**Acknowledgements**

**4.7. Influence of** *KIR* **genes and ligands on leprosy**

132 Hansen's Disease - The Forgotten and Neglected Disease

HLA ligands on the immunopathology of leprosy.

NK cells and the production of cytokines.

**5. Conclusions**

It is known that the interaction of KIRs and their HLA ligands can result in activation or inhibition of NK cells and the occurrence of different immunological and clinical responses to various types of diseases, such as infectious diseases (AIDS, malaria, tuberculosis, Chagas disease, dengue fever and leprosy) [97–101], autoimmune and inflammatory diseases (psoriasis, rheumatoid vasculitis and Crohn's disease) [102–104] in different populations and ethnicities. The pioneering studies of *KIR* genes in leprosy were carried out in Brazil. The first study was performed in the southern region of Brazil, where the *KIR2DL1* inhibitor gene with its C2 group ligand was shown to be protective for BB and its homozygous ligand (*KIR2DL1*-C2/C2) was associated with the clinical form TT. Another inhibitory gene and its ligands (*KIR3DL2*-A\*03/A\*11) were associated with susceptibility to borderline leprosy. The activating genes *KIR2DS2* and *KIR2DS3* were shown to be a risk factor for TT form, compared to the more widespread form LL. Thus, TT patients with both activating genes (*KIR2DS2* and *KIR2DS3*) may develop better activation of NK cells and a competent cellular immune response with a more localized manifestation of the disease. The inhibitory *KIR2DL3*-C1 and *KIR2DL3*-C1/C1 were associated to protection against TT form, when compared to the control group and other clinical forms [105]. The second study of *KIR* genes with leprosy was performed in a hyperendemic region of Brazil, and the *KIR2DL1* inhibitory gene was a protective factor for leprosy *per se* and its BB form. The frequency of the homozygous *KIR2DL2* gene in the presence of the C1 group (*KIR2DL2*/*KIR2DL2*-C1) was higher in leprosy patients *per se* and in clinical forms TT and LL, when compared to the control group. The *KIR2DL2*/*KIR2DL3* haplotype with its homozygous C1 ligand (C1/C1) was associated with protection for leprosy *per se* and TT and LL forms [17]. The inhibitory effect of *KIR2DL2*/*2DL2*-C1 may contribute to the development of leprosy, mainly to a worse prognosis in *M. leprae* infections. The activating *KIR2DS2* gene with its C1 ligand was a risk factor for leprosy *per se* and the clinical form TT. In this same study, it was observed that higher frequency of inhibitory genes may favor the susceptibility of the development of the disease [17]. Thus, this study confirmed the influence of *KIR* genes and their

Activating and inhibitory *KIR* genes in the presence of their HLA ligands may have an impact on the development of leprosy and its clinical forms. The balance between these genes may interfere with the progression of the disease to a more localized (TT) or disseminated (LL), or to maintain an intermediate pattern between the two poles (BB), thus highlighting the role of

This chapter outlined the contribution of the innate and adaptive immune genes to leprosy pathogenesis, highlighting the *HLA*, *KIR* and *MIC* polymorphism genes contribution for clinical forms and reactions of leprosy. Immune responses against the *M. leprae* vary considerably between populations, which can be partly attributed to the genetic variation of the immune response to ensure the survival of populations. HLA and non-HLA genes should act together This study was supported by Laboratory of Immunogenetics – UEM (Proc. No. 00639/99-DEG-UEM), Fundação Araucária (State of Parana Research Foundation), CNPq (National Council for Scientific and Technological Development) and CAPES Foundation (Coordination for the Improvement of Higher Education Personnel). The authors are grateful to Prof Steven GE Marsh, Anthony Nolan Research Institute, London, UK for permission to reproduce this graph authors.
