RESUMEN
The characteristic expansion of T CD38high/HLA-DR+CD8+ lymphocytes observed in hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) proved able to distinguish HLH/MAS from sepsis and systemic juvenile idiopathic arthritis. However, the performance of this marker in differentiating HLH/MAS from other pediatric febrile conditions with similar clinical onset and yet entirely different treatments remains unexplored. CD38high/HLA-DR+CD8+ frequencies measured in the peripheral fresh blood of pediatric patients attended for suspicion of HLH/MAS were retrospectively recorded and clinical characteristics were retrieved. CD38high/HLA-DR+CD8+ frequencies in HLH/MAS patients (15 patients; median: 22.0%, IQR: 11.0-49.0%) were compared with those who presented febrile conditions other-than-HLH (28 patients; median: 13.0%, IQR: 3.9-28.7%; p = 0.24). HLH and non-HLH patients were subsequently regrouped based on the presence of an identified infection (22 patients; median: 27.0%, IQR: 15.2-72.1%) and compared with those without infections (21 patients; median: 7.6%, IQR: 3.7-24.3%; p = 0.0035). CD38high/HLA-DR+CD8+ percentages were significantly higher only in the infection group compared with the noninfection one, with a patent pathogen-specific expansion in Epstein-Barr virus primoinfection and visceral leishmaniasis regardless of the presence of HLH. CD38high/HLA-DR+CD8+ frequencies do not appear as an HLH-specific marker as they naturally expand in other clinical situations that are common in childhood and may mimic HLH initial presentation.
RESUMEN
HLA-DQA1*01:02:24 differs from HLA-DQA1*01:02:01:03 by one nucleotide substitution in codon 167 in exon 3.
Asunto(s)
Alelos , Secuencia de Bases , Exones , Cadenas alfa de HLA-DQ , Prueba de Histocompatibilidad , Análisis de Secuencia de ADN , Humanos , Cadenas alfa de HLA-DQ/genética , Análisis de Secuencia de ADN/métodos , Codón , Alineación de SecuenciaRESUMEN
HLA-B*49:01:01:22 differs from HLA-B*49:01:01:01 by a single nucleotide C->G change in intron 5 at gDNA 2451.
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Alelos , Secuenciación de Nucleótidos de Alto Rendimiento , Prueba de Histocompatibilidad , Intrones , Trasplante de Riñón , Donantes de Tejidos , Humanos , Prueba de Histocompatibilidad/métodos , India , Exones , Secuencia de Bases , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodos , Antígeno HLA-B39/genéticaRESUMEN
The novel HLA-B*18:37:03 allele, first described in a potential bone marrow donor from Brazil.
Asunto(s)
Alelos , Exones , Humanos , Brasil , Antígeno HLA-B18/genética , Antígeno HLA-B18/inmunología , Prueba de Histocompatibilidad , Secuencia de Bases , Donantes de Tejidos , Análisis de Secuencia de ADN , Alineación de Secuencia , Trasplante de Médula ÓseaRESUMEN
HLA-DQB1*05:305 shows one single nucleotide substitution at position 664 compared with HLA-DQB1*05:03:01:01.
Asunto(s)
Alelos , Exones , Cadenas beta de HLA-DQ , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Cadenas beta de HLA-DQ/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Polimorfismo de Nucleótido Simple , Prueba de Histocompatibilidad/métodos , Secuencia de Bases , Análisis de Secuencia de ADN/métodosRESUMEN
A single nucleotide mismatch within exon 3 of HLA-DQA1 differentiates the novel allele DQA1*03:79 from DQA1*03:15.
Asunto(s)
Alelos , Exones , Cadenas alfa de HLA-DQ , Secuenciación de Nucleótidos de Alto Rendimiento , Prueba de Histocompatibilidad , Donantes de Tejidos , Humanos , Cadenas alfa de HLA-DQ/genética , Prueba de Histocompatibilidad/métodos , Médula Ósea , Polimorfismo de Nucleótido Simple , Secuencia de BasesRESUMEN
HLA-DRB3*02:202 differs from DRB3*02:112 by one nucleotide substitution in codon 51 in exon 2.
Asunto(s)
Alelos , Secuencia de Bases , Exones , Cadenas HLA-DRB3 , Prueba de Histocompatibilidad , Análisis de Secuencia de ADN , Humanos , Prueba de Histocompatibilidad/métodos , Análisis de Secuencia de ADN/métodos , Cadenas HLA-DRB3/genética , Codón , Alineación de SecuenciaRESUMEN
HLA-A*26:247 differs from HLA-A*26:01:01:01 by one nucleotide substitution in codon 245 in exon 4.
Asunto(s)
Alelos , Secuencia de Bases , Exones , Antígenos HLA-A , Prueba de Histocompatibilidad , Análisis de Secuencia de ADN , Humanos , Prueba de Histocompatibilidad/métodos , Antígenos HLA-A/genética , Análisis de Secuencia de ADN/métodos , Codón , Alineación de SecuenciaRESUMEN
The Canary Islands inhabitants, a recently admixed population with significant North African genetic influence, has the highest incidence of childhood-onset type 1 diabetes (T1D) in Spain and one of the highest in Europe. HLA accounts for half of the genetic risk of T1D. AIMS: To characterize the classical HLA-DRB1 and HLA-DQB1 alleles in children from Gran Canaria with and without T1D. METHODS: We analyzed classic HLA-DRB1 and HLA-DQB1 alleles in childhood-onset T1D patients (n = 309) and control children without T1D (n = 222) from the island of Gran Canaria. We also analyzed the presence or absence of aspartic acid at position 57 in the HLA-DQB1 gene and arginine at position 52 in the HLA-DQA1 gene. Genotyping of classical HLA-DQB1 and HLA-DRB1 alleles was performed at two-digit resolution using Luminex technology. The chi-square test (or Fisher's exact test) and odds ratio (OR) were computed to assess differences in allele and genotype frequencies between patients and controls. Logistic regression analysis was also used. RESULTS: Mean age at diagnosis of T1D was 7.4 ± 3.6 years (46% female). Mean age of the controls was 7.6 ± 1.1 years (55% female). DRB1*03 (OR = 4.2; p = 2.13-13), DRB1*04 (OR = 6.6; p ≤ 2.00-16), DRB1* 07 (OR = 0.37; p = 9.73-06), DRB1*11 (OR = 0.17; p = 6.72-09), DRB1*12, DRB1*13 (OR = 0.38; p = 1.21-05), DRB1*14 (OR = 0.0; p = 0.0024), DRB1*15 (OR = 0.13; p = 7.78-07) and DRB1*16 (OR = 0.21; p = 0.003) exhibited significant differences in frequency between groups. Among the DQB1* alleles, DQB1*02 (OR: 2.3; p = 5.13-06), DQB1*03 (OR = 1.7; p = 1.89-03), DQB1*05 (OR = 0.64; p = 0.027) and DQB1*06 (OR = 0.19; p = 6.25-14) exhibited significant differences. A total of 58% of the studied HLA-DQB1 genes in our control population lacked aspartic acid at position 57. CONCLUSIONS: In this population, the overall distributions of the HLA-DRB1 and HLA-DQB1 alleles are similar to those in other European populations. However, the frequency of the non-Asp-57 HLA-DQB1 molecules is greater than that in other populations with a lower incidence of T1D. Based on genetic, historical and epidemiological data, we propose that a common genetic background might help explain the elevated pediatric T1D incidence in the Canary Islands, North-Africa and middle eastern countries.
Asunto(s)
Diabetes Mellitus Tipo 1 , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Humanos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/epidemiología , Niño , España/epidemiología , Cadenas beta de HLA-DQ/genética , Masculino , Femenino , Cadenas HLA-DRB1/genética , Incidencia , Preescolar , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Frecuencia de los Genes , Adolescente , Alelos , GenotipoRESUMEN
BACKGROUND: The antigen processing machinery (APM) plays a critical role in generating tumor-specific antigens that can be recognized and targeted by the immune system. Proper functioning of APM components is essential for presenting these antigens on the surface of tumor cells, enabling immune detection and destruction. In many cancers, defects in APM can lead to immune evasion, contributing to tumor progression and poor clinical outcomes. However, the status of the APM in sarcomas is not well characterized, limiting the development of effective immunotherapeutic strategies for these patients. METHODS: We investigated 126 patients with 8 types of bone and soft tissue sarcoma operated between 2001-2021. Tissue microarrays mapped 11 specific areas in each case. The presence/absence of APM protein was determined through immunohistochemistry. Bayesian networks were used. RESULTS: All investigated sarcomas had some defects in APM. The least damaged component was HLA Class I subunit ß2-microglobulin and HLA Class II. The proteasome LMP10 subunit was defective in leiomyosarcoma (LMS), myxoid liposarcoma (MLPS), and dedifferentiated liposarcoma (DDLPS), while MHC I transporting unit TAP2 was altered in undifferentiated pleomorphic sarcoma (UPS), gastrointestinal stromal tumor (GIST), and chordoma (CH). Among different neoplastic areas, high-grade areas showed different patterns of expression compared to high lymphocytic infiltrate areas. Heterogeneity at the patient level was also observed. Loss of any APM component was prognostic of distant metastasis (DM) for LMS and DDLPS and of overall survival (OS) for LMS. CONCLUSION: Sarcomas exhibit a high degree of defects in APM components, with differences among histotypes and tumoral areas. The most commonly altered APM components were HLA Class I subunit ß2-microglobulin, HLA Class I subunit α (HC10), and MHC I transporting unit TAP2. The loss of APM components was prognostic of DM and OS and clinically relevant for LMS and DDLPS. This study explores sarcoma molecular mechanisms, enriching personalized therapeutic approaches.
Asunto(s)
Presentación de Antígeno , Sarcoma , Humanos , Sarcoma/inmunología , Sarcoma/patología , Presentación de Antígeno/inmunología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Microglobulina beta-2/metabolismo , Pronóstico , Miembro 3 de la Subfamilia B de Transportadores de Casetes de Unión a ATPRESUMEN
Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the HLA western blotting data shown for the HeLa cell line in Fig. 3D on p. 948 were strikingly similar to data appearing in different form in Fig. 3 in the following article written by different authors at different research institutes that was submitted for publication at around the same time, and for which an Expression of Concern has subsequently been published: Sun L, Xue H, Jiang C, Zhou H, Gu L, Liu Y, Xu C and Xu Q: LncRNA DQ786243 contributes to proliferation and metastasis of colorectal cancer both in vitro and in vivo. Biosci Rep 36: e00328, 2016. In addition, it was also noted that certain of the control western blotting data featured in Figs. 3D and 5B were strikingly similar, even though different experiments were being reported on in these figures. In view of the fact that the contentious data were submitted for publication at around the same time, the Editor of International Journal of Oncology has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 49: 943952, 2016; DOI: 10.3892/ijo.2016.3589].
RESUMEN
One of major breakthroughs in immunotherapy against tumor is from blocking immune checkpoint molecules on tumor and reactive T cells. The development of CTLA-4 and PD-1 blockage antibodies has triggered to search for additional effective therapeutic strategies. This causes recent findings that blocking the interaction of checkpoint molecule NKG2A in NK and CD8 T cells with HLA-E in tumors is effective in defensing tumors. Interestingly, gut microbiota also affects this immune checkpoint immunotherapy against tumor. Gut microbiota such as bacteria can contribute to the regulation of host immune response and homeostasis. They not only promote the differentiation and function of immunosuppressive cells but also the inflammatory cells through the metabolites such as tryptophan (Trp) and bile acid (BA) metabolites as well as short chain fatty acids (SCFAs). These gut microbiota metabolites (GMMs) educated immune cells can affect the differentiation and function of effective CD8 and NK cells. Notably, these metabolites also directly affect the activity of CD8 and NK cells. Furthermore, the expression of CD94/NKG2A in the immune cells and/or their ligand HLA-E in the tumor cells is also regulated by gut microbiota associated immune factors. These findings offer new insights for the clinical application of gut microbiota in precise and/or personalized treatments of tumors. In this review, we will discuss the impacts of GMMs and GMM educated immune cells on the activity of effective CD8 and NK cells and the expression of CD94/NKG2A in immune cells and/or their ligand HLA-E in tumor cells.
Asunto(s)
Microbioma Gastrointestinal , Antígenos HLA-E , Inmunoterapia , Subfamília C de Receptores Similares a Lectina de Células NK , Neoplasias , Humanos , Microbioma Gastrointestinal/inmunología , Subfamília C de Receptores Similares a Lectina de Células NK/inmunología , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/metabolismo , Inmunoterapia/métodos , Animales , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismoRESUMEN
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.
Asunto(s)
Selección de Donante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Masculino , Femenino , Adulto , Adolescente , Persona de Mediana Edad , Niño , Estudios Retrospectivos , Factores de Riesgo , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/genética , Adulto Joven , Antígenos HLA/genética , Antígenos HLA/inmunología , Preescolar , Trasplante Haploidéntico , Donantes de Tejidos , Evolución MolecularRESUMEN
The HLA-A*23:140 allele differs from HLA-A*23:01:01 by one nucleotide substitution (G > A), position 1968 in exon 5.
Asunto(s)
Alelos , Exones , Antígenos HLA-A , Donantes de Tejidos , Humanos , Brasil , Antígenos HLA-A/genética , Prueba de Histocompatibilidad , Secuencia de Bases , Análisis de Secuencia de ADN/métodos , Polimorfismo de Nucleótido Simple , Médula Ósea , Trasplante de Médula ÓseaRESUMEN
HLA-DPA1*01:12:03 differs from HLA-DPA1*01:12:01 by one nucleotide substitution in codon 204 in exon 4.
Asunto(s)
Alelos , Secuencia de Bases , Exones , Cadenas alfa de HLA-DP , Prueba de Histocompatibilidad , Análisis de Secuencia de ADN , Humanos , Cadenas alfa de HLA-DP/genética , Cadenas alfa de HLA-DP/inmunología , Prueba de Histocompatibilidad/métodos , Análisis de Secuencia de ADN/métodos , Codón , Alineación de SecuenciaRESUMEN
HLA-C*07:02:81 differs from HLA-C*07:02:01:01 by one nucleotide substitution at position 465 (CâA) in exon 3.
Asunto(s)
Alelos , Secuencia de Bases , Exones , Antígenos HLA-C , Prueba de Histocompatibilidad , Humanos , Antígenos HLA-C/genética , Análisis de Secuencia de ADN , Mutación Silenciosa , Alineación de Secuencia , CodónRESUMEN
Nine novel HLA alleles were identified when HLA typing individuals from the Indian population.
Asunto(s)
Alelos , Antígenos HLA , Secuenciación de Nucleótidos de Alto Rendimiento , Prueba de Histocompatibilidad , Humanos , India , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Prueba de Histocompatibilidad/métodos , Antígenos HLA/genéticaRESUMEN
HLA-B*51:411 differs from HLA-B*51:01:01:01 by one nucleotide substitution in codon 235 in exon 4.
Asunto(s)
Alelos , Secuencia de Bases , Exones , Prueba de Histocompatibilidad , Análisis de Secuencia de ADN , Humanos , Análisis de Secuencia de ADN/métodos , Codón , Antígenos HLA-B/genética , Alineación de SecuenciaRESUMEN
Immunotherapy targeting immune checkpoints (ICPs), such as programmed death-ligand-1 (PD-L1), is used as a treatment option for advanced or metastatic non-small cell lung cancer (NSCLC). However, overall response rate to anti-PD-L1 treatment is limited due to antigen heterogeneity and the immune-suppressive tumor microenvironment. Human leukocyte antigen-G (HLA-G), an ICP as well as a neoexpressed tumor-associated antigen, is previously demonstrated to be a beneficial target in combination with anti-PD-L1. In this study, a nanobody-based trispecific T cell engager (Nb-TriTE) is developed, capable of simultaneously binding to T cells, macrophages, and cancer cells while redirecting T cells toward tumor cells expressing PD-L1- and/or HLA-G. Nb-TriTE shows broad spectrum anti-tumor effects in vitro by augmenting cytotoxicity mediated by human peripheral blood mononuclear cells (PBMCs). In a humanized immunodeficient murine NSCLC model, Nb-TriTE exhibits superior anti-cancer potency compared to monoclonal antibodies and bispecific T cell engagers. Nb-TriTE, at the dose with pharmacoactivity, does not induce additional enhancement of circulating cytokines secretion from PMBCs. Nb-TriTE effectively prolongs the survival of mice without obvious adverse events. In conclusion, this study introduces an innovative therapeutic approach to address the challenges of immunotherapy and the tumor microenvironment in NSCLC through utilizing the dual ICP-targeting Nb-TriTE.
RESUMEN
HLA-DPB1*1618:01 differs from HLA-DPB1*18:01:01:01 by one nucleotide substitution in codon 215 in exon 4.