HLA-DRB1 leprogenic motifs in Nigerian population groups

Abstract

SUMMARYAmino acid residues involved in the peptide binding groove of HLA-DRB1 alleles were examined in three Nigerian ethnic groups with leprosy (n ¼ 287) and 170 controls to determine the role of DRB1 alleles in disease outcome with Mycobacterium leprae. Nine positively charged motifs and two others with neutral charge to the binding groove were detected. These motifs occurred more frequently in leprosy (leprogenic) than was expected by chance (P < 0·0001). In contrast, five motifs with net negative or 'modified' neutral charges to the pocket were negatively associated with leprosy. We conclude that clinical outcome of infection with M. leprae is largely determined by a shared epitope in DRB1 alleles marked by several motifs. These motifs occur in otherwise normal DRB1 alleles, characterized by net positive or neutral charges in the binding groove. We hypothesize that these polarities cause poor binding of DRB1 to M. leprae. On presentation, the signal via the T cell receptor results in muted cellmediated immunity. The resulting response translates to various forms of leprosy depending on degree of charge consonance between M. leprae and host DRB1 allele. Other factors within or without the HLA complex, such as the T cell receptor repertoire, may also influence the resulting disease.

TNF-α promoter single nucleotide polymorphisms are markers of human ancestry

“…14 Included were individuals randomly selected from a western African population from southern Nigeria, 15 individuals randomly selected from an eastern African population from Malawi, 16 and individuals from a population of African-American/Caribbean background enriched for a haplotype found in Southern African Xhosa individuals. 17 The results obtained confirm the positions of the SNPs at À1030, À862, À856, À574, À375, À307, À243, and À237 nucleotides upstream of the TNF-a transcription start site and the TNF-a promoter consensus sequence reported by Uglialoro et al 7 This is in contrast to an older numbering system that assigned the nucleotide positions of these SNPs one base pair upstream of their actual location.…”

“…DNA samples from 27 unrelated individuals were randomly selected from 457 individuals from a second African population from southern Nigeria. 15 Genomic DNA was also obtained from a third African-derived population of 17 individuals of African-American and African-Caribbean descent living in Boston, MA. 17 Peripheral blood mononuclear cells (PBMCs) were drawn from 20 unrelated Cambodians.…”

Genetic studies of African populations: an overview on disease susceptibility and response to vaccines and therapeutics

“…To date, several genetic studies have identiWed genes putatively important in leprosy susceptibility, including the PARK2/ PACRG and LTA genes (6q25) in inXuencing susceptibility to leprosy per se in Indian, Vietnamese and Brazilian subjects, as well as a locus on 10p13 linked to the tuberculoid, paucibacillary form in population samples from India and Vietnam (Alter et al 2008;Ranque et al 2008 for a review). Few studies have been carried out on African populations, with exceptions in Nigerians, describing the role of HLA associations (Class II DRB1 leprogenic motifs modulating the clinical outcome of infection, Uko et al 1999), and in Malians for non-HLA genes (SLC11A1 3' allele associated with lepromatous type, Meisner et al 2001). More recently, linkage and large-scale candidate gene studies with samples from the Karonga district of northern Malawi have been performed (Wallace et al 2004;).…”

Genetics of susceptibility to leprosy

“…Instead it appears that certain residues that contribute to the net charge in the putative peptide-specific binding pocket 4 may be more important. 47 It is hypothesized that net negative or neutral charges in binding pocket 4 cause poor binding of the DRB1 molecule to M. leprae antigens. As HLA molecules with the highest affinity to peptide produce the greatest T-cell proliferation and IFN-g response, 48 peptide presentation by low affinity class II molecules may result in muted cell-mediated immunity.…”

“…As HLA molecules with the highest affinity to peptide produce the greatest T-cell proliferation and IFN-g response, 48 peptide presentation by low affinity class II molecules may result in muted cell-mediated immunity. 47 Alternatively, peptide presentation by specific class II molecules may result in activation of suppressor/regulatory T-cells. 49 Transporter 2, ATP-binding cassette, sub-family B (TAP2).…”