Search PubMed⌕ Search

Biomedical subjects

C Ober

Publications and source records attributed to C Ober.

At least 73 records · Page 4Linked to original sources
PubMed1997

Thyrotropin-receptor and thyroid peroxidase-specific T cell clones and their cytokine profile in autoimmune thyroid disease.

We studied the cytokine profile and the immune responses to thyroid antigens of specific T cell clones (TCC) isolated from patients with Hashimoto's thyroiditis (HT) and Graves' disease (GD). Antigen-specific TCC were reactive to thyroid peroxidase (TPO), thyroglobulin (Tg) or human recombinant TSH-receptor extracellular domain (TSH-R), and/or their respective peptides. Of the 43 clones derived from HT patients, 65% were reactive to TPO, and 59% of the 32 clones derived from GD patients were reactive to TSH-R. TPO epitopes 100-119 and 625-644 were recognized by 75% of HT-derived clones, whereas TSH-R epitopes 158-176, 207-222, and 343-362/357-376 were recognized by 85% of GD-derived TCC. The TCC were classified according to their cytokine profile into T helper cell (Th)0 [secreting interleukin (IL)-4, IL-5, interferon (IFN)-gamma], Th1 (secreting IFN-gamma) and Th2 (secreting IL-4 and/or IL-5). Tumor necrosis factor-beta and IL-10 were produced by all subsets. The specific TCC were predominantly Th1-like cells in HT, and were Th0- and Th1-like cells in GD. Fifty three percent of Th0 clones were derived from GD patients and were reactive to TSH-R, whereas 50% of Th1 clones were derived from HT patients and were reactive to TPO or Tg. Most Th2 clones (82%) were reactive to TPO and were established from peripheral blood. All these clones produced IL-5, and 64% produced IL-4 and IL-10. Interestingly, IFN-gamma was highly produced by TPO- or Tg-specific clones established from HT thyroid tissue. These results confirm at the clonal level our previous studies regarding T cell epitopes on TPO and TSH-R molecules and support the concept that immunodominant T cell epitopes are located on amino acid residues 100-119 and 625-644 of TPO in HT and amino acid residues 158-176, 207-222 and 343-362/357-376 of TSH-R in GD. Our studies also demonstrate that thyroid-specific T cells can be classified into Th0, Th1, and Th2 subsets. TPO- or Tg-specific clones with Th1 phenotype appear to be involved in the pathogenesis of HT, mediating thyroid tissue destruction, whereas TSH-R clones with Th0 phenotype may induce thyroid-stimulating autoantibodies in GD.

Autoantigens↗
PubMed1996

Population genetic studies of HLA-G: allele frequencies and linkage disequilibrium with HLA-A1.

HLA-G is a class I gene that is expressed in the extravillous cytotrophoblast. Although the function of this gene is still unknown, its expression at the maternal-fetal interface suggests that HLA-G may play a key role in the induction of tolerance during pregnancy. Preliminary to our studies of the effects of HLA-G polymorphisms on pregnancy outcome, we have defined HLA-G alleles in the Hutterites. We report here the presence of nine HLA-G alleles that differ with respect to nucleotide sequences, including four groups of alleles that differ with respect to amino acid sequences, and striking linkage disequilibrium between HLA-G and HLA-A alleles. The levels and sites of polymorphism in HLA-G suggest that this gene had a unique evolutionary history and may perform nonclassical functions at the maternal-fetal interface.

Adult↗
PubMed1996

Cystic fibrosis mutation screening in healthy men with reduced sperm quality.

The majority of men with cystic fibrosis (CF) are infertile due to a bilateral congenital absence of the vas deferens (CBAVD). However, clinically affected CF patients present a spectrum of genital phenotypes ranging from normal fertility to severely impaired spermatogenesis and CBAVD. Recently, it has become apparent that CF can manifest itself as isolated CBAVD in the absence of other clinical symptoms. The present study was undertaken to test the possible involvement of the CF gene in the aetiology of male infertility other than CBAVD. Semen specimens from 127 unrelated healthy males with various diagnoses of reduced sperm quality were screened for a panel of 13 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Fourteen of 80 (17.5%) healthy men with infertility due to reduced sperm quality and 3 of 21 (14.3%) men with azoospermia had at least one CF mutation (one azoospermic male was a compound heterozygote). The frequency of mutations in our sample of infertile males was significantly higher than the expected CF carrier frequency in the local population (P = 0.00139). No mutations were found in a control group of 26 individuals with normal semen parameters. This increased frequency of CF mutations in healthy men with reduced sperm quality and in men with azoospermia without CBAVD suggests that the CFTR protein may be involved in the process of spermatogenesis or sperm maturation apart from playing a critical role in the development of the epididymal glands and the vas deferens.

Case-Control Studies↗
PubMed1995

Extended HLA profile of an inbred isolate: the Schmiedeleut Hutterites of South Dakota.

HLA-A, -B, -C, -DR, and -DQ typings of the Schmiedeleut Hutterites of South Dakota were collected as part of an ongoing genetic-epidemiologic study of HLA and fertility. A total of 1,082 individuals, including 852 married adults representative of the reproductive population of this isolate, were characterized for five-locus HLA haplotypes. HLA-A1, A2, A3, and A24 accounted for 75% of observed HLA-A alleles and HLA-B27, B35, B51, and B62 accounted for 55% of observed HLA-B alleles. S-leut Hutterites are derived from 68 or fewer ancestors. However, only 48 ancestral HLA haplotypes were observed and nine of these accounted for over 52% of the observed haplotypes. Measures of two-locus linkage disequilibrium derived from these haplotypes indicated that one-third to half of the observed HLA-A/B, B/DR, and A/DR allele combinations exhibited highly statistically significant linkage disequilibrium. Allele and haplotype frequencies did not differ between males and females. Recombination rates of 0.004% and 0.005% between HLA-A and -C and between HLA-B and -DR, respectively, were observed. This HLA profile points out a paucity of HLA alleles and haplotypes in this population and marked linkage disequilibrium among the HLA alleles that are present.

Alleles↗
PubMed1995

Current topic: HLA and reproduction: lessons from studies in the Hutterites.

The paradoxical observation that maternal-fetal incompatibility with respect to human leucocyte antigen (HLA) genes was not associated with spontaneous abortion, stillbirths or developmental abnormalities led to the hypothesis that fetuses with paternally-derived HLA that differ from maternal HLA may enjoy a selective advantage during pregnancy. If true, then couples who share HLA should experience poorer reproductive outcome than couples not sharing HLA. Numerous, retrospective studies of parental HLA sharing and fetal wastage in humans have yielded conflicting results and discrepancies are difficult to reconcile because of methodological differences among studies and potential heterogeneity among subjects. To explore the hypothesis that maternal-fetal HLA compatibility is deleterious in human pregnancy, we initiated prospective and population-based studies in the Hutterites, a religious isolate that lives communally and proscribes contraception. Our data suggest that HLA-DR-linked genes may affect fertilization or implantation and HLA-B-linked genes may contribute toward recognized fetal loss. Discrepant results among retrospective studies of outbred couples may be due to the fact that more than one HLA region influences reproductive outcome and that the genes influencing fertility may not be HLA genes per se, but loci in linkage disequilibrium with HLA-B and HLA-DR.

Abortion, Spontaneous↗
PubMed1995

HLA-DQA1 and HLA-DQB1 haplotypes in aborted fetuses and couples with recurrent spontaneous abortion.

HLA haplotypes may be associated with spontaneous abortion through a variety of mechanisms, including maternal hyporesponsiveness to fetal alloantigens, maternal autoimmunity, and HLA-linked t-locus homologues. HLA-DQA1 and HLA-DQB1 haplotypes were determined in 37 couples with a history of recurrent spontaneous abortion (RSAB), 40 of their abortuses, and 20 fertile control couples. The distribution of haplotype frequencies did not differ between control subjects and RSAB wives, RSAB husbands, or abortuses. The frequency of the HLA-DR5-linked haplotype, DQA1*501/DQB1*301, which was considered a marker for immune hyporesponsiveness, did not differ between RSAB wives and control subjects (P = 0.353). The frequency of the autoimmune-associated HLA-DR3-linked haplotype, DQA1*0501/DQB1*0201, did not differ significantly between RSAB wives and control subjects (P = 0.103). The frequency of the DQA1*0201/DQB1*0201 haplotype in RSAB husbands was greater than the 95th percentile confidence limit of the frequency of this haplotype in control subjects. Among seven RSAB husbands who were heterozygous for this haplotype and did not share a DQA1*0201 allele with his wife, the haplotype was transmitted to 6 of 7 abortuses (3.5 expected). Although the small size of this sample precludes drawing conclusions regarding HLA transmission biases in RSAB couples, these data have generated a specific hypothesis regarding the DQA1*0201/DQB1*0201 haplotype that can be investigated in future studies.

Abortion, Habitual↗
PubMed1994

HLA-G polymorphisms in African Americans.

HLA-G is a class I MHC gene most notable for its restricted tissue distribution. The unique expression of this gene in extravillous cytotrophoblast at the maternal-fetal interface suggests that HLA-G plays a critical role in human pregnancy. Previous studies have reported that HLA-G has a limited repertoire of rare alleles, unlike the classical class I alleles, which are among the most polymorphic human genes. To determine the full extent of sequence variation in this gene, we examined the nucleotide variation in the first six exons of this gene in 45 healthy African American persons. By using sensitive techniques that detect > 95% of nucleotide substitutions, we detected two sequence variations in the alpha-1 domain (exon 2) and 24 sequence variations in the alpha-2 domain (exon 3) that result in amino acid substitutions. These data indicate that HLA-G is potentially capable of presenting a wide variety of peptides and of eliciting an allogeneic response, similar to the classical class I HLA genes.

Adult↗
PubMed1994

Delta F508 genotype does not predict disease severity in an ethnically diverse cystic fibrosis population.

OBJECTIVE: As part of a study to determine population-based frequencies of CFTR mutations in an ethnically diverse, midwestern cystic fibrosis (CF) population, clinical histories were studied in 119 CF patients. METHODOLOGY: We sought to examine the association between genotype as characterized by the delta F508 and 11 other commonly occurring mutations and clinical parameters including age at diagnosis, clinical presentation, sweat chloride level, chest roentgenogram score, clinical scores, pulmonary function test results, percent weight for height, and presence of associated CF complications. RESULTS: Age at diagnosis of CF was significantly associated with homozygosity for delta F508 (mean age at diagnosis +/- SE: 1.7 +/- 0.3 years for delta F508/delta F508 vs 3.9 +/- 0.9 years for delta F508/other and other/other; P = .03). No other age-adjusted clinical parameter was significantly associated with delta F508 or any other genotype. CONCLUSION: These data suggest that in this sample of CF patients, delta F508 genotype is not predictive of disease severity. The lack of association between disease severity and genotype in this ethnically diverse sample may reflect the presence of more severe undetected mutations in our sample, or the effects of modifying genes at other, non-CF loci.

Adolescent↗
PubMed1993

Sex-biased lactational duration in a human population and its reproductive costs.

The authors tested the proposition that among humans (1) differences in lactational duration result in differences in costs of reproduction even under rich nutritional conditions; and (2) elimination of factors postulated to favor male-biased parental care will be reflected in elimination or reversal of sex-biased care. To do so, the authors examined the relationship between lactactational duration and fertility among Hutterites, a communal-living human population in which the levels of nutritional resources and fertility are high, breast feeding is the norm, contraceptive use is limited, and the collective social and economic system results in low resource variance among individuals. The authors demonstrate that even under good nutritional conditions, duration of nursing was a significant predictor of the length of time to next pregnancy and that nursing continued to suppress fertility after the resumption of menses. Moreover, the authors find that daughters were nursed longer than sons, leading to a longer interval to next pregnancy. The authors examine this uncommon, but not unique, finding of female-biased human parental care in the light of Hutterite social structure, and they explore the consistency of this finding with the most applicable models of parental investment.

Amenorrhea↗
PubMed1993

Autoantibodies and pregnancy history in a healthy population.

OBJECTIVE: Our purpose was to determine whether the presence of autoantibodies is associated with pregnancy history in healthy adults. STUDY DESIGN: Antibodies against phospholipid, histone, and nucleotide antigens were determined in 102 male and 99 female subjects. The effects of age, sex, marital status, and pregnancy history on antibody positivity were assessed. RESULTS: Women showed higher levels of autoantibodies, but differences were not statistically significant in this sample. Age was not associated with antibody positivity in men. In women age was associated with positivity for (1) immunoglobulin G antibodies (p = 0.009), (2) antihistone antibodies (p = 0.024), and (3) more than one antibody (p = 0.020). Immunoglobulin M antibodies were more common in unmarried than married females (p = 0.020). In contrast, the prevalence of immunoglobulin G antibodies was increased in married women, although differences did not reach statistical significance (p = 0.167). Gravidity and history of fetal loss were not associated with increased antibody positivity. In subjects in whom follow-up data were available, positive antibody titers were not associated with subsequent adverse pregnancy outcome. CONCLUSIONS: In this population autoantibodies are not associated with adverse pregnancy outcome. However, an increased prevalence of immunoglobulin M in unmarried women and immunoglobulin G in married women suggests that a switch from immunoglobulin M to immunoglobulin G autoantibodies is associated with marriage, as a result of either exposure to semen or trophoblast antigens.

Adult↗
PubMed1993

MHC class II compatibility in aborted fetuses and term infants of couples with recurrent spontaneous abortion.

Maternal-fetal histocompatibility for alleles at HLA class II loci, HLA-DQA1 and HLA-DQB1, was examined in 40 abortuses and 31 liveborn children of 68 couples with a history of idiopathic recurrent spontaneous abortion (RSAB) who underwent leukocyte immunization prior to the index pregnancy. Significantly more couples with RSAB shared two HLA-DQA1 alleles as compared with fertile control couples (0.18 vs. 0.03, respectively; P = 0.031). There were no differences in HLA sharing between couples with RSAB who experienced a repeat abortion in the index pregnancy as compared with couples with RSAB who were delivered of a liveborn child. Non-significant deficits of abortuses who were compatible for alleles at the HLA-DQA1 (6 observed vs. 8.5 expected; P = 0.225) and the HLA-DQB1 (7 observed vs. 9.2 expected; P = 0.254) loci were observed. A significant deficit of HLA-DQA1 compatible liveborn children was observed (1 observed vs. 5.5 expected; P = 0.0069). The overall deficit of HLA-DQA1 compatible fetuses (7 observed vs. 14.0 expected; P = 0.0018) after approximately 8 weeks gestation suggests that HLA-DQA1 compatible fetuses may be aborted early in pregnancy, prior to the time when fetal tissue can be recovered for genetic studies.

Abortion, Habitual↗
PubMed1993

Deficit of HLA homozygotes in a Caucasian isolate.

Deficits of HLA-A, -B homozygotes observed many years ago in two inbred populations suggested negative selection against HLA homozygotes. To determine whether a similar deficiency would be observed in the S-leut Hutterites, a well-characterized Caucasian isolate of European ancestry, and to determine whether selection operated at the allele, locus, or haplotype level, observed and expected numbers of homozygotes were compared in 852 adult Hutterites. Deficits ranging from 11% to 24% were observed for all five loci examined (HLA-A, -B, -C, -DR, and -DQ). However, these deficits were secondary to, and almost completely accounted for by, a 64% loss of individuals homozygous for the haplotype. There was no evidence of deficits affecting only a single allele or locus. The data indicate strong negative selection against HLA homozygotes. This could be due, at least in part, to decreased fecundability among couples sharing HLA-DR. However, these data suggest that additional selective factors acting at the level of the haplotype also operate in this population.

Adult↗
PubMed1993

Maternal-fetal histocompatibility in intrauterine growth retarded and normal weight babies.

PROBLEM: To determine whether risk for intrauterine growth retardation (IUGR) is increased in HLA-DQA1 compatible pregnancies. METHOD: Paired maternal and cord blood samples were obtained from 30 IUGR and 31 non-IUGR pregnancies delivered at a university hospital. Samples were typed for eight HLA-DQA1 alleles using 10 sequence-specific oligonucleotides probes. Associations between IUGR and HLA-DQ compatibility status, and other risk factors were examined using logistic regression analysis. RESULTS: HLA-DQ compatibility and history of spontaneous abortion were not individually significant risk factors for IUGR; however, there was an interactive effect between these two factors and IUGR (P = 0.085) that improved the overall fit of the logistic model (P < 0.001). No individual allele was more common in IUGR pregnancies. CONCLUSIONS: HLA compatibility per se is not associated with sufficient inhibition of fetal growth to result in IUGR as defined. However, in women with a history of spontaneous abortion, HLA compatibility may have an effect.

Abortion, Spontaneous↗
PubMed1992

Increased risk for polycystic ovary syndrome associated with human leukocyte antigen DQA1*0501.

OBJECTIVE: The objective of this investigation was to identify genes that confer susceptibility to polycystic ovary syndrome. STUDY DESIGN: Nineteen subjects with polycystic ovary syndrome, hirsutism, and elevated plasma androgen levels and 46 fertile, female control subjects were studied. Alleles at the human leukocyte antigen DQA1 locus were identified with dot-blot hybridizations with allele-specific oligonucleotide probes. Associations between human leukocyte antigen DQA1 alleles and polycystic ovary syndrome were examined with logistic regression analysis. RESULTS: The frequency of the human leukocyte antigen DQA1*0501 was 0.50 and 0.26 in subjects with polycystic ovary syndrome and control subjects, respectively (corrected for multiple comparisons, p = 0.067). Homozygosity for this allele was also increased among subjects with polycystic ovary syndrome (p = 0.054). The odds ratios for having polycystic ovary syndrome associated with the *0501 allele and the *0501/*0501 homozygous genotype were 2.8 and 5.8, respectively. CONCLUSION: These data suggest that a polycystic ovary syndrome susceptibility allele is linked to human leukocyte antigen and that the susceptibility allele is recessive.

Alleles↗
PubMed1992

Chimerism as the etiology of a 46,XX/46,XY fertile true hermaphrodite.

OBJECTIVE: To determine the conceptional events resulting in a 46,XX/46,XY true hermaphrodite and to report the first pregnancy in a 46,XX/46,XY true hermaphrodite with an ovotestis. DESIGN: Chromosome studies were performed on patient lymphocytes and fibroblasts. Red cell antigens, human leukocyte antigens, and presence of Y-chromosome deoxyribonucleic acid were analyzed. Findings were compared with parental and sibling blood group data. SETTING: Genetics clinic and laboratories of a university hospital. RESULTS: These studies demonstrated that our patient is a chimera, with dual maternal and paternal contributions. In addition, despite the presence of an ovotestis, she conceived and delivered a child. CONCLUSIONS: The mechanism for chimerism in this case could be fertilization of (1) the secondary oocyte and first polar body; (2) the ovum and first polar body; (3) the ovum and second polar body; or (4) fusion of two embryos.

Adult↗