Peroxynitrite in Sarcoidosis: Relation to Mycobacterium Stationary Phase

Abstract

There is evidence that the same mycobacterial heat shock proteins (Mtb-HSPs), especially HSP16, the main marker of mycobacteria dormant stage, occur in sarcoid tissues and in circulated immune complexes and prompt the immune responses against the different genetic background, leading to the development of acute sarcoidosis (SA)/Löfgren syndrome, chronic SA, latent tuberculosis (TB), or active TB. In SA there is increased monocytes phagocytic activity, decreased clearance of antigens/immune complexes by monocytes, which are resistant to apoptosis, and decreased serum microbicidal/degradable nitrate⁄nitrite (NOx) concentration. Reduction in NOx may result from the reaction of NOx with superoxide with subsequent production of peroxynitrite (ONOO-). In this study, therefore, we evaluated NOx and ONOO- levels in supernatants of peripheral blood mononuclear cells cultures treated with Mtb-HSPs from 20 SA patients, 19 TB patients, and 21 healthy volunteers using Griess and rhodamine fluorescence methods. We found significantly greater NOx and ONOO- concentrations with/without Mtb-HSPs stimulation in SA and TB patients than in controls. However, there were significantly lower NOx and higher ONOO- levels after Mtb-HSPs induction in SA than TB patients. In summary, in contrast to active TB, increased ONOO- concentration may explain the low level of NOx with induction of M. tuberculosis genetic dormancy program via higher Mtb-HSP16 expression in SA.

Moving target: shifting the focus to pulmonary sarcoidosis as an autoimmune spectrum disorder

“…Opinions differ on the exact mechanism, but it has been suggested that sarcoidosis is caused by immune reactivity against incompletely degraded and persisting bacterial antigens, rather than a conventional infection [43]. Mycobacterial and propionibacterial DNA and protein have been identified in sarcoidosis granulomas, and several studies show reactivity of lung-derived T-cells to mycobacterial proteins [4], most frequently mycobacterial catalase-peroxidase (mKatG), the 6-kDa early secretory antigenic target (ESAT-6) and heat-shock proteins [44,45]. Broad-spectrum anti-mycobacterial therapy has demonstrated positive effects on lung function in chronic sarcoidosis patients [46], although this was primarily attributed to anti-inflammatory effects rather than specific pathogen eradication [47].…”

Mycobacterial Heat Shock Proteins in Sarcoidosis and Tuberculosis

“…Long-term Mtb-HSP16 stimulation also reduces mononuclear phagocyte apoptosis [ 16 , 18 , 41 , 49 , 51 , 54 , 55 , 56 , 57 ].…”

“…Since NOx reduction can also result from the reaction of NOx with peroxide and the subsequent production of ONOO − , Dubaniewicz et al [ 54 ] assessed peroxynitrite levels in supernatants of Mtb-HSP-induced PBMC cultures from the same research groups ( Figure 3 ). Significantly higher concentrations of ONOO − with Mtb-HSP stimulation were found in patients with SA and tuberculosis than in the control group.…”

“…However, significantly higher levels of ONOO − after Mtb-HSP induction were found in sarcoidosis than in tuberculosis. An elevated concentration of peroxynitrite may explain the low level of NOx, and due to the release of cryptogenic epitopes of autoantigens, it may induce autoimmunity, considered in sarcoidosis [ 33 , 34 , 35 , 36 , 37 , 38 , 54 , 82 , 83 ].…”