Prevalence of autoantibodies associated with thyroid and celiac disease in Ullrich-Turner syndrome in relation to adult height after growth hormone treatment.

A prospective, multicenter study of patients with Ullrich-Turner syndrome (UTS) was conducted to estimate the prevalence of autoantibodies to tissue transglutaminase (tTg), thyroid stimulating hormone receptor (TSH-R), thyroglobulin (TG) and thyroid peroxidase (TPO) in relation to adult height after long-term growth hormone (GH) treatment. Out of 347 near-adult (> 16 years) patients with UTS from 96 German centers, whose longitudinal growth was documented within the Pharmacia International Growth Study (KIGS), 188 returned for a standardized follow-up visit at a median chronological age of 18.7 (16.0-23.6) years (bone age > 15 years). Serum samples of 120 patients were obtained for central measurements of TSH, thyroxine (T4) and free T4 and autoantibodies by standard immunoassays. Information regarding thyroid disease, karyotype and anthropometric data was extracted from the KIGS database. Thirty-six percent of the patients with UTS had positive TG and/or TPO autoantibodies and 4% had positive tTg autoantibodies, whereas 2% had positive TG and/or TPO autoantibodies as well as positive tTg autoantibodies. TSH-R autoantibodies were undetectable in all patients. The detection of autoantibodies was unrelated to a specific karyotype. Median height standard deviation scores (SDS, UTS) at start of GH treatment (0.43; -1.07, 1.85) and at follow-up (1.36; -0.11, 2.57) were comparable in all patients independent of their antibody status. The total deltaheight SDS, however, was higher in patients with negative autoantibody titers (1.08; -0.03, 2.25) compared to those with positive antibody titers (0.68; -0.44, 1.82; p < 0.01). Our study confirms the high prevalence of autoantibodies in patients with UTS predisposing them to autoimmune thyroid disease and celiac disease, and indicates for the first time that autoimmune pathologies may interfere with GH therapy and thus compromise final height. Therefore, medical care for patients with UTS should routinely include screening for these autoimmune disorders in order to assure early detection and appropriate treatment.

Interacting quantitative trait loci control loss of peripheral tolerance and susceptibility to autoimmune ovarian dysgenesis after day 3 thymectomy in mice.

Day 3 thymectomy (D3Tx) results in a loss of peripheral tolerance mediated by CD4(+)CD25(+) T cells and the development of autoimmune ovarian dysgenesis (AOD) in A/J and (C57BL/6J x A/J)F(1) (B6AF(1)) hybrids but not in C57BL/6J mice. Quantitative trait loci (QTL) linkage analysis using a B6AF(1) x C57BL/6J backcross population verified Aod1 and Aod2 that were previously mapped as qualitative traits. Additionally, three new QTL intervals, Aod3, Aod4, and Aod5, on chromosomes 1, 2, and 7, respectively, influencing specific subphenotypes of AOD were identified. QTL linkage analysis using the A x B and B x A recombinant inbred lines verified Aod3 and confirmed linkage to H2. Aod5 colocalized with Mater, an ovarian-specific autoantigen recognized by anti-ovarian autoantibodies in the sera of D3Tx mice. Sequence analysis of Mater identified allelic, strain-specific splice variants between A/J and C57BL/6J mice making it an attractive candidate gene for Aod5. Interaction analysis revealed significant epistatic effects between Aod1-5 and Gasa2, a locus associated with susceptibility to D3Tx-induced autoimmune gastritis, as well as with H2. These results indicate that the QTL controlling D3Tx-induced autoimmune phenomenon are both organ specific and more generalized in their effects with respect to the genesis and activity of the immunoregulatory mechanisms maintaining peripheral tolerance.

Aod2, the locus controlling development of atrophy in neonatal thymectomy-induced autoimmune ovarian dysgenesis, co-localizes with Il2, Fgfb, and Idd3.

In genetically susceptible strains of mice, such as A/J and (C57BL/6J x A/J)F1 hybrids, neonatal thymectomy-induced autoimmune ovarian dysgenesis (AOD) is characterized by the development of antiovarian autoantibodies, oophoritis, and atrophy. Temporally, atrophy may be observed during and after the regression of inflammatory infiltrates from the ovary. Histologically, lesions appear as areas devoid of ovarian follicles in all stages of development that have been replaced by luteinized interstitial cells. We report here the mapping of Aod2, the locus that controls this phenotype, to mouse chromosomes 3 within a region encoding Il2 and Fgfb. Most significant, however, is the co-localization of Aod2 to Idd3, a susceptibility gene that plays a role in autoimmune insulin-dependent type 1 diabetes mellitus in the nonobese diabetic mouse.

Aod1, the immunoregulatory locus controlling abrogation of tolerance in neonatal thymectomy-induced autoimmune ovarian dysgenesis, maps to mouse chromosome 16.

Mice thymectomized at three days of age (D3Tx) develop during adulthood a variety of organ-specific autoimmune diseases, including autoimmune ovarian dysgenesis (AOD). The phenotypic spectrum of AOD is characterized by the development of anti-ovarian autoantibodies, oophoritis, and atrophy. The D3Tx model of AOD is unique in that disease induction depends exclusively on perturbation of the normal developing immune system, is T-cell-mediated, and is strain specific. For example, D3Tx A/J mice are highly susceptible to AOD, whereas C57BL/6J mice are resistant. After D3Tx, self ovarian antigens, expressed at physiological levels, trigger an autoimmune response capable of eliciting disease. The D3Tx model provides, therefore, the opportunity to focus on the mechanisms of self-tolerance that are relevant to disease pathogenesis. Previous studies indicate that the principal mechanisms involved in AOD susceptibility are genetically controlled and govern developmental processes associated with the induction and maintenance of peripheral tolerance. We report here the mapping of the Aod1 locus to mouse chromosome 16 within a region encoding several loci of immunologic relevance, including scid, Igl1, VpreB, Igll, Igl1r, Mtv6 (Mls-3), Ly-7, Ifnar, and Ifgt.

HLA-A, B and DR antigens in patients with gonadal dysgenesis.

HLA (human leukocyte antigens) antigens A, B, and DR were determined in a series of 50 patients with gonadal dysgenesis (GD), separated into different groups according to karyotype. There were no significant differences in frequency of HLA antigen types between GD patients and the population control. When frequencies of the HLA antigens in the various GD patient groups by karyotype were compared, only one significant difference was found: HLA-A3 was more common among GD patients with isochromosome X than among GD patients with karyotype 45,X (p < 0.001, corr. p < 0.008). Although GD patients have a higher expectancy for development of autoimmune disorders, and in our 50 patients thyroglobulin and/or microsomal antibodies were detected in 20 (i.e., 40%), we failed to find any increased frequency of specific HLA antigen types known to be associated with juvenile autoimmune thyroiditis.

Lymphocyte subsets in patients with oestrogen deficiency.

We have previously shown that in patients with idiopathic premature ovarian failure there were significant changes in lymphocyte subsets. To test our hypothesis that these changes were due to oestrogen deficiency we studied lymphocyte subsets in patients with oestrogen deficiency due to other causes. Blood was taken for serum oestradiol, lymphocyte counts and lymphocyte subset counts (CD2+, CD4+, CD8+ and B cells) before oestrogen replacement in 19 patients with gonadal dysgenesis, 22 patients with hypothalamic-pituitary failure and 24 healthy female control subjects. The CD4:CD8 ratio in both groups of patients was significantly lower than that in the normal control subjects while the percentages and counts of lymphocytes and CD8+ cells were significantly higher. There was a significant positive correlation between the serum oestradiol level and the CD4:CD8 ratio. These findings support the hypothesis that the changes in lymphocyte subsets are due to oestrogen deficiency.

Gonadal tumor and H-Y antigen in 46,XY pure gonadal dysgenesis.

Six cases of Swyer's syndrome (46,XY pure gonadal dysgenesis) are reported. Three patients, without gonadal tumor, had female H-Y antigen. Three patients, after gonadal tumor ablation, had intermediate H-Y antigen levels. Repeated blood samples were obtained from two siblings. H-Y antigen level in the first sibling, who presented with a gonadoblastoma and underwent a gonadectomy before the H-Y assays, was intermediate, and did not show any significant variation for 21 months. H-Y antigen level in the second sibling showed an increase in the male range, presumably due to the presence of gonadoblastomas. After resection of the tumors, H-Y antigen level became intermediate. These findings suggest a relation between the tumorization potentiality of the gonadal remnants and the H-Y antigen levels in 46,XY pure gonadal dysgenesis.

H-Y antigen in a 46,XX female with dysgenetic ovaries.

Hypogonadism secondary to ovarian dysgenesis or resistant ovary syndrome was diagnosed in a 19-yr-old obese woman with primary amenorrhea, a 46,XX karyotype, and an H-Y+ cellular phenotype. Small ovoid gonads (1.5 X 0.6 cm) were found found bilaterally; these were encased in a dense venous network. The stroma was ovarian, and primordial follicles and some primary follicles were present, but there were no follicles at or beyond the antrum stage. There was no evidence of testicular tissue and no evidence of malignancy. Analysis of serological data indicated the possibility of residual H-Y antigen in the blood cells of the mother.

Study of H-Y antigen in abnormal sex determination with monoclonal antibody and an ELISA.

A newly developed enzyme-linked immunosorbent assay (ELISA) has been applied to the study of H-Y antigen in cases of XY, XYY, and X,dicY gonadal dysgenesis, testicular feminization syndrome, XXXXY syndrome, and XX true hermaphroditism. Monoclonal H-Y antibody was absorbed with cells from each of eight patients and from normal male and female controls, and then reacted with a plated antigen source in a system subsuming the addition of biotinylated secondary antibody, avidin-biotin-enzyme complex and substrate, and thereby the generation of a color. Positive absorption decreased the reaction, and this allowed sensitive measurement of H-Y phenotype in an electronic optical density reader. The ELISA obviates many of the technical difficulties encountered in complement-mediated cytotoxicity systems and can be used in the study of clinical cases of aberrant sex determination and in the evaluation of current models of the genetics of sex determination.

Absence of H-Y antigen in a case of sporadic pure gonadal dysgenesis.

H-Y activity, endocrine function and gonadal histology were studied in a phenotypic female presenting with features of sporadic 46,XY pure gonadal dysgenesis. H-Y activity was absent, hormonal data revealed a primary ovarian failure with a blunted response of FSH to LHRH; there was no testicular tissue nor microscopic evidence of gonadal tumor in the gonads. The current view on the role of H-Y antigen in the differentiation of the gonads and in the occurrence of gonocytoma is discussed.

Variability in serologically detected male antigen titer and some resulting problems: a critical review.

Seroologically detected male antigen" (also called H-Y antigen) was first described in normal male mammals but now appears to occur in normal female mammals as well. "Serologically detected male predominant" (SDMP) antigen is a more appropriate name since the titer in normal males usually exceeds that of normal females. As we show, in each sex there is a considerable inter-individual variability in SDMP antigen titer, and in moderate-to-large size samples the low end of the male range of titers usually coincides with the high end of the female range. Several major problems arise from failure to recognize and/or to deal adequately with this normal variation in SDMP antigen titer. The chief problem is that the "controls" used (often a single individual) may be inadequate and misleading, leading to unjustified designation of samples as "positive", "negative", or even "deviant" ("intermediate", "reduced") for SDMP antigen titer. Other problems include deficiencies in technique and lack of statistical control for test and sample variability. Adequate attention to these problems, especially to the normal variability in SDMP antigen titer, could reduce the contradictions and inconsistencies which have troubled this field.

[Role of the H-Y antigen in gonadal differentiation: contradictory data]. / Rôle de l'antigène H-Y dans la différenciation gonadique: données contradictoires.

The present knowledge of the physiology of H-Y antigen has been reviewed. It would appear that the results that have been obtained contradict one another and this brings into doubt the role that this antigen plays in testicular differentiation and the link it has with the Y chromosome.

H-Y antigen expression in a case of mixed gonadal dysgenesis.

H-Y antigen expression was studied on leukocytes and gonad-derived fibroblasts from a patient affected by mixed gonadal dysgenesis. Blood leukocytes and fibroblasts derived from the testis were typed H-Y positive, but the fibroblasts derived from the streak gonad were H-Y negative. Although the patient's karyotype was a mosaic, 45,XO/46,X+mar, as detected in-peripheral blood cells and testis-derived fibroblasts, all the fibroblasts derived from the streak gonad were 45,XO. These data suggests that the marker chromosome was in fact a Y-derived chromosome. Moreover, they showed that, at the gonadal level, a minority of H-Y positive 46,X+mar cells were able to organize a testis. Nevertheless, a large number of XO cells probably did not receive the testicular forming influence of the H-Y antigen and of the other masculinizing factors.

H-Y antigen in X,i(Xq) gonadal dysgenesis: evidence of X-linked genes in testicular differentiation.

Three years ago, we detected H-Y antigen in the white blood cells of a phenotypic female with several of the stigmata of Turner's syndrome, and the mosaic karyotype: 45,X/46,X,i(Xq). We surmised at the time that the isochromosome, i(Xq), may have contained occult Y-Chromosome-derived material. We have now confirmed the presence of H-Y in this patient and we have obtained evidence for the presence of H-Y in four of five other similar patients, all of whom are notable for carrying at least a single cell line with the karyotype 46,Xi(Xq). Although we cannot categorically exclude the presence of Y-chromosomal genes in the cells of these patients, there is no cytogenetic evidence of structural rearrangement involving the Y in any of the cases. Expression of H-Y structural genes are X-situated, or alternatively that they are autosomal and X-regulated. It would follow that the H-Y+ cellular phenotype per se is not a valid marker for the Y-chromosome, and that H-Y genes that have been mapped to the pericentric region of the Y may be regulatory.

Positive H-Y antigen testing in a case of XY gonadal absence syndrome.

H-Y antigen testing was positive in a case of pseudohermaphroditism due to XY gonadal absence syyndrome. In conclusion, H-Y antigen may be present even in the absence of testes. Also, the syndrome could not have originated from a defect in the H-Y antigen system.