Autophagy Gene Polymorphism is Associated with Susceptibility to Leprosy by Affecting Inflammatory Cytokines

Abstract

Autophagy and inflammation closely interact with each other, and together, they play critical roles in bacterial infection. Leprosy is caused by the infection of Mycobacterium leprae (M. leprae). The objective of the study was to investigate the association between polymorphisms in IRGM, an autophagy gene, and susceptibility to leprosy, and identify possible functions of the polymorphism in the infection of M. leprae. Two polymorphisms in IRGM, rs4958842 and rs13361189, were tested in 412 leprosy cases and 432 healthy controls. Levels of inflammatory cytokines including interleukin 1 beta, IL-4, IL-6, and interferon gamma (INF-γ) were measured after the infection of M. leprae in the peripheral blood mononuclear cell (PBMC) of subjects with different genotypes of rs13361189. Data showed that prevalence of rs13361189TC and CC genotypes were significantly higher in leprosy patients than in healthy controls (odds ratio (OR) = 1.49, 95 % confidence interval (CI) 1.09-2.04, P = 0.012; OR = 2.58, 95 % CI 1.65-4.05, P < 0.001; respectively). Furthermore, the frequency of rs13361189CC genotype was increased in patients with complications than those without complications (P = 0.011). When analyzing the effect of rs13361189 polymorphism on M. leprae infection, we identified that M. leprae-infected PBMC with rs13361189CC genotype expressed significantly elevated levels of INF-γ and IL-4 than those with TT genotype. Our results suggested autophagy gene polymorphism was associated with the increased risk of leprosy by affecting inflammatory cytokines.

Advances in the Immunology and Genetics of Leprosy

“…These findings indicated the involvement of autophagy or phagocytosis in leprosy pathogenesis. Moreover, two other genes that regulate autophagy, LRRK2 and IRGM, were found to be associated with leprosy (109,110). In a zebrafish model, the LRRK2 mutant showed a weakened immune response to Mycobacterium marinum infection, functionally confirming the role of LRRK2 in infectious diseases (111).…”

The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson’s disease

“…This is required to permit immune tolerance, and the inability for adaptive immune cells to recognize these self-antigens can result in an autoimmune response that promotes inflammation and cell death. Therefore LRRK2-dependent ALP deficits could result in autoimmune dysregulation, as suggested for inflammatory disorders such as Crohn’s disease, colitis, and leprosy (Wellcome Trust Case Control Consortium, 2007; Henckaerts et al, 2011; Jostins et al, 2012; Yang et al, 2014). Indeed, co-morbidity between Parkinson’s disease and Crohn’s disease indicates that people diagnosed with PD could suffer from this dysregulation within the periphery, evidence for the potential involvement of the immune system as a player in vulnerability of PD, as well (Nalls et al, 2014).…”

Autophagy Is an Innate Mechanism Associated with Leprosy Polarization

“…leprae -containing double-membrane vacuoles in mouse MΦs, a hallmark of autophagosomes, suggesting a possible involvement of autophagy in the immunomodulatory response of the disease [27,28]. It has also recently been suggested that the IRGM gene polymorphism, which is linked with the susceptibility to tuberculosis [29], is associated with an increased risk of developing leprosy by affecting the production of inflammatory cytokines such as IFN-γ [30]. Furthermore, upregulation of IRGM was seen in M .…”