CD1 proteins are expressed on dendritic cells, where they display lipid antigens to T-cell receptors (TCRs). Here we describe T-cell autoreactivity towards ubiquitous human membrane phospholipids presented by CD1b. These T-cells discriminate between two major types of lipids, sphingolipids and phospholipids, but were broadly cross-reactive towards diverse phospholipids including phosphatidylcholine, phosphatidylinositol and phosphatidylethanolamine. The crystal structure of a representative TCR bound to CD1b-phosphatidylcholine provides a molecular mechanism for this promiscuous recognition. We observe a lateral escape channel in the TCR, which shunted phospholipid head groups sideways along the CD1b-TCR interface, without contacting the TCR. Instead the TCR recognition site involved the neck region phosphate that is common to all major self-phospholipids but absent in sphingolipids. Whereas prior studies have focused on foreign lipids or rare self-lipids, we define a new molecular mechanism of promiscuous recognition of common self-phospholipids including those that are known targets in human autoimmune disease.
Ventilation heterogeneity is frequent in bronchial asthma and can be assessed using multiple breath wash-out testing (MBW). Most data is available in paediatric patients and using nitrogen as a tracer gas. We aimed to evaluate sulphur hexafluoride (SF 6) MBW in adult asthmatics. Spirometry, wholebody plethysmography, impulse oscillometry and SF 6-MBW were prospectively performed. MBW parameters reflecting global (lung clearance index, LCI), acinar (S acin) and conductive (S cond) ventilation heterogeneity were derived from three consecutive wash-outs. LCI was calculated for the traditional 2.5% and an earlier 5% stopping point that has the potential to reduce wash-out times. 91 asthmatics (66%) and 47 non-asthmatic controls (34%) were included in final analysis. LCI 2.5 and Lci 5 were higher in asthmatics (p < 0.001). Likewise, S acin and S cond were elevated (p < 0.001 and p < 0.01). Coefficient of variation was 3.4% for LCI 2.5 and 3.5% for LCI 5 in asthmatics. Forty-one asthmatic patients had normal spirometry. ROC analysis revealed an AUC of 0.906 for the differentiation from non-asthmatic controls exceeding diagnostic performance of individual and conventional parameters (AUC = 0.819, p < 0.05). Sf 6-MBW is feasible and reproducible in adult asthmatics. Ventilation heterogeneity is increased as compared to non-asthmatic controls persisting in asthmatic patients with normal spirometry. Diagnostic performance is not affected using an earlier LCI stopping point while reducing wash-out duration considerably. Disease control is the primary goal of asthma therapy being linked to absence of symptoms and exacerbations 1. Regrettably, up to half of the patients are poorly controlled 2,3. Despite therapeutic advances, numbers remained fairly unaltered during the last decade. The clinical and pathophysiological explanations associated with poor disease control are heterogenous. In general, more severe disease is related to more frequent exacerbations, health care contacts 3 and symptoms 4. Lung function is also impaired in severe disease indicated by a lower forced expiratory volume in one second (FEV 1) and lower forced vital capacity (FVC) 3. Both parameters represent rather central sites of obstruction. However, involvement of peripheral airways is common in the majority of asthmatic patients 5. This holds true across the whole spectrum of severity 6 and may be a consequence of several influencing factors. These include inflammation, wall thickening, smooth muscle hypertrophy, and mucus 7-10. However, changes in the lung periphery are still often missed by commonly used techniques such as spirometry. Impulse oscillometry (IOS) is an inexpensive non-invasive technique to measure airway resistance. It was shown to identify small airway obstruction 11 , the related characteristics of disease control 12,13 and response to
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