ABSTRACT
INTRODUCTION: Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1ß secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers. METHODS: Inflammatory mediators were detected in blood from patients with AATD (n=28) and patients with AATD receiving augmentation therapy (n=19). Inflammasome activation and IL-1ß secretion were measured in monocytes of patients with AATD, and following C3d stimulation in the presence or absence of CR3 or NLRP3 inhibitors. RESULTS: C3d acting via CR3 induces NLRP3 and pro-IL-1ß production, and through induction of endoplasmic reticulum (ER) stress and calcium flux, triggers caspase-1 activation and IL-1ß secretion. Treatment of individuals with AATD with AAT therapy results in decreased plasma levels of C3d (3.0±1.2 µg/mL vs 1.3±0.5 µg/mL respectively, p<0.0001) and IL-1ß (115.4±30 pg/mL vs 73.3±20 pg/mL, respectively, p<0.0001), with a 2.0-fold decrease in monocyte NLRP3 protein expression (p=0.0303), despite continued ER stress activation. DISCUSSION: These results provide strong insight into the mechanism of complement-driven inflammation associated with AATD. Although the described variance in C3d and NLRP3 activation decreased post AAT augmentation therapy, results demonstrate persistent C3d and monocyte ER stress, with implications for new therapeutics and clinical practice.
ABSTRACT
BACKGROUND: Pulmonary rehabilitation (PR) is recommended in the treatment of people with idiopathic pulmonary fibrosis (IPF). Little is known about the experiences of people with IPF of PR. Due to Covid-19 there has been a rapid shift of PR services to remote/virtual delivery. OBJECTIVE: To explore people living with IPFs experience of a virtual PR (VPR) programme. METHODS: All patients with a diagnosis of IPF in a stable phase of the disease were invited to participate in virtual PR: a 10 week exercise programme delivered twice-weekly for one hour. One-to-one semi- structured interviews were conducted within one week following the programme. All interviews were recorded, transcribed and analysed using Braun and Clarke thematic analysis by two independent assessors. RESULTS: N=13 participants took part in the semi-structured interviews, mean (standard deviation (SD)) age 69.5(10.4) years; 7M:6F. Mean (SD) FEV1 2.6(0.3)L, FVC 2.9(0.4)L. Four key themes were identified: 1) The impact of VPR on health and outlook, (2) The reality of VPR, (3) Being active after VPR and (4) Living with IPF during the COVID-19 Pandemic. Participants reported high levels of enjoyment and engagement with the programme regardless of the health benefits experienced. Most participants expressed a desire for a longer programme. Participants expressed different levels of maintenance with exercise since finishing the programme, specific motivators and strategies for maintenance included lung transplant, the maintenance of benefits from the programme and social support. COVID-19 and the restrictions imposed had some negative impacts on some participants lives, engaging with PR helped overcome some of these. CONCLUSION: Despite the progressive nature of IPF, all participants expressed high levels of enjoyment with the programme. Future research should explore strategies for maintenance post PR and the optimum duration of PR for people with IPF.
Subject(s)
COVID-19 , Idiopathic Pulmonary Fibrosis , Telerehabilitation , Humans , Aged , Pandemics , EmotionsABSTRACT
BACKGROUND AND AIMS: Coeliac disease (CD) is more common in those with type 1 diabetes mellitus (T1DM) and may be asymptomatic despite the presence of intestinal histological changes. Optimal screening practice guidelines differ internationally. We undertook a retrospective audit to determine the efficacy of current screening practice for CD in T1DM in our centre. METHODS: All children and adolescents < 16 years, diagnosed with T1DM in our service and continuing to attend the service in January 2017 were included. Data on CD screening was collected and compared to current NICE, NASPGHAN and ESPGHAN guidelines. RESULTS: Of the 355 patients attending our service, 253 attended from T1DM diagnosis and all had CD screening performed in our centre. In 37 of 253 patients, IgA-TTG was positive, providing a cumulative prevalence of 14.6%. Of these, 31(83.78%) with an elevated TTG on screening had no recorded gastrointestinal symptoms or CD-related clinical signs. Of the 35 TTG plus EMA-positive patients, 22/35 (59.46%) had diagnostic endoscopic biopsy. Nineteen (83.4%) had CD confirmed, 1 (4.54%) had negative biopsy and 2 (9%) had equivocal, non-diagnostic changes. CONCLUSIONS: Timely diagnosis of CD can prevent chronic ill health in affected individuals, and in patients with T1DM, CD is an independent risk factor for increased morbidity and mortality. Given the high prevalence of atypical symptoms and silent CD in those with T1DM, in this and other studies, and the benefits of detection and treatment of CD, screening is essential. Large-scale data collection allowing for the development of evidence-based guidelines is required.
