RESUMEN

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/genética

RESUMEN

Identification of seven new HLA alleles by next-generation sequencing.

Asunto(s)

Alelos , Antígenos HLA , Secuenciación de Nucleótidos de Alto Rendimiento , Prueba de Histocompatibilidad , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Antígenos HLA/genética , Prueba de Histocompatibilidad/métodos , Exones , Análisis de Secuencia de ADN/métodos , Secuencia de Bases

RESUMEN

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.

Asunto(s)

Asma , Estudio de Asociación del Genoma Completo , Inmunoglobulina G , Polimorfismo de Nucleótido Simple , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina G/genética , Adulto , Femenino , Masculino , Asma/genética , Asma/inmunología , Asma/sangre , Niño , Adolescente , Receptores de IgG/genética , Persona de Mediana Edad , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/sangre , Alelos , Adulto Joven , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/sangre , Cromosomas Humanos Par 17/genética , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Antígenos HLA/inmunología , Proteínas de la Membrana

RESUMEN

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 Molecular

RESUMEN

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.

Asunto(s)

Alelos , Dermatoglifia del ADN , ADN , Antígenos HLA , Prueba de Estudio Conceptual , Humanos , Antígenos HLA/genética , Dermatoglifia del ADN/métodos , ADN/genética , Marcadores Genéticos , Repeticiones de Microsatélite

RESUMEN

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.

Asunto(s)

Antígenos HLA , Longevidad , Humanos , Longevidad/genética , Anciano , Persona de Mediana Edad , Masculino , Adulto , Femenino , Anciano de 80 o más Años , Adolescente , Antígenos HLA/genética , Adulto Joven , Telómero/genética , Alelos , Homeostasis del Telómero , Envejecimiento/genética , Envejecimiento/inmunología , Haplotipos

RESUMEN

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.

Asunto(s)

Alelos , Proteínas del Envoltorio Viral , Humanos , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/metabolismo , Herpesviridae/inmunología , Herpesviridae/genética , Antígenos HLA/genética , Antígenos HLA/inmunología , Unión Proteica , Inmunogenética , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología

RESUMEN

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.

Asunto(s)

Citocinas , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Trasplante Homólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Masculino , Femenino , Citocinas/genética , Adulto , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/etiología , Persona de Mediana Edad , Trasplante Homólogo/efectos adversos , Adulto Joven , Adolescente , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidad , Antígenos HLA/genética , Antígenos HLA/inmunología , Polimorfismo Genético , Anciano

RESUMEN

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.

Asunto(s)

Modelos Animales de Enfermedad , Antígenos HLA , Ratones Transgénicos , Animales , Ratones , Humanos , Antígenos HLA/genética , Antígenos HLA/inmunología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/genética , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/genética , Enfermedades del Sistema Nervioso Central/inmunología , Enfermedades del Sistema Nervioso Central/genética

RESUMEN

AIMS: To study the effects of routine HLA screening and the policy of avoiding donor-dominant one-way HLA match to prevent graft-versus-host disease (GVHD) after living donor liver transplantation (LDLT). PATIENTS AND METHODS: The records of potential living liver donors and recipients who attended our center between 2007 and 2018 were reviewed retrospectively. RESULTS: Of the 149 patients who underwent LDLT and survived longer than 3 months, two developed GVHD despite our strict policy. The first patient presented with grade II GVHD limited to the skin. She was treated successfully by briefly discontinuing immunosuppression and switching to everolimus. In the second case, the policy had been relaxed due to the availability of a single donor for ABO-incompatible transplantation without any intervention to decrease anti-A antibody levels (special case: A2 to O). Nevertheless, the patient presented with grade I GVHD limited to skin and was treated successfully by adding oral methylprednisolone to tacrolimus and mycophenolate mofetil. To the best of our information, this is the second reported case who recovered from GVHD after LDLT from a donor, homozygous at HLA A, B and DR and a recipient, heterozygous for all. Sixteen potential donors (1.2% of all candidates) of 14 recipients were disqualified solely on the basis of the HLA results; five of these patients died due to unavailability of another donor. CONCLUSION: The results support the policy of avoiding HLA combinations that preclude immune recognition of graft lymphocytes as foreign to decrease the risk of GVHD after LDLT.

Asunto(s)

Enfermedad Injerto contra Huésped , Antígenos HLA , Prueba de Histocompatibilidad , Trasplante de Hígado , Donadores Vivos , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA/inmunología , Antígenos HLA/genética , Inmunosupresores/uso terapéutico , Estudios Retrospectivos

RESUMEN

Leishmaniasis is an infectious disease caused by protozoa of the genus Leishmania, which is endemic in certain areas of Europe, such as southern Spain. The disease manifests in various clinical phenotypes, including visceral, cutaneous, mucosal, or asymptomatic leishmaniasis. This diversity in clinical outcomes may be influenced by the host immune response, with human leukocyte antigen (HLA) molecules playing a crucial role in determining susceptibility and progression of the infection. This study explores the association between specific HLA variants and Leishmania infantum infection. We recruited four cohorts: a control group, asymptomatic individuals, patients with symptomatic disease, and cohabitants of infected individuals. HLA typing was performed for all participants, followed by an association analysis with infection status and disease progression. Our findings indicate that the HLA-B*38 and HLA-C*03 alleles are associated with protection against L. infantum infection. These results contribute to a better understanding of the disease's progression, offer potential for new therapeutic approaches such as vaccines, and expand the existing knowledge in the literature.

Asunto(s)

Alelos , Leishmania infantum , Humanos , Leishmania infantum/genética , España/epidemiología , Masculino , Femenino , Adulto , Predisposición Genética a la Enfermedad , Leishmaniasis Visceral/genética , Leishmaniasis Visceral/parasitología , Leishmaniasis Visceral/inmunología , Leishmaniasis Visceral/epidemiología , Estudios de Cohortes , Persona de Mediana Edad , Antígenos HLA/genética , Frecuencia de los Genes

RESUMEN

This study examines the interplay between human leukocyte antigen (HLA) compatibility and killer-cell immunoglobulin-like receptor (KIR) genotypes in influencing kidney transplantation outcomes. Understanding these interactions is crucial for improving graft survival and minimizing rejection risks. We evaluated 84 kidney transplant recipients, dividing them into two groups based on post-transplant outcomes: there were 68 with stable graft function (SGF) and 16 who experienced chronic rejection (CR). Patients were selected based on specific inclusion criteria. HLA mismatches (Class I: HLA-A, -B; Class II: HLA-DR) and KIR genotypes were determined using standard genotyping techniques. Statistical analyses, including logistic regression, were performed to correlate these factors with transplant outcomes. Significant age differences were observed, with younger patients more likely to experience graft rejection, while no significant gender-based differences were noted. A significant correlation was found between Class II mismatches and increased rejection rates, highlighting the importance of HLA-DR compatibility. Further analysis revealed that certain inhibitory KIRs, such as KIR3DL1, were associated with favorable outcomes, suggesting a protective role against graft rejection. These findings were corroborated by evaluating serum creatinine levels over multiple years, serving as a biomarker for renal function post transplant. This study underscores the critical need for meticulous HLA matching and the consideration of KIR genotypes in pre-transplant evaluations to enhance graft survival and minimize rejection risks. Integrating these genetic factors into routine clinical assessments could significantly improve personalized transplant medicine strategies, ultimately enhancing patient outcomes. Further research is needed to explore the underlying mechanisms and validate these findings in larger, diverse populations.

Asunto(s)

Genotipo , Rechazo de Injerto , Supervivencia de Injerto , Trasplante de Riñón , Receptores KIR , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Receptores KIR/genética , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Adulto , Supervivencia de Injerto/genética , Supervivencia de Injerto/inmunología , Antígenos HLA/genética , Antígenos HLA/inmunología , Anciano

RESUMEN

Molecular HLA typing techniques are currently undergoing a rapid evolution. While real-time PCR is established as the standard method in tissue typing laboratories regarding allocation of solid organs, next generation sequencing (NGS) for high-resolution HLA typing is becoming indispensable but is not yet suitable for deceased donors. By contrast, high-resolution typing is essential for stem cell transplantation and is increasingly required for questions relating to various disease associations. In this multicentre clinical study, the TGS technique using nanopore sequencing is investigated applying NanoTYPE™ kit and NanoTYPER™ software (Omixon Biocomputing Ltd., Budapest, Hungary) regarding the concordance of the results with NGS and its practicability in diagnostic laboratories. The results of 381 samples show a concordance of 99.58% for 11 HLA loci, HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQA1, -DQB1, -DPA1 and -DPB1. The quality control (QC) data shows a very high quality of the sequencing performed in each laboratory, 34,926 (97.15%) QC values were returned as 'passed', 862 (2.4%) as 'inspect' and 162 (0.45%) as 'failed'. We show that an 'inspect' or 'failed' QC warning does not automatically lead to incorrect HLA typing. The advantages of nanopore sequencing are speed, flexibility, reusability of the flow cells and easy implementation in the laboratory. There are challenges, such as exon coverage and the handling of large amounts of data. Finally, nanopore sequencing presents potential for applications in basic research within the field of epigenetics and genomics and holds significance for clinical concerns.

Asunto(s)

Antígenos HLA , Secuenciación de Nucleótidos de Alto Rendimiento , Prueba de Histocompatibilidad , Humanos , Prueba de Histocompatibilidad/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Antígenos HLA/genética , Programas Informáticos , Alelos , Genotipo , Control de Calidad , Secuenciación de Nanoporos/métodos , Técnicas de Genotipaje/métodos

RESUMEN

The expression of inflamma-miRs and human leukocyte antigen (HLA) haplotypes could indicate mild cognitive impairment (MCI) and Alzheimer's disease (AD). We used international databases to conduct a systematic review of studies on HLA variants and a meta-analysis of research on microRNAs (miRNAs). We aimed to analyze the discriminative value of HLA variants and miRNAs in MCI, AD and controls to evaluate the protective or causative effect of HLA in cognitive decline, establish the role of miRNAs as biomarkers for the early detection of AD, and find a possible link between miRNAs and HLA. Statistical analysis was conducted using Comprehensive Meta-analysis software, version 2.2.050 (Biostat Inc., Englewood, NJ, USA). The effect sizes were estimated by the logarithm base 2 of the fold change. The systematic review revealed that some HLA variants, such as HLA-B*4402, HLA-A*33:01, HLA-A*33:01, HLA-DPB1, HLA-DR15, HLA-DQB1*03:03, HLA-DQB1*06:01, HLA-DQB1*03:01, SNPs on HLA-DRB1/DQB1, and HLA-DQA1, predisposed to cognitive decline before the occurrence of AD, while HLA-A1*01, HLA-DRB1∗13:02, HLA-DRB1*04:04, and HLA-DRB1*04:01 demonstrated a protective role. The meta-analysis identified let-7 and miR-15/16 as biomarkers for the early detection of AD. The association between these two miRNA families and the HLA variants that predispose to AD could be used for the early screening and prevention of MCI.

Asunto(s)

Enfermedad de Alzheimer , Disfunción Cognitiva , Predisposición Genética a la Enfermedad , Antígenos HLA , MicroARNs , Humanos , MicroARNs/genética , Enfermedad de Alzheimer/genética , Disfunción Cognitiva/genética , Antígenos HLA/genética , Biomarcadores , Polimorfismo de Nucleótido Simple

RESUMEN

Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.

Asunto(s)

Neoplasias Colorrectales , Genómica , Mutación , Humanos , Neoplasias Colorrectales/genética , Femenino , Masculino , Inestabilidad de Microsatélites , Secuenciación Completa del Genoma , Pronóstico , Reino Unido/epidemiología , Inestabilidad Cromosómica/genética , Genoma Humano/genética , Variaciones en el Número de Copia de ADN/genética , Antígenos HLA/genética

RESUMEN

The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.

Asunto(s)

Genoma Viral , Infecciones por VIH , VIH-1 , Antígenos HLA , Humanos , VIH-1/genética , VIH-1/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/genética , Antígenos HLA/genética , Antígenos HLA/inmunología , Variación Genética , Carga Viral , Estudios de Cohortes , Selección Genética , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología

RESUMEN

BACKGROUND: the human leukocyte antigen (HLA) loci have been widely characterized to be associated with viral infectious diseases. Several studies including various ethnic groups and populations suggested associations between certain HLA alleles and SARS-CoV-2 infection. Despite the numerous associations identified, the role of HLA polymorphisms in determining the individual response to SARS-CoV-2 infection is controversial among different Saudi populations. METHOD: Here, we performed HLA typing by next-generation sequencing to investigate if variations in polymorphic HLA genes are linked to COVID-19 severity in the Saudi population. Namely, we analyzed HLA loci at allele level in 575 Saudi patients with SARS-CoV-2 infection. HLA class I and class II frequencies in patients were compared with allele frequency data from healthy Saudi population. RESULTS: in our cohort HLA-A* 02:01:01 G was associated with mild disease but was not associated with moderate and severe disease. HLA-B* 51:01:01 G was protective from severe disease while HLA-B* 50:01:01 G, HLA-C* 06:02:01 G and HLA-DRB1 * 07:01:01 G were associated with risk to severe disease as well as the total COVID-19 cohort. HLA-DRB1 * 15:01:01 G was associated with risk to all severity groups. CONCLUSION: in conclusion, we found significant associations between HLA alleles and COVID-19 disease severity in Saudis. Further studies are warranted to include HLA typing in the workup for any new COVID-19 patients.

Asunto(s)

Alelos , COVID-19 , Frecuencia de los Genes , Antígenos HLA , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Humanos , COVID-19/genética , COVID-19/inmunología , Arabia Saudita , Masculino , Femenino , Antígenos HLA/genética , Persona de Mediana Edad , Adulto , SARS-CoV-2/inmunología , Predisposición Genética a la Enfermedad , Anciano , Adulto Joven , Estudios de Cohortes , Adolescente , Polimorfismo Genético , Secuenciación de Nucleótidos de Alto Rendimiento , Prueba de Histocompatibilidad

RESUMEN

Extended sequences for 13 HLA alleles were found which had limited coverage previously.

Asunto(s)

Alelos , Antígenos HLA , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Antígenos HLA/genética , Prueba de Histocompatibilidad/métodos , Análisis de Secuencia de ADN/métodos , Exones , Secuencia de Bases

RESUMEN

Most COVID-19 vaccines elicit immunity against the SARS-CoV-2 Spike protein. However, Spike protein mutations in emerging strains and immune evasion by the SARS-CoV-2 virus demonstrates the need to develop more broadly targeting vaccines. To facilitate this, we use mass spectrometry to identify immunopeptides derived from seven relatively conserved structural and non-structural SARS-CoV-2 proteins (N, E, Nsp1/4/5/8/9). We use two different B-lymphoblastoid cell lines to map Human Leukocyte Antigen (HLA) class I and class II immunopeptidomes covering some of the prevalent HLA types across the global human population. We employ DNA plasmid transfection and direct antigen delivery approaches to sample different antigens and find 248 unique HLA class I and HLA class II bound peptides with 71 derived from N, 12 from E, 28 from Nsp1, 19 from Nsp4, 73 from Nsp8 and 45 peptides derived from Nsp9. Over half of the viral peptides are unpublished. T cell reactivity tested against 56 of the detected peptides shows CD8+ and CD4+ T cell responses against several peptides from the N, E, and Nsp9 proteins. Results from this study will aid the development of next-generation COVID vaccines targeting epitopes from across a number of SARS-CoV-2 proteins.

Asunto(s)

COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/inmunología , SARS-CoV-2/genética , COVID-19/inmunología , COVID-19/virología , Haplotipos , Péptidos/inmunología , Péptidos/química , Epítopos de Linfocito T/inmunología , Antígenos HLA/inmunología , Antígenos HLA/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Vacunas contra la COVID-19/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígenos Virales/inmunología , Antígenos Virales/genética , Línea Celular

RESUMEN

Type 1 diabetes (T1D) results from a complex interplay of genetic predisposition, immunological dysregulation, and environmental triggers, that culminate in the destruction of insulin-secreting pancreatic ß cells. This review provides a comprehensive examination of the multiple factors underpinning T1D pathogenesis, to elucidate key mechanisms and potential therapeutic targets. Beginning with an exploration of genetic risk factors, we dissect the roles of human leukocyte antigen (HLA) haplotypes and non-HLA gene variants associated with T1D susceptibility. Mechanistic insights gleaned from the NOD mouse model provide valuable parallels to the human disease, particularly immunological intricacies underlying ß cell-directed autoimmunity. Immunological drivers of T1D pathogenesis are examined, highlighting the pivotal contributions of both effector and regulatory T cells and the multiple functions of B cells and autoantibodies in ß-cell destruction. Furthermore, the impact of environmental risk factors, notably modulation of host immune development by the intestinal microbiome, is examined. Lastly, the review probes human longitudinal studies, unveiling the dynamic interplay between mucosal immunity, systemic antimicrobial antibody responses, and the trajectories of T1D development. Insights garnered from these interconnected factors pave the way for targeted interventions and the identification of biomarkers to enhance T1D management and prevention strategies.

Asunto(s)

Autoinmunidad , Diabetes Mellitus Tipo 1 , Microbioma Gastrointestinal , Predisposición Genética a la Enfermedad , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/genética , Humanos , Animales , Microbioma Gastrointestinal/inmunología , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/metabolismo , Interacción Gen-Ambiente , Autoanticuerpos/inmunología , Antígenos HLA/genética , Antígenos HLA/inmunología , Ratones , Modelos Animales de Enfermedad , Factores de Riesgo