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Biomedical subjects

D Doniach

Publications and source records attributed to D Doniach.

At least 37 records · Page 2Linked to original sources
PubMed1983

Detection of thyroid growth immunoglobulins (TGI) by [3H]-thymidine incorporation in cultured rat thyroid follicles.

A new bioassay is described for detecting the growth stimulating immunoglobulins (TGI) that contribute to goitre formation in human thyroid autoimmune diseases. It measures the incorporation of tritiated thymidine into intact rat thyroid follicles grown in tissue culture. This radiometric assay demands much less technical skill than the cytochemical bioassays (CBA) previously employed. It has good reproducibility and the techniques and apparatus are available in many clinical laboratories. Immunoglobulins (Igs) from 68% of patients with goitrous Graves' disease were positive, in proportion with goitre size, and this showed no correlation with T3 levels, or three accepted methods for conventional thyroid stimulating antibodies. Non-toxic nodular goitre cases gave positive results in 3/9 who had recurrences after one or more thyroidectomies and in 1/10 cases of familial simple goitre. All normal subjects and all endemic goitre cases were negative as well as 21 cases of sporadic non-toxic nodular goitre. Although it is less sensitive than the 'growth CBA' it clearly emphasizes the essential difference between the intensity of growth stimulus which leads to the regular hyperplasia of thyroid epithelium seen in Graves' thyrotoxicosis and the disorganized and metabolically uncoordinated hyperplasia typical of non-toxic nodular goitre.

Adult↗
PubMed1983

Etiology of Type I diabetes mellitus: heterogeneity and immunological events leading to clinical onset.

Type I diabetes is a heterogeneous disorder and the causes of pancreatic beta-cell destruction are unknown. In 1-2% of all cases, viruses (e.g. coxsackie, rubella, mumps, or beta-cell poisons) have been implicated. Twin studies suggest at most 50% of genetic predisposition. In this review we describe the autoimmune components which, in association with inheritance of HLA-haplotypes in susceptible families, allow the future selection of predisposed sibs for possible preventive therapy to retard loss of insulin secretion. The known association of the endocrine autoimmune organ-specific disorders in 10% of Type I diabetics is the extreme expression of the other main genetic ingredient in the development of insulitis in this disease, irrespective of the triggering environmental components. In this "polyendocrine" subgroup and in the "juvenile-onset" cases there is a prolonged latency period during which pancreatic autoimmunity markers are present before clinical expression of the disease.

Antibody Formation↗
PubMed1982

Autoimmunity to anterior pituitary cells and the pathogenesis of insulin-dependent diabetes mellitus.

An immunofluorescence study using unfixed cryostat sections of human pituitary glands was carried out on sera from patients with type-Ia (juvenile-onset) diabetes (61 recent onset, 48 longstanding). 63 of their selected high-risk first-degree relatives and 117 patients with type-Ib ("polyendocrine") diabetes were tested for comparison. Healthy controls included 48 sera from laboratory staff and students. Pituitary-cell antibodies were found in none of the controls, in 2% of patients with longstanding diabetes, in 16.6% of patients with diabetes of recent onset, and in 36.6% of genetically predisposed relatives with islet-cell antibodies in their sera (of whom 7 became diabetic during a 3-year follow-up period, 4 of them reacting with pituitary cells for 1-3 years before the onset of diabetes). Thus pituitary antibodies tended to disappear after onset of symptoms. Many of the sera reacted with multiple anterior-pituitary cell types. These findings suggest a wider involvement of the endocrine-organ system in the pathogenesis of insulin-dependent diabetes and are in accordance with clinical observations showing excess growth in prepubertal boys at onset of diabetic symptoms and with the results of experiments on virus-induced diabetes in mice. The connection of these pituitary antibodies with autoimmune lymphocytic hypophysitis is at present unknown.

Adolescent↗
PubMed1982

The involvement of the pentose shunt in thyroid metabolism after stimulation with TSH or with immunoglobulins from patients with thyroid disease. 1. The generation of NADPH in relation to stimulation of thyroid growth.

It has been shown previously that both thyrotrophin (TSH), and also immunoglobulins (Ig) derived from patients with goitrous Graves' disease, stimulate DNA-synthesis in guinea-pig thyroid tissue maintained in vitro. Here we describe the use of the same in vitro system and methods of quantitative cytochemistry to test the effect of these substances on the generation of NADPH, which is another indicator of the potential for growth. As could be predicted by its trophic action, TSH stimulated the generation of NADPH by glucose 6-phosphate dehydrogenase. The Ig-fraction from normal subjects depressed this activity. The Ig-fraction from Graves' disease patients with goitres stimulated the generation of NADPH, whereas the Ig from patients with Graves' disease but with minimal enlargement of the thyroid gland behaved like normal Ig. A similar lack of stimulation was found with Ig from patients with Pendred's syndrome, other dyshormonogenetic goitres, and autonomous single adenomas. In all specimens tested, there was good correlation between the amount of DNA-synthesis, measured by Feulgen cytophotometry, and the activity of glucose 6-phosphate dehydrogenase activity that generated NADPH. These results support the concept that there is a distinct type of autoantibody that influences thyroid growth.

Animals↗
PubMed1982

The involvement of the pentose shunt in thyroid metabolism after stimulation with TSH or with immunoglobulins from patients with thyroid disease. II. The reoxidation of NADPH and stimulation of hormone synthesis.

Reducing equivalents derived from the tissue re-oxidation of NADPH (NADPH-diaphorase) have been implicated in the peroxidation that is involved in the organification of iodine in the production of thyroid hormones. Immunoglobulin (Ig) fractions from patients with thyroid diseases and from normal controls, in a standard dose of 125 micrograms/ml and 0.3 microunits/ml thyrotrophin (TSH) were incubated with segments of guinea-pig thyroid gland maintained in vitro. A quantitative cytochemical study was made on how these fractions influenced the enzyme activity. A good correlation was found between the ability of such Ig fractions to stimulate the NADPH-diaphorase activity and (1) the degree of hyperthyroidism in the patients and (2) the amount of T3 secreted by the thyroid segments in vitro.

Animals↗
PubMed1982

[Can growth-stimulating immunoglobulins (TGI) explain sporadic euthyroid goiters?].

IgGs capable of stimulating thyroid growth have been demonstrated (thyroid growth stimulating IgG-TGI) using a cytochemical bioassay based upon measurement of DNA synthesis in slices of guinea-pig thyroid. This activity has been confirmed by measurement of 3H-thymidine incorporation into DNA, in rat dispersed thyroid follicles cultured in suspension. Circulating TGI has been observed in patient with "simple" goitre, Graves' disease and more rarely in Hashimoto's thyroiditis. TGI titers are correlated with goitre size or lack of suppressibility by exogenous thyroid hormones rather than with thyroid function as assessed by circulating hormone levels. In patients with primary myxoedema and thyroid atrophy, existence of TGI-blocking IgGs has also been demonstrated. Existence of natural TGI has been corroborated by experimental production of a monoclonal anti-TSH receptor antibody with thyroid growth activity. These observations raise several points: --relationship of TGI to other thyroid antibodies, specially to anti-TSH receptor antibodies; --is "simple" goitre, either diffuse or nodular, an auto-immune thyroid disorder? How to explain the usual functional and structural heterogeneity of these goitres?; --metabolic relationship between DNA synthesis and activity of glucose-6-phosphate deshydrogenase involved in hormonogenesis; mechanism of the apparent uncoupling between cell multiplication and secretory activity.

Antibodies, Heterophile↗
PubMed1981

Thyroid growth-blocking antibodies in primary myxoedema.

Adult primary myxoedema is usually due to an autoimmune thryoiditis characterized by progressive shrinking of the thyroid gland, loss of epithelium, dense infiltration by sensitized lymphocytes and plasma cells with final replacement of the gland by a fibrous scar. Antibodies directed against thyroglobulin (TgHA) and microsomal antibodies (McHA), detectable years before the onset of hormonal failure, and cell-mediated immune mechanisms contribute to the pathogenesis. When 90% of the gland is destroyed, the secretion of thyroid hormones (T3/T4) falls below normal needs and pituitary thyrotrophs react by producing over 100 times the normal amount of thyroid-stimulating hormone (TSH) which should normally lead to regrowth of the gland as happens in goitrous Hashimoto thyroiditis. The inability of the thyroid in primary myxoedema to respond to the trophic action of TSH suggested that blocking antibodies exist in this disease which compete with TSH for its receptors. The trophic effect of TSH can be assayed in vitro by measuring DNA-synthesis by Feulgen cytophotometry; elevated pentose-shunt oxidative activity correlates with DNA synthesis. Here we report that immunoglobulins from patients with adult, primary myxoedema block the trophic effect of TSH, as assessed by this in vitro system. This is in marked contrast to the growth stimulation induced by immunoglobulins from patients with thyrotoxic Graves' disease with prominent goitres.

Autoantibodies↗
PubMed1981

Autoantibodies to cartilage and type II collagen in relapsing polychondritis and other rheumatic diseases.

Cartilage antibodies were demonstrated by indirect immunofluorescence (IFL) on human fetal cartilage in 6 out of 9 patients with relapsing polychondritis (RPC), in 4 out of 260 patients with rheumatoid arthritis (RA), and in only 1 out of 1016 patients with other disorders. The antibodies were specific for cartilage and evenly stained the whole cartilage matrix. They were predominantly of IgG class and varied in titres from 1:1 to 1:320. Follow-up studies in the RPC patients indicated that higher titres were present during the early acute phase of the disease. Five of the 6 positive cases had developed the disease within the past 12 months, and the 3 negative cases had had the disease for 3 to 7 years when tested. The RA cases showing positive cartilage IFL had no clinical evidence of RPC. Sequential measurements in 2 of the 4 cases showed that these antibodies became detectable some years after the onset of arthritis. Absorption studies with human type II collagen and purified porcine proteoglycan failed to remove the cartilage IFL. Antibodies to human native type II collagen were measured by an enzyme-linked immunosorbent assay. The highest levels were found in the RA sera which also displayed cartilage IFL, but the 2 tests gave discordant results. RPC sera showed the same antibody levels by this method, as did cartilage-IFL-negative RA sera, though both groups had higher mean levels than health controls. The findings that cartilage antibodies are detected in the majority of cases of RPC and only rarely in other diseases suggests these antibodies may play an important role in the pathogenesis of cartilage destruction in RPC.

Acute Disease↗
PubMed1981

Is mitochondrial antibody diagnostic of primary biliary cirrhosis?

In a series of 218 patients diagnosed as having primary biliary cirrhosis only nine exhibited a negative serum mitochondrial antibody. On examining additional specimens from these patients, seven were found to be positive, giving a final incidence of greater than 99%. The two patients whose sera remained negative for the mitochondrial antibody had liver histology compatible with the diagnosis of primary biliary cirrhosis, but a firm diagnosis could not be reached. Three additional mitochondrial antibody positive subjects who were asymptomatic and exhibited normal serum alkaline phosphatase were shown on liver biopsy to have stage I primary biliary cirrhosis. The presence of a positive serum mitochondrial antibody in a patient with or without abnormalities in liver function tests strongly suggests the diagnosis of primary biliary cirrhosis.

Adult↗
PubMed1981

Presence of the organ-specific 'microsomal' autoantigen on the surface of human thyroid cells in culture: its involvement in complement-mediated cytotoxicity.

The presence of organ-specific cell surface-reactive antibodies in sera of patients with autoimmune thyroid diseases (ATD) has been detected by indirect immunofluorescence on viable blood group O normal thyroid cultures. The cell surface determinants involved in this reaction have been identified as the thyroid 'microsomal' antigen which is thus also represented on the outer surface of the plasma membrane. The reactivity persists when F(ab')2 fragments from positive sera are used. Non-thyroid cells present in the monolayers, as well as human adrenal or fibroblast cultures, do not show positive staining. Human thyroid cells progressively lose both cell surface and intracytoplasmic antigenic components during the first week of culture. The exposure and reactivity of this antigen on the cell surface do not depend upon unmasking effects of proteolytic enzymes used for dispersal of the cells. The 'microsomal' antigen on the cell surface is also involved in the complement-mediated cytotoxic effect of sera from ATD patients on freshly dispersed thyroid cells. Thyroglobulin antibodies failed to stain viable thyroid monolayers, even when these were previously incubated with purified human thyroglobulin, indicating that this protein or possible receptors for it cannot be detected on the cell surface under these conditions. Similarly, some thyrotoxicosis sera containing thyroid-stimulating but not microsomal antibodies, gave negative reactions on viable cultures.

Adult↗
PubMed1981

Islet cell antibodies and diabetes in Nigerians.

Pancreatic islet cell antibodies and other autoantibodies were measured in 68 Nigerian diabetics and 68 non-diabetic controls matched for age and sex. Islet cell antibodies measured at the time of diagnoses, were found in only two diabetics (a male aged 20 on insulin and a male aged 41 years on tablets) out of 30 newly diagnosed cases. In 38 other cases, islet cell antibodies were found in two patients (a female aged 17 on insulin and a male aged 41 on tablets). One of the controls, a female, aged 28 years had islet cell antibodies. None of the islet cell positive diabetic or control sera were complement fixing or had other antibodies. At least one type of antibody was seen in 20.5% of the diabetics (2 parietal cell; 2 thyroid; 4 islet cell; 6 antinuclear) and in 13.2% of the controls (1 parietal; 1 islet cell; 1 glucagon; 6 antinuclear). This study shows that the division of diabetes into type I and type II on the basis of islet cell antibodies and insulin dependence as done in the Caucasian population may not generally fit the pattern of diabetes as seen in Nigeria and possibly other parts of the tropics.

Adolescent↗
PubMed1981

Surface-reactive antibodies to human adrenal cells in Addison's disease.

Organ-specific surface-reactive antibodies to viable human adrenal cell suspensions from adult or fetal glands were detected by indirect immunofluorescence (IFL) in 24 out of 28 idiopathic Addison's disease sera with adrenal cytoplasmic antibodies. Cell-surface reactions were also present in nine out of 10 cases of polyendocrine autoimmune disorders without overt adrenal failure but possessing adrenal cytoplasmic antibodies. None of 18 Addisonian patients, 25 cases with other autoimmune disorders and 10 normal individuals, all negative for adrenal cytoplasmic antibodies, showed positive surface reactions on viable cells. When the surface IFL was done on established monolayers, the positive sera gave variable staining suggesting that more than one antigen may be expressed under different conditions. These results suggest that adrenal-specific 'microsomal' antigens are also represented on the plasma membrane, and support the hypothesis that organ-specific autoantibodies reacting with the surface of living target cells may have a pathogenic role in the development of autoimmune adrenalitis.

Addison Disease↗