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1.
Nat Immunol ; 23(8): 1256-1272, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35902638

RESUMO

The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.


Assuntos
Linfócitos B , Proteínas de Ligação a DNA , Proteínas de Homeodomínio , Proteínas Nucleares , Diferenciação Celular , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Humanos , Tolerância Imunológica , Contagem de Linfócitos , Proteínas Nucleares/deficiência
2.
Cent Eur J Immunol ; 47(4): 339-349, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36817401

RESUMO

Neonatal screening for inborn errors of immunity (IEI), based on quantification of T-cell-receptor- excision circles (TRECs) and kappa-deleting recombination-excision circles (KRECs) from dried blood spots (DBS), allows early diagnosis and improved outcomes for the affected children. Determination of TREC/KREC levels from prospectively collected newborns' Guthrie cards and from DBS samples of patients with confirmed IEI was done using a commercial kit. Retrospective assessment of flow cytometry evaluation of TREC/KREC correspondence with lymphocyte subpopulations and evaluation of the correlations between TREC and KREC with immune cells, based on the data from patients with suspected or confirmed immune disorders, were conducted. 2,228 Guthrie cards were tested, 1276 for TREC only and 952 for both TREC and KREC. Eight newborns (0.36%) were TREC positive and 10 (1.05%) had KREC below the cut-off. The re-testing rate was 1.88%. Retrospective analysis demonstrated that the TREC/KREC assay identifies 100% of severe combined immune deficiencies (SCID) cases when DBS were collected at birth. Correlation analysis showed moderate significant correlations between TREC and the absolute numbers of CD4 cells (r = 0.634, p < 0.01) and total T cells (r = 0.536, p < 0.01). The ability of KREC levels to predict abnormal absolute (AUC of 0.772) and relative (AUC 0.731) levels of B cells was demonstrated.

3.
Curr Top Med Chem ; 21(11): 938-948, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34060999

RESUMO

BACKGROUND: Schizophrenia is a complex disease with a putative genetic background. It was hypothesized that impaired mitochondrial function due to genetic alterations in mitochondrial DNA (mtDNA) could contribute to neurological conditions, including mental disorders. The aim of the study was to find out possible pathogenic mutations and/or variants in mtDNA potentially related to schizophrenia development. OBJECTIVE: The study involved 37 patients with paranoid schizophrenia, whose mtDNA profiles were compared to those of 23 healthy controls. METHODS: Patients and controls were assessed using PANSS (Positive and Negative Syndrome Scale) and General Health Questionnaire (GHQ), respectively. The entire mtDNA was sequenced by the NGS platform (MiSeq®, Illumina). Bioinformatics data were processed by mtDNA Variant Processor and Analyser (Illumina), mtDNA-Server, and SPSS-17. RESULTS: A total of 480 mtDNA variants (single nucleotide replacements, point insertions, and deletions) were found. The polymorphic variant m.1811A>G (MT-RNR2) showed the highest frequency in schizophrenia (24.3%), as compared to the controls (4.3%) (p=0.07). Increased frequency was also found mainly in polymorphisms, belonging to complex 1 genes: MT-ND4 (11251G and 11467G), MT-ND3 (10398G), MT-ND1 (4216С), and MT-ND5 (12611G and 13708А), some of which were associated with mitochondrial dysfunction. Two individual mutations were identified in the patients: a pathogenic one - m.11778 A>G (LHON) and a newly identified, potentially pathogenic - m.4115 Т>C (NADH dehydrogenase 1). CONCLUSION: Particular mtDNA variants predominantly in complex I, probably serve as a risk genetic background in schizophrenia. The presence of pathogenic mutations in patients with psychotic manifestations expands the clinical scope of mitochondrial diseases and deserves further investigation.


Assuntos
DNA Mitocondrial/genética , Polimorfismo Genético/genética , Esquizofrenia/etnologia , Esquizofrenia/genética , Sequência de Bases , Biologia Computacional , Complexo I de Transporte de Elétrons/genética , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Mutação , NADH Desidrogenase/genética
4.
Case Reports Immunol ; 2020: 6694957, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33343952

RESUMO

Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare disease described in 1966. It is characterized by severe dermatitis, a peculiar face, frequent infections, extremely high levels of serum IgE and eosinophilia, all resulting from a defect in the STAT3 gene. A variety of mutations in the SH2 and DNA-binding domain have been described, and several studies have searched for associations between the severity of the clinical symptoms, laboratory findings, and the type of genetic alteration. We present two children with AD-HIES-a girl with the most common STAT3 mutation (R382W) and a boy with a rare variant (G617E) in the same gene, previously reported in only one other patient. Herein, we discuss the clinical and immunological findings in our patients, focusing on their importance on disease course and management.

5.
Arch Immunol Ther Exp (Warsz) ; 64(Suppl 1): 73-81, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28083606

RESUMO

Many studies have described the role of killer immunoglobulin-like receptors (KIRs) and their cognate human leukocyte antigen (HLA) class I ligands in the immune protection against melanoma, but the effect of these markers on intra-individual variations in tumor development and progression has remained less clear. We performed KIR, HLA, and KIR/ligand analysis in 283 patients with malignant melanoma in order to evaluate their integrated influence on disease stage and progression. The patients were grouped according to AJCC staging, histological type of the primary tumor, progression, and survival rate. Analysis of HLA class I alleles revealed positive association of HLA-C*14 (Pc = 0.026, OR = 5.99) and negative association of HLA-C*02 (Pc = 0.026, OR = 0.43) with the disease. Decreased frequency of KIR2DS5 was observed in patients with rapid progression, as compared to those with slow progression. KIR BB genotype was prevalent in patients with metastasis (p = 0.004, OR = 0.025). KIR AA genotype was nearly twice as frequent in rapidly progressive cases, but without statistical relevance (p = 0.055, OR = 2.6). Significantly increased frequency of KIR2DL2 in the presence of C1 ligand (strong inhibition) was found in patients with AJCC III and IV, as compared to individuals with AJCC I stage (p = 0.045, OR = 1.93). In summary, our data imply that KIR/ligand gene content in patients could modulate the disease course towards unfavorable tumor behavior.


Assuntos
Regulação Neoplásica da Expressão Gênica , Antígenos HLA/genética , Melanoma/genética , Receptores KIR/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Motivos de Aminoácidos , Progressão da Doença , Feminino , Predisposição Genética para Doença , Genótipo , Antígeno HLA-A3/genética , Antígenos HLA-C/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Células Matadoras Naturais/citologia , Ligantes , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Polimorfismo Genético , Receptores KIR2DL3/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Resultado do Tratamento , Melanoma Maligno Cutâneo
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