Although SOD has been suggested as a possible neoantigen in

Although SOD2 has been suggested as a possible neoantigen in non-PLA2R associated MN, it is not clear whether or not the anti-SOD2 rgd peptide could worsen the existing disease or be informative as to its immunologic duration [19]. Together, our data lend further support to the view that SOD2 is not a primary antigen in MN, and in our patient. On the other hand, the early nature of anti-CAII IgG4-dependent podocyte injury could be suggested by findings that among additional patients with IgG4-related disease, only the sera of those with IgG4 anti-CAII antibodies promoted in vitro externalization and clustering of SOD2. The fact that not all of them could develop full-blown MN can be explained by multiple factors that possibly include genetic risks, epitope spreading, preformed or natural IgG against SOD2, duration, or insults such as a microbial infection as suggested for PLA2R-associated MN [19]. Duration in particular might be important both in primary and secondary forms of the disease. In patients with autoimmune pathologies like systemic lupus erythematosus, a series of autoimmune changes leads to the appearance of different autoantibodies that usually precede the onset of clinical illness by many years [26]. Remarkably in this context, in all IgG4-related disease patients described to date, CAII antibodies were mutually exclusive with PLA2R antibodies, like the recently recognized Thrombospondin Type-1 Domain-Containing 7A antibodies do in idiopathic MN patients [27], which would be entirely consistent with CAII as a primary target in podocytes at least in our patient. The following are the supplementary data related to this article.
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Introduction Heart failure (HF) remains a leading cause of morbidity and mortality in the United States and worldwide (Go et al., 2014; Bui et al., 2011). The failing circulation is characterized not only by depressed cardiac function, but also by endothelial dysfunction (Blum, 2009). Endothelial dysfunction—defined by impaired flow-mediated vasodilation (FMD) and endothelial progenitor cell (EPC) function—produces increased systemic vascular resistance, which augments stress on the failing heart, and contributes to HF symptomology (Marti et al., 2012). Endothelial dysfunction is also a crucial component of the pathophysiology of numerous cardiovascular (CV) disorders and manifests in patients with CV risk factors such as atherosclerosis, hypertension, and diabetes mellitus (Schulman et al., 2006). Moreover, EPCs regulate the health of the vasculature by incorporating into the endothelium, replacing injured endothelial cells, and secreting angiogenic factors that activate mature endothelial cells (Zampetaki et al., 2008). Notably, HF patients have decreased circulating EPC levels and bioactivity (Schmidt-Lucke et al., 2005). Mesenchymal stem cells (MSCs), under evaluation as a regenerative therapeutic approach for HF (Hare et al., 2012; Heldman et al., 2014; Karantalis and Hare, in press), have the potential for clinical benefit in CV disease by virtue of their antifibrotic, anti-inflammatory, and pro-angiogenic properties (Williams and Hare, 2011; Cao et al., 2015), and their ability to stimulate endogenous progenitor cells (Hatzistergos et al., 2010; Chen et al., 2008). Given this capacity of MSCs and the role of impaired EPCs in human HF (Werner et al., 2005; Shantsila et al., 2007a), we hypothesized that MSCs would stimulate the bioactivity of circulating EPCs and improve endothelial function in the failing circulation. Accordingly, we tested the hypothesis that MSCs stimulate EPC function and augment vascular relaxation in patients with HF due to either idiopathic dilated cardiomyopathy (DCM) or ischemic cardiomyopathy (ICM). Our results show that allogeneic, but not autologous, MSCs improve EPC bioactivity and endothelial function in HF patients, regardless of the etiology. These findings demonstrate a novel clinical beneficial effect of allogeneic MSCs transplantation in patients with HF and have implications for all disorders associated with endothelial dysfunction.