the nucleus4. Consistent with this observation, we found that SP140 inhibits replication of the gammaherpesvirus MHV68. The antiviral activity of SP140 was independent of its ability to regulate Ifnb1. Our results establish dual antiviral and interferon regulatory functions for SP140. We propose that SP140 and RESIST participate in antiviral effector-triggered immunity6,7.

Mitochondrial electron transport chain (ETC) function modulates macrophage biology; however, mechanisms underlying mitochondria ETC control of macrophage immune responses are not fully understood. Here, we report that mutant mice with mitochondria ETC complex III (CIII)-deficient macrophages exhibit increased susceptibility to influenza A virus (IAV) and LPS-induced endotoxic shock. Cultured bone marrow-derived macrophages (BMDMs) isolated from these mitochondria CIII-deficient mice released less IL-10 than controls following TLR3 or TLR4 stimulation. Unexpectedly, restoring mitochondrial respiration without generating superoxide using alternative oxidase (AOX) was not sufficient to reverse LPS-induced endotoxic shock susceptibility or restore IL-10 release. However, activation of protein kinase A (PKA) rescued IL-10 release in mitochondria CIII-deficient BMDMs following LPS stimulation. In addition, mitochondria CIII deficiency did not affect BMDM responses to interleukin-4 (IL-4) stimulation. Thus, our results highlight the essential role of mitochondria CIII-generated superoxide in the release of anti-inflammatory IL-10 in response to TLR stimulation.

Crohn's disease (CD) is a chronic inflammatory condition of the intestines with a rising global incidence. Traditional diagnostic and therapeutic methods have limitations, necessitating the exploration of more effective strategies.

In this study, we employed the Gene Expression Omnibus database to identify genes that are differentially expressed in CD. RT-PCR and immunohistochemical analysis were used to SLC6A14 RNA and protein expression in the colons of CD mice and CD tissues from patients. The mouse model of CD was induced by dextran sodium sulfate (DSS). Infiltrating immune cells in mouse model were screened by flow cytometry.

We discovered that SLC6A14 is significantly overexpressed in CD samples, and its expression is positively correlated with the degree of infiltration by CD4+ and CD8+ T cells. The elevated levels of SLC6A14 RNA and protein were confirmed in clinical CD tissues. The SLC6A14 inhibitor α-methyl-tryptophan (α-MT) significantly decreased the expression of SLC6A14 RNA and protein in the colons of CD mice. The α-MT treatment group also exhibited reduced levels of cytokines involved in T cell differentiation (IFN-γ and TNF-α) and the expression of immune cell surface markers CXCR-3 and LAG-3. Flow cytometry analysis revealed a significant increase in the infiltration of CD4+ and CD8+ T cells in the DSS-treated group compared to the control group. Conversely, the α-MT treatment group showed a significant reduction in CD4+ and CD8+ T cell infiltration and the restoration of intestinal parameters in CD mice. These findings underscore the role of SLC6A14 in regulating intestinal immune cell infiltration during CD progression.

Our findings suggest that SLC6A14 could serve as a potential diagnostic biomarker and therapeutic target for CD. Furthermore, α-MT offers a novel approach for the clinical diagnosis and treatment of CD by targeting SLC6A14 for therapeutic intervention.

An association has been observed between alcohol and cheese intake and the onset of inflammatory bowel disease (IBD), necessitating further exploration from a genetic structural perspective.

The present analysis was focused on the intake of alcohol and cheese in conjunction with IBD genome-wide association study (GWAS) data, with the objective of exploring genetic correlations and identifying common loci. Initially, overall genetic correlations were assessed employing two methodologies: linkage disequilibrium score regression (LDSC) and genetic covariance analyzer (GNOVA). Subsequently, local correlations were examined through the SUPERGNOVA method. A genetic overlap analysis between various traits was then conducted based on the statistical theory of conditional/conjunctional false discovery rate (cond/conjFDR). Ultimately, shared loci between the two traits were identified via conjFDR analysis and multi-trait analysis of GWAS (MTAG).

Substantial overall correlations were noted at the genome-wide level between alcohol and cheese intake and both IBD and Crohn's disease (CD), whereas the association with ulcerative colitis (UC) was of lesser significance. In the local genetic analysis, chromosome 16 emerged as a key region implicated in the relationship between alcohol and cheese intake and IBD (including both CD and UC). The conjFDR analysis confirmed the genetic overlap between the two diseases. Furthermore, both conjFDR and MTAG analyses identified multiple shared genetic loci, with nine genes (Y_RNA, DENND1B, GCKR, KPNA7, CLN3, SLC39A8, FUT2, ERAP2, and SMAD3) being.

The present study provides genetic evidence supporting the comorbidity of alcohol and cheese intake with IBD, offering novel insights into potential strategies for the prevention and treatment of IBD through the modulation of alcohol and cheese consumption.

Therapeutics promoting the endogenous production of IL-10 have the potential to restore homeostasis in inflammatory disorders such as inflammatory bowel disease (IBD). Here we describe the identification of a series of IL-10 upregulators based on a pyrimidyl-piperidine scaffold through a high throughput phenotypic CD4+ T-cell multiplex assay. In vitro optimization of the initial hit yielded a lead with good potency and an in vitro clearance profile, compound 3-7, which additionally demonstrated efficacy in a murine endotoxin challenge PK-PD mechanistic model. Target deconvolution efforts identified compound 3-7 as a highly selective CDK8/19 inhibitor, and crystallographic studies unveiled its binding mode to the CDK8/Cyclin-C complex, characterized by an unusual water-mediated hydrogen bond to the kinase hinge region.

The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals that mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. The natural history of IBD progression begins with early subclinical stages of disease that occur before clinical diagnosis. Improved understanding of those early subclinical stages could lead to new or improved strategies for IBD diagnosis, prognostication, or prevention. Here, we review our current understanding of the early subclinical stages of IBD in humans including studies from first-degree relatives of patients with IBD and members of the general population who go on to develop IBD. We also discuss representative mouse models of IBD that can be used to investigate disease dynamics and host-microbiota relationships during these early stages. In particular, we underscore how mouse models of IBD that develop disease later in life with variable penetrance may present valuable opportunities to discern early subclinical mechanisms of disease before histological inflammation and other severe symptoms become apparent.

Whole-genome sequencing was used to identify a dominant inherited NLRP12 c.1382dup mutation in refractory familial Crohn's disease (CD) patients. Additionally, we observed a T insertion at position 1382 in the third exon of NLRP12, leading to a frameshift mutation. Isolation of peripheral blood from mutation carriers and subsequent experiments demonstrated increased interleukin (IL)-1β in CD patients with the NLRP12 c.1382dup mutation. However, the mechanisms by which the NLRP12 c.1382dup mutation mediates IL-1β remain unclear. Our research findings reveal a close correlation between elevated p-ERK levels and increased expression of NLRP3 and IL-1β in the presence of the NLRP12 c.1382dup mutation. Further experiments demonstrate that inhibiting p-ERK with PD98059 effectively reduces the production of NLRP3 and IL-1β. This discovery provides new insights into the pathogenesis of CD, highlighting the significant role of the ERK/NLRP3/IL-1β pathway in the progression of CD. Not only does this offer novel therapeutic targets for treating CD, but it also lays the groundwork for the development of treatment strategies targeting this pathway.

Microbiome influences multiple human systems, but its effects on gene methylation is unknown. We investigated the relations between gene methylation in blood and the abundance of common gut bacteria profiled by 16s rRNA gene sequencing in two population-based Dutch cohorts: LifeLines-Deep (LLD, n = 616, discovery) and the Netherlands Twin Register (NTR, n = 296, replication). In LLD, we also explored microbial pathways using data generated by shotgun metagenomic sequencing (n = 683). Methylation in both cohorts was profiled in blood samples using the Illumina 450K array. Discovery and replication analysis identified two independent CpGs associated with the genus Eggerthella: cg16586104 (Pmeta-analysis = 3.21 × 10-11) and cg12234533 (Pmeta-analysis = 4.29 × 10-10). We also show that microbiome can mediate the effect of environmental factors on host gene methylation. In this first association study linking epigenome to microbiome, we found and replicated the associations of two CpGs to the abundance of genus Eggerthella and identified microbiome as a mediator of the exposome. These associations are observational and suggest further investigation in larger and longitudinal set-ups.

Integrin heterodimers containing an Integrin alpha V subunit are essential for development and play critical roles in cell adhesion and signaling. We identified biallelic variants in the gene coding for Integrin alpha V (ITGAV) in three independent families (two patients and four fetuses) that either caused abnormal mRNA and the loss of functional protein or caused mistargeting of the integrin. This led to eye and brain abnormalities, inflammatory bowel disease, immune dysregulation, and other developmental issues. Mechanistically, the reduction of functional Integrin αV resulted in the dysregulation of several pathways including TGF-β-dependent signaling and αVβ3-regulated immune signaling. These effects were confirmed using immunostaining, RNA sequencing, and functional studies in patient-derived cells. The genetic deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation. Taken together, the ITGAV variants identified in this report caused a previously unknown human disease characterized by brain and developmental defects in the case of complete loss-of-function and atopy, neurodevelopmental defects, and colitis in cases of incomplete loss-of-function.

Despite growing knowledge regarding the pathogenesis of autoimmune diseases (ADs) onset, the current treatment remains unsatisfactory. This study aimed to identify innovative therapeutic targets for ADs through various analytical approaches.

Utilizing Mendelian randomization, Bayesian co-localization, phenotype scanning, and protein-protein interaction network, we explored potential therapeutic targets for 14 ADs and externally validated our preliminary findings.

This study identified 12 circulating proteins as potential therapeutic targets for six ADs. Specifically, IL12B was judged to be a risk factor for ankylosing spondylitis (p = 1.61E - 07). TYMP (p = 6.28E - 06) was identified as a protective factor for ulcerative colitis. For Crohn's disease, ERAP2 (p = 4.47E - 14), HP (p = 2.08E - 05), and RSPO3 (p = 6.52E - 07), were identified as facilitators, whereas FLRT3 (p = 3.42E - 07) had a protective effect. In rheumatoid arthritis, SWAP70 (p = 3.26E - 10), SIGLEC6 (p = 2.47E - 05), ISG15 (p = 3.69E - 05), and FCRL3 (p = 1.10E - 10) were identified as risk factors. B4GALT1 (p = 6.59E - 05) was associated with a lower risk of Type 1 diabetes (T1D). Interestingly, CTSH was identified as a protective factor for narcolepsy (p = 1.58E - 09) but a risk factor for T1D (p = 7.36E - 11), respectively. External validation supported the associations of eight of these proteins with three ADs.

Our integrated study identified 12 potential therapeutic targets for ADs and provided novel insights into future drug development for ADs.

In the intestinal tract, where numerous intestinal bacteria reside, intestinal epithelial cells produce and release various antimicrobial molecules that form a complex barrier on the mucosal surface. These barrier molecules can be classified into two groups based on their functions: those that exhibit bactericidal activity through chemical reactions, such as antimicrobial peptides, and those that physically hinder bacterial invasion, like mucins, which lack bactericidal properties. In the small intestine, where Paneth cells specialize in producing antimicrobial peptides, the chemical barrier molecules primarily inhibit bacterial growth. In contrast, in the large intestine, where Paneth cells are absent, allowing bacterial growth, the primary defense mechanism is the physical barrier, mainly composed of mucus, which controls bacterial movement and prevents their invasion of intestinal tissues. The expression of these barrier molecules is regulated by metabolites produced by bacteria in the intestinal lumen and cytokines produced by immune cells in the lamina propria. This regulation establishes a defense mechanism that adapts to changes in the intestinal environment, such as alterations in gut microbial composition and the presence of pathogenic bacterial infections. Consequently, when the integrity of the gut mucosal barrier is compromised, commensal bacteria and pathogenic microorganisms from outside the body can invade intestinal tissues, leading to conditions such as intestinal inflammation, as observed in cases of inflammatory bowel disease.

Dysregulated signaling from TNF and TNFR proteins is implicated in several immune-mediated inflammatory diseases (IMIDs). This review centers around seven IMIDs (rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, and asthma) with substantial unmet medical needs and sheds light on the signaling mechanisms, disease relevance, and evolving drug development activities for five TNF/TNFR signaling axes that garner substantial drug development interest in these focus conditions. The review also explores the current landscape of therapeutics, emphasizing the limitations of the approved biologics, and the opportunities presented by small-molecule inhibitors and combination antagonists of TNF/TNFR signaling.

Human infectious diseases are unique in that the discovery of their environmental trigger, the microbe, was sufficient to drive the development of extraordinarily effective principles and tools for their prevention or cure. This unique medical prowess has outpaced, and perhaps even hindered, the development of scientific progress of equal magnitude in the biological understanding of infectious diseases. Indeed, the hope kindled by the germ theory of disease was rapidly subdued by the infection enigma, in need of a host solution, when it was realized that most individuals infected with most infectious agents continue to do well. The root causes of disease and death in the unhappy few remained unclear. While canonical approaches in vitro (cellular microbiology), in vivo (animal models), and in natura (clinical studies) analyzed the consequences of infection with a microbe, considered to be the cause of disease, in cells, tissues, or organisms seen as a uniform host, alternative approaches searched for preexisting causes of disease, particularly human genetic and immunological determinants in populations of diverse individuals infected with a trigger microbe.

Genome-wide association Studies (GWAS), initially developed for human genetics, have been highly effective in plant research, particularly for vegetable crops. GWAS is a robust tool for identifying genes associated with key traits such as yield, nutritional value, disease resistance, adaptability, and bioactive compound biosynthesis. Unlike traditional methods, GWAS does not require prior biological knowledge and can accurately pinpoint loci, minimizing false positives. The process involves developing a diverse panel, rigorous phenotyping and genotyping, and sophisticated statistical analysis using various models and software tools. By scanning the entire genome, GWAS identifies specific loci or single nucleotide polymorphisms (SNPs) linked to target traits. When a causal SNP variant is not directly genotyped, GWAS identifies SNPs in linkage disequilibrium (LD) with the causal variant, mapping the genetic interval. The method begins with careful panel selection, phenotyping, and genotyping, controlling for environmental effects and utilizing Best Linear Unbiased Prediction (BLUP). High-correlation, high-heritability traits are prioritized. Various genotyping methods address confounders like population structure and kinship. Bonferroni correction (BC) prevents false positives, and significant associations are shown in Manhattan plots. Candidate genes are identified through LD analysis and fine mapping, followed by functional validation. GWAS offers critical insights for enhancing vegetable crop breeding efficiency and precision, driving breakthroughs through advanced methods.

(1) Background: Autoimmune pancreatitis (AIP) is mainly treated with steroids. Using an AIP mouse model, we investigated two potential alternatives, the transforming growth factor-β-activated kinase 1 inhibitor, takinib, and the Janus kinase inhibitor, tofacitinib. (2) Methods: In a multicenter preclinical study, MRL/MpJ mice were injected with polyinosinic/polycytidylic acid (poly I:C) for two weeks to induce AIP. They were then treated for four weeks with either takinib (25, 50, or 75 mg/kg body weight), tofacitinib (5, 10 or 15 mg/kg), dexamethasone (1 mg/kg), or solvent, while the poly I:C injections were continued. The severity of AIP was assessed histopathologically. Flow cytometry was used to examine lymphocyte subtypes in the spleen and mesenteric lymph nodes. The pancreatic gene expression profiles were analyzed by RNA sequencing. (3) Results: Poly I:C-treated mice developed severe AIP with inflammation, destruction of acinar tissue, and fibrosis. Dexamethasone significantly attenuated the disease, while takinib or tofacitinib had no effects. Dexamethasone also antagonized the effects of poly I:C on the relative frequencies of the AIP-associated lymphocyte subtypes CD4/CD69, CD8/CD44high, and CD4/CD25/FoxP3 in the spleen. In the principal component analysis of pancreatic transcriptomics, poly I:C-injected mice treated with tofacitinib, takinib, or solvent clustered together, while untreated and dexamethasone-treated mice formed separate, unique clusters. (4) Conclusions: Dexamethasone effectively reduced AIP severity, while takinib and tofacitinib were ineffective. The unique gene expression profile in dexamethasone-treated mice may provide a basis for identifying new drug targets for AIP treatment.

Studies have shown that breastfeeding can reduce the risk and severity of inflammatory bowel disease (IBD) in children and adults. Probiotics in breast milk have also been isolated and their effects on IBD have been studied. However, based on current evidence, the exact efficacy and mechanisms of probiotics in the treatment of IBD cannot be determined. In this study, Bifidobacterium breve FPHC4024 (BB FPHC4024) and Limosilactobacillus reuteri FPHC2951 (LR FPHC2951) were isolated from feces of exclusively breastfed healthy infants and administered by gavage to dextran sulfate sodium (DSS)-induced IBD mice. The results showed that LR FPHC2951 improved the symptoms of DSS-induced IBD, increased the expression of interleukin (IL)-10 mRNA and upregulated the abundance of Verrucomicrobiaceae Akkermansia. Combined with Kyoto Encyclopedia of Genes and Genomes (KEGG)-based Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) function prediction results, we hypothesized that LR FPHC2951 improved DSS-induced colitis symptoms in mice by increasing of IL-10 mRNA, altering the structure of intestinal flora, and reducing proinflammatory pathways and enhancing pathways associated with anti-inflammatory and intestinal protection.

Background: Receptor-interacting protein kinases (RIPKs) and mixed-lineage kinase domain-like protein (MLKL) are crucial in regulating innate immune responses and cell death signaling (necroptosis and apoptosis), and are potential candidates for genetic improvement in breeding programs. Knowledge about the RIPK family and MLKL in sea cucumber remains limited. Methods: We searched the genomes of sea cucumber Holothuria leucospilota for genes encoding RIPKs and MLKL, performed phylogenetic tree, motif and functional domain analyses, and examined tissue distribution and embryonic development patterns using qPCR. Results: RIPK5 (Hl-RIPK5), RIPK7 (Hl-RIPK7) and MLKL (Hl-MLKL) were identified in sea cucumber H. leucospilota. Hl-RIPK5 and Hl-RIPK7 were mainly expressed in coelomocytes, suggesting that they play a role in innate immunity, whereas Hl-MLKL exhibited relatively low expression across tissues. During embryonic development, Hl-MLKL was highly expressed from the 2-cell stage to the morula stage, while Hl-RIPK5 and Hl-RIPK7 were primarily expressed after the morula stage, indicating different roles in embryonic development. In primary coelomocytes, Hl-RIPK5 transcriptional activity was significantly depressed by LPS, poly(I:C), or pathogen Vibrio harveyi. Hl-RIPK7 expression levels were unchanged following the same challenges. Hl-MLKL mRNA levels were significantly decreased with poly(I:C) or V. harveyi, but did not change with LPS. Conclusions: These findings provide valuable insights into the evolutionary tree and characterization of RIPK and MLKL genes in sea cucumber, contributing to the broader understanding of the RIPK gene family and MLKL in ancient echinoderms.

In many applications, the process of identifying a specific feature of interest often involves testing multiple hypotheses for their joint statistical significance. Examples include mediation analysis, which simultaneously examines the existence of the exposure-mediator and the mediator-outcome effects, and replicability analysis, aiming to identify simultaneous signals that exhibit statistical significance across multiple independent studies. In this work, we present a new approach called the joint mirror (JM) procedure that effectively detects such features while maintaining false discovery rate (FDR) control in finite samples. The JM procedure employs an iterative method that gradually shrinks the rejection region based on progressively revealed information until a conservative estimate of the false discovery proportion is below the target FDR level. Additionally, we introduce a more stringent error measure known as the composite FDR (cFDR), which assigns weights to each false discovery based on its number of null components. We use the leave-one-out technique to prove that the JM procedure controls the cFDR in finite samples. To implement the JM procedure, we propose an efficient algorithm that can incorporate partial ordering information. Through extensive simulations, we show that our procedure effectively controls the cFDR and enhances statistical power across various scenarios, including the case that test statistics are dependent across the features. Finally, we showcase the utility of our method by applying it to real-world mediation and replicability analyses.

Understanding the functions of human transcriptional regulatory genes SP110 and SP140 during Mycobacterium tuberculosis infection is crucial; in a mouse model, homologous genes Sp110 and Sp140 have been shown to negatively regulate inflammatory response genes, including the type I interferon (IFN) response. The reduction of these genes in mice is associated with susceptibility to M. tuberculosis infection and the development of necrotizing granulomatous lesions. To investigate the involvement of SP110 and SP140 in human inflammatory response, we analyzed their regulatory manner in THP-1 macrophages infected with M. tuberculosis. Genome-wide transcriptional profiling revealed that the depletion of SP110 and/or SP140 impaired the induction of gene expression associated with inflammatory responses, including IFN response genes, although it had little effect on the intracellular proliferation of M. tuberculosis. By contrast, genes related to phosphorylation were upregulated in infected macrophages with SP110 and/or SP140 knockdown, but downregulated in infected control macrophages without their knockdown. Reverse transcription-quantitative PCR and ELISA further confirmed the impairment of the induction of IFN response genes by the depletion of SP110 and/or SP140 in M. tuberculosis-infected macrophages. These findings suggest that human SP110 and SP140 act as positive regulators for genes associated with inflammatory responses in M. tuberculosis-infected macrophages.

Tuberculosis (TB) is one of the most serious infectious diseases, with high morbidity and mortality worldwide. C3HeB/FeJ mice are widely utilized for evaluating anti-TB drugs because their drug sensitivity and pathology during M. tuberculosis infection resemble those of human TB, including the development of necrotizing granulomas. Downregulation of the transcriptional regulatory genes Sp110 and Sp140 in C3HeB/FeJ mice has been demonstrated to activate gene expression associated with inflammatory responses during M. tuberculosis infection, resulting in susceptibility to the infection. Here, we examined the regulatory manner of SP110 and SP140 using transcriptomic analysis in M. tuberculosis-infected human macrophages. Depletion of SP110 and/or SP140 in M. tuberculosis-infected THP-1 macrophages impaired the induction of gene expression associated with inflammatory responses, including interferon response genes, compared with that in control macrophages. These results suggest that human SP110 and SP140 act as positive regulators for genes associated with inflammatory responses upon M. tuberculosis infection.