Increased proportions of circulating PD-1 CD4 memory T cells and PD-1 regulatory T cells associate with good response to prednisone in pulmonary sarcoidosis.

Background: The treatment response to corticosteroids in patients with sarcoidosis is highly variable. CD4 T cells are central in sarcoid pathogenesis and their phenotype in peripheral blood (PB) associates with disease course. We hypothesized that the phenotype of circulating T cells in patients with sarcoidosis may correlate with the response to prednisone treatment.

Predominance of M2 macrophages in organized thrombi in chronic thromboembolic pulmonary hypertension patients.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease characterized by thrombotic occlusion of pulmonary arteries and vasculopathy, leading to increased pulmonary vascular resistance and progressive right-sided heart failure. Thrombotic lesions in CTEPH contain CD68 macrophages, and increasing evidence supports their role in disease pathogenesis. Macrophages are classically divided into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages, which are involved in wound healing and tissue repair.

Aberrant B cell receptor signaling in circulating naïve and IgA memory B cells from newly-diagnosed autoantibody-positive rheumatoid arthritis patients.

Objective: Altered B cell receptor (BCR) signaling has been implicated in the pathogenesis of rheumatoid arthritis (RA). Here we aimed to identify signaling aberrations in autoantibody-positive and autoantibody-negative RA patients by performing a comprehensive analysis of the BCR signaling cascade in different B cell subsets.

Methods: We first optimized phosphoflow cytometry for an in-depth analysis of BCR signaling across immunoglobulin isotypes in healthy donors.

Circulating T cells in sarcoidosis have an aberrantly activated phenotype that correlates with disease outcome.

Rationale: Disease course in sarcoidosis is highly variable. Bronchoalveolar lavage fluid and mediastinal lymph nodes show accumulation of activated T cells with a T-helper (Th)17.1 signature, which correlates with non-resolving sarcoidosis.

Evidence for a Role of CCR6+ T Cells in Chronic Thromboembolic Pulmonary Hypertension.

Introduction: Previous studies have shown an increase of T cells and chemokines in vascular lesions of patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, detailed characterization of these T cells is still lacking, nor have treatment effects been evaluated.

Methods: We included 41 treatment-naive CTEPH patients at diagnosis, 22 patients at 1-year follow-up, and 17 healthy controls (HCs).

Central Role of Dendritic Cells in Pulmonary Arterial Hypertension in Human and Mice.

The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully understood, but evidence is accumulating that immune dysfunction plays a significant role. We previously reported that 31-week-old mice develop pulmonary hypertension (PH) symptoms. These mice harbor a targeted deletion of the TNFα-induced protein-3 () gene, encoding the NF-κB regulatory protein A20, specifically in type I conventional dendritic cells (cDC1s).

DNGR1-Cre-mediated Deletion of /A20 in Conventional Dendritic Cells Induces Pulmonary Hypertension in Mice.

Chronic perivascular inflammation is a prominent feature in the lungs of idiopathic pulmonary arterial hypertension. Although the proportions of conventional dendritic cells (cDCs) and plasmacytoid DCs are increased in idiopathic pulmonary arterial hypertension lungs, it remains unknown whether activated cDCs play a pathogenic role. The gene encodes the ubiquitin-binding protein A20, which is a negative regulator of NF-κB, critically involved in DC activation.

Tnfaip3 expression in pulmonary conventional type 1 Langerin-expressing dendritic cells regulates T helper 2-mediated airway inflammation in mice.

Background: Conventional type 1 dendritic cells (cDC1s) control anti-viral and anti-tumor immunity by inducing antigen-specific cytotoxic CD8 T-cell responses. Controversy exists whether cDC1s also control CD4 T helper 2 (Th2) cell responses, since suppressive and activating roles have been reported. DC activation status, controlled by the transcription factor NF-κB, might determine the precise outcome of Th-cell differentiation upon encounter with cDC1s.

Notch signaling licenses allergic airway inflammation by promoting Th2 cell lymph node egress.

Allergic asthma is mediated by Th2 responses to inhaled allergens. Although previous experiments indicated that Notch signaling activates expression of the key Th2 transcription factor Gata3, it remains controversial how Notch promotes allergic airway inflammation. Here we show that T cell-specific Notch deficiency in mice prevented house dust mite-driven eosinophilic airway inflammation and significantly reduced Th2 cytokine production, serum IgE levels, and airway hyperreactivity.

DNGR1-mediated deletion of A20/Tnfaip3 in dendritic cells alters T and B-cell homeostasis and promotes autoimmune liver pathology.

Dendritic cells (DCs) are central regulators of tolerance versus immunity. The outcome depends amongst others on DC subset and activation status. Whereas CD11b type 2 conventional DCs (cDC2s) initiate proinflammatory helper T (Th)-cell responses, CD103 cDC1s are crucial for regulatory T-cell (Treg) induction and CD8 T-cell activation.

House dust mite-driven neutrophilic airway inflammation in mice with TNFAIP3-deficient myeloid cells is IL-17-independent.

Background: Asthma is a heterogeneous disease of the airways that involves several types of granulocytic inflammation. Recently, we have shown that the activation status of myeloid cells regulated by TNFAIP3/A20 is a crucial determinant of eosinophilic or neutrophilic airway inflammation. However, whether neutrophilic inflammation observed in this model is dependent on IL-17 remains unknown.

T cells and ILC2s are major effector cells in influenza-induced exacerbation of allergic airway inflammation in mice.

Influenza virus infection is an important cause of severe asthma exacerbations, but it remains unclear how a Th1-mediated antiviral response triggers a prototypical Th2 disease. We investigated CD4 T cells and group 2 innate lymphoid cells (ILC2s) in influenza virus-infected mice. We found that ILC2s accumulated in the lung rapidly after influenza virus infection, but the induction of IL-5 and IL-13 secretion was delayed and concomitant with T cell activation.

The Notch pathway inhibitor stapled α-helical peptide derived from mastermind-like 1 (SAHM1) abrogates the hallmarks of allergic asthma.

Background: The Notch signaling pathway has been implicated in the pathogenesis of allergic airway inflammation. Targeting the active Notch transactivation complex by using the cell-permeable, hydrocarbon-stapled synthetic peptide stapled α-helical peptide derived from mastermind-like 1 (SAHM1) resulted in genome-wide suppression of Notch-activated genes in leukemic cells and other models. However, the efficacy of SAHM1 in allergic asthma models has remained unexplored.

TNF-α-induced protein 3 levels in lung dendritic cells instruct T2 or T17 cell differentiation in eosinophilic or neutrophilic asthma.

Background: It is currently unknown why allergen exposure or environmental triggers in patients with mild-to-moderate asthma result in T2-mediated eosinophilic inflammation, whereas patients with severe asthma often present with T17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both T2 and T17 cell differentiation and is mediated through nuclear factor κB activation. Ablation of TNF-α-induced protein 3 (TNFAIP3), one of the crucial negative regulators of nuclear factor κB activation in myeloid cells and DCs, was shown to control DC activation.

The DNA-binding factor Ctcf critically controls gene expression in macrophages.

Macrophages play an important role in immunity and homeostasis. Upon pathogen recognition via specific receptors, they rapidly induce inflammatory responses. This process is tightly controlled at the transcriptional level.

Cytokines in nasal lavages and plasma and their correlation with clinical parameters in cystic fibrosis.

Background: Because persistent inflammation plays a dominant role in cystic fibrosis (CF), we assessed systemic and local upper airway responses during and after pulmonary exacerbation.

Methods: We followed a cohort of Pseudomonas aeruginosa-infected adult CF patients (n=16) over time in pulmonary exacerbation and in stable disease. Interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17A, IL-22, interferon-γ and TNFα levels were measured in sputum, nasal lavages and plasma.

Allelic exclusion of the immunoglobulin heavy chain locus is independent of its nuclear localization in mature B cells.

In developing B cells, the immunoglobulin heavy chain (IgH) locus is thought to move from repressive to permissive chromatin compartments to facilitate its scheduled rearrangement. In mature B cells, maintenance of allelic exclusion has been proposed to involve recruitment of the non-productive IgH allele to pericentromeric heterochromatin. Here, we used an allele-specific chromosome conformation capture combined with sequencing (4C-seq) approach to unambigously follow the individual IgH alleles in mature B lymphocytes.

T helper 17 cells are involved in the local and systemic inflammatory response in community-acquired pneumonia.

Background: Recent findings in mouse models suggest that T helper (Th)17 cells, characterised by production of interleukin (IL)-17A and IL-22, are involved in the immunopathogenesis of pneumonia.

Objective: In this study, we aimed to identify the involvement of Th17 cells in human community-acquired pneumonia (CAP).

Design: Within 24 h of admission, T cells from peripheral blood (n=39) and bronchoalveolar lavage (BAL, n=20) of CAP patients and of 10 healthy individuals were analysed by intracellular flow cytometry for the production of various cytokines, including IL-17A and IL-22.

Local and systemic cytokine profiles in nonsevere and severe community-acquired pneumonia.

Local inflammatory responses in community-acquired pneumonia (CAP) remain insufficiently elucidated, especially in patients with nonsevere CAP. In this study we determined local and systemic cytokine responses in CAP patients and correlated these with disease severity and other clinical parameters. Levels of interleukin (IL)-6, IL-8, IL-10, IL-1β, tumour necrosis factor-α, interferon (IFN)-γ, IL-22, IL-17A and IL-4 were determined in bronchoalveolar lavage fluid and serum of 20 CAP patients upon admission and 10 healthy individuals.

Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma.

Allergic asthma is characterized by chronic airway inflammation and hyperreactivity and is thought to be mediated by an adaptive T helper-2 (Th2) cell-type immune response. Here, we demonstrate that type 2 pulmonary innate lymphoid cells (ILC2s) significantly contribute to production of the key cytokines IL-5 and IL-13 in experimental asthma. In naive mice, lineage-marker negative ILC2s expressing IL-7Rα, CD25, Sca-1, and T1/ST2(IL-33R) were present in lungs and mediastinal lymph nodes (MedLNs), but not in broncho-alveolar lavage (BAL) fluid.

Systemic CD4+ and CD8+ T-cell cytokine profiles correlate with GOLD stage in stable COPD.

Chronic obstructive pulmonary disease (COPD) is associated with pulmonary and systemic inflammation. Both CD4+ and CD8+ T-lymphocytes play a key role in COPD pathogenesis, but cytokine profiles in circulating T-lymphocytes have not been well characterised. Here we report the analysis of peripheral blood T-cells from 30 stable COPD patients and 10 healthy never-smokers for interferon (IFN)-γ, interleukin (IL)-4, tumour necrosis factor (TNF)-α and the T-helper 17 cytokines IL-17A, IL-17F and IL-22 by intracellular flow cytometry.

Increased IL-17A expression in granulomas and in circulating memory T cells in sarcoidosis.

Objective: Sarcoidosis is a systemic inflammatory disorder characterized by granulomas. Although the aetiology is unknown, sarcoidosis is thought to be mediated by Th1 lymphocytes. Recently, IL-17A has been implicated in granuloma formation in various diseases, including tuberculosis.

The DNA-binding protein CTCF limits proximal Vκ recombination and restricts κ enhancer interactions to the immunoglobulin κ light chain locus.

Regulation of immunoglobulin (Ig) V(D)J gene rearrangement is dependent on higher-order chromatin organization. Here, we studied the in vivo function of the DNA-binding zinc-finger protein CTCF, which regulates interactions between enhancers and promoters. By conditional deletion of the Ctcf gene in the B cell lineage, we demonstrate that loss of CTCF allowed Ig heavy chain recombination, but pre-B cell proliferation and differentiation was severely impaired.