Neutralizing Autoantibodies against Interleukin-10 in Inflammatory Bowel Disease.

We discovered high-titer neutralizing autoantibodies against interleukin-10 in a child with infantile-onset inflammatory bowel disease (IBD), a phenocopy of inborn errors of interleukin-10 signaling. After B-cell-depletion therapy and an associated decrease in the anti-interleukin-10 titer, conventional IBD therapy could be withdrawn. A second child with neutralizing anti-interleukin-10 autoantibodies had a milder course of IBD and has been treated without B-cell depletion. We conclude that neutralizing anti-interleukin-10 autoantibodies may be a causative or modifying factor in IBD, with potential implications for therapy. (Funded by the National Institute for Health and Care Research and others.).

Genomic testing identifies monogenic causes in patients with very early-onset inflammatory bowel disease: a multicenter survey in an Iranian cohort.

Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. This multicenter study was carried out on 16 Iranian patients with VEO-IBD. We reviewed clinical and basic immunologic evaluation including flow cytometry and immunoglobulin levels. All patients underwent clinical whole exome sequencing (WES). Sixteen patients (8 females and 8 males) with a median age of 43.5 months were enrolled. The median age at the onset of symptoms was 4 months. Most patients (12, 75%) had consanguineous parents. Chronic non-bloody diarrhea (13, 81.3%) and perianal diseases including perianal abscess (6, 37.5%), anal fissure (6, 37.5%), or anal fistula (2, 12.5%) were the most common manifestations. WES identified a spectrum of genetic variants in 13 patients (81.3%): IL10RB (6, 37.5%), MVK (3, 18.8%), and CASP8, SLC35C1, G6PC3, and IKBKB in 1 patient, respectively. In 3 patients (18.7%), no variant was identified. Flow cytometry identified a spectrum of abnormalities that helped to assess the evidence of genetic diagnosis. At the end of the survey, 3 (18.8%) patients were deceased. This high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD.

The impact of prediabetes and diabetes on endothelial function in a large population-based cohort.

BACKGROUND: Diabetes and prediabetes are well-recognized risk factors for cardiovascular disease (CVD) and are marked by vascular endothelial dysfunction (ED). However, there is a scarcity of thorough population-based studies examining ED in individuals with diabetes/prediabetes free from manifest CVD. Here, we examined the association between ED assessed by reactive hyperaemia index (RHI) in the finger and diabetes/prediabetes in a large middle-aged population cohort. METHODS: Within the Malmö Offspring Study, following the exclusion of participants <30 years and participants with prevalent CVD, 1384 participants had complete data on all covariates. The RHI was calculated using pulse amplitude tonometry. ED was defined as RHI < 1.67. Multivariable logistic and linear regression models were conducted to investigate associations between ED and RHI with diabetes and prediabetes. RESULTS: The study population had a mean age of 53.6 ± 7.6 years (53% women). In study participants with manifest diabetes (n = 121) and prediabetes (n = 514), ED was present in 42% and 25% respectively, compared to 23% in those with normal glucometabolic status. In multivariable logistic regression analyses, prevalent diabetes was significantly associated with ED (OR 1.95; 95%CI 1.57-3.39; p = 0.002), as well as with lower RHI (ß-coeff. -0.087; p = 0.002). However, prediabetes showed no association with neither ED nor RHI. CONCLUSION: In a population free from CVD, vascular endothelial dysfunction was primarily associated with manifest diabetes, but not with prediabetes, implying that finger ED may develop when diabetes is established, rather than being an early sign of glucose intolerance. Further research is needed to explore whether addressing glucose intolerance could potentially delay or prevent vascular ED onset.

What is the context?Diabetes and prediabetes are known to increase the risk of cardiovascular disease (CVD) through a condition called vascular endothelial dysfunction (ED). However, there is a lack of comprehensive studies on ED in individuals with diabetes/prediabetes who do not already have CVD. In this study, we investigated the association between ED, assessed using the reactive hyperaemia index (RHI) in a finger, and diabetes/prediabetes in a large group of middle-aged individuals.What is new?We conducted this study within the Malmö Offspring Study, involving 1384 participants who were over 30 years old and did not have pre-existing CVD. The average age of the participants was 53 years, with 53% being women. Among those with diagnosed diabetes (121 individuals) and prediabetes (5141 individuals), 42% and 25% respectively showed signs of ED, compared to 23% in those with normal glucose metabolism. In our analyses, we found that established diabetes was significantly associated with ED, as well as with lower finger RHI values. However, prediabetes did not show any significant association with either ED or RHI.What is the impact? In a healthy population without pre-existing CVD, vascular endothelial dysfunction was predominantly linked to diagnosed diabetes, rather than prediabetes. This suggests that ED may develop once diabetes is established, rather than being an early indicator of glucose intolerance. Further research is necessary to investigate whether addressing glucose intolerance could potentially delay or prevent the onset of vascular ED.

The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants.

Genetic variants in IL6ST encoding the shared cytokine receptor for the IL-6 cytokine family GP130 have been associated with a diverse number of clinical phenotypes and disorders. We provide a molecular classification for 59 reported rare IL6ST pathogenic or likely pathogenic variants and additional polymorphisms. Based on loss- or gain-of-function, cytokine selectivity, mono- and biallelic associations, and variable cellular mosaicism, we grade six classes of IL6ST variants and explore the potential for additional variants. We classify variants according to the American College of Medical Genetics and Genomics criteria. Loss-of-function variants with (i) biallelic complete loss of GP130 function that presents with extended Stüve-Wiedemann Syndrome; (ii) autosomal recessive hyper-IgE syndrome (HIES) caused by biallelic; and (iii) autosomal dominant HIES caused by monoallelic IL6ST variants both causing selective IL-6 and IL-11 cytokine loss-of-function defects; (iv) a biallelic cytokine-specific variant that exclusively impairs IL-11 signaling, associated with craniosynostosis and tooth abnormalities; (v) somatic monoallelic mosaic constitutively active gain-of-function variants in hepatocytes that present with inflammatory hepatocellular adenoma; and (vi) mosaic constitutively active gain-of-function variants in hematopoietic and non-hematopoietic cells that are associated with an immune dysregulation syndrome. In addition to Mendelian IL6ST coding variants, there are common non-coding cis-acting variants that modify gene expression, which are associated with an increased risk of complex immune-mediated disorders and trans-acting variants that affect GP130 protein function. Our taxonomy highlights IL6ST as a gene with particularly strong functional and phenotypic diversity due to the combinatorial biology of the IL-6 cytokine family and predicts additional genotype-phenotype associations.

Short-chain fatty acids: linking diet, the microbiome and immunity.

The short-chain fatty acids (SCFAs) butyrate, propionate and acetate are microbial metabolites and their availability in the gut and other organs is determined by environmental factors, such as diet and use of antibiotics, that shape the diversity and metabolism of the microbiota. SCFAs regulate epithelial barrier function as well as mucosal and systemic immunity via evolutionary conserved processes that involve G protein-coupled receptor signalling or histone deacetylase activity. Indicatively, the anti-inflammatory role of butyrate is mediated through direct effects on the differentiation of intestinal epithelial cells, phagocytes, B cells and plasma cells, and regulatory and effector T cells. Intestinally derived SCFAs also directly and indirectly affect immunity at extra-intestinal sites, such as the liver, the lungs, the reproductive tract and the brain, and have been implicated in a range of disorders, including infections, intestinal inflammation, autoimmunity, food allergies, asthma and responses to cancer therapies. An ecological understanding of microbial communities and their interrelated metabolic states, as well as the engineering of butyrogenic bacteria may support SCFA-focused interventions for the prevention and treatment of immune-mediated diseases.

Cellular and molecular basis of proximal small intestine disorders.

The proximal part of the small intestine, including duodenum and jejunum, is not only dedicated to nutrient digestion and absorption but is also a highly regulated immune site exposed to environmental factors. Host-protective responses against pathogens and tolerance to food antigens are essential functions in the small intestine. The cellular ecology and molecular pathways to maintain those functions are complex. Maladaptation is highlighted by common immune-mediated diseases such as coeliac disease, environmental enteric dysfunction or duodenal Crohn's disease. An expanding spectrum of more than 100 rare monogenic disorders inform on causative molecular mechanisms of nutrient absorption, epithelial homeostasis and barrier function, as well as inflammatory immune responses and immune regulation. Here, after summarizing the architectural and cellular traits that underlie the functions of the proximal intestine, we discuss how the integration of tissue immunopathology and molecular mechanisms can contribute towards our understanding of disease and guide diagnosis. We propose an integrated mechanism-based taxonomy and discuss the latest experimental approaches to gain new mechanistic insight into these disorders with large disease burden worldwide as well as implications for therapeutic interventions.

An isoform quantitative trait locus in SBNO2 links genetic susceptibility to Crohn's disease with defective antimicrobial activity.

Despite major advances in linking single genetic variants to single causal genes, the significance of genetic variation on transcript-level regulation of expression, transcript-specific functions, and relevance to human disease has been poorly investigated. Strawberry notch homolog 2 (SBNO2) is a candidate gene in a susceptibility locus with different variants associated with Crohn's disease and bone mineral density. The SBNO2 locus is also differentially methylated in Crohn's disease but the functional mechanisms are unknown. Here we show that the isoforms of SBNO2 are differentially regulated by lipopolysaccharide and IL-10. We identify Crohn's disease associated isoform quantitative trait loci that negatively regulate the expression of the noncanonical isoform 2 corresponding with the methylation signals at the isoform 2 promoter in IBD and CD. The two isoforms of SBNO2 drive differential gene networks with isoform 2 dominantly impacting antimicrobial activity in macrophages. Our data highlight the role of isoform quantitative trait loci to understand disease susceptibility and resolve underlying mechanisms of disease.

Identification and validation of a blood- based diagnostic lipidomic signature of pediatric inflammatory bowel disease.

Improved biomarkers are needed for pediatric inflammatory bowel disease. Here we identify a diagnostic lipidomic signature for pediatric inflammatory bowel disease by analyzing blood samples from a discovery cohort of incident treatment-naïve pediatric patients and validating findings in an independent inception cohort. The lipidomic signature comprising of only lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (18:0p/22:6) improves the diagnostic prediction compared with high-sensitivity C-reactive protein. Adding high-sensitivity C-reactive protein to the signature does not improve its performance. In patients providing a stool sample, the diagnostic performance of the lipidomic signature and fecal calprotectin, a marker of gastrointestinal inflammation, does not substantially differ. Upon investigation in a third pediatric cohort, the findings of increased lactosyl ceramide (d18:1/16:0) and decreased phosphatidylcholine (18:0p/22:6) absolute concentrations are confirmed. Translation of the lipidomic signature into a scalable diagnostic blood test for pediatric inflammatory bowel disease has the potential to support clinical decision making.

A metabolic perspective of the neutrophil life cycle: new avenues in immunometabolism.

Neutrophils are the most abundant innate immune cells. Multiple mechanisms allow them to engage a wide range of metabolic pathways for biosynthesis and bioenergetics for mediating biological processes such as development in the bone marrow and antimicrobial activity such as ROS production and NET formation, inflammation and tissue repair. We first discuss recent work on neutrophil development and functions and the metabolic processes to regulate granulopoiesis, neutrophil migration and trafficking as well as effector functions. We then discuss metabolic syndromes with impaired neutrophil functions that are influenced by genetic and environmental factors of nutrient availability and usage. Here, we particularly focus on the role of specific macronutrients, such as glucose, fatty acids, and protein, as well as micronutrients such as vitamin B3, in regulating neutrophil biology and how this regulation impacts host health. A special section of this review primarily discusses that the ways nutrient deficiencies could impact neutrophil biology and increase infection susceptibility. We emphasize biochemical approaches to explore neutrophil metabolism in relation to development and functions. Lastly, we discuss opportunities and challenges to neutrophil-centered therapeutic approaches in immune-driven diseases and highlight unanswered questions to guide future discoveries.