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Y Tomer

Publications and source records attributed to Y Tomer.

At least 37 records · Page 2Linked to original sources
PubMed1999

Mapping the major susceptibility loci for familial Graves' and Hashimoto's diseases: evidence for genetic heterogeneity and gene interactions.

The autoimmune thyroid diseases (AITDs), comprising Graves' disease (GD) and Hashimoto's thyroiditis (HT), appear to develop as a result of a complex interaction between predisposing genes and environmental triggers. The goals of the present study were to identify the susceptibility loci for GD and HT and to study the relationships between them. We performed a whole genome linkage study on a dataset of 56 multiplex, multigenerational AITD families (354 individuals), using 387 microsatellite markers. We identified 6 loci that showed evidence for linkage to AITD. Only one locus, on chromosome 6 [AITD-1; 80 centimorgans (cM)], was linked with both GD and HT [maximum LOD score (MLS), 2.9]. This locus was close to, but distinct from, the human leukocyte antigen region. One locus on chromosome 13 (HT-1; 96 cM) was linked to HT (MLS, 2.1), and another locus on chromosome 12 (HT-2; 97 cM) was linked to HT in a subgroup of the families (MLS, 3.8). Three loci showed evidence for linkage with GD: GD-1 on chromosome 14 (99 cM; MLS, 2.5), GD-2 on chromosome 20 (56 cM; MLS, 3.5), and GD-3 on chromosome X (114 cM; MLS, 2.5). Since GD-2 showed the strongest evidence for linkage to GD we fine-mapped this locus to a 1-cM interval between markers at 55 and 56 cM on chromosome 20. These results demonstrated that 1) Graves' and Hashimoto's diseases are genetically heterogeneous, with only one locus in common to both diseases on chromosome 6; 2) only one HT locus was identified in all families, probably due to heterogeneity of the HT phenotype; and 3) three loci were shown to induce genetic susceptibility to GD by interacting with each other. One of them (GD-2) was fine-mapped to a 1-cM interval.

Chromosome Mapping↗
PubMed1998

A new Graves disease-susceptibility locus maps to chromosome 20q11.2. International Consortium for the Genetics of Autoimmune Thyroid Disease.

The autoimmune thyroid diseases (AITDs) include two related disorders, Graves disease (GD) and Hashimoto thyroiditis, in which perturbations of immune regulation result in an immune attack on the thyroid gland. The AITDs are multifactorial and develop in genetically susceptible individuals. However, the genes responsible for this susceptibility remain unknown. Recently, we initiated a whole-genome linkage study of patients with AITD, in order to identify their susceptibility genes. We studied a data set of 53 multiplex, multigenerational AITD families (323 individuals), using highly polymorphic and densely spaced microsatellite markers (intermarker distance <10 cM). Linkage analysis was performed by use of two-point and multipoint parametric methods (classic LOD-score analysis). While studying chromosome 20, we found a locus on chromosome 20q11.2 that was strongly linked to GD. A maximum two-point LOD score of 3.2 was obtained at marker D20S195, assuming a recessive mode of inheritance and a penetrance of.3. The maximum nonparametric LOD score was 2.4 (P=.00043); this score also was obtained at marker D20S195. Multipoint linkage analysis yielded a maximum LOD score of 3.5 for a 6-cM interval between markers D20S195 and D20S107. There was no evidence for heterogeneity in our sample. In our view, these results indicate strong evidence for linkage and suggest the presence of a major GD-susceptibility gene on chromosome 20q11.2.

Autoantibodies↗
PubMed1998

Linkage analysis of candidate genes in autoimmune thyroid disease. III. Detailed analysis of chromosome 14 localizes Graves' disease-1 (GD-1) close to multinodular goiter-1 (MNG-1). International Consortium for the Genetics of Autoimmune Thyroid Disease.

The autoimmune thyroid diseases [Graves' and Hashimoto's diseases (GD and HT)] develop in genetically susceptible individuals, but the genes responsible for this susceptibility remain unknown. To identify such genes, we have been testing candidate genes and chromosomal regions using highly polymorphic microsatellite markers. We recently reported evidence for the first locus linked to GD (GD-1) on chromosome 14q31 in a small group of families. We have now extended these studies and analyzed 53 multiplex families with GD and/or HT (323 individuals). Chromosome 14 was screened using 16 microsatellite markers spanning the entire chromosome. Three additional markers located inside candidate genes on chromosome 14 were also studied. Microsatellite markers were amplified using fluorescent-labeled primers and separated on an ABI-310 genetic analyzer. The data were analyzed using LIPED software for two-point logarithm of odds (LOD) score analysis and GeneHunter software for multipoint linkage analysis. No linkage of any marker was found to HT or autoimmune thyroid diseases (GD+HT). The previously identified GD-1 locus on 14q31 continued to show evidence of linkage to GD in this much larger set of families. The maximum LOD score was 2.1 obtained for marker D14S81 (theta=0.01), assuming a recessive mode of inheritance and a penetrance of 0.3. Multipoint analysis yielded a maximum LOD score of 2.5 between markers D14S81 and D14S1054. There was no evidence for heterogeneity in our sample. These data again suggest the presence of a major Graves' disease susceptibilitygene (GD-1) on chromosome 14q31. This locus is close to the recently identified multinodular goiter-1 locus.

Autoimmune Diseases↗
PubMed1998

Linkage analysis of candidate genes in autoimmune thyroid disease: 1. Selected immunoregulatory genes. International Consortium for the Genetics of Autoimmune Thyroid Disease.

Graves' and Hashimoto's diseases are autoimmune thyroid diseases in which the genetic contribution is complex. For this reason, identification of necessary susceptibility genes has been difficult. However, a number of immunoregulatory genes have been implicated by association studies, including: CTLA-4, a recently described protein involved in antigen presentation, located on chromosome 2q33; the T-cell receptor V alpha and V beta gene complexes, located on 14q11 and 7q35, respectively; and the Ig gene complex (IgH), located on 15q11. We used polymorphic microsatellite markers located within these genes, or gene complexes, to test for linkage (rather than association), to each of these candidates. Using markers within the loci allowed us to assume a fixed recombination fraction of 0.01 in the tested model. Three hundred eight subjects from 48 multiplex families were studied, with 142 affected subjects. Using this set of families, we have previously shown evidence of linkage with a major susceptibility locus for Graves' disease (GD-1) on 14q24.3-31, with a maximum lod (logarithm + odds) score of 2.1, at a penetrance of 80% and with a dominant mode of inheritance. In the present study, we obtained consistently negative lod scores for each of the candidate genes, assuming either dominant or recessive modes of inheritance. These data, therefore, showed evidence against linkage with all the candidate genes. Unlike association studies, linkage analyses detect major genetic influences on disease susceptibility exerted by the linked loci. The lack of linkage for the immunoregulatory genes that were studied indicated, therefore, that they were not major contributors to disease etiology.

Abatacept↗
PubMed1998

Linkage analysis of candidate genes in autoimmune thyroid disease. II. Selected gender-related genes and the X-chromosome. International Consortium for the Genetics of Autoimmune Thyroid Disease.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are autoimmune thyroid diseases (AITD) in which multiple genetic factors are suspected to play an important role. Until now, only a few minor risk factors for these diseases have been identified. Susceptibility seems to be stronger in women, pointing toward a possible role for genes related to sex steroid action or mechanisms related to genes on the X-chromosome. We have studied a total of 45 multiplex families, each containing at least 2 members affected with either GD (55 patients) or HT (72 patients), and used linkage analysis to target as candidate susceptibility loci genes involved in estrogen activity, such as the estrogen receptor alpha and beta and the aromatase genes. We then screened the entire X-chromosome using a set of polymorphic microsatellite markers spanning the whole chromosome. We found a region of the X-chromosome (Xq21.33-22) giving positive logarithm of odds (LOD) scores and then reanalyzed this area with dense markers in a multipoint analysis. Our results excluded linkage to the estrogen receptor alpha and aromatase genes when either the patients with GD only, those with HT only, or those with any AITD were considered as affected. Linkage to the estrogen receptor beta could not be totally ruled out, partly due to incomplete mapping information for the gene itself at this time. The X-chromosome data revealed consistently positive LOD scores (maximum of 1.88 for marker DXS8020 and GD patients) when either definition of affectedness was considered. Analysis of the family data using a multipoint analysis with eight closely linked markers generated LOD scores suggestive of linkage to GD in a chromosomal area (Xq21.33-22) extending for about 6 cM and encompassing four markers. The maximum LOD score (2.5) occurred at DXS8020. In conclusion, we ruled out a major role for estrogen receptor alpha and the aromatase genes in the genetic predisposition to AITD. Estrogen receptor beta remains a candidate locus. We found a locus on Xq21.33-22 linked to GD that may help to explain the female predisposition to GD. Confirmation of these data in HT may require study of an extended number of families because of possible heterogeneity.

Aromatase↗
PubMed1997

Anti-neutrophil cytoplasmic antibody-enriched IgG induces adhesion of human T lymphocytes to extracellular matrix proteins.

Recent studies have shown that anti-neutrophil cytoplasmic antibodies (ANCA) can activate neutrophils to adhere to endothelium, degranulate, and cause endothelial cell injury. These data have lead to the hypothesis that the T cell inflammatory response causing the vasculitis in Wegener's granulomatosis (WG) is secondary to stimulation of neutrophils by ANCA. So far there is no evidence for a direct effect of ANCA on lymphocytes. The present study was designed to examine whether lymphocytes can be directly stimulated by ANCA to adhere to endothelial extracellular matrix (ECM) proteins. Human and mouse ANCA-enriched IgG were tested for their ability to increase adhesion of human T lymphocytes to fibronectin, laminin, and intact ECM. Incubation of human T lymphocytes with human ANCA-enriched IgG increased adhesion of the lymphocytes in a dose-dependent manner to fibronectin, laminin, and intact ECM (the percentage adhesion to intact ECM was 55.7 +/- 3.1 and 45.0 +/- 1.0% for lymphocytes incubated with human IgG containing ANCA or control human IgG, respectively; P = 0.0045). The same induction of adhesion to fibronectin, laminin, and intact ECM was observed when the cells were incubated with the F(ab)2 fragment of ANCA-enriched IgG. Similarly, ANCA-enriched IgG produced in mice increased the adhesion of lymphocytes to fibronectin (the percentage adhesion to fibronectin was 29.7 +/- 4.3 and 16.6 +/- 1.9% for lymphocytes incubated with mouse IgG-ANCA or control mouse IgG, respectively; P = 0.0008). These results may suggest that ANCA can directly stimulate lymphocytes to adhere to endothelial ECM and to induce the vasculitic lesions of WG. It remains to be shown by which mechanisms ANCA stimulate lymphocytes to adhere to ECM.

Animals↗
PubMed1997

The genetic susceptibility to Graves' disease.

Graves' disease (GD) develops as a result of a complex interaction between genetic susceptibility genes and likely environmental factors. Most epidemiological data support an important genetic contribution to the development of GD. The concordance rate of GD in monozygotic twins is 30-60% and in dizygotic twins 3-9%, and thyroid autoantibodies have been reported in up to 50% of the siblings of patients with GD. For many years now, HLA studies have consistently shown an increased frequency of HLA-DR3 in Caucasian patients with GD; but with only a risk ratio of 3-5. However, recent advances in human genome mapping techniques have enabled the study of many other candidate genes. Of these additional, non-HLA genes, only CTLA-4 has been consistently found to be associated with GD. Using a linkage based approach which only detects highly significant susceptibility genes we have recently reported preliminary results which demonstrated that a marker located approximately 25 cM from the TSH receptor gene on chromosome 14q31 is linked to GD and in the same vicinity as the IDDM-11 locus. Such results, if confirmed, may signal the presence of a gene family related to endocrine autoimmunity on chromosome 14q31.

Epidemiologic Methods↗
PubMed1997

Mapping of a major susceptibility locus for Graves' disease (GD-1) to chromosome 14q31.

The autoimmune thyroid diseases (AITD), encompassing Graves' disease (GD) and Hashimoto's thyroiditis (HT), occur in genetically susceptible individuals. In order to identify the AITD susceptibility genes, we have studied DNA markers in the regions of 8 candidate genes: (1) the HLA region, (2) the TSH receptor, (3) thyroid peroxidase, (4) thyroglobulin, (5) IDDM-4, (6) IDDM-5, (7) Immunoglobulin heavy chain gene and (8) CTLA-4. One hundred and seven subjects from 19 informative families were studied, 14 subjects had GD and 32 subjects had HT. LOD scores were maximized assuming both dominant and recessive modes of inheritance. No linkage was found for any marker in patients with HT. In patients with GD, negative LOD scores were obtained for all the candidate genes, except for markers in the TSH receptor region on chromosome 14q31. Positive LOD scores were found for several markers on 14q31. Marker D14S81 gave the highest score (Z max = 2.05, theta = 0.01) assuming a dominant mode of inheritance and a penetrance of 0.8. These data confirm our previous observations of a lack of a necessary disease locus for AITD in the HLA gene region. Further, the data suggest the presence of an important susceptibility gene on 14q31 but at a considerable distance from the TSH receptor gene.

Chromosome Mapping↗
PubMed1996

Induction of thyroid autoantibodies in naive mice by idiotypic manipulation.

Previously, we have shown that it is possible to induce, in naive mice, systemic autoimmune diseases (e.g., antiphospholipid syndrome and systemic lupus erythematosus) by idiotypic manipulation. In the present study we expanded our experience to examine whether idiotypic manipulation could be utilized to induce organ-specific autoantibodies and a disease mediated by cellular mechanisms, namely, experimental autoimmune thyroiditis. Fifteen BALB/c mice were immunized with a monoclonal mouse anti-human thyroglobulin (hTg) antibody; controls were immunized with an irrelevant mouse IgG. The mice immunized with anti-hTg antibody developed, 6 weeks after immunization, autoantibodies to human thyroglobulin, but not to dsDNA, cardiolipin, or myeloperoxidase. The presence of specific autoantibodies was associated with low production of thyroid hormones, and during a follow-up of 20 weeks the mice did not develop characteristic histological signs of thyroiditis. We conclude that idiotypic manipulation can induce anti-thyroglobulin autoantibodies.

Animals↗
PubMed1995

Transfer of experimental antiphospholipid syndrome by bone marrow cell transplantation. The importance of the T cell.

OBJECTIVE: To investigate the potential of bone marrow cells from mice with primary antiphospholipid syndrome (APS) to transfer the disease to naive mice, and to determine the importance of the role of T cells in the APS. METHODS: Experimental primary APS was induced in naive mice following active immunization with anticardiolipin (aCL) monoclonal antibody (MAb). Whole-population or T cell-depleted bone marrow cells from mice with experimental primary APS were infused into total body-irradiated naive BALB/c recipients. RESULTS: Bone marrow cells (in the presence of T cells) had the potential to induce experimental APS in naive mice, which resulted in high serum titers of aCL, antiphosphatidylserine, and antiphosphatidylinositol antibodies; an increased number of antibody-forming cells specific for each of the above phospholipids; a positive lymph node cell proliferative response to aCL MAb; and clinical features of primary APS, including thrombocytopenia, prolonged activated partial thromboplastin time (indicating the presence of lupus anticoagulant), and a high frequency of fetal resorptions (the equivalent of human fetal loss). T cell-depleted bone marrow cells did not transfer the disease. CONCLUSION: This study demonstrates the important role of T cells in the development and transfer of experimental primary APS and raises the possibility of T cell manipulations in treatments to prevent this condition.

Animals↗
PubMed1995

Characterization of biologically active antineutrophil cytoplasmic antibodies induced in mice. Pathogenetic role in experimental vasculitis.

OBJECTIVE: To investigate the pathogenetic role of antineutrophil cytoplasmic antibodies (ANCA) in Wegener's granulomatosis (WG). METHODS: BALB/c mice were immunized with human IgG ANCA from a patient with WG. Control mice were immunized with normal human IgG. Levels of mouse ANCA and other autoantibodies were determined. Mouse ANCA were tested for their ability to induce adhesion and respiratory burst of neutrophils. The mouse lungs and kidneys were examined for the development of vasculitis. RESULTS: Mice immunized with human ANCA developed anti-human ANCA and anti-anti-human ANCA (mouse ANCA), while the controls did not develop these antibodies. Mouse ANCA were capable of inducing adhesion of neutrophils to fibronectin and activating the respiratory burst in neutrophils. Moreover, the mice that were immunized with human ANCA developed perivascular mononuclear cell infiltrates in the lungs, suggesting vasculitis. CONCLUSION: The results suggest a pathogenic role of ANCA in WG, and may imply that activation of neutrophils is the initiating event in the development of vasculitis in WG.

Animals↗
PubMed1995

Natural autoantibodies in sera of patients with Gaucher's disease.

Gaucher's disease (GD) is associated with hyperactivity of the immune system, which manifests by polyclonal hypergamma-globulinemia and an increased incidence of monoclonal gammopathies in GD patients. We analyzed sera of 43 patients with GD for the presence of autoantibodies against 14 autoantigens. The results demonstrated a significant increase in the incidence of all autoantibodies tested, ranging from 11% for anti-RNP, pyruvate dehydrogenase (PDH), and DNA antibodies to 57% for rheumatoid factor. The autoantibodies were of all three isotypes, namely, IgG, IgM, and IgA. There was no correlation between the levels of immunoglobulins in the serum and the titer of autoantibodies found. Immunization of naive mice with a pool of purified anti-DNA antibodies form GD patients did not result in induction of experimental systemic lupus erythematosus (SLE), suggesting that they may represent natural autoantibodies that are not pathogenic. In conclusion, we found high titers of natural, polyspecific, nonpathogenic autoantibodies in the sera of GD patients.

Adolescent↗
PubMed1995

Infections and autoimmune endocrine disease.

The literature examined in this review points to the possible involvement of infectious agents in the pathogenesis of autoimmune endocrine diseases, primarily autoimmune thyroid disease and diabetes mellitus. Various mechanisms have been proposed to explain induction of autoimmunity by infection but it seems that three possibilities may be important in individuals susceptible to developing autoimmune disease: molecular mimicry (perhaps to retroviruses); polyclonal T cell activation (by an endogenous superantigen or an infecting organism); and MHC class II antigen induction. It seems reasonable that all three mechanisms operate together or separately in different individuals. Data continue to accumulate in favour of infectious agents being important initiators of autoimmune disease.

Animals↗
PubMed1995

Immunization with anti-neutrophil cytoplasmic antibody (ANCA) induces the production of mouse ANCA and perivascular lymphocyte infiltration.

Wegener's granulomatosis (WG) is a granulomatous necrotizing vasculitis associated with the presence of ANCA, predominantly directed against proteinase 3 (PR3). The titres of ANCA correlate with disease activity and titre increases may precede disease exacerbations. Previously, we have shown that it is possible to induce autoimmune disease (systemic lupus erythematosus (SLE) and anti-phospholipid syndrome) in naive mice following active immunization with human autoantibodies, namely anti-DNA and anti-cardiolipin, respectively. The mice developed first anti-autoantibodies and, after about 4 months anti-anti-autoantibodies (Ab3), simulating auto-antibodies (Ab1) in their binding activities, and their presence was associated with the development of disease manifestations, characteristic of the human disease. So far, there is no good animal model for WG. In the current study we have immunized mice with human ANCA with the aim of inducing experimental WG. In two separate studies 30 mice were immunized in their footpads with autoantigen-purified IgG fraction (ANCA) from the sera of two patients with untreated WG, emulsified in Freund's complete adjuvant, followed 3 weeks later by ANCA injection in PBS. In the first experiment mice immunized with ANCA developed sterile microabscesses in the lungs after 8 months, and died after 8-15 months. In the second experiment, mice immunized with ANCA developed after 4 months mouse ANCA, with specificity both to PR3 and to myeloperoxidase, as well as anti-endothelial autoantibodies (AECA), as shown by radioimmunoprecipitation. Pathologically, the immunized mice developed proteinuria but not haematuria, and histological sections of the lungs demonstrated mononuclear perivascular infiltration, while diffuse granular deposition of immunoglobulins was noted in the kidneys. Our results point to a pathogenic role of ANCA in WG, and confirm the importance of the idiotypic network in the etiopathogenesis of autoimmune conditions.

Animals↗
PubMed1995

Induction of tolerance to experimental anti-phospholipid syndrome (APS) by syngeneic bone marrow cell transplantation.

Previously, we have shown the ability to induce experimental autoimmune conditions (e.g. SLE, APLS, Wegener's granulomatosis) following active immunization with the pathogenic autoantibody emulsified in adjuvant. The mice first develop anti-autoantibodies (Ab2: anti-id) and eventually generate anti-anti-autoantibodies (Ab3: anti-anti-id) which carry the same antigen binding characteristic as the autoantibody (Ab1). The appearance of the specific autoantibodies in mice sera was associated with the emergence of the compatible laboratory and with the clinical findings characteristic to the respective autoimmune disease. The effects of syngeneic bone marrow transplantation (BMT) on experimental anti-phospholipid syndrome (APS) were investigated. BALB/c mice were immunized with anti-cardiolipin monoclonal antibody (MoAb) named CAM and developed elevated serum titres of anti-phospholipid Abs accompanied by prolonged activated partial thromboplastin time, thrombocytopenia and a high percentage of fetal resorptions. These mice were then lethally irradiated and transfused with bone marrow (BM) cells (T cell depleted) from syngeneic naive mice. The titres of antiphospholipid antibodies were reduced in the recipients. The decrease in titre of autoantibodies was found to be related to depletion of antibody forming cells in vivo, associated with reduced proliferative response of lymph node cells to anti-cardiolipin MoAbs. The recipients showed improvement in clinical parameters following syngeneic BMT. The same recipients developed specific unresponsiveness to a second challenge with the anticardiolipin MoAb (CAM), but developed experimental systemic lupus erythematosus upon immunization with a monoclonal anti-DNA antibody. We conclude that acute myeloablative immunosuppression combined with syngeneic bone marrow transplantation may induce a state of tolerance to the pathogenic autoantibodies in mice with experimental APLS. Our results suggest that a similar approach may be useful in treating life-threatening autoimmune syndromes (e.g. catastrophic APLS) in clinical practice.

Animals↗