This case-control study investigated the genetic variation present in HLA-DRB1, DQA1 and DQB1 genes, and its relation to leprosy in Southern Brazil.
In infection caused by M. leprae
, HLA alleles influence not only susceptibility or resistance to the disease, but also the course of the disease. The main role of HLA molecules is to present peptides derived from M. leprae
to the T cells of the host. Susceptibility to an infectious disease may be due to imperfections in some stages of this system. An individual that has a particular combination of HLA alleles that are not linked to the peptide in an appropriate way, or for whom the HLA-peptide linkage does not develop a proper lymphocyte response, will be less able to resist the invasion of the infectious agent than an individual that does not have such deficiencies [21
]. In patients whose HLA systems offer protection against the disease, these genes probably select and stimulate T cells that multiply and eliminate the agent with inflammatory cytokine production, or else destroy the infected cells [22
Several studies identify a consistent form for the participation of HLA alleles and haplotypes, especially class II genes, as an important genetic factor associated to leprosy. The clinical manifestation of the disease depends on the type of immune response shown by the host, and exchanges between Th1 and Th2 response types may be partially controlled by a mechanism of antigen presentation involving HLA molecules [23
]. In the TT form of the disease, the production of proinflammatory cytokines by Th1 cells may help in the clearance of the bacillus. However, in the LL form, the immunosuppressor cytokines produced by the Th2 response may make this response difficult.
In the present study, HLA-DRB1*16, a subtype of DR2, participates as a susceptibility marker for leprosy per se
, confirming previous serological results that showed an association between HLA-DR2 and leprosy per se
in patients from an equivalent geographical area (South Brazil) [11
]. The association of HLA-DR2 (now DRB1*15 and DRB1*16) with susceptibility to leprosy per se
has been highlighted in other studies [24
] and in LL and TT patients, compared to healthy controls, in many populations around the world (Surinam, India, Venezuela, Egypt, Chine, Japan, Korea, Mexico, Turkey, Brazil) [reviewed in [12
]]. Associations with the class II region are thought to occur due to the class II restriction of the presentation of mycobacterial epitopes to T-helper cells.
Rani et al. (1992), in Korean, showed positive associations of HLA-DR2 and DQ1 with LL leprosy, and DR9 and DQ7 with Borderline leprosy; and negative associations between DR4 and DQ3 and LL leprosy [7
]. The present study is in accord with these results: HLA-DRB1*DR9 was associated with susceptibility to Borderline leprosy and HLA-DRB1*04 was associated with protection against LL leprosy, as a lower frequency was observed in these patients compared to in the TT group, and DQB1*03 showed a tendency towards protection. Strong linkage disequilibria, in some populations, are known to exist within the MHC (gene order: HLA-DQB1, DQA1, DRB1) [27
]. The weak positive association of DQB1*03 with protection against leprosy (Table ) may be due to the strong linkage disequilibrium between DRB1*04 and this DQ allele.
Similar results for DRB1*04 were reported by Joko et al
. (2000) for leprosy per se
in a Japanese population [30
] and, more recently, by both Vanderborght et al
. (2007) in both Brazilian and Vietnamese populations [14
] and Motta et al
. (2007) in an Argentinean population [31
In addition, according to the data of the present study, HLA-DRB1*08 frequency was higher in lepromatous patients than tuberculoid patients, indicating a role in susceptibility to the most severe form of leprosy.
Rani et al
. (1993) found a significantly higher frequency of DQB1*0601 in leprosy patients than in healthy controls, while DQA1*0103 was most frequent in LL patients and DQA1*0102 was selectively higher in borderline lepromatous patients [32
]. On the other hand, DRB1*0701, DQB1*0201 and DQA1*0201 frequencies were all lower in multibacillary leprosy patients compared to TT patients and controls, and DQB1*0503 was selectively lower in TT patients. In the present study, HLA-DQA1*05 frequency was significantly higher in leprosy patients, while DQA1*02 and *04 frequencies were lower.
An unrelated genome-wide scan in 71 multi-case families from Brazil found chromosome region 6p21 (lod = 3.23) to be weakly linked to leprosy [33
]. More detailed analysis indicated that more than one locus
in each of these dense immune-response gene regions might affect susceptibility to leprosy, including genes that contribute to leprosy per se
and to lepromatous, as opposed to tuberculoid, disease subtypes [13
]. Early candidate-gene analysis, usually involving the HLA region on chromosome 6p21, has provided the first experimental evidence for the complex nature of the genetic variations involved in host genetic susceptibility to leprosy. It is therefore necessary that research be continued via a study with a larger number of patients in each group in order to verify the genes that are possibly related to protection against and susceptibility to leprosy, and to disease progression, in this Brazilian population.