Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses

Abstract: IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and this is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R. We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3 and ZNF341, genes encoding different components of the IL-6 signalling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.J.E.D.T. is supported by the MRC (RG95376 and MR/L006197/1). KB is supported by the European Research Council (ERC StG 310857) and the Austrian Science Fund (P29951-B30). This work is supported, in part, by the intramural research program of the NIAID, NIH. A.J.T. is supported by the Wellcome Trust (104807/Z/14/Z) and the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. KGCS is supported by the Medical Research Council (program grant MR/L019027) and is a Wellcome Investigator. M.G. and S.T. are supported in part by Cancer Research UK. RCA and MT are supported by a DOC fellowship of the Austrian Academy of Sciences. This research was made possible through access to the data and findings generated by two pilot studies for the 100,000 Genomes Project. The enrolment for one pilot study was coordinated by the NIHR BioResource (preprint from doi: https://doi.org/10.1101/507244) and the other by Genomics England Limited (GEL), a wholly owned company of the Department of Health in the UK. Over 90% of participants in the pilot studies have been enrolled in the NIHR BioResource. These pilot studies were mainly funded by grants from the National Institute for Health Research (NIHR) in England to the University of Cambridge and GEL, respectively. Additional funding was provided by the BHF, MRC, NHS England, the Wellcome Trust, amongst many other funders. The pilot studies use data provided by patients and their close relatives and collected by the NHS and other healthcare providers as part of their care and support. We thank all volunteers for their participation, and also gratefully acknowledge NIHR Biomedical Research Centres, NIHR BioResource Centres, NHS Trust Hospitals, NHS Blood and Transplant and staff for their contribution. ST is on the scientific advisory board for Ipsen, and is a consultant for Kallyope Inc. The authors declare no competing financial interests

Prior exposure to inhaled allergen enhances anti-viral immunity and T cell priming by dendritic cells

<div><p>Influenza and asthma are two of the major public health concerns in the world today. During the 2009 influenza pandemic asthma was found to be the commonest comorbid illness of patients admitted to hospital. Unexpectedly, it was also observed that asthmatic patients admitted to hospital with influenza infection were less likely to die or require admission to intensive care compared with non-asthmatics. Using an <i>in vivo</i> model of asthma and influenza infection we demonstrate that prior exposure to <i>Blomia tropicalis</i> extract (BTE) leads to an altered immune response to influenza infection, comprised of less severe weight loss and faster recovery following infection. This protection was associated with significant increases in T cell numbers in the lungs of BTE sensitised and infected mice, as well as increased IFN-γ production from these cells. In addition, elevated numbers of CD11b+ dendritic cells (DCs) were found in the lung draining lymph nodes following infection of BTE sensitised mice compared to infected PBS treated mice. These CD11b+ DCs appeared to be better at priming CD8 specific T cells both <i>in vivo</i> and <i>ex vivo</i>, a function not normally attributed to CD11b+ DCs. We propose that this alteration in cross-presentation and more efficient T cell priming seen in BTE sensitised mice, led to the earlier increase in T cells in the lungs and subsequently faster clearance of the virus and reduced influenza induced pathology. We believe this data provides a novel mechanism that explains why asthmatic patients may present with less severe disease when infected with influenza.</p></div

Augmented innate immune and adaptive immune response in the MLN of asthmatic influenza infected mice.

<p>MLN from PBS and BTE exposed and infected mice were analysed at day 3 p.i. The total number of (A) eosinophils, (B) neutrophils, (C) NK cells, (D) B cells, (E) CD4 T cells and (F) CD8 T cells are shown. Graphs represent means ± SEM of pooled data from at least two independent experiments with n≥5 mice in each group. Significant differences between BTE/Flu and PBS/Flu treated mice are shown as *p<0.05 and ***p<0.001.</p

Low dose BTE exposure leads to the induction of the asthmatic phenotype.

<p>Mice were sensitized with either PBS or 0.5μg of BTE 3 times a week, for 2 weeks. 24 hr after the last sensitization mice were culled and cellular infiltrate into the MLN and lungs were measured. The total number of (A) eosinophils, (B) NK cells, (C) CD4 T cells, (D) CD8 T cells, (E) CD11b+ DCs and (F) CD103+ DCs in the MLN are shown. The total number of (G) eosinophils, (H) NK cells, (I) CD4 T cells, (J) CD8 T cells, (K) CD11b+ DCs and (L) CD103+ DCs in the lungs are shown. Graphs represent mean ± SEM representing pooled date from two independent experiments with n≥5 mice in each group. Significant differences between PBS and BTE treated mice are shown as *p<0.05; **p<0.01 and ***p<0.001.</p

Earlier increase in lung inflammation and sustained mucus production in the lungs of infected BTE treated mice.

<p>Mice were sensitized and infected as described previously. Lungs were harvested on day 4 and 8 p.i., sectioned and stained with H&E and PAS. (A) Representative images of airways stained for H&E and PAS are shown for day 4 and day 8 p.i. Semi-quantitative scoring was performed for H&E stained sections at (B) day 4 and (D) day 8 p.i. and for PAS stained sections at (C) day 4 p.i. and (E) 8 p.i. Original magnification X40. Scale bar = 50μm. Graphs represent means ± SEM from one of two independent experiments with n≥5 mice in each group per time point. Significant differences between groups are shown as *p<0.05; **p<0.01 and ***p<0.001.</p

Prior sensitization to influenza leads to enhanced NK and T cell recruitment to the airways and lungs.

<p>The total number of (A) eosinophils, (B) neutrophils, (C) macrophages, (D) NK cells, (E) CD4 and (F) CD8 T cells in the BAL is shown at days 4, 8, 11 and 14 p.i. Lung cells were stimulated ex vivo for 4 hr with PMA and ionomycin and surface and intracellular cytokine staining was performed. Total number of (G) CD8 T cells, (I) CD8+NP-specific cells, (J) CD8+IFN-γ+ cells, (K) CD4 T cells and (L) CD4+IFN-γ+ cells in the lungs are shown at days 4, 8, 11 and 14 p.i. (H) Representative flow plots indicating the frequencies of NP-specific CD8 T cells are shown at days 8, 11 and 14 p.i. Graphs represent means ± SEM of pooled data from at least two independent experiments with n≥5 mice in each group per time point. Significant differences between BTE/Flu and BTE/PBS treated mice are shown as +++p<0.001 and between BTE/Flu and PBS/Flu treated mice are shown as *p<0.05; **p<0.01 and ***p<0.001.</p

Prior sensitization to BTE reduces influenza induced weight loss.

<p>(A) Protocol for sensitization with BTE and influenza infection. Mice were sensitized with either PBS or 0.5μg of BTE 3 times a week, for 2 weeks. 24 hr after the last sensitization mice were infected with 10 PFU of influenza virus. Mice were culled at days 4, 8, 11 and 14 p.i. (B) Weight loss following influenza virus infection. Levels of mRNA for the matrix protein are shown at (C) day 4 and (D) day 8 p.i. Albumin leakage into the BAL was assessed by ELISA at (E) day 8 and (F) day 14 p.i. Symbols and bars represent individual animals or the mean ± SEM. Graphs represent data from one of two independent experiments with n≥5 mice in each group per time point. Significant differences between infected and non-infected groups and between BTE/Flu and PBS/Flu treated mice are shown as *p<0.05; **p<0.01 and ***p<0.001.</p

Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation

International audienceThe PI3K-AKT-mTOR signaling axis is a critical molecular pathway in humans, regulating multiple cellular processes. Phosphatidylinositol-3-kinases (PI3K) represent key signaling hubs for signal propagation, driving cell activation, cell polarization and morphological adaptations. Studies on PI3K in human disease have highlighted PI3K-gamma (PI3Kγ) as an appealing drug target for treatment of human disorders.2 Murine PI3Kγ studies showed its importance in regulating innate immune functions and development and activation of T cells, revealing its role in controlling inflammation. However, its role in the human immune system and diseases remains to be investigated

Biallelic NFATC1 mutations cause an inborn error of immunity with impaired CD8+ T-cell function and perturbed glycolysis

International audienceThe nuclear factor of activated T cells (NFAT) family of transcription factors plays central roles in adaptive immunity in murine models; however, their contribution to human immune homeostasis remains poorly defined. In a multigenerational pedigree, we identified 3 patients who carry germ line biallelic missense variants in NFATC1, presenting with recurrent infections, hypogammaglobulinemia, and decreased antibody responses. The compound heterozygous NFATC1 variants identified in these patients caused decreased stability and reduced the binding of DNA and interacting proteins. We observed defects in early activation and proliferation of T and B cells from these patients, amenable to rescue upon genetic reconstitution. Stimulation induced early T-cell activation and proliferation responses were delayed but not lost, reaching that of healthy controls at day 7, indicative of an adaptive capacity of the cells. Assessment of the metabolic capacity of patient T cells revealed that NFATc1 dysfunction rendered T cells unable to engage in glycolysis after stimulation, although oxidative metabolic processes were intact. We hypothesized that NFATc1-mutant T cells could compensate for the energy deficit due to defective glycolysis by using enhanced lipid metabolism as an adaptation, leading to a delayed, but not lost, activation responses. Indeed, we observed increased 13C-labeled palmitate incorporation into citrate, indicating higher fatty acid oxidation, and we demonstrated that metformin and rosiglitazone improved patient T-cell effector functions. Collectively, enabled by our molecular dissection of the consequences of loss-of-function NFATC1 mutations and extending the role of NFATc1 in human immunity beyond receptor signaling, we provide evidence of metabolic plasticity in the context of impaired glycolysis observed in patient T cells, alleviating delayed effector responses

CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)-associated lymphoma. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses