Summary Loss or duplication of chromosome segments can lead to further genomic changes associated with cancer. However, it is not known if only a select subset of genes is responsible for driving further changes. To determine if perturbation of any given gene in a genome suffices to drive subsequent genetic changes, we analyzed the yeast knockout collection for secondary mutations of functional consequence. Unlike wild type, most gene knockout strains were found to have one additional mutant gene affecting nutrient responses and/or heat-stress-induced cell death. Moreover, independent knockouts of the same gene often evolved mutations in the same secondary gene. Genome sequencing identified acquired mutations in several human tumor suppressor homologs. Thus, mutation of any single gene may cause a genomic imbalance with consequences sufficient to drive adaptive genetic changes. This complicates genetic analyses, but is a logical consequence of losing a functional unit originally acquired under pressure during evolution.

Eosinophils are multifunctional granulocytes that contribute to initiation and modulation of inflammation. Their role in asthma and parasitic infections has long been recognized. Growing evidence now reveals a role for eosinophils in autoimmune diseases. In this review, we summarize the function of eosinophils in inflammatory bowel diseases, neuromyelitis optica, bullous pemphigoid, autoimmune myocarditis, primary biliary cirrhosis, eosinophilic granulomatosis with polyangiitis, and other autoimmune diseases. Clinical studies, eosinophil-targeted therapies, and experimental models have contributed to our understanding of the regulation and function of eosinophils in these diseases. By examining the role of eosinophils in autoimmune diseases of different organs, we can identify common pathogenic mechanisms. These include degranulation of cytotoxic granule proteins, induction of antibody-dependent cell-mediated cytotoxicity, release of proteases degrading extracellular matrix, immune modulation through cytokines, antigen presentation, and prothrombotic functions. The association of eosinophilic diseases with autoimmune diseases is also examined, showing a possible increase in autoimmune diseases in patients with eosinophilic esophagitis, hypereosinophilic syndrome, and non-allergic asthma. Finally, we summarize key future research needs.

Background-Common causative agents in the development of inflammatory cardiomyopathy include cardiotropic viruses such as coxsackievirus B3 (CVB3). Here, we investigated the role of the ubiquitin-like modifier interferon-stimulated gene of 15 kDa (ISG15) in the pathogenesis of viral cardiomyopathy. Methods and Results-In CVB3-infected mice, the absence of protein modification with ISG15 was accompanied by a profound exacerbation of myocarditis and by a significant increase in mortality and heart failure. We found that ISG15 in cardiomyocytes contributed significantly to the suppression of viral replication. In the absence of an intact ISG15 system, virus titers were markedly elevated by postinfection day 8, and viral RNA persisted in ISG15 −/− mice at postinfection day 28. Ablation of the ISG15 protein modification system in CVB3 infection predisposed mice to long-term disease with deposition of collagen fibers, all leading to inflammatory cardiomyopathy. We found that ISG15 acts as part of the intrinsic immunity in cardiomyocytes and detected no significant effects of ISG15 modification on the cellular immune response. ISG15 modification of CVB3 2A protease counterbalanced CVB3-induced cleavage of the host cell eukaryotic initiation factor of translation eIF4G in cardiomyocytes, thereby counterbalancing the shutoff of host cell translation in CVB3 infection. We demonstrate that ISG15 suppressed infectious virus yield in human cardiac myocytes and the induction of ISG15 in patients with viral cardiomyopathy. Conclusions-The ISG15 conjugation system represents a critical innate response mechanism in cardiomyocytes to fight the battle against invading pathogens, limiting inflammatory cardiomyopathy, heart failure, and death. Interference with the ISG15 system might be a novel therapeutic approach in viral cardiomyopathy. response. Type I IFNs contribute to the suppression of viral titers and thereby ameliorate invasion of immune cells into the heart, contributing to improved survival in CVB3 infection. [6][7][8] Type I IFN-dependent processes resulted in improved cardiac function during viral cardiomyopathy 7,9 and ensured long-term survival in CVB3-positive dilated cardiomyopathy patients. 10Binding of type I IFNs to their cognate receptors results in the induction of IFN-stimulated gene of 15 kDa (ISG15), a small ubiquitin family protein consisting of 2 ubiquitinlike folds.11 ISG15 is involved in the struggle against pathogens.12-16 ISG15 modification, the process by which ISG15 is covalently attached to lysine residues of target proteins, is mediated through the sequential action of a type I IFN-induced E1-E2-E3 enzymatic cascade, 17 involving the E1-activating enzyme Ube1L, 18 E2-conjugating enzyme Ube2L6, 19 and E3 ligases Herc5 and Herc6 20 in humans and mice, respectively. The isopeptidase USP18 specifically removes ISG15 from ISG15-modified substrates. 21Pursuing the aim to define host determinants that influence the pathogenesis of viral cardiomyopathy, we provide the first evidence for the impact of the ...