Deep Proteome Profiling Reveals Common Prevalence of MZB1-Positive Plasma B Cells in Human Lung and Skin Fibrosis.

RATIONALE: Analyzing the molecular heterogeneity of different forms of organ fibrosis may reveal common and specific factors and thus identify potential future therapeutic targets. OBJECTIVES: We sought to use proteome-wide profiling of human tissue fibrosis to (1) identify common and specific signatures across end-stage interstitial lung disease (ILD) cases, (2) characterize ILD subgroups in an unbiased fashion, and (3) identify common and specific features of lung and skin fibrosis. METHODS: We collected samples of ILD tissue (n = 45) and healthy donor control samples (n = 10), as well as fibrotic skin lesions from localized scleroderma and uninvolved skin (n = 6). Samples were profiled by quantitative label-free mass spectrometry, Western blotting, or confocal imaging. MEASUREMENTS AND MAIN RESULTS: We determined the abundance of more than 7,900 proteins and stratified these proteins according to their detergent solubility profiles. Common protein regulations across all ILD cases, as well as distinct ILD subsets, were observed. Proteomic comparison of lung and skin fibrosis identified a common upregulation of marginal zone B- and B1-cell-specific protein (MZB1), the expression of which identified MZB1+/CD38+/CD138+/CD27+/CD45-/CD20- plasma B cells in fibrotic lung and skin tissue. MZB1 levels correlated positively with tissue IgG and negatively with diffusing capacity of the lung for carbon monoxide. CONCLUSIONS: Despite the presumably high molecular and cellular heterogeneity of ILD, common protein regulations are observed, even across organ boundaries. The surprisingly high prevalence of MZB1-positive plasma B cells in tissue fibrosis warrants future investigations regarding the causative role of antibody-mediated autoimmunity in idiopathic cases of organ fibrosis, such as idiopathic pulmonary fibrosis.

Heart Rate at Rest and Incident Atrial Fibrillation in Patients With Diastolic Dysfunction.

Diastolic dysfunction (DD) is associated with incident atrial fibrillation (AF). The influence of heart rate at rest (RHR) on incident AF in patients with DD has not been investigated. The goal of this study is to assess the influence of RHR on incident AF in patients with DD. Patients from a large health system with no previous history of AF, a left ventricular ejection fraction ≥50%, and documented DD on echocardiography were divided into quartiles (<66, 66 to 76, 77 to 91, >91 beats per minute) based on RHR. Incident AF was estimated using AF hospitalization during follow-up. Hazard ratios (HR) for AF hospitalization and all-cause death were calculated with a Cox proportional hazards model. A total of 19,046 patients were analyzed. Over a median follow-up of 42.2 months, 742 (3.9%) patients were hospitalized for AF. Both slower and faster RHR were associated with increased risk of AF hospitalization (HR 1.40, confidence interval [CI] 1.14 to 1.71, p = 0.001, HR 1.23, CI 0.99 to 1.53, p = 0.06 and HR 1.72, CI 1.38 to 2.14, p <0.001, for quartiles 1, 2, and 4, respectively), suggesting a J-shaped relation. Progressive increase in all-cause death was noted with faster RHR (HR1.19 per quartile increase, CI 1.16 to 1.22, p <0.001). These results persisted after adjustment for age, cardiovascular co-morbidities, grade of DD, and ß-blocker use. In conclusion, this large, real-world analysis indicates increased risk of incident AF with slower and faster RHR in patients with DD. Randomized trials are needed to evaluate the potential of RHR modification to mitigate the risk of incident AF.

FK506-Binding Protein 11 Is a Novel Plasma Cell-Specific Antibody Folding Catalyst with Increased Expression in Idiopathic Pulmonary Fibrosis.

Antibodies are central effectors of the adaptive immune response, widespread used therapeutics, but also potentially disease-causing biomolecules. Antibody folding catalysts in the plasma cell are incompletely defined. Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease with increasingly recognized autoimmune features. We found elevated expression of FK506-binding protein 11 (FKBP11) in IPF lungs where FKBP11 specifically localized to antibody-producing plasma cells. Suggesting a general role in plasma cells, plasma cell-specific FKBP11 expression was equally observed in lymphatic tissues, and in vitro B cell to plasma cell differentiation was accompanied by induction of FKBP11 expression. Recombinant human FKBP11 was able to refold IgG antibody in vitro and inhibited by FK506, strongly supporting a function as antibody peptidyl-prolyl cis-trans isomerase. Induction of ER stress in cell lines demonstrated induction of FKBP11 in the context of the unfolded protein response in an X-box-binding protein 1 (XBP1)-dependent manner. While deficiency of FKBP11 increased susceptibility to ER stress-mediated cell death in an alveolar epithelial cell line, FKBP11 knockdown in an antibody-producing hybridoma cell line neither induced cell death nor decreased expression or secretion of IgG antibody. Similarly, antibody secretion by the same hybridoma cell line was not affected by knockdown of the established antibody peptidyl-prolyl isomerase cyclophilin B. The results are consistent with FKBP11 as a novel XBP1-regulated antibody peptidyl-prolyl cis-trans isomerase and indicate significant redundancy in the ER-resident folding machinery of antibody-producing hybridoma cells.

A case report of a patient with wide complex tachycardia due to Wolff-Parkinson-White syndrome mimicking ventricular tachycardia.

BACKGROUND: Wide complex tachycardia (WCT) associated with syncope as manifestation of an underlying, life-threatening arrhythmia might potentially be the harbinger of sudden cardiac death. Identifying the aetiology of a WCT is imperative to provide appropriate treatment and prevent recurrence. CASE SUMMARY: We report the case of a 22-year-old male who had been experiencing haemodynamically significant WCT leading to syncope at the age of 13 years. As the patient and the family rejected an electrophysiological (EP) study, he had received an implantable cardioverter-defibrillator (ICD) for secondary prevention. After 7 years of experiencing multiple shocks, the patient finally gave consent to an EP study, which identified a left-sided accessory atrioventricular pathway that was successfully ablated during the same procedure. DISCUSSION: The differential diagnosis of WCT might be challenging and includes both ventricular and supraventricular tachycardias. In young patients without structural heart disease experiencing WCT, an EP study should be offered before ICD implantation to make a final diagnosis with the potential to provide definitive treatment.