RESUMO
Trichloroethylene (TCE) has been associated with a variety of immunotoxic effects and may be associated with an increased risk of non-Hodgkin lymphoma (NHL). Altered serum immunoglobulin (Ig) levels have been reported in NHL patients and in animals exposed to TCE. Recently, we reported that occupational exposure to TCE is associated with immunosuppressive effects and immune dysfunction, including suppression of B-cell counts and activation, even at relatively low levels. We hypothesized that TCE exposure would also affect Ig levels in humans. We measured serum levels of IgG, IgM and IgE, by enzyme-linked immunosorbent assay, in TCE-exposed workers (n = 80) and unexposed controls (n = 45), matched by age and gender, in a cross-sectional, molecular epidemiology study of occupational exposure to TCE in Guangdong, China. Exposed workers had about a 17.5% decline in serum levels of IgG compared with unexposed controls (P = 0.0002). Similarly, serum levels of IgM were reduced by about 38% in workers exposed to TCE compared with unexposed controls (P < 0.0001). Serum levels of both IgG and IgM were significantly decreased in workers exposed to TCE levels below 12 p.p.m., the median exposure level. Adjustment for B-cell counts had minimal impact on our findings. IgE levels were not significantly different between exposed and control subjects. These results provide further evidence that TCE is immunotoxic at relatively low exposure levels and provide additional biologic plausibility for the reported association of TCE with NHL.
Assuntos
Imunoglobulina E/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Exposição Ocupacional/efeitos adversos , Tricloroetileno/toxicidade , Adulto , Linfócitos B/efeitos dos fármacos , China/epidemiologia , Feminino , Humanos , Contagem de Linfócitos , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/epidemiologia , Linfoma não Hodgkin/imunologia , Masculino , Epidemiologia MolecularRESUMO
In a recent genome-wide association study of follicular lymphoma (FL), we identified novel risk alleles on chromosome 6p21.33 that appeared to be part of an extended haplotype including HLA-DRB1*0101, DQA1*0101, and DQB1*0501. To follow up on these findings, we obtained 2-4 digit HLA-DQB1 allelotypes on a subset of 265 cases of FL and 757 controls using a novel assay that applies multiplexed ligation-dependent probe amplification (MLPA). We confirmed a positive association between FL and the HLA-DQB1*05 allele group (ORâ=â1.70, 95% CI 1.28-2.27; adjusted p-valueâ=â0.013) and also identified an allele group inversely associated with FL risk, HLA-DQB1*06 (ORâ=â0.51, 95% CI 0.38-0.69; adjusted p-valueâ=â4.46â×â10(-5)). Although these findings require verification, the role of HLA class II proteins in B-cell survival and proliferation makes this a biologically plausible association.
Assuntos
Cromossomos Humanos Par 6/genética , Antígenos HLA-DR/genética , Linfoma Folicular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Feminino , Cadeias HLA-DRB1 , Humanos , Linfoma Folicular/epidemiologia , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , São Francisco/epidemiologia , Taxa de Sobrevida , Adulto JovemRESUMO
We conducted genome-wide association studies of non-Hodgkin lymphoma using Illumina HumanHap550 BeadChips to identify subtype-specific associations in follicular, diffuse large B-cell and chronic lymphocytic leukemia/small lymphocytic lymphomas. We found that rs6457327 on 6p21.33 was associated with susceptibility to follicular lymphoma (FL; N = 189 cases, 592 controls) with validation in another 456 FL cases and 2,785 controls (combined allelic P = 4.7 x 10(-11)). The region of strongest association overlapped C6orf15 (STG), located near psoriasis susceptibility region 1 (PSORS1).
Assuntos
Cromossomos Humanos Par 6/genética , Predisposição Genética para Doença , Variação Genética , Linfoma Folicular/genética , Humanos , Linfoma Difuso de Grandes Células B/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
As benzene has been linked with elevated risk of both acute myeloid leukemia and lymphoma, we explored the effect of benzene exposure on levels of t(8;21), t(15;17), and t(14;18) translocations. Circulating lymphocytes of normal individuals also often contain t(14;18). Quantitative polymerase chain reaction analysis showed that 37 workers with benzene exposure had a decreased level of t(14;18) in their blood with only 16.2% having 10 or more copies of the t(14;18) BCL-2/IgH fusion gene/microg DNA, as opposed to 55% of 20 controls (P = .0063 by Fisher's exact test). This decline may be related to the immunotoxicity to specific subtypes of circulating B-lymphocytes, but the data do not support the use of t(14;18) as a biomarker of increased lymphoma risk in benzene-exposed populations. None of 88 individuals (31 controls and 57 exposed) exhibited detectable t(8;21) transcripts, and while t(15;17) transcripts were detected in two individuals, the result is inconclusive as one was exposed and the other was unexposed.
Assuntos
Benzeno/toxicidade , Carcinógenos/toxicidade , Cromossomos Humanos/genética , Linfoma/induzido quimicamente , Linfoma/genética , Exposição Ocupacional , Translocação Genética/efeitos dos fármacos , Adulto , Estudos de Casos e Controles , Feminino , Genes bcl-2/genética , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Masculino , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
CD40 and its ligand, CD154, are major costimulatory molecules whose interactions are important in humoral and cellular immunity. We hypothesized that single nucleotide polymorphisms (SNPs) in TNFRSF5 and TNFSF5 encoding the CD40 and CD154 proteins, respectively, influence lymphoma risk, particularly a functional TNFRSF5 SNP (-1C>T, rs1883832) associated with reduced B-cell CD40 expression. TNFRSF5 and TNFSF5 SNPs were examined in a population-based case-control study of non-Hodgkin lymphoma (376 cases/801 controls with DNA), and compelling findings were followed up in 2 independent populations. Pooled analyses of all 3 case-control studies (total N = 1776 non-Hodgkin lymphoma cases, N = 2482 controls) revealed an increased risk of follicular lymphoma (FL) associated with the TNFRSF5 -1TT genotype (odds ratio = 1.6; 95% confidence interval, 1.1-2.4). In addition, among women, an inverse association was found between the variant A allele for a TNFSF5 6809G>A SNP and FL risk (OR = .61; 95% CI, 0.36-0.98). In genotype-phenotype studies, significantly reduced circulating soluble CD40 was observed in TNFRSF5 -1TT compared with -1CC carriers. Further, dendritic cells from those with -1TT versus -1CC genotypes exhibited lower CD40 cell surface expression. These results suggest that the TNFRSF5 -1C>T polymorphism may increase FL susceptibility through mechanisms that hinder cellular immune responses. Further studies are needed to explore these findings.
Assuntos
Antígenos CD40/genética , Predisposição Genética para Doença , Linfoma Folicular/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Antígenos CD40/sangue , Ligante de CD40/genética , Intervalos de Confiança , Citosina , Células Dendríticas/efeitos dos fármacos , Humanos , Lipopolissacarídeos/farmacologia , Pessoa de Meia-Idade , Razão de Chances , Solubilidade , TiminaRESUMO
The V(D)J recombinase catalyzes DNA transposition and translocation both in vitro and in vivo. Because lymphoid malignancies contain chromosomal translocations involving antigen receptor and protooncogene loci, it is critical to understand the types of "mistakes" made by the recombinase. Using a newly devised assay, we characterized 48 unique TCRbeta recombination signal sequence (RSS) end insertions in murine thymocyte and splenocyte genomic DNA samples. Nearly half of these events targeted "cryptic" RSS-like elements. In no instance did we detect target-site duplications, which is a hallmark of recombinase-mediated transposition in vitro. Rather, these insertions were most likely caused by either V(D)J recombination between a bona fide RSS and a cryptic RSS or the insertion of signal circles into chromosomal loci via a V(D)J recombination-like mechanism. Although wild-type, p53, p53 x scid, H2Ax, and ATM mutant thymocytes all showed similar levels of RSS end insertions, core-RAG2 mutant thymocytes showed a sevenfold greater frequency of such events. Thus, the noncore domain of RAG2 serves to limit the extent to which the integrity of the genome is threatened by mistargeting of V(D)J recombination.
Assuntos
Diferenciação Celular/imunologia , Cromossomos de Mamíferos/genética , Recombinação Genética/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Sequência de Bases , Linhagem Celular , DNA/genética , Camundongos , Camundongos Knockout , Mutação/genética , Timo/metabolismoRESUMO
Genetic susceptibility studies of lymphoma may serve to identify at risk populations and clarify important disease mechanisms. This review considered all studies published through October 2006 on the contribution of genetic polymorphisms in the risk of lymphoma. Numerous studies implicate the role of genetic variants that promote B-cell survival and growth with increased risk of lymphoma. Several reports including a large pooled study by InterLymph, an international consortium of non-Hodgkin lymphoma (NHL) case-control studies, found positive associations between variant alleles in TNF -308G>A and IL10 -3575T>A genes and risk of diffuse large B-cell lymphoma. Four studies reported positive associations between a GSTT1 deletion and risk of Hodgkin and non-Hodgkin lymphoma. Genetic studies of folate-metabolizing genes implicate folate in NHL risk, but further studies that include folate and alcohol intakes are needed. Links between NHL and genes involved in energy regulation and hormone production and metabolism may provide insights into novel mechanisms implicating neuro- and endocrine-immune cross-talk with lymphomagenesis. However, this links will need replication in larger populations. Numerous studies suggest that common genetic variants with low penetrance influence lymphoma risk, though replication studies will be needed to eliminate false positive associations.
Assuntos
Predisposição Genética para Doença , Linfoma/genética , Humanos , Penetrância , Polimorfismo GenéticoRESUMO
Introduction of a double-strand DNA break at the junction between a rearranging gene segment and its flanking recombination signal sequence (RSS) is the first step of V(D)J recombination. Such DNA breaks can be detected by either Southern blot hybridization or ligation-mediated PCR. While Southern blotting is easily quantifiable, it is often insufficiently sensitive and while LM-PCR is far more sensitive, it is poorly quantifiable. Reported here is a LM-qPCR assay which relies on real-time qPCR to provide an absolute measure of recombinase-mediated, or any other specific, double-strand DNA break in genomic DNA. The efficiency of the initial ligation reaction was found to be relatively low with just 3% of potential targets undergoing linker ligation. Using this assay, approximately 16% of murine bone marrow pre-B cells were determined to contain a dsDNA break adjacent to the Jkappa1 gene segment. In addition, the kinetics of Jkappa1 dsDNA breaks in a temperature-sensitive cell line induced to recombine its kappa locus was determined.
Assuntos
Linfócitos B/imunologia , Rearranjo Gênico de Cadeia Leve de Linfócito B , Região de Junção de Imunoglobulinas/genética , Cadeias kappa de Imunoglobulina/genética , Reação em Cadeia da Polimerase/métodos , Animais , Linfócitos B/química , Células da Medula Óssea/química , Células da Medula Óssea/imunologia , DNA/análise , DNA/genética , Dano ao DNA , Proteínas de Ligação a DNA/genética , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina , Região de Junção de Imunoglobulinas/imunologia , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/imunologia , Camundongos , Proteínas Nucleares/genética , Recombinação Genética/genética , VDJ Recombinases/fisiologiaRESUMO
Epidemiological studies suggest that populations consuming typical Asian diets have a lower incidence of hormone-dependent cancers than populations consuming Western diets. These dietary differences have been mainly attributed to higher soy intakes among Asians. However, studies from our laboratory suggest that the anti-estrogenic effects of dietary kelp also may contribute to these reduced cancer rates. As a follow-up to previous findings of endocrine modulation related to kelp ingestion in a pilot study of premenopausal women, we investigated the endocrine modulating effects of kelp (Fucus vesiculosus) in female rats and human luteinized granulosa cells (hLGC). Kelp administration lengthened the rat estrous cycle from 4.3 +/- 0.96 to 5.4 +/- 1.7 d at 175 mg . kg(-1) body wt . d(-1) (P = 0.05) and to 5.9 +/- 1.9 d at 350 mg . kg(-1) . d(-1) (P = 0.002) and also led to a 100% increase in the length of diestrus (P = 0.02). Following 175 mg . kg(-1) . d(-1) treatment for 2 wk, serum 17beta-estradiol levels were reduced from 48.9 +/- 4.5 to 40.2 +/- 3.2 ng/L (P = 0.13). After 4 wk, 17beta-estradiol levels were reduced to 36.7 +/- 2.2 ng/L (P = 0.02). In hLGC, 25, 50, and 75 micromol/L treatment reduced 17beta-estradiol levels from 4732 +/- 591 to 3632 +/- 758, 3313 +/- 373, and 3060 +/- 538 ng/L, respectively. Kelp treatment also led to modest elevations in hLGC culture progesterone levels. Kelp extract inhibited the binding of estradiol to estrogen receptor alpha and beta and that of progesterone to the progesterone receptor, with IC(50) values of 42.4, 31.8, and 40.7 micromol/L, respectively. These data show endocrine modulating effects of kelp at relevant doses and suggest that dietary kelp may contribute to the lower incidence of hormone-dependent cancers among the Japanese.
Assuntos
Suplementos Nutricionais , Estradiol/sangue , Estro/fisiologia , Células da Granulosa/fisiologia , Kelp , Progesterona/sangue , Animais , Células Cultivadas , Feminino , Células da Granulosa/metabolismo , Humanos , Ratos , Ratos Sprague-DawleyRESUMO
TAL1 disruption at 1p32 [del(1p)] is a common rearrangement in the development of T-cell acute lymphocytic leukemia (T-ALL). The del(1p) are usually interstitial 90kb deletions placing TAL1 under control of the SCL interrupting locus (SIL) gene forming the SIL-TAL1 fusion product. A reverse transcriptase real-time PCR assay to quantify SIL-TAL1 fusion genes is described. A SIL-TAL1 fusion gene RNA transcript was built that permitted absolute standard curves to be generated. Sensitivity of the RT-PCR assay was determined to be 10 cells (CEM cell line) in 10(6) human lymphocytes. Peripheral blood lymphocytes from 10 healthy adults and 10 neonates were assayed. None of the samples showed any SIL-TAL1 expression. However, when lymphocytes from three adults were cultured in vitro the SIL-TAL1 transcript was detectable in the RNA isolates. No RAG2 expression was detected in these expanded samples, suggesting that the clones bearing the SIL-TAL1 fusion gene may have existed at low levels prior to the ex vivo expansion.