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Association between killer-cell immunoglobulin-like receptor genotypes and leprosy in Brazil

22 Sep 2008

Marcia Triunfol

Source: Tissue Antigens (see original article)

Citation: Franceschi DS, Mazini PS, Rudnick CC, Sell AM, Tsuneto LT, de Melo FC, Braga MA, Peixoto PR, Visentainer JE (2008). Association between killer-cell immunoglobulin-like receptor genotypes and leprosy in Brazil. Tissue Antigens. 2008 Sep 5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18778326

Apart from the differences in economic and educational levels, exposure to pathogens, and access to health care, what are the other factors playing a role in the variability of symptoms, and disease severity, seen in so many infectious diseases? Most would agree that it is genetics. Several studies have shown the influence that genetics can play in infectious diseases. Diseases such as HIV/AIDS, hepatitis C and tuberculosis are just three examples in which the host’s genes have been shown to play an important role in disease severity and outcome.

In this paper, the researchers wanted to investigate the influence that host genetics might have on leprosy, the infectious disease caused by Mycobacterium leprae.

A group of molecules known as KIR (killer cell immunoglobulin-like receptors) was studied in parallel with the molecules that they interact with – the HLA class I molecules.

KIRs are regulatory molecules found in a subset of lymphoid cells that are believed to play an important role in the control of the immune response. This control is achieved through a balance established between two major types of KIR molecules, namely the long-tailed KIR molecules and the short-tailed KIR molecules. While long-tailed KIR molecules present an inhibitory effect through their interaction with HLA class I molecules, which inhibit natural killer (NK) cells from destroying health cells, the short-tailed KIR molecules activate the same NK cells, which in turn have the effect of destroying infected cells.

Both KIR and HLA molecules have been shown to be highly polymorphic, with several different alleles been found in all human populations. More recently, researchers have found that specific KIR-HLA allelic combinations have significant association with disease severity, in some cases. In this paper, the authors investigated whether a significant association exists between specific pairs of KIR-HLA genes and tuberculoid leprosy (TT), lepromatous leprosy (LL), and borderline leprosy (BB), which are the three different clinical manifestations of leprosy.

To do so, the researchers studied a group of 165 leprosy patients (94 men and 71 women) and found that the frequency of a specific KIR allele, KIR2DS3, was significantly higher in TT patients than in LL patients. Likewise, KIR2DS2 was also higher in TT patients. However, because KIR2DS2 and KIR2DS3 were found to be in linkage disequilibrium in this population, one of the two alleles could just be ‘taking a ride’ with the other. In other words, KIR2DS2 and KIR2DS3 were frequently found in the same patient, which makes it difficult to establish which one between the two alleles was actually responsible for the association with the TT phenotype. Alternatively, it is also possible that the effect is caused by both alleles, which together promote a more efficient activation of NK-cells, which in turn results in the better cell-mediated immune response that is seen in TT patients.

As for the HLA class I genes, which are the genes that encode the molecules that work as ligands for KIR genes, some differences in frequency were found among the three leprosy groups and the control group. For instance, HLA-A3 and/or A11 alleles, as well as the HLA-C1 group of alleles, were higher in BB patients.

Analysis of KIR genes together with their HLA ligands produced no significant association between the genotypes and any of the three leprosy groups, although the inhibitory KIR haplotype KIR2DL1-C2/C2 was found to be elevated in TT patients.

However, when testing for an association between one of the KIR alleles showing high frequency in TT patients (KIR2DS2) along with its ligand (HLA-CI), no association could be detected. As for KIR2DS3, which is another KIR allele showing high frequency in TT patients, no analysis could be done because the ligand for this KIR allele is yet to be found.

Although not very informative, the study indicates some of the trends and possible associations that could explain the variability found in the three clinical forms of leprosy, and should be repeated further in a larger population to establish whether a significant association exist between KIR genes, their ligands, and the clinical manifestations seen in leprosy patients.

Note: This article is published in a journal which is not open access. To see the full article a subscription to Tissue Antigens is therefore required. In some developing countries, readers who are based in institutions may be able to access it through the HINARI programme.

2008 Blackwell Munksgaard