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.

Keywords:

• autophagy
• cytokines
• genetics
• granuloma
• infectious
• leprosy
• lipid bodies
• population
• SNPs
• TNF
• vitamin D

Acknowledgements

We are grateful to Marcelo Távora Mira and Anna Beatriz Robottom Ferreira for the critical reading of the article.

Financial & competing interests disclosure

MO Moraes is funded by FAPERJ (from Portuguese Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro), CAPES (from Portuguese Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and CNPq (from Portuguese Conselho Nacional de Desenvolvimento Científico e Tecnológico). CC Cardoso is a postdoctoral scholar from CAPES. AC Pereira is funded by FAPESP and CNPq and C de Sales Marques is a PhD fellow sponsored by CNPq. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

MO Moraes is funded by FAPERJ (from Portuguese Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro), CAPES (from Portuguese Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and CNPq (from Portuguese Conselho Nacional de Desenvolvimento Científico e Tecnológico). CC Cardoso is a postdoctoral scholar from CAPES. AC Pereira is funded by FAPESP and CNPq and C de Sales Marques is a PhD fellow sponsored by CNPq. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.