Pâmela Guimarães Reis

HLA-DR and HLA-DQ alleles in patients from the south of Brazil: markers for leprosy susceptibility and resistance

BackgroundMany epidemiological studies have shown that the genetic factors of the host play a role in the variability of clinical response to infection caused by M. leprae. With the purpose of identifying genes of susceptibility, the present study investigated the possible role of HLA-DRB1 and DQA1/DQB1 alleles in susceptibility to leprosy, and whether they account for the heterogeneity in immune responses observed following infection in a Southern Brazilian population.MethodsOne hundred and sixty-nine leprosy patients and 217 healthy controls were analyzed by polymerase chain reaction amplification and reverse hybridization with sequence-specific oligonucleotide probes and sequence-specific primers(One Lambda®, CA, USA).ResultsThere was a positive association of HLA-DRB1*16 (*1601 and *1602) with leprosy per se (7.3% vs. 3.2%, P = 0.01, OR = 2.52, CI = 1.26–5.01), in accord with previous serological studies, which showed DR2 as a marker of leprosy. Although, HLA-DQA1*05 frequency (29.8% vs. 20.9%, P = 0.0424, OR = 1.61, CI = 1.09–2.39) was higher in patients, and HLA-DQA1*02 (3.0% vs. 7.5%, P = 0.0392, OR = 0.39, CI = 0.16 – 0.95) and HLA-DQA1*04 (4.0% vs. 9.1%, P = 0.0314, OR = 0.42, CI = 0.19 – 0.93) frequencies lower, P-values were not significant after the Bonferronis correction. Furthermore, HLA-DRB1*1601 (9.0% vs. 1.8%; P = 0.0016; OR = 5.81; CI = 2.05–16.46) was associated with susceptibility to borderline leprosy compared to control group, and while HLA-DRB1*08 (11.2% vs. 1.2%; P = 0.0037; OR = 12.00; CI = 1.51 – 95.12) was associated with susceptibility to lepromatous leprosy, when compared to tuberculoid leprosy, DRB1*04 was associated to protection.ConclusionThese data confirm the positive association of HLA-DR2 (DRB1*16) with leprosy per se, and the protector effect of DRB1*04 against lepromatous leprosy in Brazilian patients.

Genetic Susceptibility to Chagas Disease: An Overview about the Infection and about the Association between Disease and the Immune Response Genes

Chagas disease, which is caused by the flagellate parasite Trypanosoma cruzi, affects 8–10 million people in Latin America. The disease is endemic and is characterised by acute and chronic phases that develop in the indeterminate, cardiac, and/or gastrointestinal forms. The immune response during human T. cruzi infection is not completely understood, despite its role in driving the development of distinct clinical manifestations of chronic infection. Polymorphisms in genes involved in the innate and specific immune response are being widely studied in order to clarify their possible role in the occurrence or severity of disease. Here we review the role of classic and nonclassic MHC, KIR, and cytokine host genetic factors on the infection by T. cruzi and the clinical course of Chagas disease.

Gene Association with Leprosy: A Review of Published Data

Leprosy is a chronic infectious disease caused by an obligate intracellular bacterium known as Mycobacterium leprae. Exposure to the bacillus is necessary, but this alone does not mean an individual will develop clinical symptoms of the disease. In recent years, several genes have been associated with leprosy and the innate immune response pathways converge on the main hypothesis that genes are involved in the susceptibility for the disease in two distinct steps: for leprosy per se and in the development of the different clinical forms. These genes participate in the sensing, main metabolic pathway of immune response activation and, subsequently, on the evolution of the disease into its clinical forms. The aim of this review is to highlight the role of innate immune response in the context of leprosy, stressing their participation in the signaling and targeting processes in response to bacillus infection and on the evolution to the clinical forms of the disease.

Role of HLA, KIR, MICA, and Cytokines Genes in Leprosy

Many genes including HLA, KIR, and MICA genes, as well as polymorphisms in cytokines have been investigated for their role in infectious disease. HLA alleles may influence not only susceptibility or resistance to leprosy, but also the course of the disease. Some combinations of HLA and KIR may result in negative as well as positive interactions between NK cells and infected host cells with M. leprae, resulting in activation or inhibition of NK cells and, consequently, in death of bacillus. In addition, studies have demonstrated the influence of MICA genes in the pathogenesis of leprosy. Specifically, they may play a role in the interaction between NK cells and infected cells. Finally, pro- and anti-inflammatory cytokines have been influencing the clinical course of leprosy. Data from a wide variety of sources support the existence of genetic factors influencing the leprosy pathogenesis. These sources include twin studies, segregation analyses, family-based linkage and association studies, candidate gene association studies, and, most recently, genome-wide association studies (GWAS). The purpose of this brief review was to highlight the importance of some immune response genes and their correlation with the clinical forms of leprosy, as well as their implications for disease resistance and susceptibility.

Killer Cell Immunoglobulin-like Receptors and Their HLA Ligands are Related with the Immunopathology of Chagas Disease

The aim of this study was to investigate the influence of killer cell immunoglobulin-like receptor (KIR) genes and their human leucocyte antigen (HLA) ligands in the susceptibility of chronic Chagas disease. This case-control study enrolled 131 serologically-diagnosed Chagas disease patients (59 men and 72 women, mean age of 60.4 ± 9.8 years) treated at the University Hospital of Londrina and the Chagas Disease Laboratory of the State University of Maringa. A control group was formed of 165 healthy individuals - spouses of patients or blood donors from the Regional Blood Bank in Maringa (84 men and 81 women, with a mean age of 59.0 ± 11.4 years). Genotyping of HLA and KIR was performed by PCR-SSOP. KIR2DS2-C1 in the absence of KIR2DL2 (KIR2DS2+/2DL2-/C1+) was more frequent in Chagas patients (P = 0.020; Pc = 0.040; OR = 2.14) and, in particular, those who manifested chronic chagasic cardiopathy—CCC (P = 0.0002; Pc = 0.0004; OR = 6.64; 95% CI = 2.30–18.60) when compared to the control group, and when CCC group was compared to the patients without heart involvement (P = 0.010; Pc = 0.020; OR = 3.97). The combination pair KIR2DS2+/2DL2-/KIR2DL3+/C1+ was also positively associated with chronic chagasic cardiopathy. KIR2DL2 and KIR2DS2 were related to immunopathogenesis in Chagas disease. The combination of KIR2DS2 activating receptor with C1 ligand, in the absence of KIR2DL2, may be related to a risk factor in the chronic Chagas disease and chronic chagasic cardiopathy.

Class-I human leukocyte alleles in leprosy patients from Southern Brazil

INTRODUCTION The present study was designed to investigate a possible role of HLA (histocompatibility leucocyte antigen) class-I alleles (HLA-A, -B, and -C) in leprosy patients from Southern Brazil. METHODS Two hundred and twenty-five patients with leprosy and 450 individuals for the control group were involved in this research. HLA genotyping was performed through PCR-SSO protocols (One Lambda, USA); the frequency of these alleles was calculated in each group by direct counting, and the frequencies were then compared. RESULTS There was an association between HLA-A*11 (6.9% vs 4.1%, p=0.0345, OR=1.72, 95% CI=1.05-2.81), HLA-B*38 (2.7% vs. 1.1%, p=0.0402, OR=2.44, 95% CI=1.05-5.69), HLA-C*12 (9.4% vs. 5.4%, p=0.01, OR=1.82, 95% CI=1.17-2.82), and HLA-C*16 (3.1% vs. 6.5%, p=0.0124, OR=0.47, 95% CI=0.26-0.85) and leprosy per se. In addition, HLA-B*35, HLA-C*04, and HLA-C*07 frequencies were different between lepromatous (LL) and tuberculoid (TT) patients. However, after adjusting for the number of alleles compared, Pc values became nonsignificant. CONCLUSIONS Although our results do not support the previous findings that HLA class-I alleles play a role in leprosy pathogenesis, we suggest new studies because of the importance of the association between the HLA and KIR in the innate immune response to leprosy.

Genetic Polymorphisms of IL17 and Chagas Disease in the South and Southeast of Brazil

The aim of this study was to investigate possible associations between genetic polymorphisms of IL17A G197A (rs2275913) and IL17F T7488C (rs763780) with Chagas Disease (CD) and/or the severity of left ventricular systolic dysfunction (LVSD) in patients with chronic Chagas cardiomyopathy (CCC). The study with 260 patients and 150 controls was conducted in the South and Southeast regions of Brazil. The genotyping was performed by PCR-RFLP. The A allele and A/A genotype of IL17A were significantly increased in patients and their subgroups (patients with CCC; patients with CCC and LVSD; and patients with CCC and severe LVSD) when compared to the control group. The analysis according to the gender showed that the A/A genotype of IL17A was more frequent in female with LVSD and mild to moderate LVSD and also in male patients with LVSD. The frequency of IL17F T/C genotype was higher in male patients with CCC and severe LVSD and in female with mild to moderate LVSD. The results suggest the possible involvement of the polymorphisms of IL17A and IL17F in the susceptibility to chronic Chagas disease and in development and progression of cardiomyopathy.

HLA-A, -B, -DRB1, -DQA1, AND -DQB1 PROFILE IN A POPULATION FROM SOUTHERN BRAZIL

The aim of this study was to determine the allele and haplotype frequencies of HLA‐A, ‐B, ‐DRB1, and ‐DQB1 in a self‐declared White population from the north and northwestern state of Paraná, southern Brazil, and compare the data with populations worldwide. The genotyping was performed with a group of 641 individuals, based on PCR‐SSO and ‐SSP methods, and allele and haplotype frequencies were estimated. Comparisons with European, African, Asian, and Amerindian populations were performed. The most frequent allelic groups, alleles and haplotypes were: HLA‐A*02, HLA‐B*35, HLA‐DRB1*07:01, HLA‐DQB1*03:01, and HLA‐A*01/B*08/DRB1*03:01. The results reinforced a predominance of a European composition in the self‐declared White population from the north and northwestern Paraná.

Cytokine gene polymorphisms in populations from Parana, Southern Brazil

In this study, were genotyped 22 single nucleotide polymorphisms (SNPs) in 13 genes that encode the pro-inflammatory (IL-1α, IL-1β, IL-1R, IL-4Rα, IL-12, IFN-γ, TNF-α, and IL-2) and anti-inflammatory (IL-1RA, TGF-β, IL-4, IL-6 and IL-10) cytokines of 350 individuals by PCR-SSP (polymerase chain reaction - sequence specific primer). A total of 473 individuals were genotyped for IL17A and IL17F genes by PCR-RFLP (restriction fragment length polymorphism). The sample consisted of healthy and unrelated subjects from a mixed population from Parana state, in the South region of Brazil. The frequency analyses and genotype data are available in the Supplementary materials and are accessible at Allele Frequency Net Database (AFND).