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1.
Stem Cell Res ; 41: 101612, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31678777

RESUMO

Primary immunodeficiency (PID) comprises a heterogeneous group of over 330 genetic disorders, caused mainly by single-gene mutations, such as CD70. We generated human induced pluripotent stem cell lines, PHAi003-A and PHAi003-B, from a PID patient carrying the homozygous frameshift CD70 mutation c.250delT. The CD70 c.250delT genotype results in a complete loss of expression variant. This patient is one of the five CD70 deficient individuals described to date, and presented hypogammaglobulinemia, EBV associated Hodgkin's lymphoma and susceptibility to other viral infections. The PHAi003-A and PHAi003-B lines are a unique resource for PID modeling and studying CD70-mediated immunity in human cells.

2.
Stem Cell Res ; 41: 101613, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31689593

RESUMO

Selective immunoglobulin-A deficiency (IgAD) is the most common primary immunodeficiency (PID) in the Western world and results in higher susceptibility to infections, autoimmune disorders and malignancies. We generated human induced pluripotent stem cell lines from two patients with selective IgAD, PHAi001 and PHAi002. Patient samples were reprogrammed using non-integrative based methods. Pluripotency of the PHAi001 and PHAi002 cell lines was confirmed by their expression of stem cell markers and capacity to differentiate into cells of the three germ layers. The PHAi001 and PHAi002 lines are a unique resource for experimental modeling of selective IgAD and associated disorders.

3.
Br J Haematol ; 2019 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-31423576

RESUMO

The clinical course of follicular lymphoma (FL) is highly variable. Recently the m7-FL international prognostic index (FLIPI) integrating performance status, FLIPI score and the mutational status of seven genes, was shown to stratify patients into "low-risk" and "high-risk" with respect to 5-year failure-free survival after first-line immunochemotherapy. Our aim was to evaluate the model after rituximab without chemotherapy. The Nordic Lymphoma Group performed two randomized clinical trials on indolent lymphoma patients receiving single rituximab and rituximab with interferon-α2a. In total, 95 FL patients had sufficient fresh-frozen diagnostic material for sequencing. A targeted panel for the genes EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11 was utilized for m7-FLIPI score calculation. With a median follow-up of 10·6 years, 76% of patients were alive. No difference in time to treatment failure (TTF), defined as the interval between start of trial therapy and initiation of new therapy or death, nor overall survival (OS) was found between the m7-FLIPI risk groups (log-rank P = 0·94 and 0·99, respectively). EZH2 mutations were associated with longer TTF (log-rank P = 0·04) and in EP300 mutations were associated with shorter TTF (log-rank P = 0·01). We conclude that the prognostic value of the m7-FLIPI clinicogenetic model seems dependent on therapeutic regimen.

5.
Genet Med ; 2018 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-29921932

RESUMO

PURPOSE: The etiology of 80% of patients with primary antibody deficiency (PAD), the second most common type of human immune system disorder after human immunodeficiency virus infection, is yet unknown. METHODS: Clinical/immunological phenotyping and exome sequencing of a cohort of 126 PAD patients (55.5% male, 95.2% childhood onset) born to predominantly consanguineous parents (82.5%) with unknown genetic defects were performed. The American College of Medical Genetics and Genomics criteria were used for validation of pathogenicity of the variants. RESULTS: This genetic approach and subsequent immunological investigations identified potential disease-causing variants in 86 patients (68.2%); however, 27 of these patients (31.4%) carried autosomal dominant (24.4%) and X-linked (7%) gene defects. This genetic approach led to the identification of new phenotypes in 19 known genes (38 patients) and the discovery of a new genetic defect (CD70 pathogenic variants in 2 patients). Medical implications of a definite genetic diagnosis were reported in ~50% of the patients. CONCLUSION: Due to misclassification of the conventional approach for targeted sequencing, employing next-generation sequencing as a preliminary step of molecular diagnostic approach to patients with PAD is crucial for management and treatment of the patients and their family members.

6.
Front Immunol ; 9: 908, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29755475

RESUMO

The dietary pattern can influence the immune system directly, but may also modulate it indirectly by regulating the gut microbiota. Here, we investigated the effect of a 3-months lacto-ovo-vegetarian diet on the diversity of gut microbiota and the immune system in healthy omnivorous volunteers, using high-throughput sequencing technologies. The short-term vegetarian diet did not have any major effect on the diversity of the immune system and the overall composition of the metagenome. The prevalence of bacterial genera/species with known beneficial effects on the intestine, including butyrate-producers and probiotic species and the balance of autoimmune-related variable genes/families were, however, altered in the short-term vegetarians. A number of bacterial species that are associated with the expression level of IgA, a key immunoglobulin class that protects the gastrointestinal mucosal system, were also identified. Furthermore, a lower diversity of T-cell repertoire and expression level of IgE, as well as a reduced abundance of inflammation-related genes in the gut microbiota were potentially associated with a control group with long-term vegetarians. Thus, the composition and duration of the diet may have an impact on the balance of pro-/anti-inflammatory factors in the gut microbiota and immune system.

8.
Blood ; 131(24): 2670-2681, 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29545328

RESUMO

Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa, and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types of B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with concomitant HBV infection (surface antigen positive [HBsAg+]) are characterized by a younger age, a more advanced disease stage at diagnosis, and reduced overall survival. Furthermore, by whole-genome/exome sequencing of 96 tumors and the respective peripheral blood samples and targeted sequencing of 179 tumors from these patients, we observed an enhanced rate of mutagenesis and a distinct set of mutation targets in HBsAg+ DLBCL genomes, which could be partially explained by the activities of APOBEC and activation-induced cytidine deaminase. By transcriptome analysis, we further showed that the HBV-associated gene expression signature is contributed by the enrichment of genes regulated by BCL6, FOXO1, and ZFP36L1. Finally, by analysis of immunoglobulin heavy chain gene sequences, we showed that an antigen-independent mechanism, rather than a chronic antigenic simulation model, is favored in HBV-related lymphomagenesis. Taken together, we present the first comprehensive genomic and transcriptomic study that suggests a link between HBV infection and B-cell malignancy. The genetic alterations identified in this study may also provide opportunities for development of novel therapeutic strategies.

9.
Nat Commun ; 9(1): 1006, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29520062

RESUMO

Class switch recombination (CSR) has a fundamental function during humoral immune response and involves the induction and subsequent repair of DNA breaks in the immunoglobulin (Ig) switch regions. Here we show the role of Usp22, the SAGA complex deubiquitinase that removes ubiquitin from H2B-K120, in the repair of programmed DNA breaks in vivo. Ablation of Usp22 in primary B cells results in defects in γH2AX and impairs the classical non-homologous end joining (c-NHEJ), affecting both V(D)J recombination and CSR. Surprisingly, Usp22 depletion causes defects in CSR to various Ig isotypes, but not IgA. We further demonstrate that IgG CSR primarily relies on c-NHEJ, whereas CSR to IgA is more reliant on the alternative end joining pathway, indicating that CSR to different isotypes involves distinct DNA repair pathways. Hence, Usp22 is the first deubiquitinase reported to regulate both V(D)J recombination and CSR in vivo by facilitating c-NHEJ.


Assuntos
Reparo do DNA por Junção de Extremidades , Enzimas Desubiquitinantes/metabolismo , Endopeptidases/metabolismo , Imunidade Humoral/genética , Switching de Imunoglobulina , Recombinação V(D)J , Animais , Linfócitos B , Enzimas Desubiquitinantes/genética , Endopeptidases/genética , Feminino , Histonas/genética , Histonas/metabolismo , Isotipos de Imunoglobulinas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Ubiquitina/metabolismo
10.
Clin Immunol ; 188: 94-102, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29305966

RESUMO

The CTLA-4 checkpoint regulates the activation of T cells. Individuals with heterozygous mutations in CTLA-4 have a complex phenotype typically characterized by antibody deficiency alongside variable autoimmunity. Despite severe disease in some individuals, others remain largely unaffected with reasons for this variation unknown. We studied a large family carrying a single point mutation in CTLA-4 leading to an amino acid change R75W and compared both unaffected with affected individuals. We measured a variety of features pertaining to T cell and CTLA-4 biology and observed that at the cellular level there was complete penetrance of CTLA-4 mutations. Accordingly, unaffected individuals were indistinguishable from those with disease in terms of level of CTLA-4 expression, percentage of Treg, upregulation of CTLA-4 upon stimulation and proliferation of CD4 T cells. We conclude that the wide variation in disease phenotype is influenced by immune variation outside of CTLA-4 biology.

13.
J Clin Immunol ; 38(1): 35-44, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29098565

RESUMO

Bloom's syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA repair. DNA repair is especially important for the development and maturation of the T and B cells. Since BLM is involved in DNA repair, we aimed to study if BLM deficiency affects T and B cell development and especially somatic hypermutation (SHM) and class switch recombination (CSR) processes. Clinical data of six BS patients was collected, and immunoglobulin serum levels were measured at different time points. In addition, we performed immune phenotyping of the B and T cells and analyzed the SHM and CSR in detail by analyzing IGHA and IGHG transcripts using next-generation sequencing. The serum immunoglobulin levels were relatively low, and patients had an increased number of infections. The absolute number of T, B, and NK cells were low but still in the normal range. Remarkably, all BS patients studied had a high percentage (20-80%) of CD4+ and CD8+ effector memory T cells. The process of SHM seems normal; however, the Ig subclass distribution was not normal, since the BS patients had more IGHG1 and IGHG3 transcripts. In conclusion, BS patients have low number of lymphocytes, but the immunodeficiency seems relatively mild since they have no severe or opportunistic infections. Most changes in the B cell development were seen in the CSR process; however, further studies are necessary to elucidate the exact role of BLM in CSR.

14.
Front Immunol ; 9: 2912, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619276

RESUMO

Patients with inborn errors of immunity or DNA repair defects are at significant risk of developing malignancy and this complication of their underlying condition represents a substantial cause of morbidity and mortality. Whilst this risk is increasingly well-recognized, our understanding of the causative mechanisms remains incomplete. Diagnosing cancer is challenging in the presence of underlying co-morbidities and frequently other inflammatory and lymphoproliferative processes. We lack a structured approach to management despite recognizing the competing challenges of poor response to therapy and increased risk of toxicity. Finally, clinicians need guidance on how to screen for malignancy in many of these predisposing immunodeficiencies. In order to begin to address these challenges, we brought together representatives of European Immunology and Pediatric Haemato-Oncology to define the current state of our knowledge and identify priorities for clinical and research development. We propose key developmental priorities which our two communities will need to work together to address, collaborating with colleagues around the world.


Assuntos
Distúrbios no Reparo do DNA/complicações , Síndromes de Imunodeficiência/complicações , Neoplasias/diagnóstico , Neoplasias/terapia , Pesquisa , Alergia e Imunologia/tendências , Criança , Humanos , Comunicação Interdisciplinar , Oncologia/métodos , Oncologia/tendências , Neoplasias/complicações , Pediatria/métodos , Pediatria/tendências
15.
Curr Opin Hematol ; 24(4): 367-376, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28406802

RESUMO

PURPOSE OF REVIEW: Here, we give an updated overview of the subtype distribution of lymphomas in East Asia and also present the genome sequencing data on two major subtypes of these tumors. RECENT FINDINGS: The distribution of lymphoma types/subtypes among East Asian countries is very similar, with a lower proportion of B-cell malignancies and a higher proportion of T/natural killer (NK)-cell lymphomas as compared to Western populations. Extranodal NK/T-cell lymphoma is more frequently observed in East Asia, whereas follicular lymphoma and chronic lymphocytic leukemia, are proportionally lower. The incidence rate of lymphoma subtypes in Asians living in the US was generally intermediate to the general rate in US and Asia, suggesting that both genetic and environmental factors may underlie the geographical variations observed.Key cancer driver mutations have been identified in Asian patients with diffuse large B-cell lymphoma or extranodal NK/T-cell lymphoma through genome sequencing. A distinct somatic mutation profile has also been observed in Chinese diffuse large B-cell lymphoma patients. SUMMARY: The incidence and distribution of lymphoma subtypes differed significantly between patients from East Asia and Western countries, suggesting subtype-specific etiologic mechanisms. Further studies on the mechanism underlying these geographical variations may give new insights into our understanding of lymphomagenesis.


Assuntos
Linfoma/diagnóstico , Linfoma/genética , Mutação , Ásia/epidemiologia , Biomarcadores , Predisposição Genética para Doença , Humanos , Linfoma/epidemiologia , Linfoma/etiologia , Taxa de Mutação , Transdução de Sinais
16.
Leuk Res ; 56: 29-35, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28171799

RESUMO

Chidamide (CS055) is a new and highly selective histone deacetylase inhibitor displaying significant single-agent activity in peripheral T-cell lymphoma (PTCL). But there is little known the synergistic effect between CS055 and chemotherapy. The purpose of this study is to explore the synergistic effect and molecular mechanisms of CS055 combination with Doxorubicin in PTCL cells. We found that CS055 showed dose- and time-dependent inhibition effects on PTCL cell. Meanwhile, the synergistic effect was significantly observed after combination treatment with lower drug-concentration of CS055 and Doxorubicin. Lower drug-concentration of CS055 induced weak apoptosis in PTCL cells, but combination treatment with CS055 and Doxorubicin promoted more significant apoptosis. Combination treatment with CS055 and Doxorubicin significantly changed mitochondrial membrane potential and H3 acetylated level, resulting in up-regulating DNA damage protein p-γH2AX and apoptosis proteins including cleaved-caspase-3, cleaved-caspase-9 and cleaved-PARP, and down-regulating anti-apoptosis protein Bcl-2. In a word, Doxorubicin could increase the CS055-induced inhibition effects on PTCL cells, suggesting that CS055 combination with Doxorubicin or Doxorubicin-based chemotherapy drugs might be a new therapy approach for PTCL patients.


Assuntos
Doxorrubicina/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Humanos , Linfoma de Células T Periférico/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Células Tumorais Cultivadas
17.
Clin Immunol ; 176: 71-76, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28093361

RESUMO

We report the first patient with an interstitial deletion of chromosome 15q24.1-q24.3 associated with common variable immunodeficiency (CVID). The 18-year old female patient's clinical and immunological phenotype was compared with 8 additional previously published patients with chr15q24 deletions. A CGH analysis estimated the deletion to be 3.767Mb in size (chr15: 74,410,916-78,178,418) and the result was confirmed using qRT-PCR. We defined an immune-related commonly deleted region (ICDR) within the chromosomal band 15q24.2, deleted in all four patients with different forms of antibody deficiencies. Mutations in the 14 genes within this ICDR were not identified in the remaining allele in our patient by WES and gene expression analyses showed haploinsufficiency of all the genes. Among these genes, we consider Nei Like DNA Glycosylase 1 (NEIL1) as a likely candidate gene due to its crucial role in B-cell activation and terminal differentiation.


Assuntos
Transtornos Cromossômicos/genética , Imunodeficiência de Variável Comum/genética , DNA Glicosilases/genética , Deficiência Intelectual/genética , Adolescente , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Feminino , Humanos , Ativação Linfocitária/genética
18.
J Exp Med ; 214(1): 91-106, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28011864

RESUMO

In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)-related diseases. Three patients presented with EBV-associated Hodgkin's lymphoma and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27. Blood lymphocyte numbers were normal, but the proportions of memory B cells and EBV-specific effector memory CD8+ T cells were reduced. Furthermore, although T cell proliferation was normal, in vitro-generated EBV-specific cytotoxic T cell activity was reduced because of CD70 deficiency. This reflected impaired activation by, rather than effects during killing of, EBV-transformed B cells. Notably, expression of 2B4 and NKG2D, receptors implicated in controlling EBV infection, on memory CD8+ T cells from CD70-deficient individuals was reduced, consistent with their impaired killing of EBV-infected cells. Thus, autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of inherited CD27 deficiency. Overall, human CD70-CD27 interactions therefore play a nonredundant role in T and B cell-mediated immunity, especially for protection against EBV and humoral immunity.


Assuntos
Linfócitos B/imunologia , Ligante CD27/deficiência , Infecções por Vírus Epstein-Barr/complicações , Doença de Hodgkin/etiologia , Síndromes de Imunodeficiência/complicações , Adolescente , Adulto , Ligante CD27/genética , Linfócitos T CD8-Positivos/imunologia , Criança , Citotoxicidade Imunológica , Feminino , Herpesvirus Humano 4/imunologia , Humanos , Memória Imunológica , Masculino , Mutação , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologia
19.
Nat Genet ; 48(11): 1425-1429, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27723758

RESUMO

Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our genome-wide association study (GWAS) meta-analysis of 1,635 patients with IgAD and 4,852 controls identified four new significant (P < 5 × 10-8) loci and association with a rare IFIH1 variant (p.Ile923Val). Peak new variants (PVT1, P = 4.3 × 10-11; ATG13-AMBRA1, P = 6.7 × 10-10; AHI1, P = 8.4 × 10-10; CLEC16A, P = 1.4 × 10-9) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including expression quantitative trait loci (eQTLs) for AHI1 and DEXI and DNase hypersensitivity sites in FOXP3+ regulatory T cells. Pathway analysis of the meta-analysis results showed striking association with the KEGG pathway for IgA production (pathway P < 0.0001), with 22 of the 30 annotated pathway genes containing at least one variant with P ≤ 0.05 in the IgAD meta-analysis. These data suggest that a complex network of genetic effects, including genes known to influence the biology of IgA production, contributes to IgAD.


Assuntos
Variação Genética , Deficiência de IgA/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Relacionadas à Autofagia/genética , Estudos de Coortes , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Lectinas Tipo C/genética , Proteínas de Transporte de Monossacarídeos/genética , RNA Longo não Codificante/genética
20.
Oncotarget ; 7(22): 33350-62, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27147575

RESUMO

Programmed death-1 (PD-1) /programmed death-ligand 1 (PD-L1) engagement usually leads to diminished antitumor T-cell responses, which mediates the immune escape of tumor cells. However, little is known whether PD-1/PD-L1 could directly activates intracellular oncogenic signaling pathways in tumor cells. The purpose of this study is to investigate whether intracellular AKT/mTOR signaling could be directly activated by PD-1/PD-L1 during the malignant progression in diffuse large B-cell lymphoma (DLBCL). Detection of the expression of PD-L1 and p-AKT by immunohistochemistry (IHC) showed that both proteins were overexpressed in 54% and 48% DLBCL cases, respectively. Spearman test showed that PD-L1 expression was correlated with p-AKT expression (R=0.244, χ2=5.962; P=0.017) and the expression of PD-L1 and p-AKT were also correlated with clinic-pathological characteristics. In addition, survival analysis showed that DLBCL patients who co-expressed PD-L1 and p-AKT had significantly poorer outcome than patients with single positive or both negative expression (P<0.05). In vitro, total PD-L1 and membrane PD-L1 (mPD-L1) proteins were overexpressed in five DLBCL cell lines by western blot and flow cytometry. We observed that AKT/mTOR pathway was activated in DLBCL cells after stimulated with human recombination PD-1/Fc. Taken together, these results suggested that the combination of PD-1/PD-L1 antibodies and AKT/mTOR inhibitor might be a promising and novel therapeutic approach for DLBCL in the future.


Assuntos
Antígeno B7-H1/metabolismo , Linfoma Difuso de Grandes Células B/enzimologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Ativação Enzimática , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Fosforilação , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
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