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1.
Scand J Immunol ; : e13374, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38750640

RESUMEN

Autoimmune neutropaenia (AIN) in early childhood is characterized by chronic neutropaenia and positivity for human neutrophil antibodies (HNA), resulting in the excessive destruction of neutrophils. The association between regulatory T cells (Tregs) and AIN has been described, and in this study, we investigated three Treg-associated genes, IL-2, IL-10 and FOXP3. The frequencies of three single nucleotide polymorphisms (SNPs) in IL-2 -330T>G (rs2069762), +114G>T (rs2069763) and IVS3-116 A>G (rs2069772), four SNPs in IL-10 -3575T>A (rs1800890), -1082G>A (rs1800896), -819 C>T (rs1800871) and -592 C>A (rs1800872) and three SNPs in FOXP3 -3499 A>G (rs3761547), -3279 C>A (rs3761548) and -924 A>G (rs2232365) were compared between 166 Danish AIN patients and 358 healthy controls. Disease association was observed for IL-2 IVS3-116 GG (p = 0.0081, OR = 0.35 [0.15-0.80]), IL-10 -3575 TT (p = 0.0078, OR = 1.71 [1.16-2.54]) and IL-10 -1082 AA (p = 0.014, OR = 1.76 [1.14-2.72]) in all patients and FOXP3 -924 (p = 0.0005, A OR = 0.41 [0.25-0.68] and G OR = 2.42 [1.46-4.01]) in male patients. None of the associations were linked to antibody specificity. Disease-associated haplotypes were observed in IL-2 and FOXP3. IL-2 -330T/+114 T/IVS3-116A was associated with anti-FcγRIIIb-positive patients (p = 0.012, OR = 2.07 [1.18-3.62]). FOXP3 -3499A/-3279C/-924A was associated with anti-HNA-1a-positive male patients (p = 0.016, OR = 0.41 [0.20-0.83]), and ACG was associated with female patients, both in the combined group (p = 0.006, OR = NA) and the anti-FcγRIIIb-positive group (p = 0.002, OR = NA). We conclude that our findings reveal a correlation between SNP in Treg-associated genes and AIN, indicating that AIN could be driven by dysfunction of immune homeostatic-evolving Tregs.

2.
Int J Immunogenet ; 50(2): 65-74, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36754570

RESUMEN

Autoimmune neutropenia (AIN) in early childhood is caused by autoantibodies directed against antigens on the neutrophil membrane and is a frequent cause of neutropenia in children. Association of AIN with Fcγ receptor (FCGR) 3B variants is well described. In this study, we investigate genetic variations in the FCGR locus and copy number variation of FCGR3B. A total of 130 antibody-positive AIN patients, 64 with specific anti-HNA-1a antibodies and 66 with broad-reacting anti-FcγRIIIb antibodies, were genotyped with a multiplex ligation probe assay and compared with healthy controls. Positive findings were confirmed with real-time q-PCR. We determined copy numbers of the FCGR2 and FCGR3 genes and the following SNPs: FCGR2A Q62W (rs201218628), FCGR2A H166R (rs1801274), FCGR2B I232T (rs1050501), FCGR3A V176F (rs396991), haplotypes for FCGR2B/C promoters (rs3219018/rs780467580), FCGR2C STOP/ORF and HNA-1 genotypes in FCGR3B (rs447536, rs448740, rs52820103, rs428888 and rs2290834). Generally, associations were antibody specific, with all associations being representative of the anti-HNA-1a-positive group, while the only association found in the anti-FcγRIIIb group was with the HNA-1 genotype. An increased risk of AIN was observed for patients with one copy of FCGR3B; the HNA genotypes HNA-1a, HNA-1aa or HNA-1aac; the FCGR2A 166H and FCGR2B 232I variations; and no copies of FCGR2B 2B.4. A decreased risk was observed for HNA genotype HNA-1bb; FCGR2A 166R; FCGR2B 232T; and one copy of FCGR2B promoter 2B.4. We conclude that in our Danish cohort, there was a strong association between variation in the FCGR locus and AIN. The findings of different genetic associations between autoantibody groups could indicate the presence of two different disease entities and disease heterogeneity.


Asunto(s)
Predisposición Genética a la Enfermedad , Neutropenia , Preescolar , Niño , Humanos , Variaciones en el Número de Copia de ADN , Receptores de IgG/genética , Genotipo , Dinamarca
3.
Transfusion ; 62(8): 1636-1642, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35792132

RESUMEN

BACKGROUND: Autoimmune neutropenia of early childhood (AIN) is caused by autoantibodies directed against antigens on the neutrophil membrane. The ABO, secretor, and Lewis histo-blood group systems control the expression of carbohydrate antigens and have previously been linked to autoimmune diseases. We aimed to investigate the association between genotypes and the risk of AIN in Danish patients. STUDY DESIGN AND METHODS: One hundred fifty-four antibody-positive AIN patients were included. Controls (n = 400) were healthy unrelated Danish blood donors. Molecular determination of ABO, secretor (FUT2), and Lewis (FUT3) genotypes were determined using real-time polymerase chain reaction (qPCR) or Sanger sequencing to infer the prevalence of Lewis antigens (Lea and Leb ) and secretor (SeSe or Sese) or nonsecretor (sese) phenotypes. RESULTS: Blood type O was more common in controls (46.8%) than in AIN patients (36.4%) (OR = 0.65; p = 0.028). Secretors of H Leb antigens were less frequent among AIN patients (25.2%) than controls (35.0%) (OR = 0.62; p = 0.037). DISCUSSION: ABO blood group antigens and the secretion of these antigens are associated with a diagnosis of AIN. The mechanism underlying the association between autoimmunity and interaction among ABO, secretor, and Lewis genotypes has not yet been elucidated, but several studies indicate a connection to the gut microbiota.


Asunto(s)
Autoinmunidad , Neutropenia , Sistema del Grupo Sanguíneo ABO/genética , Antígenos , Carbohidratos , Preescolar , Dinamarca , Humanos , Antígenos del Grupo Sanguíneo de Lewis/genética , Neutropenia/genética , Fenotipo
4.
Pediatr Allergy Immunol ; 32(4): 756-761, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33421202

RESUMEN

BACKGROUND: Autoimmune neutropenia of infancy (AIN) is a frequent cause of neutropenia in children. The disease is caused by antibodies against epitopes on the immunoglobulin G (IgG) Fc receptor type 3b (FcγIIIb). We investigated the possible association of human neutrophil antigens (HNA), human leukocyte antigen (HLA)-DR, and HLA-DQ alleles with AIN and the association of these genotypes with the presence of autoantibodies. METHODS: Eighty AIN cases with a median age of 13.5 months were included. Controls were healthy unrelated Danish blood donors. Anti-HNA-1a autoantibodies were detected using a flow cytometric granulocyte immunofluorescence test (Flow-GIFT) with phenotyped donor cells for detection of antibody specificity. Molecular determination of HNA genotypes was determined using real-time polymerase chain reaction (q-PCR). High-resolution HLA-DRB1 and HLA-DQB1 were determined by next-generation sequencing. RESULTS: Antibodies against HNA-1a were detected in 51% (n = 41) of AIN patients, and anti-HNA-1b was detected in 3% (n = 2) of cases. In 46% of cases, the antibodies were anti-FcγIIIb-reactive. FCGR3B*01+,*02-,*03- was more common (odds ratio, 6.70; P < .0001), and FCGR3B*01-,*02+,*03- was less common (odds ratio, 0.30; P < .0001) among AIN cases. HNA-1a antibodies were significantly more frequent among AIN cases with the FCGR3B*01+,*02-,*03- genotype (odds ratio, 3.86; P < .007). The HLA-DRB1*14 - HLA-DQB1*05:03 haplotype was significantly more common (odds ratio, 7.44; P < .0001) in AIN patients. CONCLUSION: The HLA haplotype HLA-DRB1*14 - DQB1*05:03 is associated with Danish AIN cases. Among Danish AIN patients, anti-HNA-1a is the most common autoantibody, and the antibody is more common in cases with the FCGR3B*01+,*02-,*03- genotype.


Asunto(s)
Neutropenia , Neutrófilos , Autoinmunidad , Dinamarca , Genotipo , Antígenos HLA , Humanos , Lactante
5.
J Allergy Clin Immunol Glob ; 3(3): 100274, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38817346

RESUMEN

The clinical presentation of CD21 deficiency in 2 siblings caused by a novel mutation in the CD21 gene is reported, and the frequency of this mutation in the Danish population is explored. Successful treatment with IgG replacement in both patients with CD21 deficiency is also reported.

6.
HLA ; 103(3): e15429, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38450943

RESUMEN

HLA studies in patients with autoimmune neutropenia (AIN) have shown very consistent results for the association with HLA class II alleles at low resolution. This study aimed to examine the association of both HLA class I and class II at high resolution to clarify the contribution of risk alleles to the disease. A total of 107 AIN patients were genotyped for six loci of HLA class I (HLA-A, -B and -C) and class II (HLA-DRB1, -DQB1, and -DPB1) genes by a high-resolution (3-field, 6-digit) analysis and compared with HLA typing of 1000 healthy controls. Compared with the controls, the allele frequencies were significantly higher in AIN patients for A*02:17:01G, C*01:02:01G, DRB1*10:01:01G, DRB1*14:01:01G, DRB1*16:01:01G, DQB1*05:02:01G, and DQB1*05:03:01G but lower significant for C*03:04:01G, DRB1*04:01:01G, DRB1*13:02:01G, DQB1*03:02:01G, and DQB1*06:04:01G. Frequently associated two-locus haplotypes were found to be DRB1*10:01:01G-DQB1*05:01:01G and DRB1*16:01:01G-DQB1*05:02:01G, while the S2 (Q- or D-KRAA) shared epitope (SE) was associated with lower risk. A unique association with HLA alleles was observed between patients with specific anti-HNA-1a antibodies and broad-reacting anti-FcγRIIIb. Anti-HNA-1a antibody-positive patients were associated with C*01:02:01G, DRB1*01:01:01G, DRB1*16:01:01G, DQB1*05:01:01G, DQB1*05:02:01G, DQB1*06:04:01G, and DPB1*10:01:01G; the two-locus haplotypes DRB1*01:01:01G-DQB1*05:01:01G and DRB1*16:01:01G-DQB1*05:02:01G; and the S3P (Q- or R-RRAA) SE. Anti-FcγRIIIb antibody-positive patients were associated with the alleles A*02:17:01G, DRB1*10:01:01G, and DQB1*05:02:01G; the haplotypes DRB1*10:01:01G-DQB1*05:01:01G and DRB1*11:01:02G-DQB1*05:02:01G; and the S3D (DRRAA) SE. The different associations regarding FcγRIIIb antibody specificities could indicate disease heterogeneity.


Asunto(s)
Neutropenia , Preescolar , Humanos , Alelos , Genotipo , Especificidad de Anticuerpos , Epítopos , Neutropenia/genética , Dinamarca
7.
Clin Case Rep ; 9(6): e03818, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34136223

RESUMEN

Transfusion-Related Acute Lung Injury (TRALI) has been associated with neutrophil reacting antibodies in transfused blood products. We report a case of life-threatening TRALI in an obstetric patient triggered by transfusion from a non-transfused male blood donor. A residual risk of TRALI exist, even in a male-only plasma setting.

8.
Ugeskr Laeger ; 183(48)2021 11 29.
Artículo en Danés | MEDLINE | ID: mdl-34852904

RESUMEN

Amniotic fluid embolism (AFE) is a rare obstetric emergency with high maternal morbidity and mortality. Despite ongoing research, the pathogenesis of AFE remains unresolved, and AFE is a diagnostic and therapeutic challenge. We present a case report of suspected AFE and disseminated intravascular coagulation occurring during caesarean delivery in a pregnancy with oocyte donation and intracytoplasmic sperm injection. Awareness of the diagnosis, rapid initiation of treatment and the use of rapid tests of haemostasis in targeted coagulopathy treatment may improve clinical outcome.


Asunto(s)
Coagulación Intravascular Diseminada , Embolia de Líquido Amniótico , Insuficiencia Cardíaca , Cesárea/efectos adversos , Coagulación Intravascular Diseminada/etiología , Coagulación Intravascular Diseminada/terapia , Embolia de Líquido Amniótico/diagnóstico , Embolia de Líquido Amniótico/terapia , Femenino , Humanos , Donación de Oocito , Embarazo
9.
Blood Adv ; 4(20): 4990-4993, 2020 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-33057631

RESUMEN

Identification of risk factors for contracting and developing serious illness following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of paramount interest. Here, we performed a retrospective cohort analysis of all Danish individuals tested for SARS-CoV-2 between 27 February 2020 and 30 July 2020, with a known ABO and RhD blood group, to determine the influence of common blood groups on virus susceptibility. Distribution of blood groups was compared with data from nontested individuals. Participants (29% of whom were male) included 473 654 individuals tested for SARS-CoV-2 using real-time polymerase chain reaction (7422 positive and 466 232 negative) and 2 204 742 nontested individuals, accounting for ∼38% of the total Danish population. Hospitalization and death from COVID-19, age, cardiovascular comorbidities, and job status were also collected for confirmed infected cases. ABO blood groups varied significantly between patients and the reference group, with only 38.41% (95% confidence interval [CI], 37.30-39.50) of the patients belonging to blood group O compared with 41.70% (95% CI, 41.60-41.80) in the controls, corresponding to a relative risk of 0.87 (95% CI, 0.83-0.91) for acquiring COVID-19. This study identifies ABO blood group as a risk factor for SARS-CoV-2 infection but not for hospitalization or death from COVID-19.


Asunto(s)
Sistema del Grupo Sanguíneo ABO/sangre , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/epidemiología , Neumonía Viral/sangre , Neumonía Viral/epidemiología , Betacoronavirus/aislamiento & purificación , COVID-19 , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Pandemias , Prevalencia , Factores Protectores , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2
10.
Leuk Lymphoma ; 56(12): 3257-66, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26044172

RESUMEN

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) both depend on immune-mediated survival and proliferation signals from the tumor microenvironment. Inherited genetic variation influences this complex interaction. A total of 89 studies investigating immune-response genes in DLBCL and FL were critically reviewed. Relatively consistent association exists for variation in the tumor necrosis factor alpha (TNFA) and interleukin-10 loci and DLBCL risk; for DLBCL outcome association with the TNFA locus exists. Variations at chromosome 6p31-32 were associated with FL risk. Importantly, individual risk alleles have been shown to interact with each other. We suggest that the pathogenetic impact of polymorphic genes should include gene-gene interaction analysis and should be validated in preclinical model systems of normal B lymphopoiesis and B-cell malignancies. In the future, large cohort studies of interactions and genome-wide association studies are needed to extend the present findings and explore new risk alleles to be studied in preclinical models.


Asunto(s)
Variación Genética , Inmunidad/genética , Linfoma Folicular/genética , Linfoma Folicular/inmunología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Animales , Susceptibilidad a Enfermedades , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Linfoma Folicular/metabolismo , Linfoma Folicular/mortalidad , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/mortalidad , Polimorfismo de Nucleótido Simple , Pronóstico , Riesgo
11.
PLoS One ; 10(10): e0139329, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26448050

RESUMEN

BACKGROUND: Malignant B-cell clones are affected by both acquired genetic alterations and by inherited genetic variations changing the inflammatory tumour microenvironment. METHODS: We investigated 50 inflammatory response gene polymorphisms in 355 B-cell non-Hodgkin's lymphoma (B-NHL) samples encompassing 216 diffuse large B cell lymphoma (DLBCL) and 139 follicular lymphoma (FL) and 307 controls. The effect of single genes and haplotypes were investigated and gene-expression analysis was applied for selected genes. Since interaction between risk genes can have a large impact on phenotype, two-way gene-gene interaction analysis was included. RESULTS: We found inherited SNPs in genes critical for inflammatory pathways; TLR9, IL4, TAP2, IL2RA, FCGR2A, TNFA, IL10RB, GALNT12, IL12A and IL1B were significantly associated with disease risk and SELE, IL1RN, TNFA, TAP2, MBL2, IL5, CX3CR1, CHI3L1 and IL12A were, associated with overall survival (OS) in specific diagnostic entities of B-NHL. We discovered noteworthy interactions between DLBCL risk alleles on IL10 and IL4RA and FL risk alleles on IL4RA and IL4. In relation to OS, a highly significant interaction was observed in DLBCL for IL4RA (rs1805010) * IL10 (rs1800890) (HR = 0.11 (0.02-0.50)). Finally, we explored the expression of risk genes from the gene-gene interaction analysis in normal B-cell subtypes showing a different expression of IL4RA, IL10, IL10RB genes supporting a pathogenetic effect of these interactions in the germinal center. CONCLUSIONS: The present findings support the importance of inflammatory genes in B-cell lymphomas. We found association between polymorphic sites in inflammatory response genes and risk as well as outcome in B-NHL and suggest an effect of gene-gene interactions during the stepwise oncogenesis.


Asunto(s)
Linfoma Folicular/genética , Linfoma de Células B Grandes Difuso/genética , Anciano , Alelos , Femenino , Genotipo , Haplotipos , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Subunidad beta del Receptor de Interleucina-10/genética , Subunidad beta del Receptor de Interleucina-10/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Subunidad alfa del Receptor de Interleucina-4/genética , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Desequilibrio de Ligamiento , Linfoma Folicular/etiología , Linfoma Folicular/mortalidad , Linfoma de Células B Grandes Difuso/etiología , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , Riesgo , Análisis de Supervivencia , Transcriptoma
12.
Ugeskr Laeger ; 176(7)2014 Mar 31.
Artículo en Danés | MEDLINE | ID: mdl-25096345

RESUMEN

Transfusion-related acute lung injury (TRALI) is recognized as the most frequent cause of transfusion-related severe morbidity and mortality. TRALI is characterized by post-transfusional respiratory distress, hypoxaemia and radiographic verified lung infiltration, in the absence of sign of circulatory overload. TRALI is predominantly triggered by human leukocyte antigen or human neutrophil antigen (HNA) antibodies from the transfused blood component. Particularly antibodies against the HNA-3a are involved in severe and fatal TRALI cases. The serological investigation is important to trace and exclude blood donors with TRALI antibodies.


Asunto(s)
Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda Postransfusional/complicaciones , Lesión Pulmonar Aguda/diagnóstico , Lesión Pulmonar Aguda/fisiopatología , Lesión Pulmonar Aguda/terapia , Algoritmos , Donantes de Sangre , Antígenos HLA/inmunología , Humanos , Leucocitos/inmunología , Neutrófilos/inmunología
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