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    • br Materials and Methods br Results

    2018-10-23


    Materials and Methods
    Results
    Discussion Our work was inspired by the classic observation that the intradermal injection of a suspension of granulomatous splenic tissue (Kveim–Siltzbach test) induces granuloma formation weeks later in patients with sarcoidosis, suggesting the presence of antigen(s) in granuloma tissue and host immunoreactivity to those antigen(s) (Iannuzzi et al., 2007; Hajizadeh et al., 2007; Hiramatsu et al., 2003; Dubaniewicz et al., 2006). Kveim-like effects have also been observed using non-viable BAL cell extracts or PBMCs derived from sarcoidosis subjects (Munro and Mitchell, 1987; Siltzbach and Ehrlich, 1954; Holter et al., 1992; Kataria and Holter, 1996). Several studies have attempted to identify specific antigens that can discriminate sarcoidosis from healthy subjects or from patients with other granulomatous diseases such as TB (Hajizadeh et al., 2007; Chen and Moller, 2007). Most of these studies used limited proteomics or genomics to search for tissue antigens (Hajizadeh et al., 2007; Richter et al., 1999; Song et al., 2005). The average length of identified peptides for sarcoidosis antigens was between 9 and 130 thapsigargin (AA), while the average peptide length for TB antigens was 9–209 AA. Among 10 sarcoidosis specific phage peptides, we identified 5 expression sequence tags with in frame epitopes. Five other reactive antigens were relatively short out of frame peptides meeting the criteria to be considered as mimotopes (mimetic sequence of a true epitope) (Wang et al., 2005). Similarly, among 10 sequenced TB specific phage peptides, we identified 5 in frame epitopes with full length in frame proteins with homology to known human sequences. Five other sequences were relatively short peptides with homology to various known MTB proteins (Table 4). Interestingly, TB antigens had much higher specificity and sensitivity as compared to antigens selective to sarcoidosis as indicated by higher AUCs (Table 4). Although the significance of mimotopes is not clear, it has been shown that some out of frame peptides are immunogenic and can activate MHC class I molecules (Schirmbeck et al., 2005). Due to smaller peptide sequences of mimotopes, they may have homology with diverse proteins. Prior studies using similar techniques in various cancers had similarly identified out of frame peptides (Lin et al., 2007; Chatterjee et al., 2006; Wang et al., 2005). Detection of mimotopes in this method may be due to out of frame peptide synthesis secondary to altered ribosomal function, or may correspond to open reading frames or generation of displayed peptides due to competition for binding during phage selection during phage insertion. Although our primary goal in this study was to identify the immune signature in sarcoidosis, we have identified a panel of antigens differentially expressed in sarcoidosis and tuberculosis as compared to healthy subjects. Tables 3 and 4 summarize the 10 most significant clones we identified in sarcoidosis and tuberculosis respectively. Further studies with larger sample sizes need to verify current data.
    Contributors
    Conflicts of Interest
    Acknowledgments We thank all patients and healthy volunteers for their participation in this study. This project has been funded by NIH grant R21HL104481-01A1 awarded to L.S. and with the support of the Department of Medicine, Wayne State University. We would like to thank Dr. Michael A. Tainsky for his invaluable assistance in completing this study.
    Introduction A high plasma concentration of low-density lipoprotein cholesterol (LDL-C) is one of the major risk factors for coronary heart disease (CHD) (Collaboration CTT, 2010; Reiner et al., 2011). Epidemiological surveys have shown that LDL-C levels were log-linearly correlated with CHD risk in a broad range of cholesterol levels (Grundy et al., 2004). Clinical trials also demonstrated that effective reduction in LDL-C can substantially reduce the risk of CHD (Collaboration CTT, 2010; Anon., 1984; Canner et al., 1986). High potency statins have been used to treat patients with hypercholesterolemia. However, taking statins alone might not always achieve the optimal low level of LDL-C (Kuklina et al., 2009; Karalis et al., 2011). The effect of statins in primary prevention of CHD, i.e. among those with elevated cholesterol levels but without CHD, is also limited (Reiner, 2013). Moreover, 10–20% of the patients taking statins experienced moderate to severe side effects, especially muscle damage (Zhang et al., 2013). It\'s also known that some patients do not respond to statin treatment. Thus, additional options for the treatment of hypercholesteremia are required.