The impact of KIR/HLA genes on the risk of developing multibacillary leprosy

Abstract

Killer-cell immunoglobulin-like receptors (KIRs) are a group of regulatory molecules able to activate or inhibit natural killer cells upon interaction with human leukocyte antigen (HLA) class I molecules. Combinations of KIR and HLA may contribute to the occurrence of different immunological and clinical responses to infectious diseases. Leprosy is a chronic neglected disease, both disabling and disfiguring, caused mainly by Mycobacterium leprae. In this case–control study, we examined the influence of KIRs and HLA ligands on the development of multibacillary leprosy. Genotyping of KIR and HLA genes was performed in 264 multibacillary leprosy patients and 518 healthy unrelated controls (238 healthy household contacts and 280 healthy subjects). These are unprecedented results in which KIR2DL2/KIR2DL2/C1/C2 and KIR2DL3/2DL3/C1/C1 indicated a risk for developing lepromatous and borderline leprosy, respectively. Concerning to 3DL2/A3/A11+, our study demonstrated that independent of control group (contacts or healthy subjects), this KIR receptor and its ligand act as a risk factor for the borderline clinical form. Our finding suggests that synergetic associations of activating and inhibitory KIR genes may alter the balance between these receptors and thus interfere in the progression of multibacillary leprosy. Leprosy is a neglected disease with the highest worldwide prevalence, and remains a public health problem in Brazil. The innate immune mechanisms are determinants in the management of leprosy and its different clinical manifestations. Accordingly, genetic association study provides information about the contribution of host genetic factors and the environment in which the individual lives on the development of leprosy. The individuals considered most affected and associated with a major risk for developing leprosy are household contacts with an intimate relation to patients living in crowded households. For this reason, we chose the contacts as one of our control groups, since they are more exposed to infection compared to the general population. We investigated the influence of KIR and HLA genes on the susceptibility to multibacillary leprosy. Our results reinforce the importance of host genetic background in the susceptibility to leprosy demonstrating that, independent from the control group (contacts or healthy subjects) the KIR and HLA act as risk factors in the development of lepromatous and borderline leprosy.