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Transplantation of stem cells derived from donors with CCR5Δ32 homozygous genotype is a potential strategy to achieve both the control of malignant hematological disease as well as sustained remission of the HIV infection, and researchers in different countries are looking for CCR5Δ32 homozygous donors to replicate such a 'double-target' strategy. We determined the frequency of the CCR5Δ32 variant in a sample of 1,398 bone marrow donors from Rio Grande do Sul State, Brazil. This study also evaluated whether HLA-A, HLA-B and HLA-DRB1 genotypes are homogeneously distributed between CCR5Δ32 carriers and non-carriers in a population characterized by a significant genetic admixture. The CCR5Δ32 allele frequency was 7.4% (CI0.95 6.4-8.4%), and the frequency of the Δ32/Δ32 homozygous genotype was 0.72% (CI0.95 0.34-1.31%). In general, HLA genotypes are homogeneously distributed between CCR5Δ32 carriers and non-carriers. Considering the large number of bone marrow donors in Brazil and the high CCR5Δ32 allele frequency observed in our study, our results clearly indicate the existence of a considerable amount of potential CCR5Δ32 homozygous bone marrow donors in southern Brazil, suggesting that an active search for these donors is not only feasible but an attractive and promising strategy towards effective HIV infection control and treatment.
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CONCLUSIONS: Chimerism is a phenomenon in which an individual has cells with different genetic content from different zygotes. In dizygotic twins (DTs), chimerism is believed to occur through placental anastomoses that enable the bidirectional exchange of hematopoietic stem cells. Little is still known about chimerism frequency in twins, but several studies have shown a relation between chimerism and some conditions such as autism, Alzheimer's disease, and a group of autoimmune diseases such as Sjögren syndrome, systemic lupus erythematosus, and systemic sclerosis. In addition to chimerism of ABO blood groups being possibly mistaken for ABO subgroups, these autoimmune diseases may affect other serologic immunohematologic tests. This study aimed to determine the frequency of chimerism in DTs through ABO and D testing using the tube method, column agglutination, and short tandem repeat (STR) assays. Among the 103 subjects assessed for this study, 24 subjects (12 pairs) were excluded because STR assays showed they were monozygotic; of the remaining, 70 subjects (35 pairs) were DTs and 9 subjects came from gestations of trizygotic triplets. No ABO or D chimerism was detected in any subject through serologic assays, and STR assays did not detect any blood chimerism. Although there was no evidence of chimerism found in this study, we emphasize the importance of observing the family background of individuals with suspected ABO subgroup in complex immunohematologic studies because ABO antigen-antibody reactions are similar in both circumstances, and chimerism can be overlooked. Moreover, the use of the STR analysis method in chimerism studies can be important to help differentiate chimerism and ABO subgroups.
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Sistema ABO de Grupos Sanguíneos , Quimerismo , Feminino , Humanos , GravidezRESUMO
BACKGROUND: Gaucher disease (GD) is caused by the reduced activity of lysosomal enzyme glucocerebrosidase, which leads to the accumulation of glucocerebroside in macrophages and a chronic stimulation of the immune system. GD is divided into 3 main types according to the presence or absence of neurological involvement and to its presentation (acute or chronic). Gaucher cells show an increase in their expression of HLA-DR antigens on their surface, and there is an increase in levels of antigen-presenting molecules. Over 100 diseases have already been associated to HLA antigens; however, this association has never been studied in GD. OBJECTIVES: To analyze the variability of HLA genes in a Southern Brazilian sample of GD patients, to compare it with controls, and to look for associations with clinical manifestations. METHODOLOGY: Thirty-one GD patients (24 mild, 4 moderate, and 3 severe) were included in the study. They were typed for HLA A, B, and DR and compared to 250 healthy controls. The clinical data were obtained from the review of medical records. RESULTS/DISCUSSION: There was a significant difference in the frequency of B37 allele among patients when compared to controls (p=0.011, OR 13.28). An association was found between DR11 (p=0.008) and DR13 (p=0.011) alleles and the severity of the disease. DR11 allele seems to be associated to neurologic compromise, while DR13 seems to be associated to osteonecrosis. CONCLUSION: Our data suggest a possible association of HLA variants and GD. The HLA variants must be further studied, for they seem to be a phenotype-modifier factor for GD.
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Doença de Gaucher/genética , Doença de Gaucher/imunologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Adolescente , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
UNLABELLED: A previous study suggested that the CXCR2 (+1208) TT genotype was associated with increased risk of systemic sclerosis (SSc). In the present study, we investigated the influence of variation in the CXCL8 and CXCR2 genes on susceptibility to SSc and combined the variant alleles of these genes to analyze their effects on SSc. METHODS: One fifty one patients with SSc and 147 healthy bone marrow donors were enrolled in a case-control study. Blood was collected for DNA extraction; typing of CXCL8 (-251) T/A and CXCR2 (+1208) T/C genes was made by polymerase chain reaction with sequence specific primers (PCR-SSP), followed by agarose gel electrophoresis. RESULTS: The CXCR2-TC genotype was significantly less frequent in patients (23.8% versus 55.1% in controls; P<0.001, OR=0.26, 95%CI=0.15-0.43), whereas the CXCR2-CC genotype was significantly more frequent (44.4% versus 22.4% in controls; P<0.001, OR=2.76, 95%CI, 1.62-4.72). When CXCR2 and CXCL8 combinations were analyzed, the presence of CXCR2 T in the absence of CXCL8 A (CXCR2 T+/CXCL8 A-) was more frequent in patients than in controls (34.5% versus 3.5%; P<0.001, OR=14.50, 95%CI=5.04-41.40). However, CXCR2 TT and CXCL8 A were significantly more common in controls (100%) than in patients (58.3%) (P<0.001). Likewise, the presence of CXCR2 TC and CXCL8 A was more frequent in controls (95.1%) than in patients (75%) (P=0.004). Furthermore, the CXCR2-CC genotype in CXCL8 A was more frequent in patients (59.7% versus 0% in controls; P<0.001, adjusted OR=98.67, 95%CI=6.04-1610.8). In patients, a high frequency was observed in combination with the CXCL8 TA and AA genotypes (P<0.001; OR=28.92), whereas in controls, there was a high frequency of combination with CXCL8 T (P<0.001; OR=0.03) and TT (P<0.001; OR=0.01). CONCLUSIONS: These findings suggest a protective role of CXCL8 (-251) A in the CXCR2 (+1208) TT and TC genotypes and an increased risk of CXCL8 (-251) A in association with the CXCR2 (+1208) CC genotype in SSc patients.
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Predisposição Genética para Doença , Interleucina-8/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Interleucina-8B/genética , Escleroderma Sistêmico/genética , Estudos de Casos e Controles , Frequência do Gene/genética , HumanosRESUMO
We developed two multiplex systems for the coamplification of X-chromosomal short tandem repeats (STRs). X-Multiplex 1 consisted of DXS6807, DXS6800, DXS7424, DXS101, GATA172D05 and HPRTB and X-Multiplex 2 consisted of DXS8378, DXS9898, DXS6801, DXS6809, DXS6789, DXS7133, DXS8377 and DXS7423. In addition, we present allele frequencies for these loci in a south Brazilian population comprising 124 females and 141 males and haplotype frequencies of linked markers for males. Hardy-Weinberg equilibrium (HWE) was tested in the female sample and no significant deviations were found after applying Bonferroni's correction. Linkage disequilibrium (LD) tests were performed for all pairs of loci and three significant results, out of 91 pairwise comparisons, were obtained. We did not find any evidence of linkage disequilibrium between close or linked markers. The power of discrimination in females (PD(F)) varied between 0.832 for DXS6801 and 0.987 for DXS8377. DXS6801 was the least informative marker (PIC = 0.605), while DXS8377 was the most polymorphic (PIC = 0.911), followed by DXS101 (PIC = 0.872). Genetic distances were estimated for each STR marker applying the calculation of F (ST) between our total sample and other studies from Brazil, Europe, Asia and Africa. The most distant populations were Japan, Korea, China, Ghana and Uganda.
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Cromossomos Humanos Par 14/genética , Cromossomos Humanos X/genética , Repetições de Microssatélites , Reação em Cadeia da Polimerase Multiplex/métodos , Sequência de Bases , Brasil , Feminino , Genética Forense , Amplificação de Genes , Frequência do Gene , Ligação Genética , Marcadores Genéticos/genética , Genética Populacional , Haplótipos , Humanos , Masculino , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Multiplex/instrumentaçãoRESUMO
Crossmatching either by complement-dependent cytotoxicity (CDC) and/or by flow cytometry (FCXM) are routinely used for assessing anti-HLA donor antibodies before kidney transplantation. FCXM has demonstrated greater sensitivity and many transplant centers have opted for its use without the concomitant CDC assay. The objective of this study was to evaluate the accuracy of the median channel shift (MCS) in the FCXM in predicting the CDC assay results. A total of 1516â¯T cell FCXM and 1408 B cell FCXM were studied in deceased donors lymphocytes between January/2016 and March/2017. The high detection rate of CDC+ results by FCXM+ resulted in 87% (FCXM-T) and 90% (FCXM-B) sensitivity, and 98% negative predictive value, for both. The low specificity of FCXM B (43%) is atributed to cases of CDC-/FCXMB+. FCXM T and B were able to detect 53% and 76% of cases with donor specific antibodies of classes I and II with intensity of fluorescence ≥5001. The MCS differentiated CDC+ (Md, P25 and P75) results: MCS-T 390 (245-469) and MCS-B 282 (180-350). Through ROC curve analysis (AUC), the MCS showed satisfactory performance in detecting CDC+: MCS-T 0.909 (0.886-0.933) and MCS-B 0.775 (0.724-0.826). Considering the accuracy and sensitivity evaluation, the MCS-T 245 and MCS-B 282 cutoffs showed a better prediction of CDC+. This study showed that it is possible to calibrate MCS based on CDC+ with accuracy >90%, however, that leads to a risk in terms of non-detection of low-titer anti-HLA antibodies.
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Linfócitos B/imunologia , Tipagem e Reações Cruzadas Sanguíneas/métodos , Citometria de Fluxo/métodos , Transplante de Rim , Linfócitos T/imunologia , Homólogo 5 da Proteína Cromobox , Proteínas do Sistema Complemento/metabolismo , Citotoxicidade Imunológica , Antígenos HLA/imunologia , Humanos , Isoanticorpos/sangue , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Transplantados , Listas de EsperaRESUMO
Preformed anti-human leukocyte antigen (HLA) antibodies may be present in the blood of kidney transplant candidates. The production of these antibodies may occur in the post-transplant period, with the possible development of donor-specific antibodies (DSA). Luminex-based tests, such as the single antigen (SA) assay and the Luminex crossmatch (Xm-DSA) assay are the most commonly used tools to detect anti-HLA antibodies, due to their high sensitivity and specificity. This cross-sectional study aimed to compare the findings of two methods for the detection of DSAs after kidney transplant: SA and Xm-DSA. A total of 122 patients who underwent deceased donor kidney transplant at Hospital de Clínicas de Porto Alegre were included. The SA assay detected anti-class I HLA DSAs in 17 patients (13.9%) and anti-class II HLA DSAs in 22 patients (19.6%), whereas the Xm-DSA detected DSAs in 18 patients (14.8%) both against class I and class II antigens. There was agreement between the two methods for class I (kappaâ¯=â¯0.66, pâ¯=â¯0.001) and class II (kappaâ¯=â¯0.54, pâ¯=â¯0.025) antigens. The incidence of DSAs as obtained by the SA assay was 15.57%, and the most prevalent DSAs were those against HLA-DR antigens. Patient survival at 3â¯years was 92%. The two techniques assessed in this study provide important information on the presence of DSAs and may help in the post-transplant patient monitoring and in immunosuppressive strategy.
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Rejeição de Enxerto/diagnóstico , Teste de Histocompatibilidade/métodos , Isoanticorpos/sangue , Nefropatias/terapia , Transplante de Rim , Adulto , Estudos Transversais , Feminino , Rejeição de Enxerto/mortalidade , Antígenos HLA/imunologia , Humanos , Isoantígenos/imunologia , Nefropatias/mortalidade , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Testes Sorológicos , Análise de Sobrevida , Doadores de Tecidos , Transplante HomólogoRESUMO
Colorectal cancer (CRC) can occur anywhere in the colon or rectum and represents the third most common cancer in the world in both sexes. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study was to evaluate the association between the KIR genes and HLA ligands in patients with colorectal cancer and healthy controls. We examined the polymorphism of 16 KIR genes and their HLA ligands in 154 caucasoid CRC patients and 216 controls. When both groups were compared, no significant differences were found for HLA ligands and KIR genes after Bonferroni correction. However, the Bx haplotypes (heterozygous and homozygous for the haplotype B) were more frequent in controls, when compared with patients. These findings suggest that individuals with Bx haplotypes could have some protection to colorectal cancer. The hypothesis is not related with the presence of a special KIR gene and HLA ligand related to the disease, but to the presence of several activating genes in the individuals with no better action of one in relation to other. Further studies to confirm this observation are warranted.
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Neoplasias Colorretais/genética , Antígenos HLA/genética , Receptores KIR/genética , População Branca/genética , Idoso , Brasil , Neoplasias Colorretais/etnologia , Feminino , Frequência do Gene , Genótipo , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Haplótipos , Humanos , Ligantes , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo Genético , Isoformas de Proteínas/genéticaRESUMO
Natural killer (NK) cell activity is regulated by activating and inhibitory signals transduced by killer cell immunoglobulin-like receptors (KIR). Diversity in KIR gene repertoire among individuals may affect disease outcome. Sepsis development and severity may be influenced by genetic factors affecting the immune response. Here, we examined sixteen KIR genes and their human leucocyte antigen (HLA) class I ligands in critical patients, aiming to identify patterns that could be associated with sepsis. Male and female patients (ages ranging between 14 and 94years-old) were included. DNA samples from 211 patients with sepsis and 60 controls (critical care patients with no sepsis) collected between 2004 and 2010 were included and genotyped for KIR genes using the polymerase chain reaction method with sequence-specific oligonucleotide (PCR-SSO), and for HLA genes using the polymerase chain reaction method with sequence-specific primers (PCR-SSP). The frequencies of activating KIR2DS1 and KIR3DS1 in sepsis patients when compared to controls were 41.23% versus 55.00% and 36.49% versus 51.67% (p=0.077 and 0.037 respectively before Bonferroni correction). These results indicate that activating KIR genes 2DS1 and 3DS1 may more prevalent in critical patients without sepsis than in patients with sepsis, suggesting a potential protective role of activating KIR genes in sepsis.
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Antígenos HLA/genética , Células Matadoras Naturais/fisiologia , Polimorfismo Genético , Receptores KIR/genética , Sepse/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Imunidade/genética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
There is a great variety of HIV-1 subtypes circulating in Brazil, including subtype C, whose prevalence is on the rise, particularly in the southern region. Many host and viral genetic factors may be involved in this trend. We evaluated the influence of human leukocyte antigen (HLA) class I alleles and killer-cell immunoglobulin-like receptor (KIR) genotypes on viral set point and T-CD4(+) parameters in 84 treatment-naïve HIV-1-positive individuals. Frequency data in the infected group were compared to data of 548 healthy control subjects. Individuals with the KIR AA genotype had a higher viral load (VL) than individuals with the KIR Bx genotype. The HIV-1 group was subdivided into three subgroups according to HLA-B allele presence: those with protection to disease alleles (HLA-B(+)), accelerated disease progression alleles (HLA-B(-)), or neither (HLA-B(o)) were grouped. We observed a significant effect of the HLA-B allele presence on VL. The HLA-B(+) group had significantly lower VL than the HLA-B(-) group and trended toward a lower VL than the HLA-B(o) group. There were significant differences between groups expressing extreme VL values: KIR-AA+HLA-B(-) vs. KIR Bx+HLA-B(+) and KIR-AA+HLA-B(o)vs. KIR Bx+HLA-B(+). The relationship of KIR/HLA host genetics with slow HIV disease progression in southern Brazil may be useful for vaccine developers, epidemiologists, and clinicians.
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Infecções por HIV/genética , HIV-1/fisiologia , Antígeno HLA-B27/genética , Receptores KIR/genética , Carga Viral , Adulto , Idoso , Brasil , Estudos de Coortes , Feminino , Seguimentos , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto JovemRESUMO
The simultaneous detection of Neisseria meningitidis, Haemophilus influenzae, and Streptococcus sp. was assessed by polymerase chain reaction (PCR) for the diagnosis of bacterial meningitis, as well as the applicability of PCR as a routine test. A cohort study was carried out with 182 children (2 months to 12 years of age) with suspicion of bacterial meningitis. Routine tests identified the etiologic agent in 65/84 children whose clinical status and laboratory findings suggested the presence of bacterial meningitis. Bacterial meningitis was ruled out in 98 children. In 19 children, the etiologic diagnosis was not possible using standard methods; in 14 of these patients, the etiologic agent was identified by PCR (N. meningitidis=12; H. influenzae=1; Streptococcus sp.=1). The sensitivity of PCR was 88.1%; specificity, 99.0%; positive predictive value, 98.7%; and negative predictive, 90.1%. PCR is a useful complementary diagnostic technique, especially when Gram stain, culture, or antigenic detection are negative or inconclusive.
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Haemophilus influenzae/isolamento & purificação , Meningites Bacterianas/diagnóstico , Neisseria meningitidis/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , Streptococcus/isolamento & purificação , Criança , Pré-Escolar , Estudos de Coortes , Haemophilus influenzae/genética , Humanos , Lactente , Meningites Bacterianas/microbiologia , Meningite por Haemophilus/diagnóstico , Meningite Meningocócica/diagnóstico , Neisseria meningitidis/genética , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Streptococcus/genéticaRESUMO
Hematopoietic stem cell transplantation is the curative option for patients with myelodysplastic syndrome; however, it requires a long post-transplantation follow-up. A 53-year-old woman with a diagnosis of myelodysplastic syndrome underwent related donor allogeneic hematopoietic stem cell transplantation in July 2006. Three months after transplantation, a comparative short tandem repeat analysis between donor and recipient revealed full chimerism, indicating complete, healthy bone marrow reconstitution. Three years and ten months after hematopoietic stem cell transplantation, the patient developed leukopenia and thrombocytopenia. Another short tandem repeat analysis was carried out which showed mixed chimerism (52.62%), indicating relapsed disease. A donor lymphocyte infusion was administered. The purpose of donor lymphocyte infusion is to induce a graft-versus-leukemia effect; in fact, this donor's lymphocyte infusion induced full chimerism. Successive short tandem repeat analyses were performed as part of post-transplantation follow-up, and in July 2010, one such analysis again showed mixed chimerism (64.25%). Based on this finding, a second donor lymphocyte infusion was administered, but failed to eradicate the disease. In September 2011, the patient presented with relapsed disease, and a second related donor allogeneic hematopoietic stem cell transplantation was performed. Subsequent short tandem repeat analyses revealed full chimerism, indicating complete bone marrow reconstitution. We conclude that quantitative detection of mixed chimerism is an important diagnostic tool that can guide early therapeutic intervention.
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OBJECTIVES: To evaluate B-cell expression patterns and association with function and survival in dysfunctional kidney allografts. MATERIALS AND METHODS: There were 110 kidney transplant recipients included who had for-cause biopsies. Demographic and transplant data were collected. Immunostaining for B cells, plasma cells, and C4d was performed by the immunoperoxidase technique in paraffin-embedded samples. Circulating antihuman leukocyte antigen donor-specific antibodies were detected in a single-antigen assay at biopsy. The main outcomes were kidney graft survival and function. The patients were evaluated in 3 groups according to the Banff classification: no rejection (40 patients), T-cell-mediated rejection (50 patients), and antibody-mediated rejection (20 patients). RESULTS: The CD138-positive plasma cell-rich infiltrates predominated in antibody-mediated rejection and were associated with stronger reactivity against panel antibodies (r = 0.41; P ≤ .001) and positive donor-specific antibodies (r = 0.32; P ≤ .006). The CD20-positive lymphocytes were associated with T-cell-mediated rejection, increased human leukocyte antigen mismatch, and frequency of retransplant. The CD138-positive cell infiltrates also were significantly greater in patients who had late than early rejection. There was no correlation between cellular CD20 and CD138 expression, and neither CD20 nor CD138 predicted worse graft function or survival. Other markers of antibody-mediated rejection such as C4d and donor-specific antibodies were associated with worse graft function and survival at 4 years after transplant. In multivariate analysis, C4d was the only risk factor associated with graft loss. CONCLUSIONS: After kidney transplant, CD20-positive B-cell infiltrates were associated with T-cell-mediated rejection, and CD138-positive plasma cells were associated with antibody-mediated rejection. Graft loss was associated with the presence of C4d.
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Linfócitos B/imunologia , Rejeição de Enxerto/imunologia , Transplante de Rim/efeitos adversos , Rim/imunologia , Linfócitos T/imunologia , Doença Aguda , Adolescente , Adulto , Antígenos CD20/análise , Autoanticorpos/sangue , Linfócitos B/metabolismo , Biomarcadores/análise , Biópsia , Distribuição de Qui-Quadrado , Complemento C4b/análise , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Sobrevivência de Enxerto , Antígenos HLA/imunologia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Rim/metabolismo , Rim/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fragmentos de Peptídeos/análise , Plasmócitos/imunologia , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Sindecana-1/análise , Linfócitos T/metabolismo , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Previous studies have shown an increased expression of natural killer (NK) cells in the peripheral blood of patients with systemic sclerosis (SSc). NK cells are part of innate immunity, recognizing infected cells through killer immunoglobulin-like receptors (KIR), which show marked polymorphism. A novel model has been proposed predicting the activity of NK cells, evaluating whether there is excessive activation (EA), excessive inhibition (EI) or balance (B) (neutral). OBJECTIVE: To evaluate the activity of NK cells in patients with SSc and compare it with that of a control group. METHOD: This study comprised 110 patients with SSc and 115 healthy controls. A novel model that predicts the activity of NK cells was used. For that, cells with their respective KIR/HLA-C and Bw4 ligands were considered. The activity of NK cells was defined as EA, EI, or B. RESULTS: Our results showed that 63.5% of healthy controls had the KIR phenotype characterized by EI, as compared with 39.1% of the patients with SSc (P = 0.001). Considering only KIR2DL2-positive individuals, 34.7% of EI was found in healthy controls and 10.9% in patients with SSc (P < 0.001). CONCLUSION: In our study, the model that predicts the action of NK cells showed that healthy controls have higher frequency of EI as compared with SSc patients, suggesting a protective effect of the EI profile against the development of SSc. These results suggest a potential role of NK cells in the pathogenesis of SSc, but further studies should be conducted to confirm our data.
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Células Matadoras Naturais/imunologia , Escleroderma Sistêmico/imunologia , HumanosRESUMO
UNLABELLED: Gaucher disease (GD) is caused by reduced activity of the lysosomal enzyme glucocerebrosidase, which leads to a buildup of glucocerebroside within the cells and chronic stimulation of the immune system. GD is associated with clinical variability even in the same family, which suggests the influence of modifier genes. Natural killer (NK) cells play an important role in the immune response, and their number is decreased in GD. Killer-cell immunoglobulin-like receptors (KIR) regulate the activity of NK cells through an interaction with specific human leukocyte antigen (HLA) class I molecules on target cells. OBJECTIVES: To analyze the variability of KIR genes in a sample of GD patients from Southern Brazil, and look for associations between variants and clinical manifestations. METHODOLOGY: Thirty-one GD patients (24 mild, 4 moderate, and 3 severe) were included in the study. Fifteen KIR genes, HLA-C and HLA-Bw4 were analyzed using SSP-PCR. Clinical, biochemical, and radiological data were collected by means of a chart review. RESULTS/DISCUSSION: Age at symptom onset was associated with KIR2DL2 and KIR2DS2 in combination with the ligand HLA-C1 (p=0.038). Patients who have the HLA-C2 variant appear to have more mono- and polyclonal bands on protein electrophoresis (p=0.007, OR 21.3). There was no between-group significant difference in the frequencies of KIR/HLA variants. CONCLUSION: Although exploratory our data suggest a possible association of KIR/HLA variants and the severity of GD. Further study of KIR/HLA variants is required, as they seem to be a phenotype-modifying factor in this disease.
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Doença de Gaucher/genética , Genes MHC Classe I/genética , Antígenos de Histocompatibilidade Classe I/genética , Receptores KIR/genética , Adolescente , Adulto , Brasil , Feminino , Doença de Gaucher/imunologia , Frequência do Gene , Variação Genética , Genótipo , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Células Matadoras Naturais/metabolismo , Ligantes , Masculino , Fenótipo , Receptores KIR/metabolismo , Adulto JovemRESUMO
Breast cancer is the main cause of cancer-related death among women, with a 0.5% increase in incidence per year. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study was to evaluate the association between the KIR genes and HLA alleles in patients with breast cancer and healthy controls. Two hundred thirty patients with breast cancer and 272 healthy controls were typed for HLA class I and KIR genes by PCR-SSO. When both groups were compared, the presence of inhibitory KIR2DL2 receptors was significantly higher in breast cancer patients than in healthy controls. No significant differences were found for HLA-C2 and HLA-Bw4. However, a higher frequency of HLA-C1 in breast cancer patients was observed. These findings suggest a potential role for the KIR gene system in breast cancer. Further studies to confirm this observation are warranted.
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Neoplasias da Mama/genética , Genes MHC Classe I , Células Matadoras Naturais/imunologia , Receptores KIR/genética , Adulto , Brasil , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Teste de Histocompatibilidade , Humanos , Pessoa de Meia-Idade , Receptores KIR2DL2/genética , População BrancaRESUMO
Killer Immunoglobulin-like Receptor (KIR) genes express as receptors that activate or inhibit Natural Killer (NK) cells. The NK cells are part of the innate immune response and, through their KIR receptors, they identify target cells that have modified or different HLA (Human Leukocyte Antigen) molecules, inducing their lysis. The KIR receptors result from the expression of KIR genes (19q13.14) on the cell membrane of NK cells, which are polymorphic, and form haplotypes. The diversity of the frequency of KIR haplotypes in certain populations suggests that some individuals have different levels of protection against some diseases. The balance between cell inhibition and activation enables the NK cell to help the organism in immunological surveillance. In addition, there is evidence of the association of activating KIR genotypes with an increased risk for autoimmune disease.
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Doenças Autoimunes/genética , Receptores KIR/genética , Doenças Reumáticas/genética , Doenças Reumáticas/imunologia , Predisposição Genética para Doença , Humanos , Células Matadoras Naturais/fisiologiaRESUMO
Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the bowel, of unknown origin. Exposure to specific environmental factors by genetically susceptible individuals, leading to an inadequate response of the immune system, is one of the potential explanations for the occurrence of these diseases. Natural killer cells are part of the innate immune system recognizing class I HLA (human leukocyte antigen) molecules on target cells through their membrane receptors. The main receptors of the natural killer cells are the killer immunoglobulinlike receptors (KIRs). Our study aimed to evaluate the association between the KIR genes in patients with inflammatory bowel diseases and healthy controls. We typed 15 KIR genes and HLA class I ligands in 248 unrelated Brazilian Caucasians, of which 111 had UC and 137 had CD, and 250 healthy controls by polymerase chain reaction using sequence-specific oligonucleotides and sequence-specific primers. We found an increase in KIR2DL2 in controls (inflammatory bowel disease [IBD]: p < 0.001; UC: p = 0.01; CD: p = not significant [NS]). The genotype 2DL2+/HLA-C lys(80)+ was also more common in controls (IBD: p = 0.005; UC: p = 0.01; CD: p = NS); as well as 2DL1+/HLA-C Asn(80)+ (IBD: p = 0.026; UC: p = NS;CD: p = NS). The imbalance between activating and inhibitory KIR and HLA ligands may explain, at least in part, the pathogenesis of these inflammatory bowel diseases.
Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Genes MHC Classe I/genética , Receptores KIR/genética , Adulto , Brasil , Colite Ulcerativa/epidemiologia , Doença de Crohn/epidemiologia , Feminino , Humanos , Masculino , População BrancaRESUMO
Type 1 diabetes mellitus (T1D) is a multifactorial and chronic autoimmune disease caused by the deficiency of insulin synthesis and or by its secretion or action defects. Genetic and environmental factors are known to be involved in its pathogenesis. The human leukocyte antigen complex (human leukocyte antigen (HLA)) constitutes the most relevant region contributing with 50% of the inherited risk for T1D. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer immunoglobulin-like receptors (KIR). The aim of our study is to evaluate the association between the KIR genes and HLA alleles in patients with T1D and healthy controls. Two hundred forty-eight T1D patients and 250 healthy controls were typed for HLA and KIR genes by PCR-SSP. Our results showed an increase of C2 in controls (p = 0.002). The genotype 2DL1/C2+ was also more common in controls (p = 0.001), as well as haplotype association KIR2DL2/DR3/DR4+ and the combination with only DR3+ (p < 0.001; p < 0.001). The maximum protection was seen when KIR2DL2/DR3-were absent when the combination of KIR2DL1/C2+ were present (p < 0.001) and the maximum risk was observed when KIR2DL2/DR3/DR4+ were present in the absence of KIR2DL1/C2- (p = 0.005). Our results confirmed the association of the KIR2DL2/DR3 increasing risk for T1D and suggest a protective role of KIR2DL1/C2.