Leprosy is a chronic infectious disease caused by the intracellular acid-fast Mycobacterium leprae (M. leprae) bacilli. It affects the skin and peripheral nerves of susceptible individuals, causing irreversible impairment of nerve function and consequent chronic disability (1). As a result of the use of multidrug therapy, promoted by the World Health Organization, the global prevalence of this disease has been significantly reduced (2,3). However, leprosy remains a public health problem (4), affecting ~500,000 individuals annually worldwide (3). In Mexico, 215 new cases of leprosy were reported until the end of the first quarter of 2012, resulting in an estimated prevalence of 0.480 cases per 100,000 inhabitants, with a predominance of males over females. In addition, the proportion of multibacillary cases has been found to increase in several Mexican populations, concomitantly with the declining incidence (2,5). However, a previous epidemiological study demonstrated that only a small percentage of individuals exposed to the bacillus develop the disease, suggesting that the majority of individuals are immunologically competent to reject infection by developing effective cellular immune responses (6).

The clinical spectrum of leprosy includes two poles, the tuberculoid (TT) or paucibacillary (PB) and the lepromatous (LL) or multibacillary (MB) poles, with several intermediate (I) or borderline forms [borderline tuberculoid (BT), borderline borderline (BB) and borderline lepromatous (BL)]. Immunologically, the LL pole is characterized by a Th2 T-cell immune response, antibody complex formation, absence of granulomas and failure to restrain M. leprae growth. By contrast, the TT pole presents with a Th1 T-cell cytokine response, a vigorous T-cell response to M. leprae antigens and containment of the infection in well-formed granulomas (7).

Accumulated evidence currently indicates that exposure to M. leprae is necessary but not sufficient to explain the susceptibility to leprosy and previous studies demonstrated that the pathogenesis of leprosy is a two-step process, in which a group of genes controls susceptibility to infection per se, whereas a different group of genes controls the clinical manifestation of the disease (1,8). Evidence that host genes affect susceptibility to leprosy or its various clinical forms is supported by data from a wide variety of sources, including twin studies, segregation analyses, family-based linkage and association studies, candidate gene association studies and, most recently, genome-wide association studies (GWASs) (7,9). One recent genome-wide scan pinpointed chromosome 6p21 as a leprosy susceptibility locus (10). This region harbors the human leukocyte antigens (HLA) gene cluster, which has been extensively investigated for its role in the pathogenesis of leprosy. Previous candidate gene studies detected an association of leprosy with class I and II genes. However, class II genes, particularly the DRB1 locus, were found to be more consistently associated with leprosy (6,11).

Several studies reported an association of the HLA-DR locus with susceptibility or resistance to leprosy in different populations, demonstrating the significance of this locus in the pathogenesis of leprosy and highlighting the fact that certain HLA-DR alleles are associated with susceptibility to leprosy per se, whereas other alleles are associated with predisposition towards a particular clinical spectrum of this disease (12). In this context, independent replication studies in several ethnically different populations are required for multifactorial diseases, such as leprosy (6). Considering these facts and taking into consideration that the genetic susceptibility to leprosy in the Mexican Mestizo population has received little attention, the aim of this study was to investigate the association of HLA-DRB1 alleles with leprosy in a Mexican Mestizo population.

It has been established that certain individuals who are exposed to the M. leprae bacillus are resistant to disease and raise an effective immune response, whereas others will develop clinical disease (18), suggesting that the development of leprosy is significantly affected by host genetics factors. An observation supporting the significant role of genetic factors in the development of leprosy is that several genes and genomic regions have been implicated in the complex genetic mechanisms controlling host susceptibility to disease (1).

Leprosy is one of the first human diseases in which human leukocyte antigen genes were demonstrated to co-determine disease outcome (18). These associations with HLA molecules may be the major genetic determinants of the disease phenotype, which is consistent with the large numbers of available studies that demonstrated an association between the DR alleles and the different clinical subtypes of leprosy, or even with leprosy per se(19).

It was previously demonstrated that, in Mexicans, the HLA-DRB1*03 allele is associated with the TT clinical subgroup (20) and a previous family study demonstrated an association of the HLA-DRB1*1501 allele with LL leprosy (21). In this study, we reported the association of the HLA-DRB1*01 allele with susceptibility to LL and D leprosy and we observed that the HLA-DRB1*08 allele was associated with protection against leprosy. Of note, the HLA-DRB1*01 allele appears to have been introduced in this population through admixture with Caucasians, whereas the HLA-DRB1*08 allele is the second most common allele encountered in the normal Mexican population and it is present in Mestizos, as well as in autochthonous populations from Mexico, which may be associated with natural selection from infectious diseases following contact with Europeans during the 16th century (22). These data confirm the role of HLA in the genetic susceptibility to the development of leprosy in several populations worldwide and also confirm the role of HLA-DR in the clinical outcome of this disease.

As regards other endemic countries, such as Vietnam and Brazil, the HLA-DRB1*10 allele has been associated with susceptibility to leprosy, whereas the HLA-DRB1*04 allele has been associated with protection against leprosy (6). A previous study from Brazil demonstrated that the HLA-DRB1*09 allele was associated with susceptibility to and the HLA-DRB1*04 allele with protection against BL (23). In Argentina, the HLADRB1*04 allele was found to be associated with protection against MB and the HLA-DRB1*0402 allele with protection against leprosy per se(24).

In a Chinese population, the HLA-DRB1*09 allele was associated with the development of indeterminate leprosy only in young people, whereas the HLA-DRB1*15 allele was associated with susceptibility to leprosy per se(12). The HLA-DRB1*1501, HLA-DRB1*1502 and HLADR-B1*1404 alleles were associated with an increased susceptibility to TT in an Indian population (25). A study from Indonesia demonstrated that the HLA-DRB1*02 allele confers susceptibility to, whereas the HLA-DRB1*12 allele is associated with protection against leprosy (26). In Egypt, HLA-DR2 was associated with susceptibility to leprosy per se(27) and in northern India, the HLA-DRB1*15 allele (a HLA-DR2 subtype) was associated with MB (28).

Considering those results, to the best of our knowledge, this study was the first to report evidence of an association between the HLA-DRB1*01 allele and susceptibility to LL and between the HLA-DRB1*08 and protection against leprosy per se in a Mexican Mestizo population, which possesses a high degree of genetic heterogeneity. HLA type studies demonstrated that, in general, Mexican Mestizos harbour several more Amerindian genes compared to European and African haplotypes (29).

In conclusion, our study described the genotyping of the HLA-DRB1 locus in Mexican Mestizos diagnosed with leprosy and healthy individuals. Our findings suggest that the HLA-DRB1*01 and HLA-DRB1*08 alleles may be novel genetic markers for susceptibility to and protection against leprosy, respectively, in a Mexican Mestizo population. The investigation of leprosy in different endemic regions may provide more insight into the pathogenesis of this disease and its heterogeneous distribution in Mexico.