Leprosy Susceptibility: Genetic Variations Regulate Innate and Adaptive Immunity, and Disease Outcome

Abstract

The past few years have been very productive concerning the identification of genes associated with leprosy. Candidate gene strategies using both case-control and family-based designs, as well as large-scale approaches such as linkage and gene-expression genomic scans and, more recently, genome-wide association studies, have refined and enriched the list of genes highlighting the most important innate and adaptive immune pathways associated with leprosy susceptibility or resistance. During the early events of host-pathogen interaction identified genes are involved in pattern recognition receptors, and mycobacterial uptake (TLRs, NOD2 and MRC1), which modulate autophagy. Another gene, LTA4H, which regulates the levels of lipoxin A4 and possibly interacts with lipid droplet-related events, also plays a role in the early immune responses to Mycobacterium leprae. Together, the activation of these pathways regulates cellular metabolism upon infection, activating cytokine production through NF-κB and vitamin D-vitamin D receptor pathways, while PARK2 and LRRK2 participate in the regulation of host-cell apoptosis. Concomitantly, genes triggered to form and maintain granulomas (TNF, LTA and IFNG) and genes involved in activating and differentiating T-helper cells (HLA, IL10, as well as the TNF/LTA axis and the IFNG/IL12 axis) bridge immunological regulation towards adaptive immunity. Subtle variations in these genes, mostly single nucleotide polymorphisms, alter the risk of developing the disease or the severity of leprosy. Knowing these genes and their role will ultimately lead to better strategies for leprosy prevention, treatment and early diagnosis. Finally, the same genes associated with leprosy were also associated with autoimmune (Crohn's disease, rheumathoid arthritis, psoriasis) or neurodegenerative diseases (Parkinson's and Alzheimer's). Thus, information retrieved using leprosy as a model could be valuable to understanding the pathogenesis of other complex diseases.

Deciphering the contribution of lipid droplets in leprosy: multifunctional organelles with roles in Mycobacterium leprae pathogenesis

“…Given the importance of TLR-mediated signalling for host resistance to microbial pathogens, much of the research exploring the influence of the genetic background on leprosy has focused on polymorphisms in various TLR genes (Alcais et al 2005, Cardoso et al 2011 or other PAMP receptors (de Messias et al 2009). Genetic factors almost certainly also play a key role in determining whether an infection leads to the TT form of the disease, the LL form of the disease or an intermediate manifestation.…”

Original article Low prevalence of most frequent pathogenic variants of six PARK genes in sporadic Parkinson’s disease

“…Nevertheless, biological mech anisms linking LRRK2 polymorphisms to neurode generation are still unclear. Interestingly, LRRK2 is expressed by immune cells and upregulated follow ing recognition of microbial structures [12]; allelic var iants in LRRK2 and PARK2, have been associated to leprosy [3], celiac disease [7], Crohn's disease [20] and PD [2]; thus, there is a possible role for the immune system in the neurodegenerative process conferring populationspecific susceptibility for PD.…”

Insights from animal models on the immunogenetics of leprosy: a review

“…Polymorphisms in several genes in both the innate and adaptive phases of the immune response have been associated with susceptibility to intracellular infections (reviewed in van de Vosse et al 2009, Alter et al 2011, Cardoso et al 2011b. Below is an overview of the outcomes of M. leprae infection in mice with a knockout in some of the genes associated with leprosy.…”

“…In humans, an association between leprosy resistance and the single nucleotide polymorphism (SNP), IFNG + 874T, has been found (Cardoso et al 2011b). To study the role of IFNγ in experimental leprosy, control and IFNγ -/-mice were infected in the foot pads as per the Shepard model (Adams et al 2002).…”

“…There is evidence that IL-10 -/-mice have increased resistance to mycobacterial infection, forming larger granulomas containing macrophages with enhanced antimicrobial activity (Jacobs et al 2000) and IL-10 supplementation in vitro prolongs M. leprae survival in macrophages (Fukutomi et al 2004). In human genetic studies, the -819T allele, located in the promoter region of the IL10 gene, is associated with leprosy susceptibility (Cardoso et al 2011b).…”