Combined plasma protein and memory T cell profiling discern IBD-patient-immunotypes related to intestinal disease and treatment outcomes.

Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn's disease, CD: n = 62; ulcerative colitis, UC: n = 20; age-matched controls n = 43), and after 10-12 weeks' induction therapy.

Management of Autoimmune Encephalitis in a 7-Year-Old Child With CTLA-4 Haploinsufficiency and AMPA Receptor Antibodies: A Case Report.

Objectives: We report on the therapeutic management of early-onset severe neurologic symptoms in cytotoxic T lymphocyte antigen-4 haploinsufficiency (CTLA-4h) and the presence of antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) as an important finding.

Methods: This is a case report from a Dutch academic hospital. Repeated clinical examinations, repeated brain MRI and extended diagnostics on serum and CSF were performed.

Serum Immune Profiling in Paediatric Crohn's Disease Demonstrates Stronger Immune Modulation With First-Line Infliximab Than Conventional Therapy and Pre-Treatment Profiles Predict Clinical Response to Both Treatments.

Background: Despite its efficacy, rational guidance for starting/stopping first-line biologic treatment in individual paediatric Crohn's disease [CD] patients is needed. We assessed how serum immune profiles before and after first-line infliximab [FL-IFX] or conventional [CONV] induction therapy associate with disease remission at week 52.

Methods: Pre- [n = 86], and 10-14-week post-treatment [n = 84] sera were collected from patients with moderate-to-severe paediatric CD in the TISKids trial, randomized to FL-IFX [n = 48; five 5-mg/kg infusions over 22 weeks] or CONV [n = 43; exclusive enteral nutrition or oral prednisolone]; both groups received azathioprine maintenance.

Endogenous secretory leukocyte protease inhibitor inhibits microbial-induced monocyte activation.

In the intestine, epithelial factors condition incoming immune cells including monocytes to adapt their threshold of activation and prevent undesired inflammation. Colonic epithelial cells express Secretory Leukocyte Protease Inhibitor (SLPI), an inhibitor of NF kappa light chain enhancer of activated B cells (NF-κB) that mediates epithelial hyporesponsiveness to microbial stimuli. Uptake of extracellular SLPI by monocytes has been proposed to inhibit monocyte activation.

Proteomic analyses do not reveal subclinical inflammation in fatigued patients with clinically quiescent inflammatory bowel disease.

Fatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD), occurring in ~ 50% of patients with quiescent disease. In this study, we aimed to investigate whether fatigue in patients with clinically quiescent IBD is reflected by circulating inflammatory proteins, which might reflect ongoing subclinical inflammation. Ninety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with clinically quiescent IBD.

High expression of secretory leukocyte protease inhibitor (SLPI) in stage III micro-satellite stable colorectal cancer is associated with reduced disease recurrence.

Secretory leukocyte protease inhibitor (SLPI) is a pleiotropic protein produced by healthy intestinal epithelial cells. SLPI regulates NF-κB activation, inhibits neutrophil proteases and has broad antimicrobial activity. Recently, increased SLPI expression was found in various types of carcinomas and was suggested to increase their metastatic potential.

Long-Term Dietary Patterns Are Reflected in the Plasma Inflammatory Proteome of Patients with Inflammatory Bowel Disease.

Diet plays an important role in the development and progression of inflammatory bowel disease (IBD, comprising Crohn’s disease (CD) and ulcerative colitis (UC)). However, little is known about the extent to which different diets reflect inflammation in IBD beyond measures such as faecal calprotectin or C-reactive protein. In this study, we aimed to unravel associations between dietary patterns and circulating inflammatory proteins in patients with IBD.

The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease.

Background And Aims: Protein profiling in patients with inflammatory bowel diseases [IBD] for diagnostic and therapeutic purposes is underexplored. This study analysed the association between phenotype, genotype, and the plasma proteome in IBD.

Methods: A total of 92 inflammation-related proteins were quantified in plasma of 1028 patients with IBD (567 Crohn's disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess protein-phenotype associations.

Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease.

FOXP3 regulatory T cells (Treg cells) are a specialized population of CD4 T cells that restrict immune activation and are essential to prevent systemic autoimmunity. In the intestine, the major function of Treg cells is to regulate inflammation as shown by a wide array of mechanistic studies in mice. While Treg cells originating from the thymus can home to the intestine, the majority of Treg cells residing in the intestine are induced from FOXP3 conventional CD4 T cells to elicit tolerogenic responses to microbiota and food antigens.

Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis.

Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy.

Secretory Leukocyte Protease Inhibitor (SLPI) in mucosal tissues: Protects against inflammation, but promotes cancer.

The immune system is continuously challenged with large quantities of exogenous antigens at the barriers between the external environment and internal human tissues. Antimicrobial activity is essential at these sites, though the immune responses must be tightly regulated to prevent tissue destruction by inflammation. Secretory Leukocyte Protease Inhibitor (SLPI) is an evolutionarily conserved, pleiotropic protein expressed at mucosal surfaces, mainly by epithelial cells.

First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn's disease: an open-label multicentre randomised controlled trial.

Objective: In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment.

Design: In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional).

Expression of the immune modulator secretory leukocyte protease inhibitor (SLPI) in colorectal cancer liver metastases and matched primary tumors is associated with a poorer prognosis.

Secretory leukocyte protease inhibitor (SLPI), a pleiotropic protein expressed by healthy intestinal epithelial cells, functions as an inhibitor of NF-κB and neutrophil proteases and exerts antimicrobial activity. We previously showed SLPI suppresses intestinal epithelial chemokine production in response to microbial contact. Increased SLPI expression was recently detected in various types of carcinoma.

International prospective observational study investigating the disease course and heterogeneity of paediatric-onset inflammatory bowel disease: the protocol of the PIBD-SETQuality inception cohort study.

Introduction: Patients with paediatric-onset inflammatory bowel disease (PIBD) may develop a complicated disease course, including growth failure, bowel resection at young age and treatment-related adverse events, all of which can have significant and lasting effects on the patient's development and quality of life. Unfortunately, we are still not able to fully explain the heterogeneity between patients and their disease course and predict which patients will respond to certain therapies or are most at risk of developing a more complicated disease course. To investigate this, large prospective studies with long-term follow-up are needed.

Yap1-Driven Intestinal Repair Is Controlled by Group 3 Innate Lymphoid Cells.

Tissue repair requires temporal control of progenitor cell proliferation and differentiation to replenish damaged cells. In response to acute insult, group 3 innate lymphoid cells (ILC3s) regulate intestinal stem cell maintenance and subsequent tissue repair. ILC3-derived IL-22 is important for stem cell protection, but the mechanisms of ILC3-driven tissue regeneration remain incompletely defined.

Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD.

Infiltration of the lamina propria by inflammatory CD4 T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4 T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with disease flares and a more complicated disease course. Therefore, a tightly controlled balance between regulatory and inflammatory CD4 T-cell populations is crucial to prevent uncontrolled CD4 T-cell responses and subsequent intestinal tissue damage.

A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization.

Human renal membrane transporters play key roles in the disposition of renally cleared drugs and endogenous substrates, but their ontogeny is largely unknown. Using 184 human postmortem frozen renal cortical tissues (preterm newborns to adults) and a subset of 62 tissue samples, we measured the mRNA levels of 11 renal transporters and the transcription factor pregnane X receptor (PXR) with quantitative real-time polymerase chain reaction, and protein abundance of nine transporters using liquid chromatography tandem mass spectrometry selective reaction monitoring, respectively. Expression levels of p-glycoprotein, urate transporter 1, organic anion transporter 1, organic anion transporter 3, and organic cation transporter 2 increased with age.

Expression of Plet1 controls interstitial migration of murine small intestinal dendritic cells.

Under homeostatic conditions, dendritic cells (DCs) continuously patrol the intestinal lamina propria. Upon antigen encounter, DCs initiate C-C motif chemokine receptor 7 (CCR7) expression and migrate into lymph nodes to direct T cell activation and differentiation. The mechanistic underpinnings of DC migration from the tissues to lymph nodes have been largely elucidated, contributing greatly to our understanding of DC functionality and intestinal immunity.

Tipping the balance: inhibitory checkpoints in intestinal homeostasis.

The small intestinal and colonic lamina propria are populated with forkhead box P3 (FOXP3)CD4 regulatory T cells (Tregs) and interleukin-10-producing T cells that orchestrate intestinal tolerance to harmless microbial and food antigens. Expression of co-inhibitory receptors such as CTLA-4 and PD-1 serve as checkpoints to these cells controlling their T-cell receptor (TCR)-mediated and CD28-mediated activation and modulating the phenotype of neighboring antigen presenting cells. Recent discoveries on the diversity of co-inhibitory receptors and their selective cellular expression has shed new light on their tissue-dependent function.

Activation of NF-κB driven inflammatory programs in mesenchymal elements attenuates hematopoiesis in low-risk myelodysplastic syndromes.

Activation of NF-κB signaling in mesenchymal cells is common in LR-MDS. Activation of NF-κB in mesenchymal cells leads to transcriptional overexpression of inflammatory factors including negative regulators of hematopoiesis. Activation of NF-κB attenuates HSPC numbers and function ex vivo.

Frequencies of circulating regulatory TIGITCD38 effector T cells correlate with the course of inflammatory bowel disease.

Disease heterogeneity hampers achieving long-term disease remission in inflammatory bowel disease (IBD). Monitoring ongoing tissue-localized regulatory and inflammatory T-cell responses in peripheral blood would empower disease classification. We determined whether regulatory and inflammatory phenotypes of circulating CD38 effector (CD62LCD4) T cells, a population enriched for cells with mucosal antigen specificity, classify disease course in pediatric IBD patients.

Ceramides in tracheal aspirates of preterm infants: Marker for bronchopulmonary dysplasia.

Background: In an experimental mouse model we showed that ceramides play a role in the pathogenesis of bronchopulmonary dysplasia (BPD) and are a potential target for therapeutic intervention. We investigated whether ceramides are detectable in tracheal aspirates (TAs) of preterm infants and differ between infants with or without BPD.

Methods: Infants born ≤ 32 weeks of gestational age in need of mechanical ventilation in the first week of life were included.

The Role of B Cells in Carriage and Clearance of Mycoplasma pneumoniae From the Respiratory Tract of Mice.

Background: Carriage of Mycoplasma pneumoniae (Mp) in the nasopharynx is considered a prerequisite for pulmonary infection. It is interesting to note that Mp carriage is also detected after infection. Although B cells are known to be involved in pulmonary Mp clearance, their role in Mp carriage is unknown.