Hugo Vicentin Alves

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.

Red blood cell alloimmunization in patients with sickle cell disease: correlation with HLA and cytokine gene polymorphisms.

The reason for the difference in susceptibility to red blood cell (RBC) alloimmunization among patients with sickle cell disease (SCD) is not clearly understood and is probably the result of multiple factors. Our hypothesis is that genetic polymorphisms are associated with RBC alloimmunization.

Influence of KIR genes and their HLA ligands in the pathogenesis of leprosy in a hyperendemic population of Rondonópolis, Southern Brazil

BackgroundThe objective of this study was to investigate the association between KIR genes and the immunopathogenesis of leprosy.MethodsThe types of KIR and HLA genes were evaluated by PCR-SSOP-Luminex in 408 patients with leprosy and 413 healthy individuals. Statistical analysis was performed using the Chi-square or Fisher’s exact test and stepwise multivariate analysis.ResultsThere was a higher frequency of activating KIR genes (KIR2DS1, 2DS2 and 3DS1) together with their HLA ligands in the tuberculoid (TT) group as compared to the lepromatous leprosy (LL) group. KIR2DL2/2DL2-C1 was more frequent in the patient, TT and LL groups than in the control group. Borderline patients presented a higher frequency of inhibitory pairs when compared to the control group, and a higher frequency of activating pairs as compared to the LL group. Multivariate analysis confirmed the associations and demonstrated that being a female is a protective factor against the development of the disease per se and the more severe clinical form.ConclusionsThis study showed that activating and inhibitory KIR genes may influence the development of leprosy – in particular, activating genes may protect against the more aggressive form of the disease – thereby demonstrating the role of NK cells in the immunopathology of the disease.

Evidence of HLA-DQB1 Contribution to Susceptibility of Dengue Serotype 3 in Dengue Patients in Southern Brazil

Dengue infection (DI) transmitted by arthropod vectors is the viral disease with the highest incidence throughout the world, an estimated 300 million cases per year. In addition to environmental factors, genetic factors may also influence the manifestation of the disease; as even in endemic areas, only a small proportion of people develop the most serious form. Immune-response gene polymorphisms may be associated with the development of cases of DI. The aim of this study was to determine allele frequencies in the HLA-A, B, C, DRB1, DQA1, and DQB1 loci in a Southern Brazil population with dengue virus serotype 3, confirmed by the ELISA serological method, and a control group. The identification of the HLA alleles was carried out using the SSO genotyping PCR program (One Lambda), based on Luminex technology. In conclusion, this study suggests that DQB1∗06:11 allele could act as susceptible factors to dengue virus serotype 3, while HLA-DRB1∗11 and DQA1∗05:01 could act as resistance factors.

Killer-cell immunoglobulin-like receptors associated with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) affects the endocrine system and is associated with low-grade inflammation. Natural killer (NK) cells are involved in the defense of the female reproductive tract, folliculogenesis, ovulation and the menstrual cycle. The killer-cell immunoglobulin-like receptors (KIR) on the surface of NK cells modulate the activation and function of these cells after interacting with human leukocyte antigen (HLA) class I ligands. The objective of this study was to evaluate the possible association of the KIR and their HLA ligands with polycystic ovary syndrome. METHODS Ninety-three patients with PCOS according to the Rotterdam criteria and 104 healthy controls were included in this study. The HLA class I and KIR genotypes were determined using a PCR-SSO technique, rSSO Luminex®. In order to assess whether the distribution of the HLA and KIR genotypes was in Hardy-Weinberg equilibrium, Arlequin 3.1 software was used. The frequency distributions in the two study groups were compared using the chi-squared statistic with Yates´s correction using Open Epi software. RESULTS The higher frequencies of KIR3DS1-Bw4 (41% vs. 19%, Pc = 0.002; OR = 2.90) and homozygotic KIR2DS4-del (54% vs. 26%, Pc = 0.0002; OR = 3.316) in patients compared with controls suggest they confer susceptibility to PCOS. A lower frequency of KIR2DS4-full was observed in patients (43% vs. 70%, Pc = 0.0004, OR = 0.320). CONCLUSION KIR and its HLA ligands were associated with the development of PCOS in the studied population.

IL8 and IL17A polymorphisms associated with multibacillary leprosy and reaction type 1 in a mixed population from southern Brazil

We evaluated the influence of the IL8 T‐738A (nonidentified rs), IL8 T‐353A (rs4073), IL17A G197A (rs2275913), and IL17F T7488C (rs763780) single‐nucleotide polymorphisms on leprosy. The AA genotype of IL8 T‐353A was observed as a risk factor for multibacillary leprosy, regardless of gender and age‐of‐onset of disease, considering the recessive model (OR, 3.8; 95% CI, 1.1–13.5; P, 0.023). Furthermore, the AA genotype of IL17A G197A was associated with leprosy type 1 reaction (OR, 2.4; 95% CI, 1.1–5.1; P, 0.026) when compared to the group without reaction, which was adjusted for gender and age‐of‐onset of disease by the model log additive. These results indicate association of IL8 and IL17A polymorphisms with the progression to multibacillary leprosy and with the type 1 reaction, respectively.

Concerning the KIR gene frequencies reported by Dr Araujo et al.

Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer cells and subsets of T cells. The KIR genes are polymorphic, highly homologous and found in a cluster on chromosome 19q13.4 within the 1Mb leukocyte receptor complex. The gene content of the KIR gene cluster varies among haplotypes, although several framework genes are found in all haplotypes (including KIR3DL3, KIR3DP1, KIR2DL4 and KIR3DL2). In spite of the extended diversity of the KIR genomic region, these four framework loci are nearly ubiquitous in the population, and the pseudogene (KIR3DP1) is not expressed.1 In the article published by Araujo et al. in Cellular and Molecular Immunology,2 the authors investigated the interaction between KIR genes and their human leukocyte antigen ligands in order to understand the mechanisms involved in the susceptibility or resistance to hepatitis B virus (HBV) infection. They used 20 individuals with occult HBV infection, 40 spontaneous HBV resolvers, 42 HBV carriers and 80 healthy blood donors recruited from the COLSAN blood bank (Associação Beneficente de Coleta de Sangue, São Paulo, Brazil). However, we have concerns about the gene frequencies found in those populations, especially for the well-defined haplotype including the framework genes KIR3DL3, KIR3DP1, KIR2DL4 and KIR3DL2. The frequencies of these genes, published by Araujo et al., were lower than those found in the Allele Frequency Database (http://www.allele frequencies.net/) in different populations. Taking the healthy blood donors, a control group, as an example, the gene frequencies were 41.2% (vs 99–100%, the range found in databases from different worldwide populations) for KIR3DL3, 51.2% (vs 86–100%) for KIR3DP1, 46.2% (vs 95–100%) for KIR2DL4 and 45.0% (vs 95.7–100%) for KIR3DL2. The same was also observed for other genes, including KIR2DP1 (50.0% vs 80–100%) and KIR2DS4 (43.7% vs 80–100%). Highlighting the framework genes and healthy blood donors, the distribution of KIR gene frequencies found by the authors2 seems to be inconsistent with those published in the literature. We believe that this remarkable difference is not justified. Brazilians are an admixed population presenting differences in genetic characteristics and geographic distribution. Even when considering this fact, the KIR distribution was similar in different studies (also included in the allele frequency database), as published by our research group on a population from Southern Brazilian (Paraná).3 Perce-da-Silva et al.4 published a study on a population from Northern Brazil in which 377 randomly selected unrelated individuals from rural communities, descendants of Amazon Amerindians, European settlers and Sub-Saharan Africans displayed framework gene frequencies equal to 100% for all groups. Supporting the allele frequency database, Hollenbach et al.5 presented the data at the 15th International Histocompatibility Workshop on KIR loci distribution in 27 populations worldwide from six broad ethnic groups, including two from Brazil. The range of frequency distributions was the same for the framework genes (76–100%). Underlying the diversity of the KIR genomic region, it has been accepted that there are patterns that appear conserved within the population, such as the regular spacing of KIR genes 2.4 kb between each other, and the presence of the framework genes KIR3DL3 and KIR3DL2 at the terminus of the region with KIR2DL4 in the Immunogenetics Laboratory, Department of Basic Health Sciences, Maringa State University, CEP 87020-900, Maringa, PR, Brazil and Department of Biotechnology, Genetics and Cellular Biology, Maringa State University, CEP 87020-900, Maringa, PR, Brazil. Correspondence: Dr JEL Visentainer, Department of Basic Health Sciences, Maringá State University, Av. Colombo, n. 5790, Jardim Universitário, CEP 87020-900, Maringá, PR, Brazil. E-mail: jelvisentainer@gmail.com Received: 22 October 2016; Accepted: 23 October 2016 Cellular & Molecular Immunology (2017) 14, 235–236 & 2017 CSI and USTC All rights reserved 2042-0226/17

P022 HLA-DRB1 and HLA-DQA1/B1 alleles in association with leprosy compared to household contacts

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