J.R. Moraes

Susceptibility to leprosy is associated with PARK2 and PACRG

Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year. It has long been thought that leprosy has a strong genetic component, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25–q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5′ regulatory region shared by the Parkinsons disease gene PARK2 and the co-regulated gene PACRG. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.

Desmoglein-1–specific T lymphocytes from patients with endemic pemphigus foliaceus (fogo selvagem)

Fogo selvagem (FS), the endemic form of pemphigus foliaceus, is a cutaneous autoimmune disease characterized by subcorneal blistering of the epidermis and the production of autoantibodies against the desmosomal antigen desmoglein-1 (Dsg1). Previously, we showed that mice injected with autoantibodies from FS patients develop a skin disease that reproduces the clinical, histological, and immunological features of FS, indicating that autoantibodies play an essential role in the development of this disease. The purpose of this study was to characterize the autoimmune T-cell response associated with FS. We provide here the first evidence, to our knowledge, that the great majority of FS patients have circulating T lymphocytes that specifically proliferate in response to the extracellular domain of Dsg1. Long-term T cells developed from these patients also responded to Dsg1, and this antigen-specific response was shown to be restricted to HLA-DR molecules. These Dsg1-reactive FS T cells exhibited a CD4-positive memory T-cell phenotype and produced a T helper 2-like cytokine profile. These findings represent the initial steps in defining the role of T cells in FS autoimmunity.

Interleukin-10 promoter single-nucleotide polymorphisms as markers for disease susceptibility and disease severity in leprosy

We have determined IL-10 promoter genotypes of five single-nucleotide polymorphisms (SNPs): T−3575A, A−2849G, C−2763A, -A−1082G and C−819T. The haplotype frequencies were defined in healthy subjects compared to leprosy patients, and analyzed for their occurrence in multi- (MB) vs paucibacillary (PB) as severe and mild forms of leprosy, respectively. Haplotypes defined by three SNP positions (−3575, −2849 and −2763) captured significant differences between controls and patients (P=0.04). The haplotype carrying −3575A, −2849G and −2763C was associated with resistance to leprosy and to the development of severe forms of the disease using either a binomial (controls vs cases, P=0.005, OR=0.35, CI=0.13–0.91) or ordinal (controls vs PB vs MB, P=0.006, OR=0.32, CI=0.12–0.83) model. By contrast, the IL-10 haplotype −3575T/−2849A/−2763C was found to be associated with susceptibility to leprosy per se (P=0.027, OR=2.37, CI=1.04–5.39), but not leprosy type. The data suggest that the IL-10 locus contributes to the outcome of leprosy.

Interleukin–10 promoter haplotypes are differently distributed in the Brazilian versus the Dutch population

Abstract.The frequency of five different single nucleotide polymorphisms of the promoter interleukin-10 (IL–10) gene (–3575, –2849, 2763, –1082, –819) was compared between two healthy populations, one originating from the Netherlands and one from Rio de Janeiro, Brazil. A total of 321 Caucasian Dutch individuals and 293 Brazilians, grouped as Afro–Brazilians and Euro–Brazilians, were genotyped using PCR–RFLP. The frequencies of the genotypes in the Brazilian population were different (P<0.05) from the frequencies in the Dutch population in all but one (–2763) genotype. The comparison of genotype frequencies between Afro– and Euro–Brazilians did not demonstrate any differences. The haplotype combination of the most-distant three polymorphisms showed strong linkage disequilibrium. All eight possible combinations were observed in Brazilians, but only seven in Dutch Caucasians. The haplotype frequencies were also significantly different between Brazilians when compared with Dutch and also between Euro–Brazilians and Dutch. No differences were observed in haplotype frequencies between Afro–Brazilians and Euro–Brazilians. The −3575T/–2849G/–2763C is more frequent, while the AAA haplotype was much less represented in the Brazilian than in the Dutch population. The haplotype TAC, which was described in African–Americans, was observed only in Brazilians, almost exclusively among those of European origin. The results corroborate the data indicating that the Brazilian population exhibits a genetic admixture of Africans, Europeans, and Amerindians, and the data may serve as a background for clinical and immunological studies involving the IL-10 locus.

Endemic pemphigus foliaceus (fogo selvagem) in Native Americans from Brazil

BACKGROUND Fogo selvagem (FS) is an autoimmune disease that is endemic in certain regions of Brazil and appears to be precipitated by an environmental factor. OBJECTIVE Our purpose was to confirm the occurrence and prevalence of FS in a population of Xavante Indians living in an endemic region of central Brazil. METHODS Clinical, anthropologic, and immunologic studies were carried out in patients and in normal inhabitants of the Pimentel Barbosa Indian Reservation, Mato Grosso, Brazil. RESULTS FS was identified and confirmed in 10 patients from a patient pool of 295 with various skin diseases. The Xavante settlement has a total population of 746. Anti-desmoglein 1 autoantibodies were detected in all patients with FS and were absent from more than 300 serum samples collected from randomly selected unaffected persons. CONCLUSION FS is strongly linked to outdoor activities and is largely restricted to immunogenetically predisposed persons. FS appears to have been endemic in certain regions of South America for several centuries.

HLA in Brazilian Ashkenazic Jews with chronic dermatophytosis caused by Trichophyton rubrum

The frequency of HLA (Human Leucocyte Antigens) was analyzed in 25 non-consanguineous Brazilian Ashkenazic Jews, resident in the city of Sao Paulo, Brazil, suffering from chronic dermatophytosis caused by T. rubrum, and in 25 non-infected individuals belonging to the same ethnic group. Statistically significant values (p<0.05) were observed for HLA-B14 associated with resistance to chronic dermatophytosis and HLA-DQB1*06 (p=0.05) possibly related to susceptibility. These findings suggest that genes on the chromosome 6, in the region of the major histocompatibility complex, may influence the development of chronic dermatophytosis.