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1.
Biomaterials ; 312: 122741, 2025 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-39121727

RESUMO

Last twenties, tissue engineering has rapidly advanced to address the shortage of organ donors. Decellularization techniques have been developed to mitigate immune rejection and alloresponse in transplantation. However, a clear definition of effective decellularization remains elusive. This study compares various decellularization protocols using the human fascia lata model. Morphological, structural and cytotoxicity/viability analyses indicated that all the five tested protocols were equivalent and met Crapo's criteria for successful decellularization. Interestingly, only the in vivo immunization test on rats revealed differences. Only one protocol exhibited Human Leucocyte Antigen (HLA) content below 1% residual threshold, the only criterion preventing rat immunization with an absence of rat anti-human IgG switch after one month (N=4 donors for each of the 7 groups, added by negative and positive controls, n=28). By respecting a refined set of criteria, i.e. lack of visible nuclear material, <50ng DNA/mg dry weight of extracellular matrix, and <1% residual HLA content, the potential for adverse host reactions can be drastically reduced. In conclusion, this study emphasizes the importance of considering not only nuclear components but also major histocompatibility complex in decellularization protocols and proposes new guidelines to promote safer clinical development and use of bioengineered scaffolds.


Assuntos
Fascia Lata , Antígenos HLA , Engenharia Tecidual , Humanos , Animais , Engenharia Tecidual/métodos , Antígenos HLA/imunologia , Ratos , Alicerces Teciduais/química , Materiais Biocompatíveis/química , Masculino , Matriz Extracelular Descelularizada/química , Matriz Extracelular/química , Matriz Extracelular/metabolismo
2.
Cells ; 13(17)2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39273019

RESUMO

Epidermal transplantation is a common and widely used surgical technique in clinical medicine. Derivatives of embryonic stem cells have the potential to serve as a source of transplantable cells. However, allograft rejection is one of the main challenges. To investigate the immunogenicity of keratinocytes derived from human embryonic stem cells (ESKCs), we conducted a series of in vivo and in vitro experiments. The results showed that ESKCs have low HLA molecule expression, limited antigen presentation capabilities, and a weak ability to stimulate the proliferation and secretion of inflammatory factors in allogeneic PBMCs in vitro. In humanized immune mouse models, ESKCs elicited weak transplant rejection responses in the host. Overall, we found that ESKCs have low immunogenicity and may have potential applications in the field of regenerative medicine.


Assuntos
Células-Tronco Embrionárias Humanas , Queratinócitos , Humanos , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinócitos/citologia , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Embrionárias Humanas/imunologia , Células-Tronco Embrionárias Humanas/metabolismo , Animais , Camundongos , Proliferação de Células , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Antígenos HLA/metabolismo
3.
Int J Mol Sci ; 25(17)2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39273401

RESUMO

Aging is an exceptionally complex process that depends on genetic, environmental, and lifestyle factors. Previous studies within the International HLA and Immunogenetics Workshop (IHIWS) component "Immunogenetics of Ageing" showed that longevity is associated with positive selection of HLA-DRB1*11- and DRB1*16-associated haplotypes, shown to be protective against diseases. Within the 18th IHIWS, we aimed to investigate the relevance of telomere length for successful aging and its association with classical HLAs. In total 957 individuals from Bulgaria, Turkey, Romania, and Poland in two age groups, elderly individuals (age 65-99 years) and ethnically matched young group (age 18-64 years), were investigated. The obtained results confirmed interpopulation differences in the distribution of HLA alleles, documented the lengths of telomeres in analyzed populations, and demonstrated significant associations of telomere length with aging as well as with the presence of some HLA class I or class II alleles. They suggest that telomere length assessment combined with HLA genotyping may help identify immunogenetic profiles associated with longevity. The associations between HLA and telomeres support the theory that HLA genes influence the aging process. However, further research is needed to clarify the biological basis of the observed relationships.


Assuntos
Antígenos HLA , Longevidade , Humanos , Longevidade/genética , Idoso , Pessoa de Meia-Idade , Masculino , Adulto , Feminino , Idoso de 80 Anos ou mais , Adolescente , Antígenos HLA/genética , Adulto Jovem , Telômero/genética , Alelos , Homeostase do Telômero , Envelhecimento/genética , Envelhecimento/imunologia , Haplótipos
4.
Int J Mol Sci ; 25(17)2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39273511

RESUMO

Immunopeptidomics is the area of knowledge focused on the study of peptides assembled in the major histocompatibility complex (MHC), or human leukocyte antigen (HLA) in humans, which could activate the immune response via specific and selective T cell recognition. Advances in high-sensitivity mass spectrometry have enabled the detailed identification and quantification of the immunopeptidome, significantly impacting fields like oncology, infections, and autoimmune diseases. Current immunopeptidomics approaches primarily focus on workflows to identify immunopeptides from HLA molecules, requiring the isolation of the HLA from relevant cells or tissues. Common critical steps in these workflows, such as cell lysis, HLA immunoenrichment, and peptide isolation, significantly influence outcomes. A systematic evaluation of these steps led to the creation of an 'Immunopeptidome Score' to enhance the reproducibility and robustness of these workflows. This score, derived from LC-MS/MS datasets (ProteomeXchange identifier PXD038165), in combination with available information from public databases, aids in optimizing the immunopeptidome characterization process. The 'Immunopeptidome Score' has been applied in a systematic analysis of protein extraction, HLA immunoprecipitation, and peptide recovery yields across several tumor cell lines enabling the selection of peptides with optimal features and, therefore, the identification of potential biomarker and therapeutic targets.


Assuntos
Peptídeos , Proteômica , Espectrometria de Massas em Tandem , Humanos , Peptídeos/imunologia , Proteômica/métodos , Antígenos HLA/imunologia , Cromatografia Líquida/métodos , Linhagem Celular Tumoral , Proteoma/imunologia , Imunoprecipitação/métodos
5.
Med Sci (Basel) ; 12(3)2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39311157

RESUMO

This research aims to determine whether HLA heterozygosity confers a protective effect against hepatitis B virus infection by analyzing the relationship between HLA diversity and the risk of hepatitis B virus (HBV) infection. A total of 327 hepatitis B patients were selected and categorized based on their clinical status: 284 patients with chronic HBV infection and 43 patients with HBV-related liver cirrhosis (LC). The control group included 304 healthy individuals. HLA genotyping for 11 loci, including HLA class I and class II, was conducted using next-generation sequencing. The results of this study indicate a statistically significant negative correlation between HLA class II heterozygosity and the risk of HBV infection. Specifically, heterozygosity in HLA-DQB1 (OR = 0.49, 95% CI = 0.31-0.76, p = 0.01277) and HLA-DRB1 (OR = 0.42, 95% CI = 0.24-0.77, p = 0.01855) were significantly associated with protection. Subgroup analysis was conducted to explore the effect of HLA diversity among pathological subtypes (chronic hepatitis B and control group, liver cirrhosis and control group). For liver cirrhosis, compared with the control group, a decreased risk of LC was possibly associated with the heterozygosity of HLA class I locus B (OR = 0.24, 95% CI = 0.09-0.65, p = 0.0591), but this hypothesis was not confirmed by other studies. The diversity of HLA, measured by HLA heterozygosity, was associated with a protective effect against HBV infection.


Assuntos
Variação Genética , Hepatite B Crônica , Heterozigoto , Humanos , Hepatite B Crônica/genética , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Antígenos HLA/genética , Cirrose Hepática/genética , Predisposição Genética para Doença , Vírus da Hepatite B , Estudos de Casos e Controles , Genótipo
6.
Front Immunol ; 15: 1440911, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39229273

RESUMO

Introduction: The human leukocyte antigen (HLA) evolutionary divergence (HED) reflects immunopeptidome diversity and has been shown to predict the response of tumors to immunotherapy. Its impact on allogeneic hematopoietic stem cell transplantation (HSCT) is controversial in different studies. Methods: In this study, we retrospectively analyzed the clinical impact of class I and II HED in 225 acute lymphoblastic leukemia patients undergoing HSCT from related haploidentical donors. The HED for recipient, donor, and donor-recipient pair was calculated based on Grantham distance, which accounts for variations in the composition, polarity, and volume of each amino acid within the peptide-binding groove of two HLA alleles. The median value of HED scores was used as a cut-off to stratify patients with high or low HED. Results: The class I HED for recipient (R_HEDclass I) showed the strongest association with cumulative incidence of relapse (12.2 vs. 25.0%, P = 0.00814) but not with acute graft-versus-host disease. The patients with high class II HED for donor-recipient (D/R_HEDclass II) showed a significantly higher cumulative incidence of severe aGVHD than those with low D/R_HEDclass II (24.0% vs. 6.1%, P = 0.0027). Multivariate analysis indicated that a high D/R_HEDclass II was an independent risk factor for the development of severe aGVHD (P = 0.007), and a high R_HEDclass I had a more than two-fold reduced risk of relapse (P = 0.028). However, there was no discernible difference in overall survival (OS) or disease-free survival (DFS) for patients with high or low HED, which was inconsistent with the previous investigation. Discussion: While the observation are limited by the presented single center retrospective cohort, the results show that HED has poor prognostic value in OS or DFS, as well as the associations with relapse and aGVHD. In haploidentical setting, class II HED for donor-recipient pair (D/R_HEDclass II) is an independent and novel risk factor for finding the best haploidentical donor, which could potentially influence clinical practice if verified in larger cohorts.


Assuntos
Seleção do Doador , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Masculino , Feminino , Adulto , Adolescente , Pessoa de Meia-Idade , Criança , Estudos Retrospectivos , Fatores de Risco , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Adulto Jovem , Antígenos HLA/genética , Antígenos HLA/imunologia , Pré-Escolar , Transplante Haploidêntico , Doadores de Tecidos , Evolução Molecular
7.
HLA ; 104(3): e15675, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39247974

RESUMO

The determination of panel reactive antibodies (cPRA) scores plays a critical role in assessing the immunological compatibility between organ transplant recipients and potential donors. Traditional cPRA methods focus on a limited number of HLA loci using physical cytotoxicity tests. However, advancements such as the Luminex single antigen (LSA) assay, which uses mean fluorescence intensity (MFI) of individualised HLA antigens for antibody evaluation, provide a foundation for a more precise assessment. We developed cPRAdictor, a novel cPRA calculation tool using a large series of HLA-type individuals in France with NGS. cPRAdictor was applied to a cohort of 5962 kidney transplant candidates in Paris. We analysed how extending the range of HLA specificities could affect cPRA values. Implementing cPRAdictor revealed and allowed quantification of the significant discrepancies in cPRA values that appeared when HLA loci C and DP, and antigen-specific antibodies were taken into account. Notably, over 43% of the immunised transplant candidates showed an increase in calculated cPRA values when considering C/DP loci and antigen-specific antibodies, negatively impacting their eligibility and prioritisation in the transplantation programme. These findings highlight the necessity of revisiting cPRA calculation methodologies to include a broader spectrum of immunological data, as more exhaustive and precise information regarding anti-HLA antibodies in patients' sera and donor and recipient HLA typing are available prospectively. This will strongly improve both accuracy and equity at the organ allocation step, especially for highly sensitised candidates for whom organ offers are very limited in number.


Assuntos
Antígenos HLA , Teste de Histocompatibilidade , Isoanticorpos , Listas de Espera , Humanos , Teste de Histocompatibilidade/métodos , Antígenos HLA/imunologia , Isoanticorpos/sangue , Isoanticorpos/imunologia , Paris , Transplante de Rim , Doadores de Tecidos , Transplante de Órgãos/métodos , Histocompatibilidade
8.
HLA ; 104(3): e15649, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39247998

RESUMO

HLA donor specific antibodies (DSA) are implicated in antibody-mediated rejection (AMR), graft dysfunction and failure in kidney transplant (KT) recipients. Non-HLA antibodies including angiotensin II type 1 receptor (AT1R) may also play a role in AMR, impact graft function and survival. Data is limited in paediatric KT cohorts. We aimed to assess the prevalence and effect of pre-transplant AT1R antibodies on rejection, graft function and survival in paediatric KT recipients. This was a retrospective cohort study conducted across two paediatric centres including KT recipients with a pre-transplant AT1R antibody level. Outcomes included rejection, de novo DSA formation, graft function, failure, proteinuria and hypertension. Of 71 individuals, 72% recorded a positive pre-transplant AT1R Ab level (≥17 U/mL). Over a median follow-up of 4.7 years, AT1R Ab positivity demonstrated a trend towards increased risk of rejection however was not statistically significant (HR 3.45, 95% CI 0.97-12.35, p-value 0.06). Sensitivity analysis with AT1R Ab levels of ≥25 U/mL (HR 2.05 95% CI 0.78-5.39, p-value 0.14) and ≥40 U/mL (HR 1.32, CI 95% 0.55-3.17, p-value 0.53) validated this. De novo DSA formation occurred more frequently with AT1R Ab positivity (41% vs. 20%, p-value 0.9). AT1R Ab was not associated with hypertension, proteinuria, graft failure or dysfunction. In conclusion, this cohort study demonstrated a high prevalence of pre-transplant AT1R Ab positivity (72%). AT1R Ab positivity demonstrated a trend towards increased risk of rejection and de novo DSA formation however did not meet statistical significance. There was no association between AT1R Ab and hypertension, proteinuria, graft failure or dysfunction.


Assuntos
Rejeição de Enxerto , Sobrevivência de Enxerto , Transplante de Rim , Receptor Tipo 1 de Angiotensina , Humanos , Receptor Tipo 1 de Angiotensina/imunologia , Rejeição de Enxerto/imunologia , Masculino , Estudos Retrospectivos , Feminino , Criança , Adolescente , Isoanticorpos/sangue , Isoanticorpos/imunologia , Pré-Escolar , Antígenos HLA/imunologia , Proteinúria/imunologia , Proteinúria/sangue , Hipertensão/imunologia , Hipertensão/fisiopatologia , Hipertensão/sangue
11.
Sci Rep ; 14(1): 20579, 2024 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-39242614

RESUMO

During COVID-19 pandemic, cases of postvaccination infections and restored SARS-CoV-2 virus have increased after full vaccination, which might be contributed to by immune surveillance escape or virus rebound. Here, artificial linear 9-mer human leucocyte antigen (HLA)-restricted UC peptides were designed based on the well-conserved S2 region of the SARS-CoV-2 spike protein regardless of rapid mutation and glycosylation hindrance. The UC peptides were characterized for its effect on immune molecules and cells by HLA-tetramer refolding assay for HLA-binding ability, by HLA-tetramer specific T cell assay for engaged cytotoxic T lymphocytes (CTLs) involvement, by HLA-dextramer T cell assay for B cell activation, by intracellular cytokine release assay for polarization of immune response, Th1 or Th2. The specific lysis activity assay of T cells was performed for direct activation of cytotoxic T lymphocytes by UC peptides. Mice were immunized for immunogenicity of UC peptides in vivo and immunized sera was assay for complement cytotoxicity assay. Results appeared that through the engagement of UC peptides and immune molecules, HLA-I and II, that CTLs elicited cytotoxic activity by recognizing SARS-CoV-2 spike-bearing cells and preferably secreting Th1 cytokines. The UC peptides also showed immunogenicity and generated a specific antibody in mice by both intramuscular injection and oral delivery without adjuvant formulation. In conclusion, a T-cell vaccine could provide long-lasting protection against SARS-CoV-2 either during reinfection or during SARS-CoV-2 rebound. Due to its ability to eradicate SARS-CoV-2 virus-infected cells, a COVID-19 T-cell vaccine might provide a solution to lower COVID-19 severity and long COVID-19.


Assuntos
Linfócitos B , Vacinas contra COVID-19 , COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Linfócitos T Citotóxicos , Vacinas de Subunidades Antigênicas , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Humanos , Camundongos , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Linfócitos B/imunologia , Linfócitos T Citotóxicos/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Feminino , Antígenos HLA/imunologia , Camundongos Endogâmicos BALB C , Vacinas de Subunidades Proteicas
12.
J Clin Apher ; 39(5): e22144, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39291764

RESUMO

Therapeutic plasma exchange (TPE) is a cornerstone treatment for antibody-mediated rejection (AMR) post-organ transplantation, aiming to eliminate pathogenic donor-specific HLA antibodies (DSA). However, limitations in HLA antibody interpretation due to the prozone-like effect (PLE) can lead to inaccurate assessment of treatment efficacy. We present a case of a heart transplant recipient with suspected AMR, where an unexpected increase in DSA levels post-TPE prompted investigation into PLE. Solid-phase Luminex assays were employed to detect HLA antibodies. Serum was run neat as well as after treatment with ethylenediaminetetraacetic acid (EDTA). Nephelometry was used to detect complement levels. Laboratory analysis of pre-TPE serum revealed higher DSA levels with EDTA treatment, characteristic of PLE. Complement measurements supported complement-mediated interference in the pre-TPE sample. This case underscores the importance of being aware that PLE can occur in HLA testing and can impact the interpretation of TPE efficacy for AMR.


Assuntos
Rejeição de Enxerto , Antígenos HLA , Transplante de Coração , Troca Plasmática , Humanos , Transplante de Coração/efeitos adversos , Troca Plasmática/métodos , Antígenos HLA/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/terapia , Rejeição de Enxerto/prevenção & controle , Masculino , Teste de Histocompatibilidade , Isoanticorpos/sangue , Pessoa de Meia-Idade
13.
Curr Res Transl Med ; 72(3): 103464, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39232416

RESUMO

BACKGROUND: While the detrimental role of donor-specific anti-HLA antibodies (DSAs) is well-described in the setting of hematopoietic stem cell transplantation (HSCT), few studies focus on non donor-specific ones and with controversial results. METHODS: We here report our monocenter experience on 64 adult patients receiving allogeneic HSCT from a HLA-mismatched donor between 2014 and 2022 who were tested for the presence of anti-HLA antibodies before transplant, focusing on fifteen patients with non donor-specific anti-HLA antibodies. RESULTS: The survival of patients with non donor-specific anti-HLA antibodies was inferior with respect to patients without anti-HLA antibodies and similar to patients with DSAs. Median survival of patients with non donor-specific anti-HLA antibodies was 21 months (95 % CI: 9-42) vs. 61 months (95 % CI: 17-77) among the anti-HLA antibody-negative patients, with a significantly higher mortality incidence rate ratio (3.3 times-fold greater, p = 0.01). No pattern of death causes was found CONCLUSIONS: In this monocenter series of HLA-mismatched HSCTs, impaired survival was observed in adult patients having non donor-specific anti-HLA antibodies before transplant, similar to those with DSAs. Our findings support those antibodies as a negative predictive factor even if they are not directed against the donor, thus warranting further investigation on larger cohorts.


Assuntos
Antígenos HLA , Transplante de Células-Tronco Hematopoéticas , Transplante Homólogo , Humanos , Masculino , Feminino , Adulto , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pessoa de Meia-Idade , Adulto Jovem , Isoanticorpos/sangue , Isoanticorpos/imunologia , Doadores de Tecidos , Teste de Histocompatibilidade , Idoso , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/etiologia , Adolescente , Estudos Retrospectivos
14.
Sci Rep ; 14(1): 21765, 2024 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-39294236

RESUMO

To investigate the genetic relationship between end stage renal disease (ESRD) and human leukocyte antigen (HLA) alleles in the Guangxi Zhuang population. We performed polymerase chain reaction reversed sequence-specific oligonucleotide (PCR-rSSO) in 325 patients with ESRD and genotyped the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci. The direct counting method was used to determine the frequencies of HLA alleles, and Arlequin software (version 3.5.2.2) was used for haplotypic frequency analyses to compare the included ESRD patients with 350 healthy donors from the Guangxi Zhuang population. In our study, 120 HLA alleles, 284 HLA-A-B-DRB1 haplotypes, and 332 HLA-A-C-B-DRB1-DQB1 haplotypes were detected. We found that only A*11:01-B*15:02-DRB1*12:02 had a positive association with ESRD (P = 0.001, Pc = 0.020, OR = 3.106, 95% CI = 1.497-6.446) after Bonferroni correction; thus, individuals with this haplotype may be susceptible to ESRD. A*11:01-B*15:02-DRB1*12:02 is a potentially valuable haplotype for evaluating the risk of ESRD in the Guangxi Zhuang population.


Assuntos
Frequência do Gene , Predisposição Genética para Doença , Antígenos HLA , Falência Renal Crônica , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Alelos , Estudos de Casos e Controles , China/epidemiologia , Haplótipos , Antígenos HLA/genética , Falência Renal Crônica/genética , Falência Renal Crônica/epidemiologia , Polimorfismo Genético , População do Leste Asiático/genética
15.
Front Immunol ; 15: 1396284, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39247183

RESUMO

Backgrounds: Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies, it can be associated with relevant post-transplant complications. Several reports have shown that polymorphisms in immune system genes are correlated with the development of post-transplant complications. Within this context, this work focuses on identifying novel polymorphisms in cytokine genes and developing predictive models to anticipate the risk of developing graft-versus-host disease (GVHD), transplantation-related mortality (TRM), relapse and overall survival (OS). Methods: Our group developed a 132-cytokine gene panel which was tested in 90 patients who underwent an HLA-identical sibling-donor allo-HSCT. Bayesian logistic regression (BLR) models were used to select the most relevant variables. Based on the cut-off points selected for each model, patients were classified as being at high or low-risk for each of the post-transplant complications (aGVHD II-IV, aGVHD III-IV, cGVHD, mod-sev cGVHD, TRM, relapse and OS). Results: A total of 737 polymorphisms were selected from the custom panel genes. Of these, 41 polymorphisms were included in the predictive models in 30 cytokine genes were selected (17 interleukins and 13 chemokines). Of these polymorphisms, 5 (12.2%) were located in coding regions, and 36 (87.8%) in non-coding regions. All models had a statistical significance of p<0.0001. Conclusion: Overall, genomic polymorphisms in cytokine genes make it possible to anticipate the development all complications studied following allo-HSCT and, consequently, to optimize the clinical management of patients.


Assuntos
Citocinas , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante Homólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Masculino , Feminino , Citocinas/genética , Adulto , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/etiologia , Pessoa de Meia-Idade , Transplante Homólogo/efeitos adversos , Adulto Jovem , Adolescente , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Antígenos HLA/genética , Antígenos HLA/imunologia , Polimorfismo Genético , Idoso
16.
Nat Commun ; 15(1): 8054, 2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39277589

RESUMO

Immunoglobulin G (IgG) is the main isotype of antibody in human blood. IgG consists of four subclasses (IgG1 to IgG4), encoded by separate constant region genes within the Ig heavy chain locus (IGH). Here, we report a genome-wide association study on blood IgG subclass levels. Across 4334 adults and 4571 individuals under 18 years, we discover ten new and identify four known variants at five loci influencing IgG subclass levels. These variants also affect the risk of asthma, autoimmune diseases, and blood traits. Seven variants map to the IGH locus, three to the Fcγ receptor (FCGR) locus, and two to the human leukocyte antigen (HLA) region, affecting the levels of all IgG subclasses. The most significant associations are observed between the G1m (f), G2m(n) and G3m(b*) allotypes, and IgG1, IgG2 and IgG3, respectively. Additionally, we describe selective associations with IgG4 at 16p11.2 (ITGAX) and 17q21.1 (IKZF3, ZPBP2, GSDMB, ORMDL3). Interestingly, the latter coincides with a highly pleiotropic signal where the allele associated with lower IgG4 levels protects against childhood asthma but predisposes to inflammatory bowel disease. Our results provide insight into the regulation of antibody-mediated immunity that can potentially be useful in the development of antibody based therapeutics.


Assuntos
Asma , Estudo de Associação Genômica Ampla , Imunoglobulina G , Polimorfismo de Nucleotídeo Único , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina G/genética , Adulto , Feminino , Masculino , Asma/genética , Asma/imunologia , Asma/sangue , Criança , Adolescente , Receptores de IgG/genética , Pessoa de Meia-Idade , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/sangue , Alelos , Adulto Jovem , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/sangue , Cromossomos Humanos Par 17/genética , Predisposição Genética para Doença , Antígenos HLA/genética , Antígenos HLA/imunologia , Proteínas de Membrana
17.
Sci Justice ; 64(5): 533-542, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39277335

RESUMO

One of the most challenging issues still present in forensic DNA analysis is identifying individuals in samples containing DNA from multiple contributors. The introduction of novel identification markers may be a useful tool in the deconvolution of such DNA mixtures. In this study, we investigated the potential of alleles from the human leukocyte antigen system (HLA) to aid in identifying individuals in complex, multiple-donor DNA samples. The most advantageous characteristic of the HLA complex is its polymorphism in the human genome. A 22-loci multiplex with HLA markers was designed and applied to two-, three-, and four-person DNA mixtures. The results of the conducted experiments demonstrated that the identification of individuals in multiple contributor samples with the help of HLA markers is possible; however, it is clear that the reliability of the method is heavily dependent on the number of unique alleles for each individual in the analysed mixture. In order to compare this novel approach against the already established process, the same group of reference and multiple-contributor samples was analysed with a commonly used set of STR markers. This proof-of-concept research shows the importance of examining alternative solutions to the current deconvolution challenge in forensic DNA profiling.


Assuntos
Alelos , Impressões Digitais de DNA , DNA , Antígenos HLA , Estudo de Prova de Conceito , Humanos , Antígenos HLA/genética , Impressões Digitais de DNA/métodos , DNA/genética , Marcadores Genéticos , Repetições de Microssatélites
18.
Sci Rep ; 14(1): 20924, 2024 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-39251790

RESUMO

Human herpes viruses (HHV) are ubiquitous and have been implicated in numerous long-term health conditions. Since the association between viral exposure and long-term health impacts is partially influenced by variation in human leukocyte antigen (HLA) genes, we evaluated in silico the binding affinities of 9 HHV envelope glycoproteins with 127 common HLA Class I and Class II molecules. The findings show substantial variability in HHV binding affinity across viruses, HLA Class, HLA genes, and HLA alleles. Specific findings were as follows: (1) the predicted binding affinities of HHVs were characterized by four distinct groupings-[HHV1, HHV2], [HHV3, HHV4, HHV5], [HHV6A], [HHV6B, HHV7, HHV8]-with relatively lower binding affinities for HHV1, HHV2, and HHV6a compared to other HHVs; (2) significantly higher binding affinity was found for HLA Class I relative to Class II; (3) analyses within each class demonstrated that alleles of the C gene (for Class I) and DRB1 gene (for Class II) had the highest binding affinities; and (4) for each virus, predicted binding affinity to specific alleles varied, with HHV6a having the lowest affinity for HHV-HLA complexes, and HHV3, HHV4, and HHV5 having the highest. Since HLA-antigen binding is the first step in initiating an immune response to foreign antigens, these relative differences in HHV binding affinities are likely to influence long-term health impacts such that the cells infected with viruses associated with higher binding affinities across common HLA alleles may be more reduced in numbers, thereby lowering the potential for long-term sequelae of their infections.


Assuntos
Alelos , Proteínas do Envelope Viral , Humanos , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/metabolismo , Herpesviridae/imunologia , Herpesviridae/genética , Antígenos HLA/genética , Antígenos HLA/imunologia , Ligação Proteica , Imunogenética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia
19.
Zhonghua Yi Xue Za Zhi ; 104(35): 3347-3350, 2024 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-39266500

RESUMO

Clinical data of 1 494 patients with hematological diseases who were scheduled to receive allogeneic hematopoietic stem cell transplantation and received the anti-human-leukocyte-antigen (HLA) antibody test for the first time at the First Affiliated Hospital of Soochow University from 2016 to 2018 was collected to analyze the positive rates and distribution characteristics of different types of pre-existing anti-HLA antibodies in patients with different hematological diseases. Among 1 494 patients with hematological diseases, there were 849 males and 645 females, aged [31 (17, 45)] years, and included 577 cases of acute myeloid leukemia (AML), 373 cases of acute lymphocytic leukemia (ALL), 234 cases of aplastic anemia (AA), 175 cases of myelodysplastic syndrome (MDS), and 135 cases of other diseases. The total positive rate of pre-existing anti-HLA antibodies was 25.1% (375/1 494), among which the positive rates of anti-HLA class Ⅰ, anti-HLA class Ⅱ, and anti-HLA class Ⅰ+Ⅱ antibodies were 11.2% (168/1 494), 4.9% (73/1 494), and 9.0% (134/1 494), respectively.The total positive rates of pre-existing anti-HLA antibodies in patients with MDS、AA、AML、ALL and other diseases were 40.6% (71/175), 30.8% (72/234), 26.2% (151/577), 12.3% (46/373), and 25.9% (35/135), respectively, with statistically significant difference (P<0.001). The positive rates of anti-HLA class Ⅰ, anti-HLA class Ⅱ, and anti-HLA class Ⅰ+Ⅱ antibodies in patients with different hematological diseases showed statistically significant differences (all P<0.001). Given the varying positive rates and distribution characteristics of pre-existing anti-HLA antibodies among patients with different hematological diseases, anti-HLA antibody test should be performed before receiving hematopoietic stem cell transplantation.


Assuntos
Anemia Aplástica , Antígenos HLA , Doenças Hematológicas , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/imunologia , Adolescente , Antígenos HLA/imunologia , Doenças Hematológicas/imunologia , Adulto Jovem , Anemia Aplástica/imunologia , Leucemia Mieloide Aguda/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Transplante Homólogo
20.
Autoimmunity ; 57(1): 2387414, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39167553

RESUMO

It is known that certain human leukocyte antigen (HLA) genes are associated with autoimmune central nervous system (CNS) diseases, such as multiple sclerosis (MS), but their exact role in disease susceptibility and etiopathogenesis remains unclear. The best studied HLA-associated autoimmune CNS disease is MS, and thus will be the primary focus of this review. Other HLA-associated autoimmune CNS diseases, such as autoimmune encephalitis and neuromyelitis optica will be discussed. The lack of animal models to accurately capture the complex human autoimmune response remains a major challenge. HLA transgenic (tg) mice provide researchers with powerful tools to investigate the underlying mechanisms promoting susceptibility and progression of HLA-associated autoimmune CNS diseases, as well as for elucidating the myelin epitopes potentially targeted by T cells in autoimmune disease patients. We will discuss the potential role(s) of autoimmune disease-associated HLA alleles in autoimmune CNS diseases and highlight information provided by studies using HLA tg mice to investigate the underlying pathological mechanisms and opportunities to use these models for development of novel therapies.


Assuntos
Modelos Animais de Doenças , Antígenos HLA , Camundongos Transgênicos , Animais , Camundongos , Humanos , Antígenos HLA/genética , Antígenos HLA/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/genética , Neuromielite Óptica/imunologia , Neuromielite Óptica/genética , Doenças do Sistema Nervoso Central/imunologia , Doenças do Sistema Nervoso Central/genética
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