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Biomedical subjects

D A Bell

Publications and source records attributed to D A Bell.

At least 73 records · Page 4Linked to original sources
PubMed1998

Grade 1 peritoneal serous carcinomas: a report of 14 cases and comparison with 7 peritoneal serous psammocarcinomas and 19 peritoneal serous borderline tumors.

Low-grade peritoneal serous carcinomas have been the subject of limited study, and their distinction from peritoneal serous psammocarcinomas and serous borderline tumors is not always easy. The clinicopathologic features of 14 low-grade serous carcinomas, 7 psammocarcinomas, and 19 serous borderline tumors of peritoneal origin were compared. Average ages were 58 years (low-grade serous carcinomas), 48 years (borderline tumors), and 40 years (psammocarcinomas). Typical clinical presentations were abdominal pain, abdominal mass, or both, with the tumors incidental in 37% (borderline tumors), 43% (psammocarcinomas), and 36% (low-grade serous carcinoma). Operative and gross findings varied from nodules to adhesions to a dominant mass. Treatment was surgical debulking in most cases, with biopsy alone for eight borderline tumors. Seven patients with low-grade serous carcinoma were alive when last seen, but follow-up duration is short (average, 1.2 years): five were without disease, one had recurrent disease and one persistent disease. One patient with serous carcinoma died of disease at 3.5 years, and two patients died of other causes. Three patients with psammocarcinoma were alive without disease (average 3.3 years). Fourteen patients with borderline tumors were alive (average 3 years): 10 were without disease, 2 had persistent disease, and serous carcinoma developed in 2. The low-grade serous carcinomas resembled the invasive implants of ovarian serous borderline tumors. lacked high-grade nuclear atypia, showed tissue, lymphovascular space invasion, or both and had appreciable solid epithelial proliferation. Some serous carcinomas showed abundant psammomatous calcification suggesting psammocarcinoma but had too much epithelial proliferation for that diagnosis. The psammocarcinomas showed at least 75% psammoma bodies, no more than moderate cytological atypia, tissue or lymphovascular space invasion, or both, and rare epithelial proliferation less than 15 cells across. Adequate sampling was necessary to identify invasion, with highest yields of invasive foci in omental samples; individual foci in some cases of carcinoma resembled borderline tumor. The serous borderline tumors resembled the noninvasive implants of ovarian serous borderline tumors, lacked invasion, and did not show nuclear atypia of the degree seen in grade 2 or grade 3 serous carcinoma. Low-grade serous carcinoma, psammocarcinoma, and serous borderline tumors of peritoneal origin share some clinicopathologic features and may be underrecognized at surgery and gross examination. Because of overlapping microscopic patterns, adequate sampling is mandatory to identify small foci of invasion that exclude a borderline tumor and identify significant cellularity that excludes a psammocarcinoma. Conservative therapy is merited for younger women with borderline tumors. Maximum debulking is recommended for bulky symptomatic borderline tumors, low-grade serous carcinoma, and psammocarcinoma. Although short-term outcomes for the carcinomas appear favorable, follow-up is too limited to determine long-term outcomes.

Adult↗
PubMed1998

Primary stenting of the extracranial internal carotid artery in a patient with multiple cervical dissections: technical case report.

OBJECTIVE AND IMPORTANCE: Spontaneous dissection of the extracranial internal carotid artery (ICA) and vertebral artery (VA) is a well-documented cause of stroke in young, previously healthy patients. The majority of patients with spontaneous dissection are successfully treated with antiplatelet or anticoagulation therapy, but a significant proportion of patients progress to suffer devastating morbidity and mortality. Surgical intervention has primarily consisted of proximal ligation, extracranial-intracranial bypass, or endarterectomy. Generally, these procedures are technically demanding and yield disappointing clinical results. CLINICAL PRESENTATION/INTERVENTION: A 36-year-old man without a significant medical history initially presented with a several-day history of episodic right upper extremity weakness and numbness and visual obscurations. Cerebral angiography revealed bilateral ICA long segment narrowing (95%), distal left VA high-grade (95%) stenosis compatible with dissections, and right VA proximal occlusion. While therapeutically anticoagulated on heparin, the patient continued to experience crescendo episodes of right upper extremity paresis and paresthesias as well as aphasia. The patient underwent primary stenting of the left ICA, using a series of six overlapping stents (three Gianturco-Roubin coronary stents and three Palmaz-Schatz coronary stents). The patient remained symptom-free without neurological complications, and subsequent angiography performed at the 9-month follow-up examination confirmed continued patency of the stented left ICA as well as recanalization of the right ICA and VA. CONCLUSION: Neurovascular stents offer a minimally invasive and potentially efficacious treatment for the prevention of cerebral ischemia in patients with spontaneous extracranial dissection who remain symptomatic despite therapeutic anticoagulation.

Adult↗
PubMed1998

Identification and characterization of variant alleles of human acetyltransferase NAT1 with defective function using p-aminosalicylate as an in-vivo and in-vitro probe.

Although several variant alleles at the human NAT1 gene locus have been reported, their relationship to phenotypic variations in NAT1 function remains unclear. We have used in-vivo and invitro phenotyping tests, along with PCR-based cloning and heterologous expression, to investigate the extent of variation in NAT1 function and to characterize novel allelic variants at the NAT1 gene locus. The NAT1-selective substrate p-aminosalicylic acid (PAS) was used as a probe for NAT1 function. In-vivo PAS acetylation rates were estimated by determining the ratio of PAS to N-acetylated PAS (AcPAS) in urine and plasma following the oral ingestion of Nemasol Sodium. Excluding outliers, a 65-fold variation in the urinary AcPAS:PAS ratio was observed (n = 144), while a 5.6-fold variation in the plasma AcPAS:PAS ratio was seen in a subset (n = 19) of this sample. Urinary and plasma ratios correlated moderately (r = 0.74, p < 0.0005). One individual (case 244) had a marked impairment of PAS N-acetylation, with 10-fold lower urinary and plasma AcPAS:PAS ratios compared with other subjects. Biochemical investigations in whole blood lysates from case 244 suggested a NAT1 kinetic defect, with a 20-fold increased apparent K(m) for PAS and a 90-fold decreased Vmax for AcPAS formation. We subcloned, sequenced and expressed the protein-coding regions of the NAT1 alleles from case 244 and from seven other selected probands. Sequence analysis revealed the presence of two new variant alleles, designated as NAT1 x 14 and NAT1 x 15, in case 244, as well as one variant, NAT1 x 11, which has been observed in previous investigations. NAT1 x 14 contained a missense mutation (G560-->A) that is predicted to change a single amino acid (Arg187-->Gln), as well as two 3' non-coding region mutations (T1088-->A and C1095-->A) that have previously been observed in the NAT1 x 10 allelic variant. NAT1 x 15 had a single nonsense mutation (C559-->T; Arg187-->stop) and, thus, encodes a truncated protein. The activity of recombinant NAT1 14 mirrored the defective enzyme function in whole blood lysates from case 244, while NAT1 15 was completely inactive. Expressed NAT1 11, on the other hand, had identical activity to the wild type NAT1 4 allele, suggesting that the coding region mutations in this variant are functionally silent. The frequencies of NAT1 x 11, NAT1 x 14 and NAT1 x 15 were 0.021, 0.028 and 0.014 (n = 288 alleles), respectively, suggesting that they are relatively rare in our predominantly Caucasian sample.

Adolescent↗
PubMed1998

Relationship between ambient air pollution and DNA damage in Polish mothers and newborns.

Industrialized regions in Poland are characterized by high ambient pollution, including polycyclic aromatic hydrocarbons (PAHs) from coal burning for industry and home heating. In experimental bioassays, certain PAHs are transplacental carcinogens and developmental toxicants. Biologic markers can facilitate evaluation of effects of environmental PAHs on the developing infant. We measured the amount of PAHs bound to DNA (PAH-DNA adducts) in maternal and umbilical white blood cells. The cohort consisted of 70 mothers and newborns from Krakow, Poland, an industrialized city with elevated air pollution. Modulation of adduct levels by genotypes previously linked to risk of lung cancer, specifically glutathione S-transferase MI (GSTM1) and cytochrome P4501A1 (CYP1A1) Msp restriction fragment length polymorphism (RFLP), was also investigated. There was a dose-related increase in maternal and newborn adduct levels with ambient pollution at the women's place of residence among subjects who were not employed away from home (p < or = 0.05). Maternal smoking (active and passive) significantly increased maternal (p < or = 0.01) but not newborn adduct levels. Neither CYP1A1 Msp nor GSTM1 polymorphisms was associated with maternal adducts. However, adducts were significantly higher in newborns heterozygous or homozygous for the CYP1A1 Msp RFLP compared to newborns without the RFLP (p = 0.04). Results indicate that PAH-induced DNA damage in mothers and newborns is increased by ambient air pollution. In the fetus, this damage appears to be enhanced by the CYP1A1 Mspl polymorphism.

Adult↗
PubMed1998

Cigarette smoking, N-acetyltransferases 1 and 2, and breast cancer risk.

To examine the effects of smoking and N-acetylation genetics on breast cancer risk, we analyzed data from an ongoing, population-based, case-control study of invasive breast cancer in North Carolina. The study population consisted of 498 cases and 473 controls, with approximately equal numbers of African-American and white women, and women under the age of 50 and age 50 years or older. Among premenopausal women, there was no association between current smoking [odds ratio (OR), 0.9; 95% confidence interval (CI), 0.5-1.5] or past smoking (OR, 1.0; 95% CI, 0.6-1.6) and breast cancer risk. Among postmenopausal women, there was also no association with current smoking (OR, 1.2; 95% CI, 0.7-2.0); however, a small increase in risk was observed for past smoking (OR, 1.5; 95% CI, 1.0-2.4). For postmenopausal women who smoked in the past, ORs and 95% CIs were 3.4 (1.4-8.1) for smoking within the past 3 years, 3.0 (1.3-6.7) for smoking 4-9 years ago, and 0.6 (0.3-1.4) for smoking 10-19 years ago. Neither N-acetyltransferase 1 (NAT1) nor N-acetyltransferase 2 (NAT2) genotype alone was associated with increased breast cancer risk. There was little evidence for modification of smoking effects according to genotype, except among postmenopausal women. Among postmenopausal women, ORs for smoking within the past 3 years were greater for women with the NAT1*10 genotype (OR, 9.0; 95% CI, 1.9-41.8) than NAT1-non*10 (OR, 2.5; 95% CI, 0.9-7.2) and greater for NAT2-rapid genotype (OR, 7.4; 95% CI, 1.6-32.6) than NAT2-slow (OR, 2.8; 95% CI, 0.4-8.0). Future studies of NAT genotypes and breast cancer should investigate the effects of environmental tobacco smoke, diet, and other exposures.

Acetyltransferases↗
PubMed1998

The development of rheumatoid arthritis after recombinant hepatitis B vaccination.

OBJECTIVE: Hepatitis B vaccination has been associated with reactive arthritis and rarely rheumatoid arthritis (RA). We defined the clinical, serologic, and immunogenetic background of patients developing RA, soon after recombinant hepatitis B vaccination. METHODS: The clinical, serologic, and HLA antigens of a cluster of firefighters who developed arthritis after prophylactic recombinant hepatitis B vaccination (5 subjects), as well as a second group of sporadic cases of arthritis (6 patients) after hepatitis B vaccination are described. RESULTS: Ten of 11 patients fulfilled revised American College of Rheumatology criteria for RA. All cases had persistent arthritis for more than 6 months; at 48 months followup 2 cases no longer had inflammatory arthritis. Nine patients required disease modifying antirheumatic drugs. Five subjects were HLA-DR4 positive. HLA class II genes expressing the RA shared motif were identified in 9/11 patients genotyped for HLA-DRbeta1 and DQbeta1 alleles (0401, 0101, or 0404). All the firefighters shared the HLA-DRbeta1 allele 0301 and the DQbeta1 allele 0201, with which it is in linkage disequilibrium. CONCLUSION: These polymorphic residues in the binding site of the MHC class II molecules of the affected patients appear capable of binding some peptide sequences of the recombinant vaccine peptides they received and may be responsible for hepatitis B vaccine triggering development of RA in these cases. Recombinant hepatitis B vaccine may trigger the development of RA in MHC class II genetically susceptible individuals.

Adult↗
PubMed1998

Association between CYP17 polymorphisms and the development of breast cancer.

A nested case-control study was conducted to determine whether a genetic polymorphism in the CYP17 gene, which encodes for an enzyme that mediates steroid hormone metabolism, was associated with an increased risk of breast cancer. No association was found between the presence of an A2 allele and the subsequent development of breast cancer [A1/A2 odds ratio, 0.61 (95% confidence interval, 0.33-1.14); A2/A2 odds ratio, 0.89 (95% confidence interval, 0.41-1.95)]. No significant association was observed with risk factors presumed to be surrogates for endogenous estrogen exposure, nor was there an association observed with the stage of disease at diagnosis. Genotype frequencies in this Caucasian population were similar to those reported for African-American, Asian, and Latino women. Additional studies of larger size are needed to achieve a consensus regarding the relevance of CYP17 genotypes to the risk of developing breast cancer.

Breast Neoplasms↗
PubMed1997

An association between the allele coding for a low activity variant of catechol-O-methyltransferase and the risk for breast cancer.

Mounting evidence suggests that catechol metabolites of estradiol may contribute to the development of estrogen-induced cancers. O-Methylation, catalyzed by catechol-O-methyltransferase (COMT), inactivates catechol estrogens. COMT is polymorphic in the human population, with 25% of Caucasians being homozygous for a low activity allele of the enzyme (COMT(LL)). We hypothesized that low activity COMT may be a risk factor for human breast cancer and designed a PCR-based RFLP assay to determine COMT genotype in a cohort of 112 matched, nested case-control samples. In the total study population, the odds ratios for the association of breast cancer risk with COMT(HL) and COMT(LL) genotypes were 1.30 [confidence interval (CI), 0.66-2.58] and 1.45 (CI, 0.69-3.07), respectively. Postmenopausal COMT(LL) women had a greater than 2-fold increased risk of developing breast cancer [odds ratio (OR), 2.18; CI, 0.93-5.11]. The association of COMT(LL) with the development of postmenopausal breast cancer was stronger and statistically significant in those women with a body mass index >24.47 kg/m2 (OR, 3.58; CI, 1.07-11.98). When COMT(LL) was combined with either glutathione S-transferase (GST) M1 null or with GSTP1 Ile-105-Val/Val-105-Val (intermediate/low activity, respectively) genotypes, the risk for developing postmenopausal breast cancer was also significantly increased. Our findings suggest that the allele encoding low activity COMT may be an important contributor to the postmenopausal development of breast cancer in certain women.

Aged↗
PubMed1997

Pilot study of free and conjugated urinary mutagenicity during consumption of pan-fried meats: possible modulation by cruciferous vegetables, glutathione S-transferase-M1, and N-acetyltransferase-2.

Epidemiological and experimental evidence indicates that consumption of fried meats in conjunction with certain genotypes of phase I and II metabolism genes poses an elevated risk for colorectal cancer. Parallel to this, the consumption of cruciferous vegetables is associated with a reduced risk of colon cancer. Therefore, we designed a 6-week pilot feeding study to evaluate the effect of these variables on urinary mutagenicity, which is a biomarker associated with fried-meat consumption. Eight subjects were fed fried meats daily for six weeks; four ate cruciferous vegetables, and four ate non-cruciferous vegetables. Urinary mutagenicity was evaluated in the presence of S9 in strain YG1024 of Salmonella, which is a frameshift strain that overproduces acetyltransferase. C18/methanol extracts of 24-h urines collected once each week were tested unhydrolyzed (free mutagenicity) and hydrolyzed (total mutagenicity); the difference between the two was the conjugated mutagenicity. Although not significant, the levels of conjugated urinary mutagenicity doubled among crucifera consumers and decreased to 30% of the initial levels among non-crucifera consumers, suggesting the possibility that crucifera may enhance the level of conjugated urinary mutagenicity resulting from consumption of fried meats. Such an effect would be consistent with the documented ability of cruciferous vegetables to induce phase II enzymes. The NAT2 rapid phenotype was significantly associated with approximately 2-fold increases in conjugated (p = 0.05) and total (p = 0.004) urinary mutagenicity relative to NAT2 slow subjects, consistent with the elevated risk confirmed by the NAT2 rapid phenotype for colorectal cancer among meat consumers. An approximately 2-fold increase in urinary mutagenicity among the GSTM1- subjects relative to the GSTM1+ subjects approached significance for free (p = 0.18) and total (p = 0.13) urinary mutagenicity. This is the first report on (a) the mutagenicity of hydrolyzed urine, which was consistently more mutagenic than unhydrolyzed urine; (b) the potential enhancement of conjugated urinary mutagenicity by crucifera; and (c) the association of the rapid NAT2 and possibly the GSTM1- phenotype with elevated levels of fried meat-associated urinary mutagenicity.

Aged↗
PubMed1997

Identification of a 1300 kilobase deletion unit on chromosome 7q31.3 in invasive epithelial ovarian carcinomas.

We have used polymerase chain reaction (PCR) amplification of tandem repeats to study the pattern of allelic loss on chromosome 7q31 in invasive epithelial ovarian carcinomas and borderline ovarian tumors. Using 13 primer sets spanning loci from 7q31 to 7q32, 16 borderline and 54 invasive ovarian tumor tissue, together with their corresponding normal tissue, were analysed. Invasive epithelial ovarian tumors demonstrated loss of heterozygosity (LOH) at one or more loci on 7q in 32 of 54 cases (59%). The invasive epithelial ovarian tumors demonstrated the highest percentage of LOH at the loci D7S643 (20 of 40 informative cases, 50%) and GATA44F09 (18 of 42 informative cases, 43%). In contrary, only one borderline ovarian tumor showed LOH at one locus (GATA44F09, one of 14 informative cases, 7%). Our results display a sharp contrast in the pattern of LOH between invasive and borderline ovarian tumors suggesting that allelic loss at chromosome 7q31.3 may be involved in the development and progression of invasive epithelial ovarian tumors but not borderline ovarian tumors. Further analysis of the deletion map for the invasive epithelial ovarian tumors showed two regions likely to harbor ovarian tumor suppressor genes including a novel 1300 kilobase common loss region flanked by GATA44F09 and D7S643.

Alleles↗
PubMed1997

Genetic polymorphisms in human drug metabolic enzymes.

Results obtained from both epidemiologic studies and experimental animal model systems have shown a wide range of phenotypic variation in the ability of individuals to metabolize drugs and environmental chemicals. Several studies have noted correlations between specific metabolic phenotypes and the incidence of disease, suggesting that certain allelic forms of drug metabolic enzymes can render the individual either more sensitive or resistant to the toxic or therapeutic effects of exogenous drugs and chemicals. While some of this variation can be attributed to different environmental exposures, it has become clear that genetic factors also play an important role in determining the response of the individual organism to exogenous agents. Recent advances in molecular biological techniques have begun to allow scientists to correlate observed phenotypic differences with the actual differences in genetic sequence at the gene level. This has allowed a correlation between gene structure and function, thus providing a mechanistic basis to explain the interaction between genetic background and individual response to environmental exposures. Results presented at this symposium discussed how genetic polymorphisms for both Phase I and Phase II metabolic enzymes in the human population modulate the response to environmental toxicants.

Humans↗
PubMed1997

Contribution of genetic and nutritional factors to DNA damage in heavy smokers.

Prior epidemiological evidence suggests that genes controlling the metabolism of carcinogens and antioxidant/nutritional status are associated with lung cancer risk, possibly through their ability to modulate DNA damage by carcinogens. We performed a cross-sectional analysis of 159 heavy smokers from a cohort of subjects enrolled in a smoking cessation program. A total of 159 blood samples were analyzed to determine the relative contributions of genetic polymorphisms [CYP1A1 MspI and exon 7 and glutathione S-transferase M1 (GSTM1)] and plasma micronutrients to polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adduct levels. DNA damage in smokers was affected by genetic polymorphisms and nutritional status. Smokers with the CYP1A1 exon 7 valine polymorphism had significantly higher (2-fold, P < or = 0.03) levels of DNA damage than those without. In parallel models, PAH-DNA adducts were inversely associated with plasma levels of retinol (beta = -0.93, P = 0.01), beta-carotene (beta = -0.18, P = 0.09), and alpha-tocopherol (beta = -0.28, P = 0.21) in 159 subjects. The association between smoking-adjusted plasma beta-carotene levels and DNA damage was only significant in those subjects lacking the GSTM1 detoxification gene (beta = -0.30, P = 0.05, n = 75). There was a statistical interaction between beta-carotene and alpha-tocopherol; when beta-carotene was low, alpha-tocopherol had a significant protective effect (beta = -0.78, P = 0.04) on adducts, but not when beta-carotene was high (beta = -0.16, P = 0.57). Plasma alpha-tocopherol was significantly correlated with beta-carotene (r = 0.36, P = 0.0005) and less strongly with retinol (r = 0.20, P = 0.0005). These results suggest that several micronutrients may act in concert to protect against DNA damage and highlight the importance of assessing overall antioxidant status. In conclusion, a subset of smokers may be at increased risk of DNA damage and possibly lung cancer due to the combined effect of low plasma micronutrients and genetic susceptibility factors. The use of biological markers to assess efficacy of interventions and to study mechanisms of micronutrients is timely given the current debate regarding the use of chemopreventive agents in high risk populations.

Adult↗
PubMed1997

Production of human normal adult and fetal hemoglobins in Escherichia coli.

A hemoglobin expression system in Escherichia coli is described. In order to produce authentic human hemoglobin, we need to co-express both methionine aminopeptidase and globin genes under the control of a strong promoter. We have constructed three plasmids, pHE2, pHE4 and pHE7, for the expression of human normal adult hemoglobin and a plasmid, pHE9, for the expression of human fetal hemoglobin, in high yields. The globin genes can be derived from either synthetic genes or human globin cDNAs. The extra amino-terminal methionine residues of the expressed globins can be removed by the co-expressed methionine aminopeptidase. The heme is inserted correctly into the expressed alpha-globin from our expression plasmids. A fraction (approximately 25%) of the heme is not inserted correctly into the expressed beta- or gamma-globin. However, the incorrectly inserted hemes can be converted into the correct conformation by carrying out a simple oxidation-reduction process on the purified hemoglobin molecule. We have investigated the functional properties of the expressed hemoglobins by measuring their oxygen-binding properties and their structural features by obtaining their 1H-NMR spectra. Our results show that authentic human normal adult and fetal hemoglobins can be produced from our expression plasmids in E. coli and in high yields. Our expression system allows us to design and to produce any recombinant hemoglobins needed for our research on the structure-function relationship in hemoglobin.

Adult↗
PubMed1997

Transitional cell metaplasia of the uterine cervix and vagina: an underrecognized lesion that may be confused with high-grade dysplasia. A report of 59 cases.

Sixty-three examples of transitional cell metaplasia of the cervix or vagina from patients 50 to 84 (average 67.6) years of age are described. Fifty-seven of the 59 patients were postmenopausal and two perimenopausal. Only four patients were documented to have received hormonal therapy. The lesion was an incidental microscopic finding in all patients and was found in 29 hysterectomy specimens, 18 endocervical or endometrial curettage specimens, 11 cervical biopsy or cone biopsy specimens, and five vaginal biopsy specimens. The sites involved by transitional cell metaplasia were the exocervix (n = 14), transformation zone (n = 33), vagina (n = 10), or a combination (n = 4). The cervical and vaginal specimens most commonly showed involvement of the surface epithelium by transitional cell metaplasia. Other transitional cell patterns were isolated stromal nests (n = 9) and invagination of surface epithelium into the underlying stroma (n = 2). The typical appearance of transitional cell metaplasia was a hyperplastic epithelium with lack of maturation, consisting of spindled nuclei with tapered ends and frequent longitudinal nuclear grooves. The nuclei were typically oriented vertically in the deeper layers, and horizontally with a streaming pattern superficially. The cells had low nuclear to cytoplasmic ratios, perinuclear halos, and absent to rare mitotic figures. Mild to moderate atypia was seen in only two cases. Many of the cases could have been confused with squamous dysplasia due to the lack of apparent maturation. However, in most cases, attention to cytologic detail disclosed the typical features of transitional cell metaplasia. This process, usually seen in older women, has not been emphasized and can be overdiagnosed as dysplasia, leading to unnecessary treatment.

Aged↗
PubMed1997

V region gene analysis of human IgM hybridoma monoclonal anti-Sm antibodies.

Anti-Sm antibodies although highly specific for systemic lupus erythematosus can only be found in 10-25% of lupus patients and lupus-prone MRL/lpr mice. Molecular studies of these autoantibodies from mice have suggested that the anti-Sm response is Ag driven, its expression is controlled by stochastic events and may originate from the same B cell precursors as anti-DNA antibodies. However, relatively little information regarding the molecular characteristics of anti-Sm antibodies in man has been reported. We studied the V region genes of three IgM hybridoma monoclonal antibodies (BUD 45.12.8, BUD 114.4.11 and BUD 94.91.8) which were selected for Sm reactivity and derived from B cells of a healthy child. Two of these antibodies BUD 45.12.8 and BUD 114.4.11 also-reacted with ssDNA, while the third (BUD 94.91.8) did not. Each of these anti-Sm/ RNP antibodies was encoded by different and predominantly unmutated Ig heavy chain germline genes (BUD 45.12.8 by VH3-23, DXP4 and JH4b; BUD 94.91.8 by VH3-33, D21-9 and JH6b; BUD 114.4.11 by VH1-2, DK1 or DM1 or unknown D and JH4b) and light chain genes (BUD 45.12.8 by Humkv325 and JK2; BUD 94.91.8 by hsiggll150 (lambda IIIb) and J lambda 2/3; BUD 114.4.11 by Humk18 and JK3). Many of these genes are also used by antibodies with other specificities including DNA. The two anti-Sm antibodies which also bound ssDNA shared an overall V region net positive charge, while the third antibody without ssDNA reactivity carried a negative V region net charge. These findings demonstrate that (1) normal individuals have the genetic potential to generate autoantibodies to Sm/RNP; (2) acquisition of Sm/RNP binding is not dependent on somatic mutations and (3) some human B cell clones exhibit specificity for Sm and ssDNA.

Amino Acid Sequence↗