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1.
Medicine (Baltimore) ; 100(24): e26092, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34128846

RESUMO

RATIONALE: Fetal alloimmune thrombocytopenia (FAIT) is a serious life-threatening disease caused by platelet-antigen incompatibility between the mother and fetus. FAIT can lead to fetal thrombocytopenia, intracranial hemorrhage (ICH), fetal death and severe neurological disorders after birth. Noninvasive prenatal diagnosis technology has not been widely used in China, and thus few cases of FAIT can be diagnosed prenatally. In this study, we report a case of prenatal diagnosis and treatment of FAIT. PATIENT CONCERNS: A 29-year-old female was admitted at 32 weeks' gestational age (GA). Fetal ultrasound at 32 weeks' GA showed a hemorrhagic focus area in the left lateral ventricle and the sign of severe fetal anemia. Hence, fetal umbilical cord puncture was ordered to identify the etiology. DIAGNOSES: The fetal cord blood test revealed a normal hemoglobin level but severe fetal thrombocytopenia (platelet count, 23 × 109/L). Antibodies of human platelet antigens and human leukocyte antigens between mother and fetus were positive, and thus the diagnosis of FAIT was confirmed. INTERVENTIONS: The patient refused intravenous immunoglobulin (IVIG) therapy owing to financial consideration. She was treated with dexamethasone acetate tablets (Xianju Company, China) 0.75 mg twice a day until delivery and cesarean section was performed at 34 weeks' GA. The newborn received postnatal anti-platelet antibody treatment. OUTCOMES: The platelet count of the newborn progressively decreased until the third day after birth and it increased to normal level after postnatal treatment. The neonatal cerebral ultrasound showed the area of hemorrhage was in the process of absorption. During the postnatal one-year follow-up, the neonate showed normal developmental milestones and had no abnormal signs of neurological symptoms. LESSONS: For FAIT, the fetal umbilical cord puncture can be carried out by skilled fetal medical teams. Dexamethasone acetate tablets can be an alternative choice for patients from underdeveloped areas.


Assuntos
Sangue Fetal/imunologia , Doenças Fetais/diagnóstico , Diagnóstico Pré-Natal/métodos , Trombocitopenia Neonatal Aloimune/diagnóstico , Adulto , Antígenos de Plaquetas Humanas/sangue , Antígenos de Plaquetas Humanas/imunologia , Feminino , Doenças Fetais/imunologia , Antígenos HLA/sangue , Antígenos HLA/imunologia , Humanos , Recém-Nascido , Contagem de Plaquetas , Gravidez , Trombocitopenia Neonatal Aloimune/imunologia
2.
Hum Immunol ; 82(8): 551-560, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: covidwho-1265675

RESUMO

Given the highly polymorphic nature of Human Leukocyte Antigen (HLA) molecules, it is not surprising that they function as key regulators of the host immune response to almost all invading pathogens, including SARS-CoV-2, the etiological agent responsible for the recent COVID-19 pandemic. Several correlations have already been established between the expression of a specific HLA allele/haplotype and susceptibility/progression of SARS-CoV-2 infection and new ones are continuously emerging. Protective and harmful HLA variants have been described in both mild and severe forms of the disease, but considering the huge amount of existing variants, the data gathered in such a brief span of time are to some extent confusing and contradictory. The aim of this mini-review is to provide a snap-shot of the main findings so far collected on the HLA-SARS-CoV-2 interaction, so as to partially untangle this intricate yarn. As key factors in the generation of antigenic peptides to be presented by HLA molecules, ERAP1 and ERAP2 role in SARS-CoV-2 infection will be revised as well.


Assuntos
Aminopeptidases/genética , Apresentação do Antígeno , Antígenos Virais/imunologia , COVID-19/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidade Menor/genética , Polimorfismo Genético , SARS-CoV-2/imunologia , Aminopeptidases/imunologia , Animais , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/virologia , Epitopos , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno , Humanos , Antígenos de Histocompatibilidade Menor/imunologia , SARS-CoV-2/patogenicidade
3.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072923

RESUMO

Human umbilical cord blood (UCB) represents a valuable source of hematopoietic stem cells, particularly for patients lacking a matching donor. UCB provides practical advantages, including a lower risk of graft-versus-host-disease and permissive human leukocyte antigen mismatching. These advantageous properties have so far been applied for stem cell, mesenchymal stromal cell, and chimeric antigen receptor T cell therapies. However, UCB-derived professional antigen-presenting cells are increasingly being utilized in the context of immune tolerance and regenerative therapy. Here, we review the cell-specific characteristics as well as recent advancements in UCB-based cell therapies focusing on dendritic cells, monocytes, B lymphocytes, innate lymphoid cells, and macrophages.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Doença Enxerto-Hospedeiro/imunologia , Células-Tronco Hematopoéticas/imunologia , Imunidade Inata/genética , Células Apresentadoras de Antígenos/transplante , Linfócitos B/imunologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Sangue Fetal/citologia , Sangue Fetal/transplante , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Humanos
4.
Hum Immunol ; 82(8): 551-560, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34116863

RESUMO

Given the highly polymorphic nature of Human Leukocyte Antigen (HLA) molecules, it is not surprising that they function as key regulators of the host immune response to almost all invading pathogens, including SARS-CoV-2, the etiological agent responsible for the recent COVID-19 pandemic. Several correlations have already been established between the expression of a specific HLA allele/haplotype and susceptibility/progression of SARS-CoV-2 infection and new ones are continuously emerging. Protective and harmful HLA variants have been described in both mild and severe forms of the disease, but considering the huge amount of existing variants, the data gathered in such a brief span of time are to some extent confusing and contradictory. The aim of this mini-review is to provide a snap-shot of the main findings so far collected on the HLA-SARS-CoV-2 interaction, so as to partially untangle this intricate yarn. As key factors in the generation of antigenic peptides to be presented by HLA molecules, ERAP1 and ERAP2 role in SARS-CoV-2 infection will be revised as well.


Assuntos
Aminopeptidases/genética , Apresentação do Antígeno , Antígenos Virais/imunologia , COVID-19/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidade Menor/genética , Polimorfismo Genético , SARS-CoV-2/imunologia , Aminopeptidases/imunologia , Animais , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/virologia , Epitopos , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno , Humanos , Antígenos de Histocompatibilidade Menor/imunologia , SARS-CoV-2/patogenicidade
5.
Nat Commun ; 12(1): 3346, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099720

RESUMO

Characterizing the human leukocyte antigen (HLA) bound ligandome by mass spectrometry (MS) holds great promise for developing vaccines and drugs for immune-oncology. Still, the identification of non-tryptic peptides presents substantial computational challenges. To address these, we synthesized and analyzed >300,000 peptides by multi-modal LC-MS/MS within the ProteomeTools project representing HLA class I & II ligands and products of the proteases AspN and LysN. The resulting data enabled training of a single model using the deep learning framework Prosit, allowing the accurate prediction of fragment ion spectra for tryptic and non-tryptic peptides. Applying Prosit demonstrates that the identification of HLA peptides can be improved up to 7-fold, that 87% of the proposed proteasomally spliced HLA peptides may be incorrect and that dozens of additional immunogenic neo-epitopes can be identified from patient tumors in published data. Together, the provided peptides, spectra and computational tools substantially expand the analytical depth of immunopeptidomics workflows.


Assuntos
Aprendizado Profundo , Peptídeos/imunologia , Espectrometria de Massas em Tandem/métodos , Linhagem Celular , Epitopos , Proteínas da Matriz Extracelular/metabolismo , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Ligantes , Espectrometria de Massas , Medicina Molecular , Peptídeos/metabolismo , Proteômica
6.
Hum Immunol ; 82(8): 568-573, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33910707

RESUMO

HLA antibodies are typically produced after exposure to transplanted tissue, pregnancy, and blood products. Sensitization delays access to transplantation and preclude utilization of donor organs. Infections and vaccinations have also been reported to result in HLA antibody formation. It is not known if patients develop HLA antibodies after infection with SARS-CoV-2. Here we analyzed a series of eighteen patients waiting for kidney transplantation who had symptomatic COVID-19 disease and recovered. None of the patients in this initial series developed de novo HLA antibodies. Notably, there was no increase in preexisting HLA antibodies in four highly sensitized patients with a CPRA > 80%. These preliminary data suggest that there may not be a need to repeat HLA antibody testing or perform a physical crossmatch on admission serum before kidney transplant for COVID-19 recovered patients. Data from a large number of patients with different demographics needed.


Assuntos
COVID-19/imunologia , Antígenos HLA/imunologia , Histocompatibilidade , Isoanticorpos/sangue , Transplante de Rim , SARS-CoV-2/imunologia , Listas de Espera , Adulto , Idoso , COVID-19/diagnóstico , COVID-19/terapia , COVID-19/virologia , Bases de Dados Factuais , Feminino , Teste de Histocompatibilidade , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2/patogenicidade
7.
Front Immunol ; 12: 626308, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1190310

RESUMO

We have previously shown that conformational change in the ß2-integrin is a very early activation marker that can be detected with fluorescent multimers of its ligand intercellular adhesion molecule (ICAM)-1 for rapid assessment of antigen-specific CD8+ T cells. In this study, we describe a modified protocol of this assay for sensitive detection of functional antigen-specific CD4+ T cells using a monoclonal antibody (clone m24 Ab) specific for the open, high-affinity conformation of the ß2-integrin. The kinetics of ß2-integrin activation was different on CD4+ and CD8+ T cells (several hours vs. few minutes, respectively); however, m24 Ab readily stained both cell types 4-6 h after antigen stimulation. With this protocol, we were able to monitor ex vivo effector and memory CD4+ and CD8+ T cells specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and hepatitis B virus (HBV) in whole blood or cryopreserved peripheral blood mononuclear cells (PBMCs) of infected or vaccinated individuals. By costaining ß2-integrin with m24 and CD154 Abs, we assessed extremely low frequencies of polyfunctional CD4+ T cell responses. The novel assay used in this study allows very sensitive and simultaneous screening of both CD4+ and CD8+ T cell reactivities, with versatile applicability in clinical and vaccination studies.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Integrinas/metabolismo , Adulto , Idoso , Sequência de Aminoácidos , Sítios de Ligação , COVID-19/genética , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/virologia , Proteínas de Transporte/química , Citocinas/metabolismo , Citomegalovirus/imunologia , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Feminino , Antígenos HLA/química , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno/genética , Humanos , Imuno-Histoquímica , Imunofenotipagem , Integrinas/genética , Molécula 1 de Adesão Intercelular/química , Molécula 1 de Adesão Intercelular/metabolismo , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Multimerização Proteica , SARS-CoV-2/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
8.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: covidwho-1129736

RESUMO

Coronavirus disease 2019 (COVID-19) is induced by SARS-CoV-2 and may arise as a variety of clinical manifestations, ranging from an asymptomatic condition to a life-threatening disease associated with cytokine storm, multiorgan and respiratory failure. The molecular mechanism behind such variability is still under investigation. Several pieces of experimental evidence suggest that genetic variants influencing the onset, maintenance and resolution of the immune response may be fundamental in predicting the evolution of the disease. The identification of genetic variants behind immune system reactivity and function in COVID-19 may help in the elaboration of personalized therapeutic strategies. In the frenetic look for universally shared treatment plans, those genetic variants that are common to other diseases/models may also help in addressing future research in terms of drug repurposing. In this paper, we discuss the most recent updates about the role of immunogenetics in determining the susceptibility to and the history of SARS-CoV-2 infection. We propose a narrative review of available data, speculating about lessons that we have learnt from other viral infections and immunosenescence, and discussing what kind of aspects of research should be deepened in order to improve our knowledge of how host genetic variability impacts the outcome for COVID-19 patients.


Assuntos
COVID-19/imunologia , Imunogenética , Sistema ABO de Grupos Sanguíneos/imunologia , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/genética , Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Antígenos HLA/sangue , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Imunidade/genética , Índice de Gravidade de Doença
9.
Hum Immunol ; 82(8): 568-573, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: covidwho-1188594

RESUMO

HLA antibodies are typically produced after exposure to transplanted tissue, pregnancy, and blood products. Sensitization delays access to transplantation and preclude utilization of donor organs. Infections and vaccinations have also been reported to result in HLA antibody formation. It is not known if patients develop HLA antibodies after infection with SARS-CoV-2. Here we analyzed a series of eighteen patients waiting for kidney transplantation who had symptomatic COVID-19 disease and recovered. None of the patients in this initial series developed de novo HLA antibodies. Notably, there was no increase in preexisting HLA antibodies in four highly sensitized patients with a CPRA > 80%. These preliminary data suggest that there may not be a need to repeat HLA antibody testing or perform a physical crossmatch on admission serum before kidney transplant for COVID-19 recovered patients. Data from a large number of patients with different demographics needed.


Assuntos
COVID-19/imunologia , Antígenos HLA/imunologia , Histocompatibilidade , Isoanticorpos/sangue , Transplante de Rim , SARS-CoV-2/imunologia , Listas de Espera , Adulto , Idoso , COVID-19/diagnóstico , COVID-19/terapia , COVID-19/virologia , Bases de Dados Factuais , Feminino , Teste de Histocompatibilidade , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2/patogenicidade
10.
Scand J Immunol ; 94(1): e13048, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33914934

RESUMO

Not all anti-HLA donor-specific antibodies (HLA-DSAs) are detrimental to renal allograft. In this context, the C1q complement activating ability of antibodies appears to be an important parameter to distinguish clinically inert versus detrimental DSAs. We evaluated sera of 206 consecutive primary live donor renal transplant recipients before transplant and at post-operative day 7, 30, 90, 180 and at the time of graft dysfunction for quantifying HLA-DSAs using single antigen bead assay on a Luminex platform. Patients positive for these antibodies with an MFI >500 were further screened for C1q fixing nature of DSA. Fourteen of the 18 antibody-positive patients had C1q fixing DSA with MFI value >5000. Only 4 antibody-positive patients did not have C1q fixing DSA. The MFI values of DSA detected by C1q assay were generally higher at least by 25% than those detected by the conventional IgG-SAB assay. Twelve of the 14 patients (85.71%) with C1q+ DSA developed antibody-mediated rejection during the mean follow-up period of 21.43 ± 8.03 months as compared to none of the four C1q-negative DSA (85.71% vs 0%; P = .001). These results suggest deleterious effect of C1q+ DSA vis-à-vis C1q-negative DSA on renal allograft.


Assuntos
Anticorpos/imunologia , Complemento C1q/imunologia , Rejeição de Enxerto/imunologia , Adulto , Ativação do Complemento/imunologia , Feminino , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Humanos , Imunoglobulina G/imunologia , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doadores de Tecidos , Transplante Homólogo/efeitos adversos
11.
Front Immunol ; 12: 621138, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897684

RESUMO

In pre-sensitizing events, immunological memory is mainly created via indirect allorecognition where CD4+ T cells recognize foreign peptides in the context of self-HLA class II (pHLA) presented on antigen-presenting cells. This recognition makes it possible for naive CD4+ T-helper cells to differentiate into memory cells, resulting in the creation of further antibody memory. These responses contribute to effective secretion of donor-specific anti-HLA antibodies (DSA) after second encounters with the same peptide. Preformed donor-reactive CD4+ memory T cells may induce early immune responses after transplantation; however, the tools to evaluate them are limited. This study evaluated shared T cell epitopes (TEs) between the pre-sensitizing and donor HLA using an in silico assay, an alternative to estimate donor-reactive CD4+ memory T cells before transplantation. In 578 living donor kidney transplants without preformed DSA, 69 patients had anti-HLA antibodies before transplantation. Of them, 40 had shared TEs and were estimated to have donor-reactive CD4+ memory T cells. De novo DSA formation in the early phase was significantly higher in the shared TE-positive group than in the anti-HLA antibody- and shared TE-negative groups (p=0.001 and p=0.02, respectively). In conclusion, evaluation of shared TEs for estimating preformed donor-reactive CD4+ memory T cells may help predict the risk of early de novo DSA formation after kidney transplantation.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito B/genética , Epitopos de Linfócito T/genética , Rejeição de Enxerto/imunologia , Transplante de Rim , Idoso , Epitopos de Linfócito B/metabolismo , Epitopos de Linfócito T/metabolismo , Feminino , Antígenos HLA/imunologia , Humanos , Memória Imunológica , Isoanticorpos/metabolismo , Masculino , Pessoa de Meia-Idade , Doadores de Tecidos
12.
Nutrients ; 13(3)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805588

RESUMO

Our aim was to study the associations between maternal vitamin C and iron intake during pregnancy and the offspring's risk of developing islet autoimmunity and type 1 diabetes. The study was a part of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) prospective birth cohort including children genetically at risk of type 1 diabetes born between 1997-2004. The diets of 4879 mothers in late pregnancy were assessed with a validated food frequency questionnaire. The outcomes were islet autoimmunity and type 1 diabetes. Cox proportional hazards regression analysis adjusted for energy, family history of diabetes, human leukocyte antigen (HLA) genotype and sex was used for statistical analyses. Total intake of vitamin C or iron from food and supplements was not associated with the risk of islet autoimmunity (vitamin C: HR 0.91: 95% CI (0.80, 1.03), iron: 0.98 (0.87, 1.10)) or type 1 diabetes (vitamin C: 1.01 (0.87, 1.17), iron: 0.92 (0.78, 1.08)), neither was the use of vitamin C or iron supplements associated with the outcomes. In conclusion, no association was found between maternal vitamin C or iron intake during pregnancy and the risk of islet autoimmunity or type 1 diabetes in the offspring.


Assuntos
Doenças Autoimunes/imunologia , Diabetes Mellitus Tipo 1/imunologia , Dieta/efeitos adversos , Exposição Materna/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Adulto , Ácido Ascórbico/análise , Doenças Autoimunes/genética , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Dieta/estatística & dados numéricos , Inquéritos sobre Dietas , Suplementos Nutricionais , Feminino , Finlândia , Genótipo , Antígenos HLA/imunologia , Humanos , Lactente , Ferro na Dieta/análise , Ilhotas Pancreáticas/imunologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Modelos de Riscos Proporcionais , Estudos Prospectivos , Análise de Regressão
13.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807915

RESUMO

Coronavirus disease 2019 (COVID-19) is induced by SARS-CoV-2 and may arise as a variety of clinical manifestations, ranging from an asymptomatic condition to a life-threatening disease associated with cytokine storm, multiorgan and respiratory failure. The molecular mechanism behind such variability is still under investigation. Several pieces of experimental evidence suggest that genetic variants influencing the onset, maintenance and resolution of the immune response may be fundamental in predicting the evolution of the disease. The identification of genetic variants behind immune system reactivity and function in COVID-19 may help in the elaboration of personalized therapeutic strategies. In the frenetic look for universally shared treatment plans, those genetic variants that are common to other diseases/models may also help in addressing future research in terms of drug repurposing. In this paper, we discuss the most recent updates about the role of immunogenetics in determining the susceptibility to and the history of SARS-CoV-2 infection. We propose a narrative review of available data, speculating about lessons that we have learnt from other viral infections and immunosenescence, and discussing what kind of aspects of research should be deepened in order to improve our knowledge of how host genetic variability impacts the outcome for COVID-19 patients.


Assuntos
COVID-19/imunologia , Imunogenética , Sistema ABO de Grupos Sanguíneos/imunologia , COVID-19/sangue , COVID-19/epidemiologia , COVID-19/genética , Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Antígenos HLA/sangue , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Imunidade/genética , Índice de Gravidade de Doença
14.
Front Immunol ; 12: 626308, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854501

RESUMO

We have previously shown that conformational change in the ß2-integrin is a very early activation marker that can be detected with fluorescent multimers of its ligand intercellular adhesion molecule (ICAM)-1 for rapid assessment of antigen-specific CD8+ T cells. In this study, we describe a modified protocol of this assay for sensitive detection of functional antigen-specific CD4+ T cells using a monoclonal antibody (clone m24 Ab) specific for the open, high-affinity conformation of the ß2-integrin. The kinetics of ß2-integrin activation was different on CD4+ and CD8+ T cells (several hours vs. few minutes, respectively); however, m24 Ab readily stained both cell types 4-6 h after antigen stimulation. With this protocol, we were able to monitor ex vivo effector and memory CD4+ and CD8+ T cells specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and hepatitis B virus (HBV) in whole blood or cryopreserved peripheral blood mononuclear cells (PBMCs) of infected or vaccinated individuals. By costaining ß2-integrin with m24 and CD154 Abs, we assessed extremely low frequencies of polyfunctional CD4+ T cell responses. The novel assay used in this study allows very sensitive and simultaneous screening of both CD4+ and CD8+ T cell reactivities, with versatile applicability in clinical and vaccination studies.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Integrinas/metabolismo , Adulto , Idoso , Sequência de Aminoácidos , Sítios de Ligação , COVID-19/genética , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/virologia , Proteínas de Transporte/química , Citocinas/metabolismo , Citomegalovirus/imunologia , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Feminino , Antígenos HLA/química , Antígenos HLA/imunologia , Interações Hospedeiro-Patógeno/genética , Humanos , Imuno-Histoquímica , Imunofenotipagem , Integrinas/genética , Molécula 1 de Adesão Intercelular/química , Molécula 1 de Adesão Intercelular/metabolismo , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Multimerização Proteica , SARS-CoV-2/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
15.
Front Immunol ; 12: 609884, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679745

RESUMO

Predictive models are becoming more and more commonplace as tools for candidate antigen discovery to meet the challenges of enabling epitope mapping of cohorts with diverse HLA properties. Here we build on the concept of using two key parameters, diversity metric of the HLA profile of individuals within a population and consideration of sequence diversity in the context of an individual's CD8 T-cell immune repertoire to assess the HIV proteome for defined regions of immunogenicity. Using this approach, analysis of HLA adaptation and functional immunogenicity data enabled the identification of regions within the proteome that offer significant conservation, HLA recognition within a population, low prevalence of HLA adaptation and demonstrated immunogenicity. We believe this unique and novel approach to vaccine design as a supplement to vitro functional assays, offers a bespoke pipeline for expedited and rational CD8 T-cell vaccine design for HIV and potentially other pathogens with the potential for both global and local coverage.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV/imunologia , Interações Hospedeiro-Patógeno/imunologia , Aprendizado de Máquina , Antígenos Virais/genética , Antígenos Virais/imunologia , Epitopos de Linfócito T/imunologia , Variação Genética , Genoma Viral , Antígenos HLA/imunologia , Humanos , Peptídeos/imunologia , Proteoma , Proteínas Virais
16.
Transplant Proc ; 53(4): 1350-1354, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33752903

RESUMO

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is potentially curative for severe aplastic anemia (SAA). Graft failure (GF) remains a life-threatening complication after HSCT. Preexisting anti-HLA antibodies, especially HLA-specific antibodies (DSA), have been demonstrated as a risk of GF. CASE PRESENTATION: This report describes a woman with acquired SAA who presented with anti-HLA antibodies and GF. After the treatment of anti-HLA antibodies, engraftment was achieved through a second alternative donor HSCT. This work complied with the Declaration of Helsinki and the Declaration of Istanbul. CONCLUSIONS: Based on our experience in treating this case, we hold that the presence of preoperative anti-HLA antibodies could discount the efficacy of HSCT and anti-HLA antibody screening should be performed before HSCT. Additionally, a second HSCT is feasible to prolong survival.


Assuntos
Anemia Aplástica/terapia , Anticorpos/sangue , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas , Terapia de Salvação/métodos , Adulto , Anemia Aplástica/patologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA/imunologia , Haploidia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Pancitopenia/diagnóstico , Pancitopenia/etiologia , Troca Plasmática , Índice de Gravidade de Doença , Transplante Homólogo
17.
Transfusion ; 61(4): 1336-1340, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33666248

RESUMO

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a transfusion complication often mediated by recipient exposure to plasma from donors with human leukocyte antigen (HLA) and human neutrophil antigen (HNA) antibodies. Recipient anti-donor HLA or HNA antibodies have rarely been implicated. STUDY DESIGN AND METHODS: Herein, we describe a case of fatal TRALI mediated by recipient anti-HLA and anti-HNA antibodies. Cognate antibody-antigen match was confirmed with serologic and molecular assays. RESULTS: A 69-year-old G5P5 female with no prior transfusion history and metastatic cholangiocarcinoma with thromboembolic complications presented with heart failure and dyspnea. She was transfused 15 ml of a unit of Fya -negative red blood cells and subsequently developed acute onset dyspnea, hypoxemia, hypotension, and fever. Clinical investigations revealed bilateral infiltrates on chest X-ray and cognate recipient HLA and HNA antibodies to donor antigens. The patient died of acute respiratory failure within 24 h of transfusion. In total, the patient had Fya , HLA Class I, HNA, and human platelet antigen (HPA) alloantibodies. The 63-year-old female donor had detectable HLA class II antibodies (recipient class II genotype unavailable). CONCLUSION: The pathophysiology of TRALI has traditionally been ascribed to underlying conditions that put the recipient at risk in combination with donor biological response modifiers. This case illustrates alternative pathogenic mediators including alloantibodies to donor HLA and HNA. Additional studies to determine the contribution and frequency of recipient alloantibodies in TRALI may inform future mitigation strategies to further reduce the incidence of TRALI, particularly in female transfusion recipients.


Assuntos
Colangiocarcinoma/secundário , Antígenos HLA/imunologia , Neutrófilos/imunologia , Lesão Pulmonar Aguda Relacionada à Transfusão/diagnóstico , Idoso , Doadores de Sangue , Colangiocarcinoma/complicações , Dispneia/etiologia , Evolução Fatal , Feminino , Febre/etiologia , Humanos , Hipotensão/etiologia , Hipóxia/etiologia , Isoanticorpos/sangue , Pessoa de Meia-Idade , Plasma/imunologia , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/etiologia , Tromboembolia/etiologia , Reação Transfusional/complicações , Lesão Pulmonar Aguda Relacionada à Transfusão/complicações , Lesão Pulmonar Aguda Relacionada à Transfusão/imunologia , Lesão Pulmonar Aguda Relacionada à Transfusão/fisiopatologia , Transplantados
18.
Nature ; 592(7852): 138-143, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33731925

RESUMO

A variety of species of bacteria are known to colonize human tumours1-11, proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment12-14. However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune response. Here we used 16S rRNA gene sequencing and HLA peptidomics to identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumours. Our analysis of 17 melanoma metastases (derived from 9 patients) revealed 248 and 35 unique HLA-I and HLA-II peptides, respectively, that were derived from 41 species of bacteria. We identified recurrent bacterial peptides in tumours from different patients, as well as in different tumours from the same patient. Our study reveals that peptides derived from intracellular bacteria can be presented by tumour cells and elicit immune reactivity, and thus provides insight into a mechanism by which bacteria influence activation of the immune system and responses to therapy.


Assuntos
Antígenos de Bactérias/análise , Antígenos de Bactérias/imunologia , Bactérias/imunologia , Antígenos HLA/imunologia , Melanoma/imunologia , Melanoma/microbiologia , Peptídeos/análise , Peptídeos/imunologia , Apresentação do Antígeno , Bactérias/classificação , Bactérias/genética , Linhagem Celular Tumoral , Técnicas de Cocultura , Antígenos HLA/análise , Humanos , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/patologia , Metástase Neoplásica/imunologia , Filogenia , RNA Ribossômico 16S/genética
19.
Int J Hematol ; 114(1): 116-123, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33772729

RESUMO

Severe aplastic anemia and congenital amegakaryocytic thrombocytopenia are rare bone marrow failure syndromes. Treatment for aplastic anemia consists of hematopoietic stem cell transplantation (HSCT) from a matched sibling donor or immunosuppressant drugs if there is no donor available. Congenital amegakaryocytic thrombocytopenia is a rare autosomal recessive disease that causes bone marrow failure and has limited treatment options, except for transfusion support and HSCT. In the absence of a suitable matched sibling donor, matched-unrelated, haploidentical, or mismatched donors may be considered. A 2-step partial T-cell-depletion strategy can remove CD45RA+ naïve T cells responsible for graft-versus-host disease (GvHD) while preserving memory T cells. Five patients underwent transplantation using this strategy with rapid neutrophil and platelet recovery. Acute and chronic GvHD ≥ grade 2 appeared in two and one patient, respectively. No severe infections were observed before day + 100. A high (60%) incidence of transplant-associated microangiopathy was observed. Three patients (60%) remain alive, with a median follow-up of 881 (range 323-1248) days. CD45RA-depleted HSCT is a novel approach for patients lacking a suitable matched donor; however, further improvements are needed.


Assuntos
Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Antígenos Comuns de Leucócito/imunologia , Linfócitos T/imunologia , Adolescente , Anemia Aplástica/terapia , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Humanos , Reconstituição Imune , Depleção Linfocítica , Masculino , Condicionamento Pré-Transplante/métodos
20.
Mol Immunol ; 133: 154-162, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33667985

RESUMO

Identification of anti-human leukocyte antigen (HLA) antibodies (Abs) is based on Luminex™ technology. We used bioinformatics to (i) study the correlations of mean fluorescence intensities (MFIs) for all the possible allele pairs, and (ii) determine the degree of epitope homology between HLA antigens. Using MFI data on anti-HLA Abs from 6000 Luminex™ assays, we provide an updated overview of class I and II HLA antigen cross-reactivity in which each node corresponded to an allele and each link corresponded to a strong correlation between two alleles (Spearman's ρ > 0.8). We compared these correlations with the serological groups and the results of an epitope analysis. The strongest correlations concerned allele-specific Abs directed against the same antigen. For the HLA-A locus, the highest values of Spearman's ρ reflected broad specificity. For the HLA-B locus, graphs defined the HLA-Bw4 public epitope, and correlations between HLA-A and -B alleles were only present for beads with the same Bw4 public epitope. For the HLA-C locus, we identified two groups that differed with regard to their KIR ligand subclassification. Lastly, the HLA-DRB1 subgroups were part of a network. In the epitope analysis, Spearman's ρ was related to the number of matched epitopes within pairs of alleles. The combination of Spearman's ρ with simple, undirected graphing constitutes an effective tool for understanding routinely encountered cross-reactivity profiles. Based on this model, we have implemented an online data visualization tool available at http://cusureau.pythonanywhere.com/.


Assuntos
Especificidade de Anticorpos/imunologia , Epitopos/imunologia , Antígenos HLA/imunologia , Teste de Histocompatibilidade/métodos , Isoanticorpos/imunologia , Biologia Computacional/métodos , Reações Cruzadas/imunologia , Humanos , Estudos Retrospectivos
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