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

Franceschi, Danilo Santana Alessio; Mazini, Priscila Saamara; Rudnick, Cristiane Conceição Chagas; Sell, Ana Maria; Tsuneto, Luiza Tamie; Melo, Fabiano Cavalcante de; Braga, Marco Antônio; Peixoto, Paulo R.; Visentainer, Jeane Eliete Laguila

doi:10.1111/j.1399-0039.2008.01127.x

Cited by 38 publications

(37 citation statements)

References 28 publications

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“…Figure 2 compares these two clinical forms with respect to activating genes and their ligands; there is a higher frequency of all KIR-HLA combinations in the TT compared to the LL form except for the KIR2DS2-C1/C1 combination, thus supporting the results found by Franceschi et al [10]. The results for activating genes (Table 2) are also in accordance with the results described by Franceschi et al [10], who reported a higher frequency of the KIR2DS1 , 2DS2 , 2DS3 and 2DS4 genes in TT compared to LL patients. The initial step in eliminating M. leprae requires the effective participation of the innate immune system, and thus NK cells play an important role.…”

Section: Discussionsupporting

confidence: 84%

“…To date, only one study has reported an association between KIR genes and their HLA ligands with leprosy phenotypes, using a population sample of 165 patients from south Brazil [10]. Thus, the aim of this study was to investigate the association between KIR genes and their HLA ligands in the development of leprosy and its clinical forms in patients from the hyperendemic region of Rondonópolis, Mato Grosso, Mid-Western Brazil, ultimately aiming to better understand the immunopathogenic mechanisms of M. leprae .…”

Section: Introductionmentioning

confidence: 99%

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Influence of KIR genes and their HLA ligands in the pathogenesis of leprosy in a hyperendemic population of Rondonópolis, Southern Brazil

et al. 2014

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BackgroundThe objective of this study was to investigate the association between KIR genes and the immunopathogenesis of leprosy.MethodsThe types of KIR and HLA genes were evaluated by PCR-SSOP-Luminex in 408 patients with leprosy and 413 healthy individuals. Statistical analysis was performed using the Chi-square or Fisher’s exact test and stepwise multivariate analysis.ResultsThere was a higher frequency of activating KIR genes (KIR2DS1, 2DS2 and 3DS1) together with their HLA ligands in the tuberculoid (TT) group as compared to the lepromatous leprosy (LL) group. KIR2DL2/2DL2-C1 was more frequent in the patient, TT and LL groups than in the control group. Borderline patients presented a higher frequency of inhibitory pairs when compared to the control group, and a higher frequency of activating pairs as compared to the LL group. Multivariate analysis confirmed the associations and demonstrated that being a female is a protective factor against the development of the disease per se and the more severe clinical form.ConclusionsThis study showed that activating and inhibitory KIR genes may influence the development of leprosy – in particular, activating genes may protect against the more aggressive form of the disease – thereby demonstrating the role of NK cells in the immunopathology of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2334-14-438) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Influence of KIR genes and their HLA ligands in the pathogenesis of leprosy in a hyperendemic population of Rondonópolis, Southern Brazil

et al. 2014

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“…Previous studies have shown that the risk of many human diseases was associated with differences in KIR gene content, including autoimmune diseases, inflammatory disorders, infectious diseases, immunodeficiency, cancer, and reproductive disorders. 17 KIR2DL1, for instance, was specifically associated with tuberculoid leprosy, 37 microscopic polyangiitis, 38 endometriosis, 39 immunodeficiency, 40 birdshot chorioretinopathy, 41 solid tumors, 42,43 leukemia, 44 and graft-versus-host disease. 45 Mechanistically, the risk may be related to the strength of interaction between the KIR gene and its HLA ligand.…”

Section: Discussionmentioning

confidence: 99%

Significant functional heterogeneity among KIR2DL1 alleles and a pivotal role of arginine245

Bari

Bell

Leung

et al. 2009

Blood

119

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Killer immunoglobulin-like receptors (KIRs) play an essential role in the regulation of natural killer cell functions. KIR genes are highly polymorphic in nature, showing both haplotypic and allelic variations among people. We demonstrated in both in vitro and in vivo models a significant heterogeneity in function among different KIR2DL1 alleles, including their ability to inhibit YT-Indy cells from degranulation, interferon ␥ production, and cytotoxicity against target cells expressing the HLA-Cw6 ligand. Subsequent experiments showed that the molecular determinant was an arginine residue at position 245 (R245) in its transmembrane domain that mechanistically affects both the efficiency of inhibitory signaling and durability of surface expression. Specifically, in comparison with R245-negative alleles, KIR2DL1 that included R245 recruited more Src-homology-2 domaincontaining protein tyrosine phosphatase 2 and ␤-arrestin 2, showed higher inhibition of lipid raft polarization at immune synapse, and had less down-regulation of cell-surface expression upon interaction with its ligand. Thus, our findings provide novel insights into the molecular determinant of KIR2DL1 and conceivably a fundamental understanding of KIR2DL1 allelic polymorphism in human disease susceptibility, transplant outcome, and donor selection. (Blood. 2009;114:5182-5190) IntroductionNatural killer (NK) cells are a part of our immune system that eliminates virally infected cells and tumor cells through cytolytic killing and cytokine secretion. 1 An NK cell's responses to its targets are regulated by the balance of signals generated through various activating and inhibiting receptors. 2,3 NK-cell receptors may be categorized on the basis of their ligand specificity for major histocompatibility complex class I and related molecules. Expression of various combinations of receptors on the surface of NK cells creates a diverse repertoire. 4,5 In humans, one of the most important groups of receptors that regulate NK-cell function is killer immunoglobulin-like receptors (KIRs). 6,7 The KIRs make up a family of diverse glycoproteins encoded by a compact cluster of genes located on human chromosome 19q13.4. 8,9 KIRs expressed at the surface of NK cells regulate their response by interacting with human leukocyte antigen (HLA) class I molecules. The KIR family has both activating and inhibitory receptors. KIR inhibitory receptors suppress NK cells' function using the immunoreceptor tyrosine-based inhibitory motif in their long cytoplasmic tails. Activating KIR receptors have short cytoplasmic tails and do not contain the inhibitory motif.Each of the KIR genes exhibits allelic variation as well as haplotypic variability in terms of the number and types of genes on the haplotypes. 9,10 The allelic variations of KIR genes range from 2 to more than 30. 10 The polymorphisms between the alleles of a given KIR gene can occur in its extracellular, transmembrane, or cytoplasmic domains. Polymorphism at each of these 3 domains has been associated with significant bi...

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“…Instead, this observation was originally interpreted as a bias toward suppressor/cytotoxic T cells compared to helper T cells in multibacillary lepromatous patients (125,126). This could, in turn, relate to recent studies suggesting an association of different combinations of activating and inhibitory KIR alleles and HLA class I ligands with lepromatous versus tuberculoid disease (58), although further work is required to tease out the functional roles of NK cells compared to ␥␦ T-cell or ␣␤ CD8 ϩ T-cell populations. Associations have also been observed between tuberculoid leprosy and the highly variable HLA/MHC class I chain-related genes A and B (MICA and MICB), which lie between HLA-B and the TNF locus (165).…”

Section: Hla and Mycobacterial Infectionsmentioning

confidence: 96%

HLA and Infectious Diseases

2009

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SUMMARY Following their discovery in the early 1970s, classical human leukocyte antigen (HLA) loci have been the prototypical candidates for genetic susceptibility to infectious disease. Indeed, the original hypothesis for the extreme variability observed at HLA loci (H-2 in mice) was the major selective pressure from infectious diseases. Now that both the human genome and the molecular basis of innate and acquired immunity are understood in greater detail, do the classical HLA loci still stand out as major genes that determine susceptibility to infectious disease? This review looks afresh at the evidence supporting a role for classical HLA loci in susceptibility to infectious disease, examines the limitations of data reported to date, and discusses current advances in methodology and technology that will potentially lead to greater understanding of their role in infectious diseases in the future.

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

Cited by 38 publications

References 28 publications

Influence of KIR genes and their HLA ligands in the pathogenesis of leprosy in a hyperendemic population of Rondonópolis, Southern Brazil

Influence of KIR genes and their HLA ligands in the pathogenesis of leprosy in a hyperendemic population of Rondonópolis, Southern Brazil

Significant functional heterogeneity among KIR2DL1 alleles and a pivotal role of arginine245

HLA and Infectious Diseases

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