RESUMO
Viral coinfection among HIV-positive patients, coupled with the development of AIDS, remains a major public health problem. The synergism between the presence of HIV and other viruses has consequences in relation to changes in the severity of the infection, as well as changes in the natural course of both infections. Several polymorphisms present in genes that encode cytokines have a relevant influence on their transcription and consequently on the production of such immunological molecules. The present study evaluated the influence of SNPs located in the promoter regions of genes encoding the cytokines INF-É£, TNF, IL-6, IL-4, and IL-2, as well as their respective plasma concentrations, in patients infected with HIV and/or EBV in the state of Pará. Additionally, this study described the epidemiological profile and compared CD4+ and CD8+ T lymphocyte counts among the groups studied. The associative analysis between the SNPs and plasma cytokine concentrations in different groups showed statistical relevance for three polymorphisms: rs2069762 (IL2), where the GG genotype demonstrated higher IL-2 levels in HIV mono-infected individuals; rs2243250 (IL4), where the CT genotype showed higher IL-4 levels in the control group; and rs2069705 (IFNG), where the TT genotype showed higher IFN-γ levels in the coinfected group. Regarding SNP associations with CD4+/CD8+ counts, significant findings were observed in HIV mono-infected individuals: the rs2069705 (IFNG) polymorphism was linked to higher CD4+ counts with the CT genotype, and rs1799964 (TNF) was associated with higher CD8+ counts with the CC genotype. Therefore, this study provides evidence that the rs2069705 (IFNG) SNP is associated with elevated IFN-γ levels, which may have pathogenic consequences, as depletion of this cytokine is concerning for people living with HIV due to its antiviral properties.
Assuntos
Coinfecção , Citocinas , Infecções por Vírus Epstein-Barr , Infecções por HIV , HIV-1 , Herpesvirus Humano 4 , Polimorfismo de Nucleotídeo Único , Humanos , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , Infecções por HIV/complicações , Brasil/epidemiologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Masculino , Adulto , Feminino , HIV-1/imunologia , HIV-1/genética , Citocinas/genética , Citocinas/sangue , Pessoa de Meia-Idade , Coinfecção/virologia , Coinfecção/imunologia , Coinfecção/genética , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/genética , Genótipo , Linfócitos T CD8-Positivos/imunologia , Adulto Jovem , Contagem de Linfócito CD4 , ImunogenéticaRESUMO
OBJECTIVES: The aim of this study is to evaluate some mechanisms of the immune response of people infected with SARS-CoV-2 in both acute infection and early and late convalescence phases. METHODS: This is a cohort study of 70 cases of COVID-19, confirmed by RT-PCR, followed up to 60 days. Plasma Samples and clinical data were. Viral load, blood count, indicators inflammation were the parameters evaluated. Cellular immune response was evaluated by flow cytometry and Luminex immunoassays. RESULTS: In the severe group, hypertension was the only reported comorbidity. Non severe patients have activated memory naive CD4+ T cells. Critically ill patients have central memory CD4+ T cell activation. Severe COVID-19 patients have both central memory and activated effector CD8+ T cells. Non-severe COVID-19 cases showed an increase in IL1ß, IL-6, IL-10 and TNF and severely ill patients had higher levels of the cytokines IL-6, IL-10 and CXCL8. CONCLUSIONS: The present work showed that different cellular responses are observed according to the COVID-19 severity in patients from Brazil an epicenter the pandemic in South America. Also, we notice that some cytokines can be used as predictive markers for the disease outcome, possibility implementation of strategies effective by health managers.
Assuntos
COVID-19 , Humanos , SARS-CoV-2/genética , Interleucina-10 , Estudos de Coortes , Interleucina-6 , Brasil/epidemiologia , Imunogenética , Citocinas , Imunidade CelularRESUMO
HLA-B is among the most variable gene in the human genome. This gene encodes a key molecule for antigen presentation to CD8+ T lymphocytes and NK cell modulation. Despite the myriad of studies evaluating its coding region (with an emphasis on exons 2 and 3), few studies evaluated introns and regulatory sequences in real population samples. Thus, HLA-B variability is probably underestimated. We applied a bioinformatics pipeline tailored for HLA genes on 5347 samples from 80 different populations, which includes more than 1000 admixed Brazilians, to evaluate the HLA-B variability (SNPs, indels, MNPs, alleles, and haplotypes) in exons, introns, and regulatory regions. We observed 610 variable sites throughout HLA-B; the most frequent variants are shared worldwide. However, the haplotype distribution is geographically structured. We detected 920 full-length haplotypes (exons, introns, and untranslated regions) encoding 239 different protein sequences. HLA-B gene diversity is higher in admixed populations and Europeans while lower in African ancestry individuals. Each HLA-B allele group is associated with specific promoter sequences. This HLA-B variation resource may improve HLA imputation accuracy and disease-association studies and provide evolutionary insights regarding HLA-B genetic diversity in human populations.
Assuntos
Imunogenética , Polimorfismo de Nucleotídeo Único , Humanos , Alelos , Haplótipos , Antígenos HLA-B/genética , Frequência do GeneRESUMO
Introducción: Las alteraciones en el estado redox celular se han descrito como factores causales en diversas enfermedades. La depleción del glutatión reducido se ha asociado fundamentalmente a enfermedades neurodegenerativas, pulmonares, hepáticas, cardiovasculares e inmunológicas. Objetivo: Determinar las concentraciones de glutatión reducido y el estado redox celular en pacientes pediátricos con inmunodeficiencias. Métodos: Se estudiaron 21 pacientes con inmunodeficiencias procedentes de la consulta de Inmunogenética, en edades comprendidas entre 1 y 8 años, de ambos sexos, y 8 niños en el mismo rango de edad de los pacientes, como grupo control, con estudios de inmunidad humoral y celular normales. Los pacientes con diagnóstico de inmunodeficiencia se dividieron para su estudio en 2 grupos según el componente afectado de la respuesta inmune: humoral y celular. Fueron determinadas las concentraciones intraeritrocitarias de glutatión reducido y oxidado, mediante un método de HPLC-UV. Para evaluar el estado redox celular se calculó la relación entre las formas reducidas y oxidadas del glutatión (GSH/GSSG). Resultados: Las concentraciones de glutatión reducido y el estado redox celular se encontraron disminuidos en ambos grupos de pacientes en relación con los niños sin inmunodeficiencia (p=0,031 y p=0,03; respectivamente). El glutatión oxidado no mostró diferencias entre los grupos. Conclusiones: En los pacientes con inmunodeficiencia se evidenció la afectación del estado redox celular como consecuencia de la disminución del glutatión reducido. Este primer acercamiento ofreció las potencialidades del empleo de estos biomarcadores en la evaluación integral de pacientes con inmunodeficiencia(AU)
Introduction: Alterations in the cellular redox state have been described as causal factors in various diseases. Reduced glutathione depletion has been fundamentally associated with neurodegenerative, pulmonary, liver, cardiovascular and immunological diseases. Objective: To determine the concentrations of reduced glutathione and the cellular redox status in pediatric patients with immunodeficiencies. Methods: We studied 21 patients with immunodeficiencies from the immunogenetic service, aged between 1 and 8 years and as a control group, 8 children in the same age range as the patients, with normal humoral and cellular immunity studies. Patients diagnosed with immunodeficiency were divided into two groups according to the affected component of the immune response: humoral and cellular. The intraerythrocyte concentrations of oxidized and reduced glutathione were determined by means of an HPLC-UV method. To evaluate the cellular redox state, the relationship between the reduced and oxidized forms of glutathione (GSH/GSSG) was calculated. Results: Reduced glutathione concentrations and cellular redox status were found to be decreased in both groups of patients in relation to children without immunodeficiency (p=0,031 and p=0,03; respectively). Oxidized glutathione showed no difference between the groups. Conclusions: In patients with immunodeficiency, the cellular redox state is affected as a consequence of the decrease in reduced glutathione. This first approach offers the potential for the use of these biomarkers in the comprehensive evaluation of patients with immunodeficiency(AU)
Assuntos
Humanos , Lactente , Pré-Escolar , Criança , Biomarcadores , Cromatografia Líquida de Alta Pressão , Doenças Neurodegenerativas , Glutationa/análise , Imunogenética , Doenças do Sistema Imunitário , Grupos Controle , Dissulfeto de GlutationaRESUMO
Habitat fragmentation and infectious diseases threaten wildlife globally, but the interactions of these threats are poorly understood. For instance, while habitat fragmentation can impact genetic diversity at neutral loci, the impacts on disease-relevant loci are less well-studied. We examined the effects of habitat fragmentation in Brazil's Atlantic Forest on amphibian genetic diversity at an immune locus related to antigen presentation and detection (MHC IIB Exon 2). We used a custom high-throughput assay to sequence a fragment of MHC IIB and quantified Batrachochytrium dendrobatidis (Bd) infections in six frog species in two Atlantic Forest regions. Habitat fragmentation was associated with genetic erosion at MHC IIB Exon 2. This erosion was most severe in forest specialists. Significant Bd infections were detected only in one Atlantic Forest region, potentially due to relatively higher elevation. In this region, forest specialists showed an increase in both Bd prevalence and infection loads in fragmented habitats. Reduced population-level MHC IIB diversity was associated with increased Bd infection risk. On the individual level, MHC IIB heterozygotes exhibited a trend toward reduced Bd infection risk, although this was marginally non-significant. Our results suggest that habitat fragmentation increases Bd infection susceptibility in amphibians, mediated at least in part through erosion of immunogenetic diversity. Our findings have implications for management of fragmented populations in the face of emerging infectious diseases.
Assuntos
Quitridiomicetos , Micoses , Anfíbios , Animais , Anuros/genética , Brasil/epidemiologia , Ecossistema , Florestas , Imunogenética , Micoses/epidemiologia , Micoses/genética , Micoses/veterináriaRESUMO
HLA-G is a promiscuous immune checkpoint molecule. The HLA-G gene presents substantial nucleotide variability in its regulatory regions. However, it encodes a limited number of proteins compared to classical HLA class I genes. We characterized the HLA-G genetic variability in 4640 individuals from 88 different population samples across the globe by using a state-of-the-art method to characterize polymorphisms and haplotypes from high-coverage next-generation sequencing data. We also provide insights regarding the HLA-G genetic diversity and a resource for future studies evaluating HLA-G polymorphisms in different populations and association studies. Despite the great haplotype variability, we demonstrated that: (1) most of the HLA-G polymorphisms are in introns and regulatory sequences, and these are the sites with evidence of balancing selection, (2) linkage disequilibrium is high throughout the gene, extending up to HLA-A, (3) there are few proteins frequently observed in worldwide populations, with lack of variation in residues associated with major HLA-G biological properties (dimer formation, interaction with leukocyte receptors). These observations corroborate the role of HLA-G as an immune checkpoint molecule rather than as an antigen-presenting molecule. Understanding HLA-G variability across populations is relevant for disease association and functional studies.
Assuntos
Antígenos HLA-G/genética , Polimorfismo Genético , Regiões 3' não Traduzidas , Alelos , Biologia Computacional , Dimerização , Evolução Molecular , Frequência do Gene , Genes MHC Classe I , Variação Genética , Genética Populacional , Genótipo , Saúde Global , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas de Checkpoint Imunológico/genética , Imunogenética , Íntrons , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Tissue damage observed in the clinical forms of chronic symptomatic Chagas disease seems to have a close relationship with the intensity of the inflammatory process. The objective of this study was to investigate whether the MICA (MHC class I-related chain A) and KIR (killer cell immunoglobulin-like receptors) polymorphisms are associated with the cardiac and digestive clinical forms of chronic Chagas disease. Possible influence of these genes polymorphisms on the left ventricular systolic dysfunction (LVSD) in patients with chronic Chagas heart disease was also evaluated. This study enrolled 185 patients with positive serology for Trypanosoma cruzi classified according to the clinical form of the disease: cardiac (n=107) and digestive (n=78). Subsequently, patients with the cardiac form of the disease were sub-classified as with LVSD (n=52) and without LVSD (n=55). A control group was formed of 110 healthy individuals. Genotyping was performed by polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP). Statistical analyzes were carried out using the Chi-square test and odds ratio with 95% confidence interval was also calculated to evaluate the risk association. MICA-129 allele with high affinity for the NKG2D receptor was associated to the LVSD in patients with CCHD. The haplotype MICA*008~HLA-C*06 and the KIR2DS2-/KIR2DL2-/KIR2DL3+/C1+ combination were associated to the digestive clinical form of the disease. Our data showed that the MICA and KIR polymorphisms may exert a role in the LVSD of cardiac patients, and in digestive form of Chagas disease.
Assuntos
Cardiomiopatia Chagásica/etiologia , Doença de Chagas/complicações , Gastroenteropatias/etiologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Receptores KIR/genética , Disfunção Ventricular Esquerda/etiologia , Alelos , Estudos de Casos e Controles , Cardiomiopatia Chagásica/diagnóstico , Cardiomiopatia Chagásica/metabolismo , Doença de Chagas/parasitologia , Suscetibilidade a Doenças/imunologia , Gastroenteropatias/diagnóstico , Gastroenteropatias/metabolismo , Predisposição Genética para Doença , Antígenos HLA/genética , Antígenos HLA/imunologia , Haplótipos , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Imunogenética , Receptores KIR/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
The anti-inflammatory cytokine transforming growth factor beta (TGF-ß) plays an important role in Chagas disease (CD), a potentially life-threatening illness caused by Trypanosoma cruzi. In this review we revisited clinical studies in CD patients combined with in vitro and in vivo experiments, presenting three main sections: an overview of epidemiological, economic, and clinical aspects of CD and the need for new biomarkers and treatment; a brief panorama of TGF-ß roles and its intracellular signaling pathways, and an update of what is known about TGF-ß and Chagas disease. In in vitro assays, TGF-ß increases during T. cruzi infection and modulates heart cells invasion by the parasite fostering its intracellular parasite cycle. TGF-ß modulates host immune response and inflammation, increases heart fibrosis, stimulates remodeling, and slows heart conduction via gap junction modulation. TGF-ß signaling inhibitors reverts these effects opening a promising therapeutic approach in pre-clinical studies. CD patients with higher TGF-ß1 serum level show a worse clinical outcome, implicating a predictive value of serum TGF-ß as a surrogate biomarker of clinical relevance. Moreover, pre-clinical studies in chronic T. cruzi infected mice proved that inhibition of TGF-ß pathway improved several cardiac electric parameters, reversed the loss of connexin-43 enriched intercellular plaques, reduced fibrosis of the cardiac tissue, restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Finally, TGF-ß polymorphisms indicate that CD immunogenetics is at the base of this phenomenon. We searched in a Brazilian population five single-nucleotide polymorphisms (-800 G>A rs1800468, -509 C>T rs1800469, +10 T>C rs1800470, +25 G>C rs1800471, and +263 C>T rs1800472), showing that CD patients frequently express the TGF-ß1 gene genotypes CT and TT at position -509, as compared to noninfected persons; similar results were observed with genotypes TC and CC at codon +10 of the TGF-ß1 gene, leading to the conclusion that 509 C>T and +10 T>C TGF-ß1 polymorphisms are associated with Chagas disease susceptibility. Studies in genetically different populations susceptible to CD will help to gather new insights and encourage the use of TGF-ß as a CD biomarker.
Assuntos
Doença de Chagas , Trypanosoma cruzi , Animais , Biomarcadores , Doença de Chagas/parasitologia , Humanos , Imunogenética , Camundongos , Fator de Crescimento Transformador beta/metabolismo , Trypanosoma cruzi/metabolismoRESUMO
Las inmunodeficiencias primarias constituyen un grupo de más de 300 enfermedades frecuentemente graves y a menudo mortales que reflejan un déficit cuantitativo o cualitativo en uno o más componentes del sistema inmunitario. Son el resultado de defectos genéticos heredados que suelen afectar a 1 de cada 8000 a 10 000 nacidos vivos. Las manifestaciones clínicas suelen ser muy variadas, debido a que en su mayoría presentan una amplia heterogeneidad genética: infecciones (comunes recurrentes, comunes graves, o raras y graves), inflamación, autoinmunidad, malignidad o alergia. Teniendo en cuenta que a los profesionales médicos de diversas especialidades les resulta difícil identificar cuándo están en presencia de una IDP, nos proponemos describir las características clínicas, epidemiológicas, inmunitarias y genéticas de las inmunodeficiencias primarias. Para la realización de la revisión bibliográfica se utilizaron 27 referencias bibliográficas(AU)
Primary immunodeficiencies constitute a group of more than 300 frequently serious and often fatal diseases that reflect a quantitative and / or qualitative deficit in one or more components of the immune system. They are the result of inherited genetic defects that usually affect 1 in 8,000 to 10,000 live births. The clinical manifestations are usually very varied, because they mostly have a wide genetic heterogeneity, they can be caused by infections (common recurring, common serious, or rare and serious), inflammation, autoimmunity, malignancy, or allergy. Given that medical professionals of various specialties find it difficult to identify when they are in the presence of an primary immunodeficiency, it is proposed as an objective: to describe the clinical, epidemiological, immunological and genetic characteristics of Primary immunodeficiency. For the literature review, 27 bibliographic references were used(AU)
Assuntos
Humanos , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/epidemiologia , Imunogenética , AutoimunidadeRESUMO
Currently, stem cell donor registries include more than 35 million potential donors worldwide to provide HLA-matched stem cell products for patients in need of an unrelated donor transplant. DKMS is a leading stem cell donor registry with more than 9 million donors from Germany, Poland, the United States, the United Kingdom, India and Chile. DKMS donors have donated hematopoietic stem cells more than 80,000 times. Many aspects of donor registry work are closely related to topics from immunogenetics or population genetics. In this two-part review article, we describe, analyse and discuss these areas of donor registry work by using the example of DKMS. Part 1 of the review gives a general overview on DKMS and includes typical donor registry activities with special focus on the HLA system: high-throughput HLA typing of potential stem cell donors, HLA haplotype frequencies and resulting matching probabilities, and donor file optimization with regard to HLA diversity.