Comparative analysis of natural resistance-associated macrophage protein 1 gene expression and anti-PGL-1 antibodies in multibacillary leprosy and household contacts.

Leprosy continues to pose a significant challenge to public health, particularly in certain global regions. Accurate diagnosis and understanding of the disease's etiology are crucial for effective management and prevention. This study aimed to explore the contribution of Natural resistance-associated macrophage protein 1 (NRAMP1) and its genetic variations, as well as the levels of anti-PGL-1 antibodies, to the pathology of multibacillary leprosy in affected individuals and their household contacts. The study included 23 multibacillary leprosy patients and 28 household contacts. NRAMP1 protein expression and anti-PGL-1 IgG and IgM levels were measured using PCR and ELISA techniques, respectively. Genotypic variants of the NRAMP1 gene were also examined. Statistical analyses, including Mann-Whitney tests and univariate logistic regression, were employed to evaluate the data. Significant differences were observed in NRAMP1 protein expression and IgG and IgM levels between the patient and household contact groups. The study also highlighted the role of the NRAMP1 gene and its D543N and 3'UTR polymorphisms in leprosy susceptibility. No significant differences were observed in the genotype variants of INT4 between the two groups. These findings emphasize the potential of integrating PCR technology with serological tests to enhance diagnostic precision in leprosy. They also suggest the need for further research to clarify the role of NRAMP1 and its polymorphisms in leprosy susceptibility and resistance.

Anti-phospholipid syndrome in seven leprosy patients with thrombotic events on corticosteroid and/or thalidomide regimen: insights on genetic and laboratory profiles

Abstract INTRODUCTION Corticosteroids and/or thalidomides have been associated with thromboembolism events (TBE) in multibacillary (MB) leprosy. This report aimed to determine genetic and laboratory profiles associated with leprosy and TBE. METHODS Antiphospholipid antibodies (aPL), coagulation-related exams, prothrombin and Leiden's factor V mutations, and ß2-glycoprotein-I (ß2GPI) Val247Leu polymorphism were assessed. RESULTS Six out of seven patients with leprosy were treated with prednisone and/or thalidomide during TBE and presented at least one positive aPL. All patients presented ß2GPI polymorphism, and one showed prothrombin mutation. CONCLUSIONS Corticosteroid or thalidomide adverse effects and aPL and ß2GPI polymorphisms may cause TBE in patients with MB leprosy.

Association of the solute carrier family 11 member 1 gene polymorphisms with susceptibility to leprosy in a Brazilian sample

Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1) is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GT)n, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively), and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GT)n polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR) = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66). Patients carrying the 274T allele (p = 0.04; OR = 1.49) and TT homozygosis (p = 0.02; OR = 2.46), such as the 469+14C allele (p = 0.03; OR = 1.53) of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GT)n polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively.

Polimorfismos do gene NRAMP1 em indivíduos com reações hansênicas, atendidos em dois Centros de Referência no Recife, nordeste do Brasil / NRAMP1 gene polymorphisms in individuals with leprosy reactions attended at two reference centers in Recife, northeastern Brazil

INTRODUÇÃO: Para investigar susceptibilidade às reações hansênicas, três polimorfismos do gene natural resistance-associated macrophage protein (NRAMP1), foram determinados em 201 indivíduos, atendidos em dois centros de referência no Recife, entre 2007 e 2008, sendo 100 paucibacilares e 101 multibacilares. MÉTODOS: A determinação dos polimorfismos 274C/T, D543N e 1729+55del4 do gene NRAMP1 foi realizada utilizando a técnica do polimorfismo de fragmento de restrição em DNA extraído de sangue periférico e as estimativas das freqüências alélicas e genotípicas foram feitas por contagem direta. RESULTADOS: Os genótipos predominantes foram: CC (51,8 por cento) para 274C/T, GG (86,6 por cento) para D543N e +-TGTG (59,9 por cento) para 1729+55del4. O genótipo mutante 274 TT predominou na negatividade da reação reversa (p=0,03) e na positividade do eritema nodoso (p=0,04). CONCLUSÕES: Nossos resultados sugerem que o polimorfismo 274 C/T do gene NRAMP1 pode auxiliar na determinação da susceptibilidade à reação tipo II em indivíduos com hanseníase.

INTRODUCTION: To investigate susceptibility to leprosy reactions, three polymorphisms of the natural resistance-associated macrophage protein (NRAMP1) gene were determined in 201 individuals who were attended at two reference centers in Recife, between 2007 and 2008. Of these, 100 were paucibacillary and 101 were multibacillary. METHODS: The 274C/T, D543N and 1729+55del4 polymorphisms of the NRAMP1 gene were determined using the technique of restriction fragment polymorphism on DNA extracted from peripheral blood. Allelic and genotypic frequencies were estimated by direct counting. RESULTS: The predominant genotypes were: CC (51.8 percent) for 274C/T; GG (86.6 percent) for D543N; and +-TGTG (59.9 percent) for 1729+55del4. The mutant genotype 274 TT predominated in negativity of the reverse reaction (p = 0.03) and in positivity of erythema nodosum leprosum (p = 0.04). CONCLUSIONS: Our results suggest that 274 C/T polymorphism of the NRAMP1 gene may aid in determining the susceptibility to type II reactions among leprosy patients.

Polimorfismo Val247Leu do gene β2-glicoproteína 1 pode justificar a gênese de anticorpos antiβ2GP1 e síndrome do anticorpo antifosfolípide na hanseníase multibacilar / Val247Leu polymorphism of β2 glycoprotein 1 gene may justify the genesis of anti β2GP1 antibodies and Antiphospholipid Syndrome in Multibacillary Leprosy

FUNDAMENTOS - Anticorpos antifosfolípides (AAF), como antiβ2GP1 (β2-glicoproteína 1), são descritos na hanseníase multibacilar (MB) sem, contudo, caracterizar a síndrome do anticorpo antifosfolípide (SAF), constituída por fenômenos tromboembólicos (FTE). A mutação Val247Leu no V domínio da β2GP1 - substituição da leucina por valina - expõe epítopos crípticos com consequente formação de anticorpos antiβ2GP1. OBJETIVO: Avaliar a associação do polimorfismo Val247Leu do gene β2GP1 com títulos de anticorpos antiβ2GP1 na hanseníase. MÉTODO: O polimorfismo Val247Leu foi detectado por PCR-RFLP, e os títulos de anticorpos antiβ2GP1, por Elisa. RESULTADOS: O genótipo Val/Val estatisticamente predominou no grupo de hansênicos, em relação ao controle. Embora maiores títulos de anticorpos antiβ2GP1 IgM estivessem alocados no grupo MB com genótipos Val/Val e Val/Leu, não houve diferença estatística em relação ao genótipo Leu/Leu. Dos sete pacientes MB com FTE, quatro apresentaram heterozigose, e três Val/Val homozigose. CONCLUSÃO: A prevalência do genótipo Val/Val no grupo de hansênicos pode justificar parcialmente a presença de anticorpos antiβ2GP1 na forma MB. A heterozigose ou homozigose Val/Val nos sete pacientes com hanseníase MB e FTE corroboram a implicação de expressão fenotípica anômala da β2GPl e formação de anticorpos antiβ2GPl, com consequente FTE e SAF.

BACKGROUND - Multibacillary (MB) leprosy may be manifested with antiphospholipid antibodies (aPL), among which anti-β2GP1 (β2-glycoprotein 1). High titers of aPL are associated with APS (Antiphospholipid Syndrome), characterized by thrombosis. The mutation Val247Leu in the domain V of β2GP1 exposes hidden epitopes with consequent development of anti-β2GP1 antibodies. OBJECTIVE: To evaluate the Val247Leu polymorphism of β2GP1 gene and its correlation with anti-β2GP1 antibodies in leprosy patients. METHODS: The Val247Leu polymorphism was performed by PCR-RFLP and anti-β2GP1 antibodies were measured by ELISA. RESULTS: The genotypic Val/Val was more prevalent in the leprosy group, compared to controls. Regarding the 7 MB patients with APS, four presented heterozygosis and three, Val/Val homozygosis. Although higher titrations of anti-β2GP1 IgM antibodies were seen in MB leprosy group with Val/Leu and Val/Val genotypes, there was no statistical difference when compared to Leu/Leu genotype. CONCLUSION: The prevalence of Val/Val homozygosis in leprosy group can partially justify the presence of anti-β2GP1 IgM antibodies in MB leprosy. The description of heterozygosis and Val/Val homozygosis in 7 patients with MB leprosy and thrombosis corroborates the implication of anomalous phenotype expression of β2GP1 and development of anti-β2GP1 antibodies, with consequent thrombosis and APS.