IL-12p40 heterodimerizes with IL-12p19 and IL-12p35 to produce IL-23 and IL-12, respectively. The functions of IL-12 and IL-23 are best described in T cells in which IL-12 is a potent inducer of Th1 differentiation, whereas IL-23 can amplify Th17 responses in inflammatory diseases. Here we present evidence that mouse IL-12p40 can form a third heterodimer with CD5Like (CD5L). The formation of this new heterodimer, CD5L:p40, is dependent on charged residues and can be induced in myeloid cells under inflammatory conditions such as experimental models of colitis, autoimmune inflammation of the central nervous system, and airway inflammation. We demonstrate that recombinant CD5L:p40 can induce a unique transcriptome and IL-13 expression from effector Th17 cells in a dual-specificity phosphatase 2-dependent manner. We developed a monoclonal antibody that specifically targets CD5L:p40 but not its individual subunits and demonstrate that this blocking antibody exhibits efficacy in reducing an antigen-dependent Th2 response and airway inflammation.

Low Club Cell 16 kDa protein (CC16) plasma levels are linked to accelerated lung function decline in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke-exposed (CS-exposed) Cc16-/- mice have exaggerated COPD-like disease associated with increased NF-κB activation in their lungs. It is unclear whether CC16 augmentation can reverse exaggerated COPD in CS-exposed Cc16-/- mice and whether increased NF-κB activation contributes to the exaggerated COPD in CS-exposed Cc16-/- lungs. CS-exposed WT and Cc16-/- mice were treated with recombinant human CC16 (rhCC16) or an NF-κB inhibitor versus vehicle beginning at the midpoint of the exposures. COPD-like disease and NF-κB activation were measured in the lungs. RhCC16 limited the progression of emphysema, small airway fibrosis, and chronic bronchitis-like disease in WT and Cc16-/- mice partly by reducing pulmonary inflammation (reducing myeloid leukocytes and/or increasing regulatory T and/or B cells) and alveolar septal cell apoptosis, reducing NF-κB activation in CS-exposed Cc16-/- lungs, and rescuing the reduced Foxj1 expression in CS-exposed Cc16-/- lungs. IMD0354 treatment reduced exaggerated lung inflammation and rescued the reduced Foxj1 expression in CS-exposed Cc16-/- mice. RhCC16 treatment reduced NF-κB activation in luciferase reporter A549 cells. Thus, rhCC16 treatment limits COPD progression in CS-exposed Cc16-/- mice partly by inhibiting NF-κB activation and represents a potentially novel therapeutic approach for COPD.

Interleukin-23 receptor plays a critical role in inducing inflammation and autoimmunity. Here, we report that Th1-like cells differentiated in vitro with IL-12 + IL-21 showed similar IL-23R expression to that of pathogenic Th17 cells using eGFP reporter mice. Fate mapping established that these cells did not transition through a Th17 cell state prior to becoming Th1-like cells, and we observed their emergence in vivo in the T cell adoptive transfer colitis model. Using IL-23R-deficient Th1-like cells, we demonstrated that IL-23R was required for the development of a highly colitogenic phenotype. Single-cell RNA sequencing analysis of intestinal T cells identified IL-23R-dependent genes in Th1-like cells that differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1-like cells inhibited the induction of colitis. We thus uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver in Th1-like cells inducing tissue inflammation.

Key Points Question What are the characteristics of amyloid-related imaging abnormalities (ARIA) during aducanumab treatment in individuals with early Alzheimer disease? Findings In an integrated safety data set of 2 phase 3 clinical trials (EMERGE and ENGAGE) including 3285 participants, 425 patients (41.3%) in the combined 10 mg/kg aducanumab group (n = 1029) experienced ARIA; ARIA-edema occurred in 362 patients (35.2%), and 94 of these patients (26.0%) experienced associated symptoms (eg, headache, confusion, dizziness, and nausea). ARIA-microhemorrhage and ARIA–superficial siderosis occurred in 197 patients (19.1%) and 151 patients (14.7%), respectively. Meaning Amyloid-related imaging abnormalities occurred in approximately 40% of participants in the phase 3 studies of aducanumab, and approximately one-quarter of these patients experienced symptoms.

RATIONALE: Remote monitoring of COPD patients has the potential to improve clinical outcomes. The ability to successfully deploy home monitoring technologies to COPD patients remotely without in-person encounters is of particular interest during the SARS-CoV-2 pandemic. We present interim results from a prospective implementation study of a home monitoring system in COPD patients at-risk for frequent acute exacerbations of COPD (AECOPD). METHODS: We recruited non-hospitalized individuals aged 40-80 years with spirometryconfirmed COPD and increased AECOPD risk (one hospitalization or two outpatient AECOPD in the prior year). The home system includes: a GoHome™ Data Collection Platform and GoSpiro® spirometer (Monitored Therapeutics, Dublin, OH), and a 3230 pulse oximeter (Nonin Medical, Plymouth, MN). The tablet-based GoHome™ has an auto-start system requiring no computer skills for operation. Eligible participants were contacted via phone, and if interested, were sent a participation kit containing informed consent and the home system. After remotely collecting ICF, participants completed device setup and baseline spirometry using Avatar coaching. At set times, the device collects responses for an automated COPD Action Plan and displays reminders for the patient to use the integrated Bluetooth® spirometer and pulse oximeter. The GoSpiro® measures slow vital capacity (SVC) and forced vital capacity (FVC) using an Avatar-assisted technology coach on the GoHome™ (Figure). The Avatar coaches the patient through each measurement following ATS recommendations for instructions and coaching, followed by error identification and maneuver error correction without human intervention. Patients are engaged daily with the COPD Action Plan. Automated scores return immediate patient guidance along with appropriate clinician alerts. Results are cellular or Wi-Fi uploaded to a cloud server for realtime investigator review. Following demonstrated proficiency, daily measurements of spirometry (FVC Tuesday/Thursday, SVC all other days), daily pulse oximetry and COPD Action Plan were performed. Participant study duration was three months. RESULTS: To date, seven of 12 planned participants have been enrolled. All enrolled participants have successfully activated all device components and performed FVC maneuvers meeting ATS acceptability standards. All participants were able to complete collection and transmission of daily pulse oximetry and COPD Action Plan data. One participant requested study withdrawal after three weeks and six participants remain on study. CONCLUSIONS: Deployment of a COPD home telemonitoring system platform including daily spirometry, pulse oximetry and electronic questionnaire without in-person contact is feasible. This technology may be useful in settings where in-person visits are not feasible due to patient safety, remote location or access-related issues. .

We describe the design of EMBARK, a Phase 3b re-dosing study of aducanumab in participants with Alzheimer's disease (AD).

Summary The cytokine receptor IL-23R plays a fundamental role in inflammation and autoimmunity. However, several observations have been difficult to reconcile under the assumption that only Th17 cells critically depend on IL-23 to acquire a pathogenic phenotype. Here, we report that Th1 cells differentiated in vitro with IL-12 + IL-21 show similar levels of IL-23R expression as in pathogenic Th17 cells. We demonstrate that IL-23R is required for Th1 cells to acquire a highly colitogenic phenotype. scRNAseq analysis of intestinal T cells enabled us to identify novel regulators induced by IL-23R-signaling in Th1 cells which differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1 cells inhibited induction of colitis. In this process, we were able to uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver of Th1 cell-mediated tissue inflammation and disease.

Amyloid‐related imaging abnormalities (ARIA), a spectrum of imaging findings detected on brain magnetic resonance imaging (MRI), are associated with the investigational use of amyloid‐targeting monoclonal antibodies, including aducanumab, in patients with Alzheimer’s disease (AD). EMERGE (NCT02484547) and ENGAGE (NCT02477800) were Phase 3 studies that evaluated the efficacy and safety of aducanumab in patients with early AD.

Interleukin-27 (IL-27) is an immunoregulatory cytokine that suppresses inflammation through multiple mechanisms, including induction of IL-10, but the transcriptional network mediating its diverse functions remains unclear. Combining temporal RNA profiling with computational algorithms, we predict 79 transcription factors induced by IL-27 in T cells. We validate 11 known and discover 5 positive (Cebpb, Fosl2, Tbx21, Hlx, and Atf3) and 2 negative (Irf9 and Irf8) ll10 regulators, generating an experimentally refined regulatory network for ll10. We report two central regulators, Prdm1 and Maf, that cooperatively drive the expression of signature genes induced by IL-27 in type 1 regulatory T cells, mediate IL-10 expression in all T helper cells, and determine the regulatory phenotype of colonic Foxp3(+) regulatory T cells. Prdm1/Maf double-knockout mice develop spontaneous colitis, phenocopying ll10-deficient mice. Our work provides insights into IL-27-driven transcriptional networks and identifies two shared ll10 regulators that orchestrate immunoregulatory programs across T helper cell subsets.

Upon encounter with antigen and depending on the cytokine milieu, T helper (Th) cells can differentiate into various effector T cell subsets, including the well-defined Th1 and Th2 subsets as well as the more recently discovered Th17, Th9, and follicular T helper (TFH) subsets. Among these, self-reactive Th1 and Th17 cells have been associated with organ-specific autoimmunity, while self-reactive TFH cells have been shown to promote aberrant B cell responses in systemic autoimmune diseases. On the other hand, regulatory T cell subsets including Foxp3+ regulatory T cells (Tregs) and type 1 regulatory T cells (Tr1) can regulate autoimmunity by suppressing effector T cell responses. Here, we give an overview of the different Th cell subsets, their development, and how the interplay between them can promote or inhibit autoimmune tissue inflammation.

Neuroimmune interactions have emerged as critical modulators of allergic inflammation, and type 2 innate lymphoid cells (ILC2s) are an important cell type for mediating these interactions. Here, we show that ILC2s expressed both the neuropeptide calcitonin gene-related peptide (CGRP) and its receptor. CGRP potently inhibited alarmin-driven type 2 cytokine production and proliferation by lung ILC2s both in vitro and in vivo. CGRP induced marked changes in ILC2 expression programs in vivo and in vitro, attenuating alarmin-driven proliferative and effector responses. A distinct subset of ILCs scored highly for a CGRP-specific gene signature after in vivo alarmin stimulation, suggesting CGRP regulated this response. Finally, we observed increased ILC2 proliferation and type 2 cytokine production as well as exaggerated responses to alarmins in mice lacking the CGRP receptor. Together, these data indicate that endogenous CGRP is a critical negative regulator of ILC2 responses in vivo.

Hyaluronan (HA) is associated with innate immune response activation and may be a marker of allograft dysfunction in lung transplant recipients. This was a prospective, single center study comparing levels of bronchioalveolar lavage (BAL) and serum HA and the HA immobilizer LYVE-1 in lung transplant recipients with and without acute cellular rejection (ACR). Chronic lung allograft dysfunction (CLAD)-free survival was also evaluated based on HA and LYVE-1 levels. 78 recipients were enrolled with a total of 115 diagnostic biopsies and 1.5 years of median follow-up. Serum HA was correlated with BAL HA (r = 0.25, p = 0.01) and with serum LYVE-1 (r = 0.32, p = 0.002). There was significant variation in HA and LYVE-1 over time, regardless of ACR status. Levels of serum HA (median 74.7 vs 82.7, p = 0.69), BAL HA (median 149.4 vs 134.5, p = 0.39), and LYVE-1 (mean 190.2 vs 183.8, p = 0.72) were not associated with ACR. CLAD-free survival was not different in recipients with any episode of elevated serum HA (HR = 1.5, 95% CI = 0.3–7.7, p = 0.61) or BAL HA (HR = 0.94, 95% CI = 0.2–3.6, p = 0.93). These results did not differ when stratified by bilateral transplant status. In this small cohort, serum HA, BAL HA, and LYVE-1 levels are not associated with ACR or CLAD-free survival in lung transplant recipients.

Signaling abnormalities in immune responses in the small intestine can trigger chronic type 2 inflammation involving interaction of multiple immune cell types. To systematically characterize this response, we analyzed 58,067 immune cells from the mouse small intestine by single-cell RNA sequencing (scRNA-seq) at steady state and after induction of a type 2 inflammatory reaction to ovalbumin (OVA). Computational analysis revealed broad shifts in both cell-type composition and cell programs in response to the inflammation, especially in group 2 innate lymphoid cells (ILC2s). Inflammation induced the expression of exon 5 of Calca, which encodes the alpha-calcitonin gene-related peptide (α-CGRP), in intestinal KLRG1+ ILC2s. α-CGRP antagonized KLRG1+ ILC2s proliferation but promoted IL-5 expression. Genetic perturbation of α-CGRP increased the proportion of intestinal KLRG1+ ILC2s. Our work highlights a model where α-CGRP-mediated neuronal signaling is critical for suppressing ILC2 expansion and maintaining homeostasis of the type 2 immune machinery.

Advanced hepatic fibrosis and cirrhosis are absolute contraindications to lung transplantation. [ 1] However, whether fatty liver disease with mild–moderate fibrosis contributes to increased adverse outcomes post-lung transplantation remains unknown. We present a retrospective analysis of patients transplanted at Brigham and Women's Hospital between 2015 and 2017 to identify whether patients with mild–moderate non-alcoholic fatty liver disease (NAFLD) experience increased short-term complications compared to patients with normal liver architecture. Patients with advanced (F3–F4) fibrosis and/or cirrhosis were considered non-suitable transplant candidates, a priori . This study was powered for a difference in index hospital-free days within the first 30 days of 25% (α=0.05, β=0.8). Secondary outcomes included index intensive care unit (ICU)-free days within the first 10 days post-transplant, perioperative blood product transfusion, incidence of index hospitalisation arrhythmias and delirium, need for insulin on discharge post-transplant, tacrolimus dose required to maintain a trough of 8–12 ng·mL −1 at index hospital discharge, and 1-year post-transplant incidence of insulin-dependent diabetes, acute kidney injury, acute cellular rejection, unplanned hospital readmissions and infection. 150 patients underwent lung transplantation between 2015 and 2017 and were included in the analysis; of these patients 40 (27%) had evidence of NAFLD. Median index hospital-free days for patients with NAFLD were non-inferior to those without (16 days, IQR 10.5–19.5 versus 12 days, IQR 0–18.0, p=0.03). Regarding secondary outcomes, both index hospitalisation and 1-year outcomes were non-inferior between patients with NAFLD and those with normal liver architecture. This study demonstrates that mild–moderate severity NAFLD may not be a contraindication to lung transplantation.

Type 2 innate lymphoid cells (ILC2s) are important for both mucosal homeostasis as well as for initiation and progression of allergy and asthma. Alarmin cytokines produced by damaged or stressed epithelial cells activate ILC2s, however, the role of other pathways regulating the homeostatic versus inflammatory functions of ILC2s remain poorly defined. We generated transcriptional profiles of thousands of lung-resident ILCs isolated from mice challenged with either PBS or the alarmin cytokines IL-25 or IL-33 using massively parallel droplet-based single-cell RNA sequencing (scRNA-seq). We found significant transcriptional heterogeneity within activated ILCs and identified differentially expressed genes as potential novel regulators of ILC function. One of the genes, neuromedin U receptor 1 (NMUR1), is a receptor for the neuropeptide neuromedin U (NMU) and is specifically expressed by ILC2s and not by other immune cells. Nmur1 is particularly expressed by ILC2s at steady-state and after IL-25 treatment. In vivo NMU synergized with IL-25 to induce more severe airway inflammation than was seen with either IL-25 or NMU alone and this effect was dependent on ILCs. Mechanistically, IL-25 + NMU expanded highly proliferative and inflammatory ILCs with distinct transcriptional profiles and increased expression of IL-5 and IL-13. We observed reduced ILC2 frequency and function in NMU- or NMUR1-deficient mice after allergen challenge and found that ILCs from these mice had a lower score for an inflammatory ILC2 gene signature. Our data therefore establish a novel neuro-immune pathway that amplifies ILC2-driven airway inflammation.

Matrix metalloproteinase-9 (MMP-9) cleaves various proteins to regulate inflammatory and injury responses. However, MMP-9's activities during influenza A viral (IAV) infections are incompletely understood. Herein, plasma MMP-9 levels were increased in patients with pandemic H1N1 and seasonal IAV infections. MMP-9 lung levels were increased and localized to airway epithelial cells and leukocytes in H1N1-infected WT murine lungs. H1N1-infected Mmp-9-/- mice had lower mortality rates, reduced weight loss, lower lung viral titers, and reduced lung injury, along with lower E-cadherin shedding in bronchoalveolar lavage fluid (BALF) samples than WT mice. H1N1-infected Mmp-9-/- mice had an altered immune response to IAV with lower BALF PMN and macrophage counts, higher Th1-like CD4+ and CD8+ T cell subsets, lower T regulatory cell counts, reduced lung type I interferon levels, and higher lung interferon-γ levels. Mmp-9 bone marrow-chimera studies revealed that Mmp-9 deficiency in lung parenchymal cells protected mice from IAV-induced mortality. H1N1-infected Mmp-9-/- lung epithelial cells had lower viral titers than H1N1-infected WT cells in vitro. Thus, H1N1-infected Mmp-9-/- mice are protected from IAV-induced lung disease due to a more effective adaptive immune response to IAV and reduced epithelial barrier injury due partly to reduced E-cadherin shedding. Thus, we believe that MMP-9 is a novel therapeutic target for IAV infections.