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1.
Life Sci Alliance ; 6(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36328595

RESUMO

Multiple myeloma is a plasma cell neoplasm characterized by clonal immunoglobulin V(D)J signatures and oncogenic immunoglobulin gene translocations. Additional subclonal genomic changes are acquired with myeloma progression and therapeutic selection. PCR-based methods to detect V(D)J rearrangements can have biases introduced by highly multiplexed reactions and primers undermined by somatic hypermutation, and are not readily extended to include mutation detection. Here, we report a hybrid-capture approach (CapIG-seq) targeting the 3' and 5' ends of the V and J segments of all immunoglobulin loci that enable the efficient detection of V(D)J rearrangements. We also included baits for oncogenic translocations and mutation detection. We demonstrate complete concordance with matched whole-genome sequencing and/or PCR clonotyping of 24 cell lines and report the clonal sequences for 41 uncharacterized cell lines. We also demonstrate the application to patient specimens, including 29 bone marrow and 39 cell-free DNA samples. CapIG-seq shows concordance between bone marrow and cfDNA blood samples (both contemporaneous and follow-up) with regard to the somatic variant, V(D)J, and translocation detection. CapIG-seq is a novel, efficient approach to examining genomic alterations in myeloma.


Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/diagnóstico , Imunoglobulinas , Rearranjo Gênico , Análise de Sequência
2.
Methods Mol Biol ; 2552: 3-59, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36346584

RESUMO

IMGT®, the international ImMunoGeneTics information system®, http://www.imgt.org , the global reference in immunogenetics and immunoinformatics, was created in 1989 by Marie-Paule Lefranc (Université de Montpellier and CNRS) to manage the huge diversity of the antigen receptors, immunoglobulins (IG) or antibodies, and T cell receptors (TR) of the adaptive immune responses. The founding of IMGT® marked the advent of immunoinformatics, which emerged at the interface between immunogenetics and bioinformatics. IMGT® standardized analysis of the IG, TR, and major histocompatibility (MH) genes and proteins bridges the gap between sequences and three-dimensional (3D) structures, for all jawed vertebrates from fish to humans. This is achieved through the IMGT Scientific chart rules, based on the IMGT-ONTOLOGY axioms, and primarily CLASSIFICATION (IMGT gene and allele nomenclature) and NUMEROTATION (IMGT unique numbering and IMGT Colliers de Perles). IMGT® comprises seven databases (IMGT/LIGM-DB for nucleotide sequences, IMGT/GENE-DB for genes and alleles, etc.), 17 tools (IMGT/V-QUEST, IMGT/JunctionAnalysis, IMGT/HighV-QUEST for NGS, etc.), and more than 20,000 Web resources. In this chapter, the focus is on the tools for amino acid sequences per domain (IMGT/DomainGapAlign and IMGT/Collier-de-Perles), and on the databases for receptors (IMGT/2Dstructure-DB and IMGT/3D-structure-DB) described per receptor, chain, and domain and, for 3D, with contact analysis, paratope, and epitope. The IMGT/mAb-DB is the query interface for monoclonal antibodies (mAb), fusion proteins for immune applications (FPIA), composite proteins for clinical applications (CPCA), and related proteins of interest (RPI) with links to IMGT® 2D and 3D databases and to the World Health Organization (WHO) International Nonproprietary Names (INN) program lists. The chapter includes the human IG allotypes and antibody engineered variants for effector properties used in the description of therapeutical mAb.


Assuntos
Imunogenética , Imunoglobulinas , Humanos , Animais , Imunogenética/métodos , Imunoglobulinas/genética , Imunoglobulinas/química , Anticorpos/genética , Biologia Computacional/métodos , Sequência de Aminoácidos , Receptores de Antígenos de Linfócitos T/genética
3.
Physiol Rev ; 103(1): 313-346, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-35981301

RESUMO

The mechanisms underlying innate immune memory have been extensively explored in the last decades but are in fact largely unknown. Although the specificity of adaptive immune memory in vertebrates is ensured through the recombination of immunoglobulin family genes and clonal expansion, the basic mechanisms of innate immune cells' nonspecific increased responsiveness rely on epigenetic, transcriptional, and metabolic programs after transient stimulation. Changes in these programs result in enhanced responsiveness to secondary challenges with a wide variety of stimuli. This phenomenon is termed "trained immunity" or "innate immune memory." On one hand, trained immunity improves the response to infections and vaccination, facilitating stronger innate immune responses and enhanced protection against a variety of microbial stimuli. Conversely, trained immunity may contribute to the pathophysiology of cardiovascular, autoinflammatory, and neurodegenerative diseases. In this review, we gather the current body of knowledge in this field and summarize the foundations and mechanisms of trained immunity, the different cell types involved, its consequences for health and disease, and the potential of its modulation as a therapeutic tool.


Assuntos
Imunidade Inata , Memória Imunológica , Imunidade Adaptativa , Animais , Humanos , Imunoglobulinas , Memória Imunológica/genética
4.
J Cell Biol ; 222(2)2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36394541

RESUMO

Mammalian sperm-egg adhesion depends on the trans-interaction between the sperm-specific type I glycoprotein IZUMO1 and its oocyte-specific GPI-anchored receptor JUNO. However, the mechanisms and proteins (fusogens) that mediate the following step of gamete fusion remain unknown. Using live imaging and content mixing assays in a heterologous system and structure-guided mutagenesis, we unveil an unexpected function for IZUMO1 in cell-to-cell fusion. We show that IZUMO1 alone is sufficient to induce fusion, and that this ability is retained in a mutant unable to bind JUNO. On the other hand, a triple mutation in exposed aromatic residues prevents this fusogenic activity without impairing JUNO interaction. Our findings suggest a second function for IZUMO1 as a unilateral mouse gamete fusogen.


Assuntos
Imunoglobulinas , Proteínas de Membrana , Receptores de Superfície Celular , Interações Espermatozoide-Óvulo , Animais , Masculino , Camundongos , Fusão Celular , Imunoglobulinas/metabolismo , Proteínas de Membrana/metabolismo , Receptores de Superfície Celular/metabolismo , Sêmen/metabolismo , Espermatozoides/metabolismo
5.
Dev Comp Immunol ; 138: 104525, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36058383

RESUMO

Avian has a unique immune system that evolved in response to environmental pressures in all aspects of innate and adaptive immune responses, including localized and circulating lymphocytes, diversity of immunoglobulin repertoire, and various cytokines and chemokines. All of these attributes make birds an indispensable vertebrate model for studying the fundamental immunological concepts and comparative immunology. However, research on the immune system in birds lags far behind that of humans, mice, and other agricultural animal species, and limited immune tools have hindered the adequate application of birds as disease models for mammalian systems. An in-depth understanding of the avian immune system relies on the detailed studies of various regulated and regulatory mediators, such as cell surface antigens, cytokines, and chemokines. Here, we review current knowledge centered on the roles of avian cell surface antigens, cytokines, chemokines, and beyond. Moreover, we provide an update on recent progress in this rapidly developing field of study with respect to the availability of immune reagents that will facilitate the study of regulatory and regulated components of poultry immunity. The new information on avian immunity and available immune tools will benefit avian researchers and evolutionary biologists in conducting fundamental and applied research.


Assuntos
Aves , Aves Domésticas , Animais , Antígenos de Superfície , Quimiocinas , Citocinas , Imunidade Inata , Imunoglobulinas
6.
Dev Comp Immunol ; 138: 104541, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36108933

RESUMO

As the most typical example of mRNA variable splicing, Down Syndrome Cell Adhesion Molecule (Dscam) can produce a large number of mRNA isomers. It plays an important role not only in the nervous system, but also in the immune system. In Eriocheir sinensis, the extracellular region of Dscam has three variable domains, which can produce 25, 34 and 18 exons and encode the N-terminal region of immunoglobulin (Ig) 2 and Ig3 domains, and the entire Ig7 domain, respectively. In addition to three variable domains, the extracellular non-variable region of Dscam also includes many Ig domains and fibronectin type III (FNIII) domains. However, the role of the extracellular non-variable region function of Dscam in the immune defense of E. sinensis is unclear. In this study, we focused on the role of the extracellular non-variable region of Dscam in crab immune defense. The results indicate that the extracellular non-variable region of Dscam can bind bacteria and has bacteriostatic function. At the same time, the extracellular non-variable region of Dscam can also directly promote bacterial clearance by promoting phagocytosis of hemocytes.


Assuntos
Braquiúros , Sequência de Aminoácidos , Animais , Bactérias , Moléculas de Adesão Celular/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Hemócitos/metabolismo , Imunoglobulinas/genética , Fagocitose , Filogenia , RNA Mensageiro/genética , Alinhamento de Sequência
7.
Otolaryngol Clin North Am ; 56(1): 97-106, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36266110

RESUMO

Primary Ig deficiencies are a heterogeneous group of disorders with widespread implications for the unified airway. Manifestations can vary greatly, with some patients being asymptomatic, whereas others suffering from acute and chronic life-threatening pathologic conditions of the upper and lower airways. Although the diagnosis of PIDs can be complex, the onus of early diagnosis and initiation of treatment will often fall on the shoulders of the otolaryngologist.


Assuntos
Imunoglobulinas , Sistema Respiratório , Humanos , Doença Crônica
8.
Chemosphere ; 311(Pt 1): 137048, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36419273

RESUMO

Polyethylene is one of the most important plastic types with the highest consumption in the world. Plastics are prone to photodegradation and turn into microplastics, which are magnified as they move across trophic levels. Microplastics would be able to penetrate into lymph even cross cell membranes, causing harm to the lymphatic and/or circulatory systems, accumulating in secondary organs, and impacting the immune system and cell health. The objective of this study was to test that the activation of the intestinal immune network might be caused by disruption of intestinal microbiota after exposure to different polyethylene microplastics (PE-MPs) concentrations (1, 10, 100, and 1000 µg/mL) in adult zebrafish (Danio rerio) for 7 days. The concentrations of PE-MPs (100 and 1000 µg/mL) exposure decreased the goblet cell coverage. The intestinal microbial diversity index (Shannon and Simpson) was increased at 100 and 1000 µg/mL PE-MPs concentrations. The relative abundance of intestinal dominant microbiota phylum Proteobacteria and Actinobacteria increased significantly (P < 0.05); however, phylum Fusobacteria decreased significantly (P < 0.05). The relative abundance of intestinal microbiota at level of genera showed varying degrees of elevation such as Acinetobacter (6.31-fold), Plesiomonas (4.80-fold), Flavobacterium (10.54-fold) and Pseudomonas (5.17-fold) in 1000 µg/mL PE-MPs. Intestinal innate immunity-complement C3 and C4 content first increased and then declined in a dose-dependent manner. Expression of genes from the intestinal immune network for mucosal immunoglobulin production were increased also in a dose-dependent manner. The expression of immune-related genes (pigr, il10 and ighv4-5) were positively correlated with the relative abundance of genera Plesiomonas. In conclusion, PE-MPs increase the infection probability in the intestinal mucosa by altering the abundance of intestinal dominant microbiota at the level of phylum. PE-MPs exposure activated the intestinal immune network pathway for mucosal immunoglobulin production at a concentration of 100 or 1000 µg/mL for 7 days.


Assuntos
Microplásticos , Polietileno , Animais , Polietileno/toxicidade , Microplásticos/toxicidade , Peixe-Zebra , Plásticos , Mucosa Intestinal , Imunoglobulinas
9.
EBioMedicine ; 85: 104319, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36374772

RESUMO

BACKGROUND: Gallbladder cancer (GBC), the most common malignancy of the biliary tract, shows late diagnosis and low survival rate and requires continued search for new diagnostic biomarkers and therapeutic targets. Human endogenous retroviruses (HERVs) are specifically prone to be reactivated in diverse cancers and are implicated in cancer progression and immunotherapy. METHODS: Single-cell RNA sequencing was performed on tumor tissues and paired adjacent tissues from 4 GBC patients. Dual-luciferase reporter assay was applied to measure enhancer activity of HERV sequences. FINDINGS: We dissected the cellular diversity and described the HERV transcriptomic landscape for GBC. We found that HERVs were transcribed in a cell type-specific manner and different HERV families were associated with diverse biological effects. HERVs could function as enhancers, presumably causing altered expression of neighboring genes. The transcription level of HERVH was gradually elevated with the malignant transformation of epithelial cells, suggesting HERVH may be a potential early diagnostic biomarker of GBC. HHLA2, a newly emerging immune checkpoint, was derived by HERVH, exhibited an expressional correlation with HERVH, and was identified as a promising target for immunotherapy. INTERPRETATION: Exploring the transcriptional landscape and potential functional impact of HERVs highlights the important role of HERVs in GBC and provides a fresh perspective on managing GBC. FUNDING: This study was supported by the National Natural Science Foundation of China (31970176, 81972256) and the research grants from the Innovation Capacity Building Project of Jiangsu province (BM2020019).


Assuntos
Retrovirus Endógenos , Neoplasias da Vesícula Biliar , Humanos , Retrovirus Endógenos/genética , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/genética , Imunoterapia , Sequenciamento Completo do Exoma , Análise de Sequência de RNA , Imunoglobulinas/genética
11.
Front Immunol ; 13: 1016877, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36330515

RESUMO

Neonates, especially preterm neonates, have the highest risk of sepsis of all age groups. Transient immaturity of the neonatal immune system is an important risk factor. Neonates suffer from hypogammaglobulinemia as nor IgA nor IgM is transferred over the placenta and IgG is only transferred over the placenta late in gestation. In addition, neutrophil numbers and complement function are also decreased. This mini-review focuses on strategies to improve neonatal host-defense. Both clinical and preclinical studies have attempted to boost neonatal immunity to lower the incidence of sepsis and improve outcome. Recent advances in the development of (monoclonal) antibodies show promising results in preclinical studies but have yet to be tested in clinical trials. Strategies to increase complement activity seem efficient in vitro but potential disadvantages such as hyperinflammation have held back further clinical development. Increase of neutrophil numbers has been tested extensively in clinical trials but failed to show improvement in mortality. Future research should focus on clinical applicability of promising new prevention strategies for neonatal sepsis.


Assuntos
Síndromes de Imunodeficiência , Sepse Neonatal , Sepse , Recém-Nascido , Gravidez , Feminino , Humanos , Sepse/tratamento farmacológico , Neutrófilos , Imunoglobulinas/uso terapêutico
12.
Nat Commun ; 13(1): 6820, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357400

RESUMO

Serum monoclonal immunoglobulin (Ig) is the main diagnostic factor for patients with multiple myeloma (MM), however its prognostic potential remains unclear. On a large MM patient cohort (n = 4146), we observe no correlation between serum Ig levels and patient survival, while amount of intracellular Ig has a strong predictive effect. Focused CRISPR screen, transcriptional and proteomic analysis identify deubiquitinase OTUD1 as a critical mediator of Ig synthesis, proteasome inhibitor sensitivity and tumor burden in MM. Mechanistically, OTUD1 deubiquitinates peroxiredoxin 4 (PRDX4), protecting it from endoplasmic reticulum (ER)-associated degradation. In turn, PRDX4 facilitates Ig production which coincides with the accumulation of unfolded proteins and higher ER stress. The elevated load on proteasome ultimately potentiates myeloma response to proteasome inhibitors providing a window for a rational therapy. Collectively, our findings support the significance of the Ig production machinery as a biomarker and target in the combinatory treatment of MM patients.


Assuntos
Mieloma Múltiplo , Inibidores de Proteassoma , Humanos , Inibidores de Proteassoma/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Proteômica , Apoptose , Complexo de Endopeptidases do Proteassoma/metabolismo , Imunoglobulinas , Enzimas Desubiquitinantes , Proteases Específicas de Ubiquitina
13.
BMJ Open ; 12(11): e063482, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36351715

RESUMO

OBJECTIVES: Eliminating mother-to-child transmission (MTCT) of hepatitis B virus (HBV) is central to WHO's target of reducing hepatitis B infection in children to <0.1% by 2030. While Nigeria accounts for 8.3% of the global burden, interventional studies on prevention of MTCT of HBV are hardly available. This study aimed to assess the impact of prevention of MTCT interventions on vertical transmission of HBV among pregnant women in Nigeria. DESIGN: A prospective cohort study. SETTING: A University Teaching Hospitals Complex in Nigeria between 2015 and 2021. PARTICIPANTS: 10 866 pregnant women and their pre-existing children. INTERVENTIONS: Eligible pregnant women were screened for HBsAg using chromatographic immunoassay (Micropoint, USA). HbsAg-positive women had HBV serological assay done and their pre-existing children were screened. Women with HBV DNA ≥2 00 000 IU/mL and those positive for hepatitis B e-antigen (HBeAg) had 300 mg/day of Tenofovir Disoproxil Fumarate (TDF) in the third trimester. The newborns had hepatitis B vaccines and HB immunoglobulin (HBIG) administered, followed by testing for HBsAg at 9 months postnatally. PRIMARY OUTCOME MEASURES: Prevalence of chronic hepatitis B infection in pregnancy, and the incidence of MTCT of HBV. RESULTS: Overall, 395 women had chronic HBV infection, giving a prevalence of 3.64%. Their mean age was 31.51±5.71 years, with a median parity of 1.2. Thirteen women (5.2%) were positive for HBeAg, seven (3.1%) of the 225 pre-existing hepatitis B-exposed children were HbsAg positive and 17 women had prenatal TDF. Overall, 376 women completed the study, with mean birth weight of 3.21±1.86 kg and perinatal mortality rate of 29.2/1000 births. Hepatitis Bvaccine-HBIG combination was administered to 260 newborns, while the others had hepatitis B vaccine alone. All the children tested negative to the HbsAg at 9 months. CONCLUSION: Eliminating MTCT of HBV infection through validated protocols in low and middle income countries with the highest burden of chronic HBV infections is feasible. National scale-up of such protocols is recommended.


Assuntos
Hepatite B Crônica , Hepatite B , Complicações Infecciosas na Gravidez , Lactente , Feminino , Recém-Nascido , Gravidez , Humanos , Adulto , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Antígenos E da Hepatite B , Antígenos de Superfície da Hepatite B , Estudos Prospectivos , Seguimentos , Nigéria/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/prevenção & controle , DNA Viral , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Vírus da Hepatite B , Vacinas contra Hepatite B/uso terapêutico , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/prevenção & controle , Tenofovir/uso terapêutico , Imunoglobulinas/uso terapêutico
14.
Int J Mol Sci ; 23(21)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36361707

RESUMO

Around 80% of adults worldwide carry human cytomegaloviris (HCMV). The HCMV gene UL18 is a homolog of HLA class I genes and encodes a protein with high affinity for the NK and T-cell cytotoxicity inhibitor LIR-1. UL18 was deep sequenced from blood, saliva or urine from Indonesian people with HIV (PWH) (n = 28), Australian renal transplant recipients (RTR) (n = 21), healthy adults (n = 7) and neonates (n = 4). 95% of samples contained more than one variant of HCMV UL18, as defined by carriage of nonsynonymous variations. When aligned with immunological markers of the host's burden of HCMV, the S318N variation associated with high levels of antibody reactive with HCMV lysate in PWH over 12 months on antiretroviral therapy. The A107T variation associated with HCMV antibody levels and inflammatory biomarkers in PWH at early timepoints. Variants D32G, D248N, V250A and E252D aligned with elevated HCMV antibody levels in RTR, while M191K, E196Q and F165L were associated with HCMV-reactive T-cells and proportions of Vδ2- γδ T-cells-populations linked with high burdens of HCMV. We conclude that UL18 is a highly variable gene, where variation may alter the persistent burden of HCMV and/or the host response to that burden.


Assuntos
Citomegalovirus , Linfócitos T , Adulto , Recém-Nascido , Humanos , Proteínas do Capsídeo/genética , Austrália , Sequência de Bases , Imunoglobulinas/metabolismo
15.
Int J Mol Sci ; 23(22)2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36430322

RESUMO

In the immunotherapy based on immune checkpoint inhibition (IC), additional ICs are being studied to increase its effectiveness. An almost unstudied feature is the possible co-expression of ICs, which can determine the therapeutic efficacy of their inhibition. For the selection of promising ICs, information on the association of their expression with cancer development may be essential. We have obtained data on the expression correlation of ADAM17, PVR, TDO2, CD274, CD276, CEACAM1, IDO1, LGALS3, LGALS9, and HHLA2 genes in gastric cancer (GC). All but one, TDO2, have other IC genes with co-expression at some stage. At the metastatic stage, the expression of the IDO1 does not correlate with any other gene. The correlations are positive, but the expressions of the CD276 and CEACAM1 genes are negatively correlated. The expression of TDO2 and LGALS3 is associated with GC metastasis. The expression of TDO2 four-fold higher in metastatic tumors than in non-metastatic tumors, but LGALS3 was two-fold lower. The differentiation is associated with IDO1. The revealed features of TDO2, with a significant increase in expression at the metastatic stage and the absence of other IC genes with correlated expression indicates that the prospect of inhibiting TDO2 in metastatic GC. IDO1 may be considered for inhibition in low-differentiated tumors.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Galectina 3 , Triptofano Oxigenase/metabolismo , Expressão Gênica , Imunoglobulinas , Antígenos B7
16.
STAR Protoc ; 3(4): 101818, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36386885

RESUMO

Human killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail (KIR3DL3) is expressed on natural killer (NK) cells and is a newly identified inhibitory receptor for B7 family member HERV-H LTR-associating protein 2 (HHLA2). Here, we summarize the isolation and expansion of KIR3DL3+ human NK cells, and in vitro functional characterization of in-house anti-KIR3DL3 monoclonal antibody (mAb). We also describe a human NK cell-based xenogeneic lung tumor model for testing the therapeutic activity of KIR3DL3 blockade in vivo. For complete details on the use and execution of this protocol, please refer to Wei et al. (2021).


Assuntos
Células Matadoras Naturais , Neoplasias Pulmonares , Humanos , Receptores KIR/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Imunoglobulinas
18.
Biomolecules ; 12(11)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36358906

RESUMO

Recent breakthroughs in immune checkpoint inhibitors (ICIs) have shown promise in triple-negative breast cancer (TNBC). Due to the intrinsic heterogeneity among TNBC, clinical response to ICIs varies greatly among individuals. Thus, discovering rational biomarkers to select susceptible patients for ICIs treatment is warranted. A total of 422 TNBC patients derived from The Cancer Genome Atlas (TCGA) database and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset were included in this study. High immunogenic gene modules were identified using weighted gene co-expression network analysis (WGCNA). Immune-related genes (IRGs) expression patterns were generated by consensus clustering. We developed a three-gene signature named immune-related gene panel (IRGP) by Cox regression method. Afterward, the associations of IRGP with survival outcomes, infiltration of immune cells, drug sensitivity, and the response to ICIs therapy were further explored. We found five high immunogenic gene modules. Two distinct IRGclusters and IRG-related genomic clusters were identified. The IRGP was constructed based on TAPBPL, FBP1, and GPRC5C genes. TNBC patients were then subdivided into high- and low-IRGriskscore subgroups. TNBC patients with low IRGriskscore had a better survival outcome, higher infiltration of immune cells, lower TP53 mutation rate, and more benefit from ICIs treatment than high IRGriskscore patients. These findings offer novel insights into molecular subtype of TNBC and provided potential indicators for guiding ICIs treatment.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Genômica/métodos , Genoma , Tipagem Molecular , Imunoglobulinas , Proteínas de Membrana/genética
19.
Sci Rep ; 12(1): 17237, 2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36241658

RESUMO

Killer-cell immunoglobulin-like receptors (KIR) are essential for acquiring natural killer (NK) cell effector function, which is modulated by a balance between the net input of signals derived from inhibitory and activating receptors through engagement by human leukocyte antigen (HLA) class I ligands. KIR and HLA loci are polygenic and polymorphic and exhibit substantial variation between individuals and populations. We attempted to investigate the contribution of KIR complex and HLA class I ligands to the genetic predisposition to lung cancer in the native population of southern Iran. We genotyped 16 KIR genes for a total of 232 patients with lung cancer and 448 healthy controls (HC), among which 85 patients and 178 HCs were taken into account for evaluating combined KIR-HLA associations. KIR2DL2 and 2DS2 were increased significantly in patients than in controls, individually (OR 1.63, and OR 1.42, respectively) and in combination with HLA-C1 ligands (OR 1.99, and OR 1.93, respectively). KIR3DS1 (OR 0.67) and 2DS1 (OR 0.69) were more likely presented in controls in the absence of their relative ligands. The incidence of CxTx subset was increased in lung cancer patients (OR 1.83), and disease risk strikingly increased by more than fivefold among genotype ID19 carriers (a CxTx genotype that carries 2DL2 in the absence of 2DS2, OR 5.92). We found that genotypes with iKIRs > aKIRs (OR 1.67) were more frequently presented in lung cancer patients. Additionally, patients with lung cancer were more likely to carry the combination of CxTx/2DS2 compared to controls (OR 2.04), and iKIRs > aKIRs genotypes in the presence of 2DL2 (OR 2.05) increased the likelihood of lung cancer development. Here we report new susceptibility factors and the contribution of KIR and HLA-I encoding genes to lung cancer risk, highlighting an array of genetic effects and disease setting which regulates NK cell responsiveness. Our results suggest that inherited KIR genes and HLA-I ligands specifying the educational state of NK cells can modify lung cancer risk.


Assuntos
Neoplasias Pulmonares , Receptores KIR , Frequência do Gene , Genótipo , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Imunoglobulinas/genética , Ligantes , Neoplasias Pulmonares/genética , Receptores KIR/genética
20.
Iran J Immunol ; 19(3): 255-262, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36190380

RESUMO

BACKGROUND: Natural killer (NK) cells are dichotomously involved in chronic hepatitis B (CHB) infection as principal members of innate immunity. An effective treatment should enhance the antiviral potentials of NK cells and not their immunomodulatory roles. TIM-3 (T-cell immunoglobulin and mucin-containing domain) is a molecule with an essential role in controlling immune tolerance. TIM-3 demonstrated the highest expression among NK cells of patients with chronic liver disorders. Statins have been reported to attenuate the levels of TIM-3 on NK cells. OBJECTIVES: To investigate the frequencies of NK cells, NKT cells, and TIM-3+ population in patients with CHB upon rosuvastatin (RSV) intervention. METHODS: Thirty confirmed patients with CHB were randomly assigned into two groups of 15 (receiving 20 mg of RSV or placebo per day) for 12 weeks. We evaluated the percentages of TIM-3+ cells by staining the peripheral blood mononuclear cells (PBMCs) with CD3, CD16, and CD56 markers using flow cytometry. RESULTS: Our findings indicated that RSV administration could increase CD3- CD56+ NK cells (P>0.05) and CD3+ CD16+ CD56+ NKT cells (P<0.05). RSV intervention could reduce the percentages of TIM-3+ cells among NK cells (P<0.01) and NKT cells (P> 0.05) of patients with CHB compared with the placebo group. CONCLUSIONS: The increased population of NK and NKT cells and the effective reduction of TIM-3+ cells among patients with CHB delineated that rosuvastatin could be proposed as an appropriate modulator of innate immune response (regarding NK and NKT cells) in favor of enhancing their antiviral activities.


Assuntos
Hepatite B Crônica , Inibidores de Hidroximetilglutaril-CoA Redutases , Células T Matadoras Naturais , Antivirais/uso terapêutico , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo , Imunoglobulinas , Células Matadoras Naturais , Mucinas/metabolismo , Rosuvastatina Cálcica/metabolismo , Rosuvastatina Cálcica/uso terapêutico
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