In recent years several groups have attempted

In recent years several groups have attempted to identify specific signatures to distinguish between tuberculosis and sarcoidosis using transcriptomics or gene expression profilings (Koth et al., 2011; Maertzdorf et al., 2012; Berry et al., 2010). Yet, most of these methods led to the discovery of a series of markers or expression signatures that failed to discriminate between these two diseases (Koth et al., 2011; Stone et al., 2013). This is partly due to the fact that several inflammatory or infectious diseases such as CD, lupus, sarcoidosis and tuberculosis may respond to various thapsigargin with activation of similar pathways leading to similar transcriptomes and/or inflammatory gene expression profiles (Koth et al., 2011; Maertzdorf et al., 2012; Berry et al., 2010). For instance, Maertzdorf et al. found more similarity in the activated pathways than differences between sarcoidosis and MTB (Maertzdorf et al., 2012). Their results in sarcoidosis were similar to those results by Berry et al. indicating the importance of the interferon pathway (IFN) signature in MTB (Maertzdorf et al., 2012; Berry et al., 2010). In addition, considerable pathway overlap was identified between lupus, sarcoidosis and TB (Maertzdorf et al., 2012). However, despite similar genetic or transcriptomic signatures, these diseases are clinically entirely different and require different therapy. Tuberculosis, a global infectious disease caused by the intracellular bacterium Mycobacterium tuberculosis remains a worldwide health problem (http://www.who.int). One barrier for eradication of tuberculosis besides the lack of effective vaccination is the lack of reliable antigens to evaluate the activity of the disease and its response to treatment (Nahid et al., 2011). Standard methods to diagnose TB and to monitor response to treatment rely on sputum microscopy and culture. The current CDC/NIH roadmap emphasizes the need for development of new TB antigens as alternative methods (Nahid et al., 2011). In view of this background, perhaps surprisingly, our microarray platform could discriminate tuberculosis from sarcoidosis and healthy controls. In addition to antigens for sarcoidosis, we have detected more than 300 clones specifically for tuberculosis. Interestingly, a considerable number of these clones were TB specific and related to bacterial growth of M. tuberculosis, and its metabolism (Table 4). Recently a tremendous effort has been put toward elucidating the antibody response to MTB antigens, which has implications for the development of new antigens to diagnose and monitor successful treatment, as well as to develop effective vaccination (Kunnath-Velayudhan et al., 2010). Yet, a consistent immune response to MTB has not been found. Most other studies searching for antigens in TB have identified unspecific markers primarily involving host response such as C-reactive protein, serum amyloid A and others, but not MTB specific antigens (Agranoff et al., 2006; De Groote et al., 2013). MTB has the ability to survive within host macrophages, largely escaping immune surveillance and maintaining its ability for replication and person to person transmission (Meena and Rajni, 2010). The primary goal of our project was to discover antigens related to sarcoidosis. Yet, in addition we have detected specific antigens for TB. These results are surprising to us, as the question remains, how can the sarcoidosis library detect TB specific antigens? Lungs are environmentally highly exposed to numerous bacteria, and our library is predominantly derived from BAL cells that contain all types of immune cells, including macrophages that might have integrated messages from MTB. Hence, we speculate that this could be the reason why the CSL is able to detect TB specific antigens. Still, the major question is why BAL cells of patients with sarcoidosis can harbor MTB messages, yet respond to PPD skin testing negatively, since all of our donors with sarcoidosis were PPD negative.