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Recent transcriptomic-based analysis of diffuse large B cell lymphoma (DLBCL) has highlighted the clinical relevance of LN fibroblast and tumor-infiltrating lymphocyte (TIL) signatures within the tumor microenvironment (TME). However, the immunomodulatory role of fibroblasts in lymphoma remains unclear. Here, by studying human and mouse DLBCL-LNs, we identified the presence of an aberrantly remodeled fibroblastic reticular cell (FRC) network expressing elevated fibroblast-activated protein (FAP). RNA-Seq analyses revealed that exposure to DLBCL reprogrammed key immunoregulatory pathways in FRCs, including a switch from homeostatic to inflammatory chemokine expression and elevated antigen-presentation molecules. Functional assays showed that DLBCL-activated FRCs (DLBCL-FRCs) hindered optimal TIL and chimeric antigen receptor (CAR) T cell migration. Moreover, DLBCL-FRCs inhibited CD8+ TIL cytotoxicity in an antigen-specific manner. Notably, the interrogation of patient LNs with imaging mass cytometry identified distinct environments differing in their CD8+ TIL-FRC composition and spatial organization that associated with survival outcomes. We further demonstrated the potential to target inhibitory FRCs to rejuvenate interacting TILs. Cotreating organotypic cultures with FAP-targeted immunostimulatory drugs and a bispecific antibody (glofitamab) augmented antilymphoma TIL cytotoxicity. Our study reveals an immunosuppressive role of FRCs in DLBCL, with implications for immune evasion, disease pathogenesis, and optimizing immunotherapy for patients.
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Linfoma Difuso de Grandes Células B , Linfócitos T , Humanos , Camundongos , Animais , Linfoma Difuso de Grandes Células B/patologia , Fibroblastos/metabolismo , Linfonodos , Microambiente TumoralRESUMO
BACKGROUND: Epstein-Barr virus (EBV) is linked to multiple cancers, including classical Hodgkin lymphoma (cHL), endemic Burkitt lymphoma (eBL), nasopharyngeal carcinoma (NPC), and extranodal natural killer/T-cell lymphoma (NKTCL). METHODS: Anti-EBV IgG and IgA antibody responses targeting 202 sequences from 86 EBV proteins were measured using the same EBV whole proteome array across four case-control studies investigating EBV-positive cHL, eBL, NPC, and NKTCL (407 cases/620 controls). We grouped EBV-targeted antibodies into pathways by immunoglobulin type (IgA and IgG) and life-cycle stage (latent, immediate early lytic, early lytic, late lytic, and glycoprotein) and evaluated their association with each cancer type. In an additional analysis, we focused on the subset of 46 individual antibodies representing the top candidates for each cancer and compared their associations across the four cancer types using multivariable linear regression models. RESULTS: IgA antibody responses targeting all EBV life-cycle stages were associated with NPC but limited to anti-early lytic stage for cHL. NPC and eBL were associated with IgG antibodies across the viral life cycle; cHL with antibodies in the early lytic, late lytic and glycoprotein stages; and NKTCL with antibodies in the latent, immediate early lytic and early lytic phases. EBNA3A, BBLF1, BDLF4, and BLRF2 IgG antibodies were associated with all cancer types. CONCLUSIONS: Our observed similarities and differences across four EBV-associated cancers may inform EBV-related oncogenesis. IMPACT: Understanding the comparative humoral immune response across EBV-related cancers may aid in identifying shared etiologic roles of EBV proteins and inform unique pathogenic processes for each cancer.
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Linfoma de Burkitt , Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Herpesvirus Humano 4 , Proteoma , Imunidade Humoral , Carcinoma Nasofaríngeo , Anticorpos Antivirais , Neoplasias Nasofaríngeas/patologia , Imunoglobulina G , Glicoproteínas , Imunoglobulina ARESUMO
BACKGROUND: Epstein-Barr virus (EBV) infection contributes to cancers in a fraction of seropositive individuals, but much remains to be learned about variation in EBV-directed humoral immunity in cancer-free adults. METHODS: A protein microarray was used to probe serum from 175 Taiwanese and 141 Northern European adults for immunoglobulin G (IgG) antibody responses to 115 different peptide sequences, representing protein segments or protein variants, from 45 EBV proteins. It was posited that this antibody-based approach could identify EBV peptide sequences representing immunodominant regions relevant for B-cell immunity. RESULTS: Analyses of 45 EBV proteins with multiple protein segments or variants printed on the array identified eight EBV peptide sequences that appear to play a role in immunogenicity. This included: (1) three proteins with segments/regions associated with IgG reactivity (BALF5, LMP1, LMP2A); and (2) five proteins with sequence variants/amino acid changes associated with IgG reactivity (BDLF4, EBNA3A, EBNA3B, EBNA-LP, LF1). CONCLUSION: This examination of IgG antibody responses against 115 EBV peptide sequences in 316 cancer-free adults represents an important step toward identifying specific EBV protein sequences that play a role in generating B-cell immunity in humans.
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Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Formação de Anticorpos , Linfócitos B , Herpesvirus Humano 4/genética , Humanos , Imunoglobulina GRESUMO
The pandemic spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of Coronavirus Disease 2019 (COVID-19), represents an ongoing international health crisis. A key symptom of SARS-CoV-2 infection is the onset of fever, with a hyperthermic temperature range of 38 to 41°C. Fever is an evolutionarily conserved host response to microbial infection that can influence the outcome of viral pathogenicity and regulation of host innate and adaptive immune responses. However, it remains to be determined what effect elevated temperature has on SARS-CoV-2 replication. Utilizing a three-dimensional (3D) air-liquid interface (ALI) model that closely mimics the natural tissue physiology of SARS-CoV-2 infection in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection. Respiratory tissue incubated at 40°C remained permissive to SARS-CoV-2 entry but refractory to viral transcription, leading to significantly reduced levels of viral RNA replication and apical shedding of infectious virus. We identify tissue temperature to play an important role in the differential regulation of epithelial host responses to SARS-CoV-2 infection that impact upon multiple pathways, including intracellular immune regulation, without disruption to general transcription or epithelium integrity. We present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication in respiratory epithelia. Our data identify an important role for tissue temperature in the epithelial restriction of SARS-CoV-2 independently of canonical interferon (IFN)-mediated antiviral immune defenses.
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Células Epiteliais/imunologia , Temperatura Alta , Imunidade Inata/imunologia , Interferons/imunologia , Mucosa Respiratória/imunologia , SARS-CoV-2/imunologia , Replicação Viral/imunologia , Adolescente , Animais , COVID-19/genética , COVID-19/imunologia , COVID-19/virologia , Chlorocebus aethiops , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Perfilação da Expressão Gênica/métodos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/genética , Interferons/genética , Interferons/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , RNA-Seq/métodos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Técnicas de Cultura de Tecidos , Células Vero , Replicação Viral/genética , Replicação Viral/fisiologiaRESUMO
Several human leukocyte antigen (HLA) alleles are strongly associated with susceptibility to classic Hodgkin lymphoma (cHL), also in subgroups stratified for presence of the Epstein-Barr virus (EBV). We tested the hypothesis that the pressure on cHL tumour cells to lose HLA expression is associated with HLA susceptibility alleles. A meta-analysis was carried out to identify consistent protective and risk HLA alleles in a combined cohort of 839 cHL patients from the Netherlands and the United Kingdom. Tumour cell HLA expression was studied in 338 cHL cases from these two cohorts and correlated to the presence of specific susceptibility HLA alleles. Carriers of the HLA-DRB1*07 protective allele frequently lost HLA class II expression in cHL overall. Patients carrying the HLA-DRB1*15/16 (DR2) risk allele retained HLA class II expression in EBV- cHL and patients with the HLA-B*37 risk allele retained HLA class I expression more frequently than non-carriers in EBV+ cHL. The other susceptibility alleles showed no significant differences in expression. Thus, HLA expression by tumour cells is associated with a subset of the protective and risk alleles. This strongly suggests that HLA associations in cHL are related to peptide binding capacities of specific HLA alleles.
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A point-of-care blood test for the detection of an emerging biomarker, CCL17/TARC, could prove transformative for the clinical management of classic Hodgkin lymphoma (cHL). Primary care diagnosis is challenging due to nonspecific clinical presentation and lack of a diagnostic test, leading to significant diagnostic delays. Treatment monitoring encounters false-positive and negative results, leading to avoidable chemotherapy toxicity, or undertreatment, impacting patient morbidity and mortality. Here, we present an amperometric CCL17/TARC immunosensor, based on the utilization of a thiolated heterobifunctional cross-linker and sandwich antibody assay, to facilitate novel primary care triage and chemotherapy monitoring strategies for cHL. The immunosensor shows excellent analytical performance for clinical testing; linearity (R2 = 0.986), detection limit (194 pg/mL), and lower and upper limits of quantitation (387-50â¯000 pg/mL). The biosensor differentiated all 42 newly diagnosed cHL patients from healthy volunteers, based on serum CCL17/TARC concentration, using blood samples collected prior to treatment intervention. The immunosensor also discriminated between paired blood samples of all seven cHL patients, respectively, collected prior to treatment and during chemotherapy, attributed to the decrease in serum CCL17/TARC concentration following chemotherapy response. Overall, we have shown, for the first time, the potential of an electrochemical CCL17/TARC biosensor for primary care triage and chemotherapy monitoring for cHL, which would have positive clinical and psychosocial implications for patients, while streamlining current healthcare pathways.
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Técnicas Biossensoriais , Quimiocina CCL17/sangue , Doença de Hodgkin , Técnicas Eletroquímicas , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/tratamento farmacológico , Humanos , Imunoensaio , TriagemRESUMO
Unfortunately, the word "Group" is missed in the article title of the original publication. It has been corrected by this erratum.
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PURPOSE: We explored the interaction between non-Hodgkin lymphoma (NHL), infectious mononucleosis (IM) history, and immune-related genotypes in a pooled case-control analysis. METHODS: A total of 7,926 NHL patients and 10,018 controls from 12 case-control studies were included. Studies were conducted during various time periods between 1988 and 2008, and participants were 17-96 years of age at the time of ascertainment/recruitment. Self-reported IM history and immune response genotypes were provided by the InterLymph Data Coordinating Center at Mayo Clinic. Odds ratios (OR) were estimated using multivariate logistic regression, and interactions were estimated using the empirical Bayes method. PACT was used to account for multiple comparisons. RESULTS: There was evidence of an interaction effect between IM history and two variants on T-cell lymphoma (TCL) risk: rs1143627 in interleukin-1B (IL1B) (pinteraction = 0.04, ORinteraction = 0.09, 95% confidence interval [CI] 0.01, 0.87) and rs1800797 in interleukin-6 (IL6) (pinteraction = 0.03, ORinteraction = 0.08, 95% CI 0.01, 0.80). Neither interaction effect withstood adjustment for multiple comparisons. There were no statistically significant interactions between immune response genotypes and IM on other NHL subtypes. CONCLUSIONS: Genetic risk variants in IL1B and IL6 may affect the association between IM and TCL, possibly by influencing T-cell activation, growth, and differentiation in the presence of IM, thereby decreasing risk of immune cell proliferation.
Assuntos
Mononucleose Infecciosa/genética , Linfoma não Hodgkin/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Mononucleose Infecciosa/imunologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Autorrelato , Adulto JovemRESUMO
The humoral immune response to Epstein-Barr virus (EBV) in classical Hodgkin lymphoma (cHL) stratified by EBV tumor status is unclear. We examined IgG and IgA antibody responses against 202 protein sequences representing 86 EBV proteins using a microarray and sera from 139 EBV-positive cHL cases, 70 EBV-negative cHL cases and 141 population-based controls frequency matched to EBV-positive cHL cases on sex and age by area (UK, Denmark and Sweden). We leveraged existing data on the proportion of circulating B-cells infected by EBV and levels of serum CCL17, a chemokine secreted by cHL tumor cells, from a subset of the cHL cases in the UK. Total IgG but not IgA response level was significantly different between EBV-positive cHL cases and controls. The distinct serological response included significant elevations in 16 IgG antibodies and 2 IgA antibodies, with odds ratioshighest vs. lowest tertile > 3 observed for the following EBV proteins: LMP1 (oncogene), BcLF1 (VCAp160, two variants) and BBLF1 (two variants). Our cHL IgG signature correlated with the proportion of circulating EBV-infected B-cells, but not serum CCL17 levels. We observed no differences in the anti-EBV antibody profile between EBV-negative cHL cases and controls. BdRF1(VCAp40)-IgG and BZLF1(Zta)-IgG were identified as the serological markers best able to distinguish EBV-positive from EBV-negative cHL tumors. Our results support the hypothesis that differences in the EBV antibody profile are specific to patients with EBV-positive cHL and are not universally observed as part of a systematically dysregulated immune response present in all cHL cases.
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Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Doença de Hodgkin/imunologia , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Proteoma/imunologia , Adulto , Idoso , Dinamarca , Feminino , Doença de Hodgkin/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Suécia , Proteínas da Matriz Viral/imunologia , Proteínas Virais/imunologia , Adulto JovemRESUMO
The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.
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Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10-8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10-17), 6q23.3 (rs6928977, P = 4.62 × 10-11), 10p14 (rs3781093, P = 9.49 × 10-13), 13q34 (rs112998813, P = 4.58 × 10-8) and 16p13.13 (rs34972832, P = 2.12 × 10-8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.
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Predisposição Genética para Doença , Doença de Hodgkin/genética , Alelos , Estudo de Associação Genômica Ampla , Cadeias beta de HLA-DP/genética , Cadeias HLA-DRB1/genética , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The genomes of human herpesvirus 6A (HHV-6A) and HHV-6B have the capacity to integrate into telomeres, the essential capping structures of chromosomes that play roles in cancer and ageing. About 1% of people worldwide are carriers of chromosomally integrated HHV-6 (ciHHV-6), which is inherited as a genetic trait. Understanding the consequences of integration for the evolution of the viral genome, for the telomere, and for the risk of disease associated with carrier status is hampered by a lack of knowledge about ciHHV-6 genomes. Here, we report an analysis of 28 ciHHV-6 genomes and show that they are significantly divergent from the few modern nonintegrated HHV-6 strains for which complete sequences are currently available. In addition, ciHHV-6B genomes in Europeans are more closely related to each other than to ciHHV-6B genomes from China and Pakistan, suggesting regional variation of the trait. Remarkably, at least one group of European ciHHV-6B carriers has inherited the same ciHHV-6B genome, integrated in the same telomere allele, from a common ancestor estimated to have existed 24,500 ± 10,600 years ago. Despite the antiquity of some, and possibly most, germ line HHV-6 integrations, the majority of ciHHV-6B (95%) and ciHHV-6A (72%) genomes contain a full set of intact viral genes and therefore appear to have the capacity for viral gene expression and full reactivation.IMPORTANCE Inheritance of HHV-6A or HHV-6B integrated into a telomere occurs at a low frequency in most populations studied to date, but its characteristics are poorly understood. However, stratification of ciHHV-6 carriers in modern populations due to common ancestry is an important consideration for genome-wide association studies that aim to identify disease risks for these people. Here, we present full sequence analysis of 28 ciHHV-6 genomes and show that ciHHV-6B in many carriers with European ancestry most likely originated from ancient integration events in a small number of ancestors. We propose that ancient ancestral origins for ciHHV-6A and ciHHV-6B are also likely in other populations. Moreover, despite their antiquity, all of the ciHHV-6 genomes appear to retain the capacity to express viral genes, and most are predicted to be capable of full viral reactivation. These discoveries represent potentially important considerations in immunocompromised patients, in particular in organ transplantation and in stem cell therapy.
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Cromossomos Humanos , Genoma Humano , Herpesvirus Humano 6/genética , Característica Quantitativa Herdável , Telômero , Integração Viral/genética , Cromossomos Humanos/genética , Cromossomos Humanos/virologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Telômero/genética , Telômero/virologiaRESUMO
PCR for antigen receptor gene rearrangements (PARR) analysis is being increasingly used to assist diagnosis of canine lymphoma. In this study, PARR was carried out on consecutive samples received as part of routine diagnostic practice from 271 patients: 195 with lymphoid malignancies, 53 with reactive conditions and 23 with other neoplasms. Initially, published primer sets were used but later minor primer modifications were introduced and primers were rationalised to give a PARR panel that provides a good compromise between sensitivity and cost. Results were compared to diagnoses made by histology or cytology, coupled with immunophenotyping by flow cytometry or immunohistochemistry where possible. After exclusion of 11 poor quality samples, 230/260 (88%) gave a clear result with 162/163 (99%) of samples classified as clonal and 56/67 (84%) classified as polyclonal giving results concordant with the cytological/histological diagnosis. Among 30 samples with equivocal results, 21 had clonal peaks in a polyclonal background and nine showed little amplification. These were from patients with a range of neoplastic and non-neoplastic conditions emphasising the need to interpret such results carefully in concert with other diagnostic tests. The combination of primer sets used in this study resulted in a robust, highly specific and sensitive assay for detecting clonality.
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Doenças do Cão/genética , Doenças do Cão/imunologia , Rearranjo Gênico , Linfoma/veterinária , Reação em Cadeia da Polimerase/veterinária , Receptores de Antígenos/genética , Animais , Primers do DNA/genética , Doenças do Cão/diagnóstico , Cães , Feminino , Rearranjo Gênico do Linfócito B , Rearranjo Gênico do Linfócito T , Genótipo , Imunofenotipagem , Linfoma/genética , Linfoma/imunologia , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Linfoma de Células B/veterinária , Linfoma de Células T/genética , Linfoma de Células T/imunologia , Linfoma de Células T/veterinária , Masculino , Reação em Cadeia da Polimerase/métodos , Reação em Cadeia da Polimerase/estatística & dados numéricosRESUMO
Primary effusion lymphomas (PEL) are associated with human herpesvirus-8 (HHV-8) and usually occur in immunocompromised individuals. However, there are numerous reports of HHV-8-unrelated PEL-like lymphomas with unknown aetiology. Here we characterize an HHV-8-unrelated PEL-like lymphoma in an elderly woman who was negative for human immunodeficiency viruses 1 and 2, and hepatitis B and C. The woman was, however, a carrier of an inherited-chromosomally-integrated human herpesvirus-6A (iciHHV-6A) genome in one 19q telomere. The iciHHV-6A genome was complete in blood DNA, encoding a full set of protein-coding genes. Interestingly, the entire iciHHV-6A genome was absent from the HHV-8-unrelated-PEL-like lymphoma cells despite retention of both copies of chromosome 19. The somatic loss of the 19q-iciHHV-6A genome occurred very early during lymphoma development and we propose it occurred via telomere-loop formation and excision to release a circular viral genome that was subsequently lost. Whether release of the HHV-6A genome from the telomere contributed to lymphomagenesis, or was coincidental, remains unclear but this event may have deregulated the expression of HHV-6A or 19q genes or else disrupted telomere function. To establish the frequency and importance of iciHHV-6 loss from telomeres, the HHV-6 copy number should be assessed in tumours that arise in iciHHV-6 carriers.
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Cromossomos Humanos Par 19 , Herpesvirus Humano 6/genética , Linfoma de Efusão Primária/diagnóstico , Provírus/genética , Infecções por Roseolovirus/complicações , Deleção de Sequência , Telômero , Idoso , Feminino , Humanos , Linfoma de Efusão Primária/patologia , Linfoma de Efusão Primária/virologia , Masculino , Análise de Sequência de DNA , Integração ViralRESUMO
BACKGROUND: A proportion of the genetic variants involved in susceptibility to Hodgkin lymphoma differ by the tumor's Epstein-Barr virus (EBV) status, particularly within the MHC region. METHODS: We have conducted an SNP imputation study of the MHC region, considering tumor EBV status in 1,200 classical Hodgkin lymphoma (cHL) cases and 5,726 control subjects of European origin. Notable findings were genotyped in an independent study population of 468 cHL cases and 551 controls. RESULTS: We identified and subsequently replicated a novel association between a common genetic variant rs6457715 and cHL. Although strongly associated with EBV-positive cHL [OR, 2.33; 95% confidence interval (CI), 1.83-2.97; P = 7 × 10(-12)], there was little evidence for association between rs6457715 and the EBV-negative subgroup of cHL (OR, 1.06; 95% CI, 0.92-1.21), indicating that this association was specific to the EBV-positive subgroup (Phet < P = 10(-8)). Furthermore, the association was limited to EBV-positive cHL subgroups within mixed cell (MCHL) and nodular sclerosis subtypes (NSHL), suggesting that the association is independent of histologic subtype of cHL. CONCLUSIONS: rs6457715, located near the HLA-DPB1 gene, is associated with EBV-positive cHL and suggests this region as a novel susceptibility locus for cHL. IMPACT: This expands the number of genetic variants that are associated with cHL and provides additional evidence for a critical and specific role of EBV in the etiology of this disease.
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Cromossomos Humanos Par 6 , Infecções por Vírus Epstein-Barr/genética , Doença de Hodgkin/genética , Doença de Hodgkin/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Predisposição Genética para Doença , Doença de Hodgkin/epidemiologia , Doença de Hodgkin/patologia , Humanos , Complexo Principal de Histocompatibilidade/genética , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Polimorfismo de Nucleotídeo Único , Países Escandinavos e Nórdicos/epidemiologia , Adulto JovemRESUMO
Lymphoma is the most common haematopoietic malignancy in dogs, but little is known about the aetiology of this heterogeneous group of cancers. In humans, the Epstein-Barr virus (EBV) is associated with several lymphoma subtypes. Recently, it was suggested that EBV or an EBV-like virus is circulating in dogs. We therefore investigated whether EBV, or a novel herpesvirus, is associated with canine lymphoma using both serological and molecular techniques. In an assay designed to detect antibodies to EBV viral capsid antigens, 41 % of dogs were positive. Dogs with cancers, including lymphoma, were more frequently positive than controls, but no particular association with B-cell lymphoma was noted. EBV-specific RNA and DNA sequences were not detected in lymphoma tissue by in situ hybridization or PCR, and herpesvirus genomes were not detected using multiple degenerate PCR assays with the ability to detect novel herpesviruses. We therefore found no evidence that herpesviruses are directly involved in common types of canine lymphoma although cannot exclude the presence of an EBV-like virus in the canine population.
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Doenças do Cão/virologia , Gammaherpesvirinae/isolamento & purificação , Linfoma/veterinária , Animais , Anticorpos Antivirais/sangue , DNA Viral/isolamento & purificação , Cães , Gammaherpesvirinae/genética , Gammaherpesvirinae/imunologia , Hibridização In Situ , Linfoma/etiologia , Linfoma/virologia , Reação em Cadeia da Polimerase , RNA Viral/isolamento & purificação , Estudos SoroepidemiológicosRESUMO
HLA genotyping and genome wide association studies provide strong evidence for associations between Human Leukocyte Antigen (HLA) alleles and classical Hodgkin lymphoma (cHL). Analysis of these associations is complicated by the extensive linkage disequilibrium within the major histocompatibility region and recent data suggesting that associations with EBV-positive and EBV-negative cHL are largely distinct. To distinguish independent and therefore potentially causal associations from associations confounded by linkage disequilibrium, we applied a variable selection regression modeling procedure to directly typed HLA class I and II genes and selected SNPs from EBV-stratified patient subgroups. In final models, HLA-A*01:01 and B*37:01 were associated with an increased risk of EBV-positive cHL whereas DRB1*15:01 and DPB1*01:01 were associated with decreased risk. Effects were independent of a prior history of infectious mononucleosis. For EBV-negative cHL the class II SNP rs6903608 remained the strongest predictor of disease risk after adjusting for the effects of common HLA alleles. Associations with "all cHL" and differences by case EBV status reflected the subgroup analysis. In conclusion, this study extends previous findings by identifying novel HLA associations with EBV-stratified subgroups of cHL, highlighting those alleles likely to be biologically relevant and strengthening evidence implicating genetic variation associated with the SNP rs6903608.
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Infecções por Vírus Epstein-Barr/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Doença de Hodgkin/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Suscetibilidade a Doenças , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Cadeias HLA-DRB1/genética , Doença de Hodgkin/patologia , Doença de Hodgkin/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
A unique feature of both human herpesvirus 6A and B (HHV-6A and B) among human herpesviruses is their ability to integrate into chromosomal telomeres. In some individuals integrated viral genomes are present in the germ-line and result in the vertical transmission of HHV-6; however, little is known about the disease associations of germ-line transmitted, chromosomally integrated HHV-6 (ciHHV-6). Recent publications suggest that HHV-6 is associated with classical Hodgkin lymphoma (cHL). Here we examine the prevalence of ciHHV-6 in 936 cases of cHL and 563 controls by screening with a duplex TaqMan assay and confirming with droplet digital PCR. ciHHV-6 was detected in 10/563 (1.8%) controls and in all but one individual the virus was HHV-6B. Amongst cases 16/936 (1.7%) harboured ciHHV-6, thus demonstrating no association between ciHHV-6 and risk of cHL.
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Cromossomos Humanos/genética , Células Germinativas/virologia , Herpesvirus Humano 6/genética , Doença de Hodgkin/virologia , Infecções por Roseolovirus/genética , Integração Viral , Estudos de Casos e Controles , Cromossomos Humanos/virologia , DNA Viral/genética , Feminino , Herpesvirus Humano 6/fisiologia , Doença de Hodgkin/genética , Humanos , Masculino , Reação em Cadeia da Polimerase/métodos , TelômeroRESUMO
In addition to HLA, recent genome-wide association studies (GWASs) of Hodgkin's lymphoma (HL) have identified susceptibility loci for HL at 2p16.1, 8q24.21 and 10p14. In this study, we perform a GWAS meta-analysis with published GWAS (totalling 1,465 cases and 6,417 controls of European background), and follow-up the most significant association signals in 2,024 cases and 1,853 controls. A combined analysis identifies new HL susceptibility loci mapping to 3p24.1 (rs3806624; P=1.14 × 10(-12), odds ratio (OR)=1.26) and 6q23.3 (rs7745098; P=3.42 × 10(-9), OR=1.21). rs3806624 localizes 5' to the EOMES (eomesodermin) gene within a p53 response element affecting p53 binding. rs7745098 maps intergenic to HBS1L and MYB, a region previously associated with haematopoiesis. These findings provide further insight into the genetic and biological basis of inherited susceptibility to HL.