Accuracy of the median channel shift in the flow cytometry for predicting complement dependent cytotoxicity crossmatching in kidney transplant candidates.

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 1516 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.

Comparative analysis of two methods to detect donor-specific anti-HLA antibodies after kidney transplant.

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 (kappa = 0.66, p = 0.001) and class II (kappa = 0.54, p = 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 3 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.

Blood chimerism in twins.

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.

Reduced frequency of two activating KIR genes in patients with sepsis.

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.

KIR genes and HLA class I ligands in a Caucasian Brazilian population with colorectal cancer.

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.

Association between KIR genotypes and HLA-B alleles on viral load in Southern Brazilian individuals infected by HIV-1 subtypes B and C.

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.

Expression patterns of B cells in acute kidney transplant rejection.

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.

Quantification of mixed chimerism allows early therapeutic interventions.

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.

Quantification of mixed chimerism allows early therapeutic interventions

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...

Analysis of KIR gene frequencies and HLA class I genotypes in breast cancer and control group.

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.

Characteristics of NK cell activity in patients with systemic sclerosis.

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.

Características de atividade das células natural killer em pacientes com esclerose sistêmica / Characteristics of NK cell activity in patients with systemic sclerosis

INTRODUÇÃO: Estudos têm relatado um aumento da expressão das células natural killer (NK) no sangue periférico de pacientes com esclerose sistêmica (ES). Essas células fazem parte da imunidade inata, reconhecendo células infectadas por meio dos receptores killer immunoglobulin-like receptor (KIR), que apresentam acentuado polimorfismo. Um novo modelo foi proposto prevendo a atividade das células NK, avaliando o excesso de ativação (EA), excesso de inibição (EI) ou se a célula está funcionalmente em equilíbrio (balance, B) (neutra). OBJETIVO: Avaliar a atividade das células NK em pacientes com ES e comparar com grupo-controle. MÉTODO: Cento e dez pacientes com ES e 115 controles foram estudados. Foi aplicado um novo modelo que prevê a atividade das células NK. Para esse método, considerou-se cada célula com seu respectivo ligante KIR/HLA-C e Bw4. A nomenclatura utilizada foi EA, EI e B. RESULTADOS: Nossos resultados mostraram que 63,5% dos controles saudáveis apresentavam o fenótipo KIR caracterizado por EI, em comparação com 39,1% dos pacientes com ES (P = 0,001). Considerando-se somente indivíduos com presença de KIR2DL2 (KIR2DL2+), encontramos 34,7% de EI em controles sadios e 10,9% em pacientes com ES (P < 0,001). CONCLUSÃO: Em nosso estudo, o modelo que prevê a ação das células NK mostrou que controles sadios têm maior frequência de EI quando comparados a pacientes com ES, sugerindo um efeito protetor do EI contra o desenvolvimento da ES. Outros estudos, porém, devem ser realizados para confirmar nossos dados.

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.

KIR genes and HLA class I ligands in Gaucher disease.

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.

Human leukocyte antigens and Gaucher disease.

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.

Combined effects of CXCL8 and CXCR2 gene polymorphisms on susceptibility to systemic sclerosis.

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.

Development of two multiplex PCR systems for the analysis of 14 X-chromosomal STR loci in a southern Brazilian population sample.

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.

Doenças reumatológicas autoimunes e sua associação com os genes killer immunoglobulin-like receptors / Autoimmune rheumatic diseases and their association with killer immunoglobulin-like receptor genes

Os genes Killer Immunoglobulin-like Receptors (KIR) expressam-se como receptores que estimulam ou inibem as células Natural Killer (NK). As células NK fazem parte da imunidade inata e através de seus receptores KIR identificam células-alvo que apresentam moléculas HLA (Human Leukocyte Antigen) modificadas ou diferentes, induzindo à sua lise. Os receptores KIR são resultados da expressão dos genes KIR (19q13.14) na membrana celular das células NK, os quais são polimórficos e formam haplótipos. A diversidade de frequência dos haplótipos KIR em certas populações sugere que alguns indivíduos apresentam diferentes níveis de proteção contra algumas doenças e o balanço entre inibição e ativação celular mediada pelos receptores KIR e seus ligantes faz com que a célula NK possa auxiliar o organismo na vigilância imunológica. Além disso, há várias evidências da existência de associação de genótipos KIR ativadores com risco aumentado de doença autoimune.

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.

Autoimmune rheumatic diseases and their association with killer immunoglobulin-like receptor genes.

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.

Association of killer cell immunoglobulin-like receptors and human leukocyte antigen-C genotypes in South Brazilian with type 1 diabetes.

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.