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The pathogenesis of COVID-19 warrants unravelling. Genetic polymorphism analysis may help answer the variability in disease outcome. To determine the role of KIR and HLA polymorphisms in susceptibility, progression, and severity of SARS-CoV-2 infection, 458 patients and 667 controls enrolled in this retrospective observational study from April to December 2020. Mild/moderate and severe/death study groups were established. HLA-A, -B, -C, and KIR genotyping were performed using the Lifecodes® HLA-SSO and KIR-SSO kits on the Luminex® 200™ xMAP fluoroanalyser. A probability score using multivariate binary logistic regression analysis was calculated to estimate the likelihood of severe COVID-19. ROC analysis was used to calculate the best cut-off point for predicting a worse clinical outcome with high sensitivity and specificity. A p ≤ 0.05 was considered statistically significant. KIR AA genotype protected positively against severity/death from COVID-19. Furthermore, KIR3DL1, KIR2DL3 and KIR2DS4 genes protected patients from severe forms of COVID-19. KIR Bx genotype, as well as KIR2DL2, KIR2DS2, KIR2DS3 and KIR3DS1 were identified as biomarkers of severe COVID-19. Our logistic regression model, which included clinical and KIR/HLA variables, categorised our cohort of patients as high/low risk for severe COVID-19 disease with high sensitivity and specificity (Se = 94.29%, 95% CI [80.84-99.30]; Sp = 84.55%, 95% CI [79.26-88.94]; OR = 47.58, 95%CI [11.73-193.12], p < 0.0001). These results illustrate an association between KIR/HLA ligand polymorphism and different COVID-19 outcomes and remarks the possibility of use them as a surrogate biomarkers to detect severe patients in possible future infectious outbreaks.
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COVID-19 , Receptores KIR , SARS-CoV-2 , Humanos , COVID-19/genética , COVID-19/imunologia , COVID-19/virologia , Receptores KIR/genética , Masculino , Feminino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Projetos Piloto , Estudos Retrospectivos , Polimorfismo Genético , Idoso , Genótipo , Predisposição Genética para Doença , Adulto , Índice de Gravidade de Doença , Antígenos HLA/genéticaRESUMO
Inflammatory bowel disease (IBD) is the consequence of a complex interplay between environmental factors, like dietary habits, that alter intestinal microbiota in response to luminal antigens in genetically susceptible individuals. Epigenetics represents an auspicious area for the discovery of how environmental factors influence the pathogenesis of inflammation, prognosis, and response to therapy. Consequently, it relates to gene expression control in response to environmental influences. The increasing number of patients with IBD globally is indicative of the negative effects of a food supply rich in trans and saturated fats, refined sugars, starches and additives, as well as other environmental factors like sedentarism and excess bodyweight, influencing the promotion of gene expression and increasing DNA hypomethylation in IBD. As many genetic variants are now associated with Crohn's disease (CD), new therapeutic strategies targeting modifiable environmental triggers, such as the implementation of an anti-inflammatory diet that involves the removal of potential food antigens, are of growing interest in the current literature. Diet, as a strong epigenetic factor in the pathogenesis of inflammatory disorders like IBD, provides novel insights into the pathophysiology of intestinal and extraintestinal inflammatory disorders.
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Metilação de DNA , Dieta , Epigênese Genética , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/imunologia , Dieta/efeitos adversos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Comportamento Alimentar , Predisposição Genética para DoençaRESUMO
Turner syndrome (TS) is a female phenotypic condition characterized by one or more typical clinical features and the partial or complete absence of a second X chromosome as determined by karyotype analysis. TS, among the most common chromosomal abnormalities, has an estimated prevalence of approximately 1 in 2,500 live-born females, with ethnic and racial differences. TS encompasses a wide array of medical challenges, including cardiovascular, endocrine, autoimmune, and mental health issues, as well as a heightened cancer risk. The somatic stigmata of TS are thought to arise from haploinsufficiency of the X chromosomes. This review explores the lifelong medical challenges and immunogenetics of individuals with TS and aimed to investigate strategies for preventing and managing TS while considering the implications of immunogenetics.
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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.
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Alelos , Leishmania infantum , Humanos , Leishmania infantum/genética , Espanha/epidemiologia , Masculino , Feminino , Adulto , Predisposição Genética para Doença , Leishmaniose Visceral/genética , Leishmaniose Visceral/parasitologia , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/epidemiologia , Estudos de Coortes , Pessoa de Meia-Idade , Antígenos HLA/genética , Frequência do GeneRESUMO
The HLA genes are associated with various autoimmune pathologies, with the control of the immune response also being significant in organs and cells transplantation. The aim of the study is to identify the HLA-A, HLA-B, and HLA-C alleles frequencies in the analyzed Romanian cohort. We performed HLA typing using next-generation sequencing (NGS) in a Romanian cohort to estimate class I HLA allele frequencies up to a six-digit resolution. A total of 420 voluntary donors from the National Registry of Voluntary Hematopoietic Stem Cell Donors (RNDVCSH) were included in the study for HLA genotyping. Peripheral blood samples were taken and brought to the Fundeni Clinical Institute during 2020-2021. HLA genotyping was performed using the Immucor Mia Fora NGS MFlex kit. A total of 109 different alleles were detected in 420 analyzed samples, out of which 31 were for HLA-A, 49 for HLA-B, and 29 for HLA-C. The most frequent HLA-A alleles were HLA-A*02:01:01 (26.11%), HLA-A*01:01:01 (12.5%), HLA-A*24:02:01 (11.67%), HLA-A*03:01:01 (9.72%), HLA-A*11:01:01, and HLA-A*32:01:01 (each with 8.6%). For the HLA-B locus, the most frequent allele was HLA-B*18:01:01 (11.25%), followed by HLA-B*51:01:01 (10.83%) and HLA-B*08:01:01 (7.78%). The most common HLA-C alleles were HLA-C*07:01:01 (17.36%), HLA-C*04:01:01 (13.47%), and HLA-C*12:03:01 (10.69%). Follow-up studies are ongoing for confirming the detected results.
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Frequência do Gene , Antígenos HLA-A , Antígenos HLA-B , Antígenos HLA-C , Doadores de Tecidos , Humanos , Antígenos HLA-C/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Masculino , Feminino , Alelos , Romênia , Células-Tronco Hematopoéticas/metabolismo , Transplante de Células-Tronco Hematopoéticas , Adulto , Sequenciamento de Nucleotídeos em Larga Escala , Teste de Histocompatibilidade/métodos , Genótipo , Pessoa de Meia-IdadeRESUMO
Introduction: Therapeutic monoclonal antibodies (mAbs) have demonstrated promising outcomes in diverse clinical indications, including but not limited to graft rejection, cancer, and autoimmune diseases lately.Recognizing the crucial need for the scientific community to quickly and easily access dependable information on monoclonal antibodies (mAbs), IMGT®, the international ImMunoGeneTics information system®, provides a unique and invaluable resource: IMGT/mAb-DB, a comprehensive database of therapeutic mAbs, accessible via a user-friendly web interface. However, this approach restricts more sophisticated queries and segregates information from other databases. Methods: To connect IMGT/mAb-DB with the rest of the IMGT databases, we created IMGT/mAb-KG, a knowledge graph for therapeutic monoclonal antibodies connected to IMGT structures and genomics databases. IMGT/mAb-KG is developed using the most effective methodologies and standards of semantic web and acquires data from IMGT/mAb-DB. Concerning interoperability, IMGT/mAb-KG reuses terms from biomedical resources and is connected to related resources. Results and discussion: In February 2024, IMGT/mAb-KG, encompassing a total of 139,629 triplets, provides access to 1,489 mAbs, approximately 500 targets, and over 500 clinical indications. It offers detailed insights into the mechanisms of action of mAbs, their construction, and their various products and associated studies. Linked to other resources such as Thera-SAbDab (Therapeutic Structural Antibody Database), PharmGKB (a comprehensive resource curating knowledge on the impact of genetic variation on drug response), PubMed, and HGNC (HUGO Gene Nomenclature Committee), IMGT/mAb-KG is an essential resource for mAb development. A user-friendly web interface facilitates the exploration and analyse of the content of IMGT/mAb-KG.
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Anticorpos Monoclonais , Humanos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/imunologia , Imunogenética/métodos , Bases de Dados FactuaisRESUMO
Lung cancer is one of the most prevalent malignancies worldwide, contributing to over a million cancer-related deaths annually. Despite extensive research investigating the genetic factors associated with lung cancer susceptibility and prognosis, few studies have explored genetic predispositions regarding the immune system. This review discusses the most recent genomic findings related to the susceptibility to or protection against lung cancer, patient survival, and therapeutic responses. The results demonstrated the effect of immunogenetic variations in immune system-related genes associated with innate and adaptive immune responses, cytokine, and chemokine secretions, and signaling pathways. These genetic diversities may affect the crosstalk between tumor and immune cells within the tumor microenvironment, influencing cancer progression, invasion, and prognosis. Given the considerable variability in the individual immunegenomics profiles, future studies should prioritize large-scale analyses to identify potential genetic variations associated with lung cancer using highthroughput technologies across different populations. This approach will provide further information for predicting response to targeted therapy and promotes the development of new measures for individualized cancer treatment.
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The immunoglobulin heavy constant gamma (IGHG) gene cluster encoding immunoglobulin G (IgG) subclasses is highly polymorphic, resulting in amino acid variation along the antibody constant heavy chain referred to as allotypes. IGHG1 and IGHG3 are the two most polymorphic IgG subclasses in humans, with 4 classical IgG1 allotypes and 13 allotypes described for IgG3, though recent studies suggest greater allelic diversity, especially in underrepresented ethnic populations. Polymerase chain reaction (PCR) and Sanger sequencing of IGHG amplicons allow for the identification of the single nucleotide polymorphisms (SNPs) responsible for the observed amino acid substitutions. Here, we provide a detailed protocol for the amplification of IGHG1 and IGHG3 segments by PCR, sample preparation for Sanger sequencing, and analysis of sequencing data to identify SNPs associated with different IgG1 and IgG3 allotypes.
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Imunoglobulina G , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Humanos , Imunoglobulina G/genética , Reação em Cadeia da Polimerase/métodos , Alótipos de Imunoglobulina/genética , Análise de Sequência de DNA/métodosRESUMO
BACKGROUND: The Atlantic cod is a prolific species in the Atlantic, despite its inconsistent specific antibody response. It presents a peculiar case within vertebrate immunology due to its distinct immune system, characterized by the absence of MHCII antigen presentation pathway, required for T cell-dependent antibody responses. Thorough characterisation of immunoglobulin loci and analysis of the antibody repertoire is necessary to further our understanding of the Atlantic cod's immune response on a molecular level. RESULTS: A comprehensive search of the cod genome (gadmor3.0) identified the complete set of IgH genes organized into three sequential translocons on chromosome 2, while IgL genes were located on chromosomes 2 and 5. The Atlantic cod displayed a moderate germline V gene diversity, comprising four V gene families for both IgH and IgL, each with distinct chromosomal locations and organizational structures. 5'RACE sequencing revealed a diverse range of heavy chain CDR3 sequences and relatively limited CDR3 diversity in light chains. The analysis highlighted a differential impact of V-gene germline CDR3 length on receptor CDR3 length between heavy and light chains, underlining different recombination processes. CONCLUSIONS: This study reveals that the Atlantic cod, despite its inconsistent antibody response, maintains a level of immunoglobulin diversity comparable to other fish species. The findings suggest that the extensive recent duplications of kappa light chain genes do not result in increased repertoire diversity. This research provides a comprehensive view of the Atlantic cod's immunoglobulin gene organization and repertoire, necessary for future studies of antibody responses at the molecular level.
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Gadus morhua , Sequenciamento de Nucleotídeos em Larga Escala , Animais , Gadus morhua/genética , Cadeias Pesadas de Imunoglobulinas/genética , Imunoglobulinas/genética , Loci Gênicos , Genes de Imunoglobulinas , Região Variável de Imunoglobulina/genéticaRESUMO
Antigen presentation is a crucial mechanism that drives the T cell-mediated immune response and the development of Multiple Sclerosis (MS). Genetic alterations within the highly variable Major Histocompatibility Complex Class II (MHC II) have been proven to result in significant changes in the molecular basis of antigen presentation and the clinical course of patients with both Adult-Onset MS (AOMS) and Pediatric-Onset MS (POMS). Among the numerous polymorphisms of the Human Leucocyte Antigens (HLA), within MHC II complex, HLA-DRB1*15:01 has been labeled, in Caucasian ethnic groups, as a high-risk allele for MS due to the ability of its structure to increase affinity to Myelin Basic Protein (MBP) epitopes. This characteristic, among others, in the context of the trimolecular complex or immunological synapsis, provides the foundation for autoimmunity triggered by environmental or endogenous factors. As with all professional antigen presenting cells, macrophages are characterized by the expression of MHC II and are often implicated in the formation of MS lesions. Increased presence of M1 macrophages in MS patients has been associated both with progression and onset of the disease, each involving separate but similar mechanisms. In this critical narrative review, we focus on macrophages, discussing how HLA genetic alterations can promote dysregulation of this population's homeostasis in the periphery and the Central Nervous System (CNS). We also explore the potential interconnection in observed pathological macrophage mechanisms and the function of the diverse structure of HLA alleles in neurodegenerative CNS, seen in MS, by comparing available clinical with molecular data through the prism of HLA-immunogenetics. Finally, we discuss available and experimental pharmacological approaches for MS targeting the trimolecular complex that are based on cell phenotype modulation and HLA genotype involvement and try to reveal fertile ground for the potential development of novel drugs.
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Alelos , Macrófagos , Esclerose Múltipla , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Apresentação de Antígeno/genética , Predisposição Genética para Doença , Animais , Polimorfismo GenéticoRESUMO
The major histocompatibility complex (MHC) with its highly polymorphic HLA genes represents one of the most intensely studied genomic regions in the genome. MHC proteins play a key role in antigen-specific immunity and are associated with a wide range of complex diseases. Despite decades of research and many advances in the field, the characterization and interpretation of its genetic and genomic variability remain challenging. Here an overview is provided of the MHC, the nature of its exceptional variability, and the complex evolutionary processes assumed to drive this variability. Highlighted are also recent advances in the field that promise to improve our understanding of the variability in the MHC and in antigen-specific immunity more generally.
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Evolução Molecular , Variação Genética , Antígenos HLA , Complexo Principal de Histocompatibilidade , Humanos , Antígenos HLA/genética , Complexo Principal de Histocompatibilidade/genética , AnimaisRESUMO
The allele frequency net database (AFND, http://www.allelefrequencies.net ) is an online web-based repository that contains information on the frequencies of immune-related genes and their corresponding alleles in worldwide human populations. At present, the website contains data from 1784 population samples in more than 14 million individuals from 129 countries on the frequency of genes from different polymorphic regions including data for the human leukocyte antigen (HLA) system. In addition, over the last four years, AFND has also incorporated genotype raw data from 85,000 individuals comprising 215 population samples from 39 countries. Moreover, more population data sets containing next generation sequencing data spanning >3 million individuals have been added. This resource has been widely used in a variety of contexts such as histocompatibility, immunology, epidemiology, pharmacogenetics, epitope prediction algorithms for population coverage in vaccine development, population genetics, among many others. In this chapter, we present an update of the most used searching mechanisms as described in a previous volume and some of the latest developments included in AFND.
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Bases de Dados Genéticas , Frequência do Gene , Genética Populacional , Humanos , Genética Populacional/métodos , Antígenos HLA/genética , Alelos , Biologia Computacional/métodos , Internet , Navegador , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodosRESUMO
To explore the influence of genetics on homeostatic regulation of dendritic cell (DC) numbers, we present a screen of DCs and their progenitors in lymphoid and non-lymphoid tissues in Collaborative Cross (CC) and Diversity Outbred (DO) mice. We report 30 and 71 loci with logarithm of the odds (LOD) scores >8.18 and ranging from 6.67 to 8.19, respectively. The analysis reveals the highly polygenic and pleiotropic architecture of this complex trait, including many of the previously identified genetic regulators of DC development and maturation. Two SNPs in genes potentially underlying variation in DC homeostasis, a splice variant in Gramd4 (rs235532740) and a missense variant in Orai3 (rs216659754), are confirmed by gene editing using CRISPR-Cas9. Gramd4 is a central regulator of DC homeostasis that impacts the entire DC lineage, and Orai3 regulates cDC2 numbers in tissues. Overall, the data reveal a large number of candidate genes regulating DC homeostasis in vivo.
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Células Dendríticas , Locos de Características Quantitativas , Animais , Células Dendríticas/metabolismo , Camundongos , Locos de Características Quantitativas/genética , Polimorfismo de Nucleotídeo Único , Camundongos Endogâmicos C57BL , Contagem de Células , Mapeamento Cromossômico , HomeostaseRESUMO
Background: For many years, transplantation outcomes were uncertain and not hopeful, until histocompatibility testing spread. Common criteria for histocompatibility assays and communications' improvement allowed an efficient organ sharing system. The possibility of organ exchanges is closely linked to the importance of interlaboratory comparisons for histocompatibility and immunogenetics methods. The external proficiency testing (EPT) systems are the most powerful quality assurance tools. They help achieve harmonization of analyses, set a standard of performance, and a common interpretation. Methods: The external quality assurance program for diagnostic immunology laboratories (Garantía Externa de Calidad para Laboratorios de Inmunología Diagnóstica, GECLID) program nowadays runs 13 external quality assurance (EQA) histocompatibility and immunogenetics schemes, with the first of them from 2011 to date: serological and molecular: low- and high-resolution human leukocyte antigen (HLA), human platelet antigen (HPA), and killer inhibitory receptor (KIR) typing(HLA-B*27, HLA-B*57:01, and coeliac disease-related HLA), cell-dependent cytotoxicity (CDC) and flow cytometry (FC) crossmatches, anti-HLA and anti-HPA antibodies, and chimerism. Results: A total of 85 laboratories participated in this subprogram in the last 12 years reporting over 1.69 M results: 1.46 M for anti-HLA and anti-HPA antibodies, 203.810 molecular typing data (HLA, HPA, and KIR genes), 2.372 for chimerism analyses, and 39.352 for crossmatches. Based on the European Federation for Immunogenetics (EFI) standards for EPT providers, the mean success rates ranged from 99.2% for molecular typing schemes and antibodies and 94.8% for chimerism, was 96.7% regarding crossmatches, and was 98.9% in serological typing. In 2022, 61.3% of the participating laboratories successfully passed every HLA EQA scheme, although 87.9% annual reports were satisfactory. Most penalties were due to nomenclature errors or misreporting of the risk associated to HLA and disease. Conclusion: This EQA confirms the reliability of HLA and immunogenetics assays in routine care. There is little heterogeneity of results of different assays used by participating laboratories, even when in-house assays are used. Reliability of test results is reasonably granted.
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The purpose of this review is to encourage a new perspective on the question of donor-recipient compatibility and post-transplant assessment of graft health based on functional measures. The premise is that we should be better sighted on what (and how) the immune system responds toward rather than what is merely there. Continuance of the pursuit of further and better definition of antigens and antibodies is not however discouraged but seen as necessary to improved understanding of the structural correlates of functional immunity. There currently exists, in the opinion of the authors, an opportunity for histocompatibility and immunogenetics laboratories to develop and widen their scope of involvement into these new areas of laboratory activity in support and to the benefit of the transplant programmes they serve.
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Aloenxertos , Doadores de Tecidos , Humanos , Aloenxertos/imunologia , Teste de Histocompatibilidade/métodos , Transplante Homólogo , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Antígenos HLA/genética , Histocompatibilidade/imunologia , Sobrevivência de Enxerto/imunologiaRESUMO
Evolutionary changes in the hepatitis B virus (HBV) genome could reflect its adaptation to host-induced selective pressure. Leveraging paired human exome and ultra-deep HBV genome-sequencing data from 567 affected individuals with chronic hepatitis B, we comprehensively searched for the signatures of this evolutionary process by conducting "genome-to-genome" association tests between all human genetic variants and viral mutations. We identified significant associations between an East Asian-specific missense variant in the gene encoding the HBV entry receptor NTCP (rs2296651, NTCP S267F) and mutations within the receptor-binding region of HBV preS1. Through in silico modeling and in vitro preS1-NTCP binding assays, we observed that the associated HBV mutations are in proximity to the NTCP variant when bound and together partially increase binding affinity to NTCP S267F. Furthermore, we identified significant associations between HLA-A variation and viral mutations in HLA-A-restricted T cell epitopes. We used in silico binding prediction tools to evaluate the impact of the associated HBV mutations on HLA presentation and observed that mutations that result in weaker binding affinities to their cognate HLA alleles were enriched. Overall, our results suggest the emergence of HBV escape mutations that might alter the interaction between HBV PreS1 and its cellular receptor NTCP during viral entry into hepatocytes and confirm the role of HLA class I restriction in inducing HBV epitope variations.
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Vírus da Hepatite B , Mutação , Transportadores de Ânions Orgânicos Dependentes de Sódio , Simportadores , Humanos , Vírus da Hepatite B/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/genética , Simportadores/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Hepatite B Crônica/virologia , Hepatite B Crônica/genética , Genoma Viral , Antígenos de Superfície da Hepatite B/genética , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Genômica/métodos , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismoRESUMO
Immunogenetic studies have shown that specific HLA-B residues (67, 70, 97, and 156) mediate the impact of HLA class I on HIV infection, but the molecular basis is not well understood. Here we evaluate the function of these residues within the protective HLA-B∗5701 allele. While mutation of Met67, Ser70, and Leu156 disrupt CD8+ T cell recognition, substitution of Val97 had no significant impact. Thermal denaturation of HLA-B∗5701-peptide complexes revealed that Met67 and Leu156 maintain HLA-peptide stability, while Ser70 and Leu156 facilitate T cell receptor (TCR) interactions. Analyses of existing structures and structural models suggested that Val97 mediates HLA-peptide binding to inhibitory KIR3DL1 molecules, which was confirmed by experimental assays. These data thereby demonstrate that the genetic basis by which host immunity impacts HIV outcomes occurs by modulating HLA-B-peptide stability and conformation for interaction with TCR and killer immunoglobulin receptor (KIR) molecules. Moreover, they indicate a key role for epitope specificity and HLA-KIR interactions to HIV control.
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Antígenos HLA-B , Ligação Proteica , Receptores de Antígenos de Linfócitos T , Humanos , Antígenos HLA-B/química , Antígenos HLA-B/metabolismo , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/imunologia , HIV-1/imunologia , HIV-1/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/virologia , Modelos Moleculares , Receptores KIR3DL1/metabolismo , Receptores KIR3DL1/química , Receptores KIR3DL1/genética , Peptídeos/química , Peptídeos/metabolismo , Sítios de Ligação , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Polimorfismo Genético , Estabilidade ProteicaRESUMO
BACKGROUND: Triokinase and FMN cyclase (TKFC) is a bifunctional enzyme involved in fructose metabolism. Triokinase catalyses the phosphorylation of fructose-derived glyceraldehyde (GA) and exogenous dihydroxyacetone (DHA), while FMN cyclase generates cyclic FMN. TKFC regulates the antiviral immune response by interacting with IFIH1 (MDA5). Previously reported pathogenic variants in TKFC are associated with either a multisystemic disease or isolated hypotrichosis with loose anagen hairs. METHODS: Whole-exome sequencing identified a homozygous novel variant in TKFC (c.1624G>A; p.Gly542Arg) in an individual with a complex primary immunodeficiency disorder. The variant was characterised using enzymatic assays and yeast studies of mutant recombinant proteins. RESULTS: The individual presented with chronic active Epstein-Barr virus disease and multiple bacterial and viral infections. Clinical investigations revealed hypogammaglobulinaemia, near absent natural killer cells and decreased memory B cells. Enzymatic assays showed that this variant displayed defective DHA and GA kinase activity while maintaining FMN cyclase activity. An allogenic bone marrow transplantation corrected the patient's immunodeficiency. CONCLUSION: Our report suggests that TKFC may have a role in the immunological system. The pathological features associated with this variant are possibly linked with DHA/GA kinase inactivation through a yet an unknown mechanism. This report thus adds a possible new pathway of immunometabolism to explore further.