Our RR signature corroborates data showing that M. leprae components and host cell destruction continue to stimulate the immune response in a sudden and acute manner during RR. Most pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pattern molecules (DAMPs) bind specific PRRs such as Toll-like receptors and NOD-like receptors to orchestrate both, autophagy and IFN signaling [12, 13]. We hypothesized that the continued binding of PAMPs and DAMPs to TLRs caused by the pathogen components after killing destruction provides the necessary trigger for maintenance of the inflammatory process. The stimulation of innate mechanisms that comprise genes with autophagic activities such as PARK and LRRK2, in addition to the type I IFNs in the beginning of the process seems to be activated in order to clear killed mycobacteria, but it is unbalanced and exacerbated. Regarding the IFNs, the genes IFNB and OAS1 (2–5 ‘oligoadenylate synthetase-1 gene) had a greater expression in RR samples. OASL was also shown to be upregulated in M. leprae–infected human macrophage cell lineages, primary monocytes, and skin lesion from patients with a disseminated form of leprosy; whereas OASL knock down was associated with decreased viability of M. leprae and upregulation of autophagy levels [14]. Additionally, the chemokine CCL2 was the most expressed gene in our RR group. Recent reports have linked the STING signaling, type I IFN and CCL2 activation [14, 15]. During mycobacterial infection, this chemokine can be produced in a STING-dependent manner and it is actively involved in the recruitment of monocytes to the infection site [15] and also related to mycobacterial survival within macrophages [14]. Other works have pointed the participation of CCL2 in the pathogenesis of several inflammatory disorders such as atherosclerosis and autoimmune diseases [16,17,18]. Here, we could speculate that a prominent triggering of STING signaling and high expression of type I IFN and CCL2 may contribute to the attraction of immune cells and enhancement of inflammatory response during leprosy reaction.
Type 1 reaction or RR is caused by an amplified immune response possibly triggered by fragmented bacillary antigens available in the cell medium [19]. The main issue however, is that a dysregulated process of gene activation, aiming to contain the progress of M. leprae and eliminate the infection, will lead to the nerve and tissue damage. Indeed, persons with history of RR can keep an altered response to M. leprae antigens that differs from patients with unreactional leprosy for years after resolution of RR [8]. Additionally, our results show that the expression of TLR3, TLR7 and TLR10 were significantly increased in the reactions per se as well as in RR with TLR7 and TLR10 corroborating with data that fragments of bacterial destruction may be giving continuity to the characteristic inflammatory process of both reactional episodes in leprosy. On the other hand, ENL is characterized by a systemic inflammatory reaction. In this case, it might be possible that other set of genes related to the humoral immune response would be more active in these leucocytes. We need to expand our panel in order to identify which profile explains ENL.
