Elsevier

Human Immunology

Volume 70, Issue 11, November 2009, Pages 915-920
Human Immunology

Role of human leukocyte antigen, killer-cell immunoglobulin-like receptors, and cytokine gene polymorphisms in leptospirosis

https://doi.org/10.1016/j.humimm.2009.08.007Get rights and content

Abstract

Leptospirosis is an emerging zoonotic disease caused by pathogenic species of the genus Leptospira. It has a broad range of clinical presentations in humans. Although progress has been made in the characterization of the host immune system factors that may affect disease progression and outcome, to date few reports have addressed the role of genetic polymorphisms in the susceptibility to leptospirosis. In this work a group of patients with a history of leptospiral infection and a control group were compared for polymorphisms in the human leukocyte antigen (HLA), in killer-cell immunoglobulin-like receptors (KIR), and in cytokine genes. Alleles in the HLA-A and -B loci were associated with susceptibility, as were the class I haplotype A*01-B*08-Cw*07 and the 8.1 ancestral haplotype (A*01-B*08-Cw*07-DRB1*03-DQB1*02). Single nucleotide polymorphisms in the interleukin (IL)-4 and IL-4Rα genes also had significantly higher frequencies in the patient group. No association was reported between KIR gene profile and leptospirosis. This work highlights the importance of using genetic polymorphisms to better understand the mechanisms involved in the immune response to leptospirosis.

Introduction

Leptospirosis is one of the most frequent zoonoses and has a ubiquitous worldwide distribution [1], [2]. It is caused by pathogenic species of spirochaete Gram-negative bacteria belonging to the genus Leptospira. Clinical presentations can greatly vary, from subclinical manifestations to kidney and liver failure, myocarditis, and even death [3]. The traditional view on the human immunity to this disease states that response to both infection and reinfection is mostly humoral. It involves the maturation and development of B cells and the production of immunoglobulins (Ig) with specificities primarily directed at the polysaccharide components of the leptospiral lipopolysaccharides [4]. Recent reports also indicate a role for cell-mediated immunity in leptospirosis [5], [6], but it remains unclear which factors inherent to the host immune system are responsible for the wide range of clinical manifestations.

The highly polymorphic human leukocyte antigen (HLA) system, along with killer-cell immunoglobulin-like receptors (KIR), has been extensively studied and associated with susceptibility to numerous autoimmune, oncological, and infectious diseases [7], [8]. HLA has been implicated in the chronic complications of Lyme disease (caused by another spirochetal organism, of the genus Borrelia) [9], [10]. Regarding leptospirosis, Lingappa and colleagues investigated the relevance of HLA-DR and -DQ serotypes, as well as the tumor necrosis factor (TNF)-α −308 polymorphism in an outbreak among a large cohort of triathletes exposed to contaminated water [11]. Although HLA-DR and TNFα −308 demonstrated no differences correlated with case status, HLA-DQ6 was associated with an increased risk of developing leptospirosis among the triathletes who ingested contaminated water. However, Fialho et al. were unable to confirm any association between HLA class II and susceptibility to leptospirosis [12]. Few reports analyzed KIR genotypes in infections by spirochetes. A recent case–control study has, however, indicated a possible role for 2DL3, 2DL5B, 2DS1, and 2DS5 in susceptibility to leptospirosis [13].

Cytokines are crucial players in the activation and suppression of the immune response. Single nucleotide polymorphisms (SNPs) have been extensively identified in cytokine genes and associated with many diseases [14], [15], [16], [17]. Some of these SNPs are linked to variations in promoter activity, leading to low, intermediate, or high cytokine production phenotypes [14], [15], [16], [17]. It is reasonable to expect they exert some type of influence in the overall cytokine balance and thus in the outcome of inflammatory processes.

The aim of this work was to determine whether HLA, KIR, and cytokine gene polymorphisms could influence the susceptibility to leptospirosis in an endemic context such as the Azores Islands (Portugal).

Section snippets

Subjects and methods

DNA was extracted from peripheral blood mononuclear cells from 64 patients with clinical history and confirmed serology of leptospirosis (patient group) between 1998 and 2007 and 117 unrelated randomly selected individuals (control group) using a salting-out protocol. The mean age of the patients and the control groups was 51 and 58 years old, respectively. All individuals in both groups were born and lived on Terceira Island (Azores, Portugal). HLA genotyping was performed by polymerase chain

HLA genotyping

The results of the HLA genotyping in the patient and control groups are presented in Table 1, Table 2. Results that indicate a statistically significant difference between the groups are highlighted in bold. Statistically significant differences were reported in the Class I alleles HLA-A*24 (p = 0.020; OR = 0.365 with 95% CI = 0.160–0.836), HLA-A*31 (p = 0.005; OR = 5.824 with 95% CI = 1.668–20.241), and HLA-B*08 (p = 0.047; OR = 2.656 with 95% CI = 1.068–6.599). In the Class II alleles there

Discussion

In this study, a group of individuals with clinical background of leptospirosis was compared with a control group in terms of HLA allele and haplotype frequencies, KIR gene content, and cytokine gene polymorphisms. Such comparison is viable because in Terceira Island the contact with potentially contaminated sites in both rural and urban areas is common among the general population, so it is reasonable to consider the whole population as being an at-risk group.

The results demonstrated

Acknowledgments

This work was supported by Project MANSEEBMO (MI.2.1/004/2005) from the Direcção Regional da Ciência e Tecnologia (Azores Regional Government).

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