Autosomal dominant inheritance of the tendency of develop thyroid autoantibodies.
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Adult↗
Biomedical subjects
D I Phillips
Publications and source records attributed to D I Phillips.
Severe combined immunodeficient (SCID) mice: a model for investigating human thyroid autoantibody synthesis.
We have studied the ability of lymphocytes from the blood, thyroid and lymph nodes of patients with autoimmune thyroid disease (AITD) to produce autoantibodies to thyroglobulin (Tg) and/or thyroid peroxidase (TPO) in SCID mice. Human IgG class Tg and/or TPO antibodies were detectable in plasma from SCID mice 7 days after transfer of 15-25 x 10(6) cells/mouse and the highest levels were recorded 2-3 weeks later. In contrast, Tg and/or TPO antibodies were undetectable in recipients of lymphocytes from thyroid antibody negative controls. AITD thyroid lymphocytes produced the most antibody in recipient mice and lower levels were observed in recipients of AITD blood and lymph node lymphocytes. The amounts of Tg and/or TPO antibody detected were in accordance with the ability of thyroid and lymph node lymphocytes to secrete these autoantibodies spontaneously in culture (indicating the presence of cells activated in the patient) and with the capacity of blood lymphocytes (probably B memory cells) to secrete Tg and/or TPO antibodies in culture in response to pokeweed mitogen. Tg antibodies in plasma from SCID recipients of thyroid lymphocytes were of subclasses IgG1, IgG2 and IgG4 and the proportions closely resembled those of the donor's serum Tg antibodies. Blood lymphocytes transferred to SCID recipients were also able to produce Tg antibodies of subclasses 1, 2 and 4 but the subclass distribution varied between mice and the reason for this is not clear at present. Since SCID mice provide an environment in which B lymphocytes from patients with AITD can be activated without mitogen to secrete thyroid antibodies, this model will provide a powerful system for elucidating the mechanisms regulating the secretion of human antibodies to Tg and TPO.
Animals↗
Effect of low dose iodide supplementation on thyroid function in potentially susceptible subjects: are dietary iodide levels in Britain acceptable?
OBJECTIVE The aim of the study was to evaluate the risk of exposure to an increase in dietary iodide intake amongst potentially susceptible population groups in Britain. DESIGN A randomized controlled trial was performed in healthy women and in women with underlying thyroid abnormalities due to subclinical Hashimoto's thyroiditis (diagnosed on the basis of antithyroid antibodies) or previous iodide deficiency of supplementation with 500 micrograms/day iodide (giving a total intake of approximately 750 micrograms/day) for 28 days versus placebo. PATIENTS Two hundred and twenty-five women aged 25-54, randomly selected from a general practice in Cardiff, were screened for thyroid microsomal antibody. Antibody positive women (n = 20), and antibody negative controls (n = 30) were recruited into the trial comparing iodide and placebo. In addition, groups of patients aged 60-75 randomly selected from the Cardiff practice (n = 29), an iodide sufficient area, and a practice in Dowlais (n = 35), a previously iodide deficient area, were also enrolled into the trial. MEASUREMENTS Changes in free thyroxine and thyrotrophin levels were measured after 14 and 28 days of iodide supplementation. RESULTS All the iodide supplemented groups responded in the same way with a small fall in free thyroxine and rise in thyrotrophin levels (combined fall in free thyroxine 14 days after the start of supplementation -1.22 (95% confidence interval -0.59 to -1.84) pmol/l and at 28 days -0.86 (-0.30 to -1.43) pmol/l and rise in thyrotrophin at 14 days 0.55 (0.19 to 0.92) mU/l and at 28 days 0.59 (0.12 to 1.07) mU/l). In two of the iodide supplemented subjects thyrotrophin levels rose above the laboratory reference range and in a further three subjects initially elevated thyrotrophin values increased further. In contrast, no changes in thyroid function were observed in the placebo treated controls and none developed biochemical hypothyroidism. CONCLUSIONS Dietary iodide intakes of 750 micrograms/day or more may adversely affect thyroid function, especially in individuals with borderline hypothyroidism.
Adult↗
Smoking, humoral immunity, and ulcerative colitis.
Since ulcerative colitis predominantly affects non-smokers and ex-smokers we have examined the possibility that smoking modifies the humoral immune response to an antigenic challenge from the gut lumen. Gut lavage was used in healthy subjects and patients with ulcerative colitis, including both smokers and non-smokers. Antibodies in the intestinal fluid to Escherichia coli (five pooled serotypes), Candida albicans, gliadin, ovalbumin, and beta lactoglobulin were measured by ELISA to determine specific antibody concentrations of IgG, IgA, and IgM classes. Total IgG, IgA, and IgM were also measured in intestinal secretions and serum. In addition, circulating antibody concentrations of IgG, IgA, and IgM to three gut commensals - E coli (five pooled serotypes) C albicans, and Poroteus mirabilis were measured. There was a significant reduction in the IgA concentration in intestinal fluid of smokers with ulcerative colitis compared with healthy non-smoking controls. No other significant differences were found between the groups. Overall, these data are not consistent with the idea that smoking suppresses immune responses in the gut and suggest that the effect of smoking in colitis is mediated by another mechanism.
Adult↗
Papilloedema and cranial nerve palsies complicating apparent benign aseptic meningitis.
Three patients who presented with apparently uncomplicated aseptic meningitis subsequently developed papilloedema and sixth cranial nerve palsies between 11 and 16 days after the onset of the illness. All three patients recovered completely without treatment. Raised intracranial pressure is a poorly recognized complication of aseptic meningitis that may represent a post-infective or 'allergic' response to an enteroviral infection. While clinicians should be aware of this possible complication of aseptic meningitis, differentiation from tuberculous meningitis may be difficult necessitating empirical treatment with anti-TB drugs.
Abducens Nerve↗
Thyroid autoantigens and human T cell responses.
We investigated the ability of T cells from patients with Hashimoto's thyroiditis and with Graves' disease as well as control donors to proliferate in response to thyroid peroxidase (TPO) and thyroglobulin using (i) lymphoid cells from different lymphoid organs; (ii) unfractionated or CD8- depleted lymphoid suspensions or T cells + autologous low density cells (LDC); (iii) 200-microliters well cultures and 20-microliters hanging-drop microcultures; and (iv) intact TPO and thyroglobulin, denatured thyroglobulin and 12 synthetic peptides predicted on the basis of the amino acid sequence of TPO to be T cell epitopes. In 200-microliters well cultures, proliferative responses (assessed in terms of 3H-thymidine uptake) to intact TPO or thyroglobulin, digested thyroglobulin or synthetic TPO peptides were not significantly different in unfractionated or CD8-depleted lymphoid suspensions from blood, thyroid or lymph nodes of TPO/thyroglobulin autoantibody-positive patients, autoantibody-negative patients or control donors. In contrast, blood T cells from some high titre patients with Hashimoto's thyroiditis (but not from healthy individuals) proliferated in response to intact thyroglobulin or TPO presented by autologous LDC in hanging-drop microcultures. Heat denatured thyroglobulin (with which thyroglobulin autoantibodies do not interact) did not stimulate proliferation and this observation, together with the ability of T cells from some patients to respond to intact thyroglobulin in the absence of LDC, indicated that thyroglobulin-specific B cells may be involved in antigen presentation. As we were unable to demonstrate proliferation by blood T cells + LDC from all thyroglobulin antibody-positive patients with Hashimoto's thyroiditis, our studies suggest that the presence of sufficient precursor T cells, as well as the number and type of antigen-presenting cells, are critical for T cell proliferative responses to human TPO and thyroglobulin.
Antigen-Presenting Cells↗
The influence of pregnancy and reproductive span on the occurrence of autoimmune thyroiditis.
A study comparing the reproductive histories of 89 women affected by Hashimoto's thyroiditis (HT) with 89 matched controls has been carried out to determine whether endogenous hormones contribute to the development of the disease. There was no evidence of an association between HT and parity and no trend to an increasing disease risk with increasing parity. However, patients with HT had a longer reproductive span. There was a significant trend to a lower risk with later age at menarche (relative risk (RR) of menarche at 13-14 years compared with less than or equal to 12 years = 0.71, and greater than or equal to 15 years compared with less than or equal to 12 years = 0.45), and an increased risk with a later menopause (greater than or equal to 51 years compared with less than or equal to 50 years, RR = 3.00, P less than 0.025). An additional finding was an increased hysterectomy rate among the cases. These observations may be explained if the hyperoestrogenic state associated with a longer reproductive span acted to modulate the immune process in autoimmune thyroid disease.
Adolescent↗
A long-term follow-up of postpartum thyroiditis.
To investigate the long-term outcome of postpartum thyroiditis (PPT), 43 patients with PPT and 171 control women were evaluated 3.5 (range 2-4) years postpartum. Ten (23%) PPT patients were hypothyroid compared to none of the controls (P less than 0.001). Factors associated with the development of hypothyroidism were high antimicrosomal antibody titre measured at 16 weeks gestation (P less than 0.01), severity of hypothyroid phase of PPT, multiparity, and a previous history of spontaneous abortion. The presence of microsomal antibody but no PPT in one pregnancy did not prevent the occurrence of PPT in the next pregnancy in two patients and a further five patients had PPT in two successive pregnancies. There was no association between HLA haplotype, family history of thyroid disease, smoking or frequency of oral contraception, and the development of long-term hypothyroidism after PPT. It is concluded that permanent hypothyroidism is an important sequel to PPT and patients with PPT should be followed up appropriately.
Adult↗
Geographical distribution of subclinical autoimmune thyroid disease in Britain: a study using highly sensitive direct assays for autoantibodies to thyroglobulin and thyroid peroxidase.
In order to determine whether the geographical distribution of autoimmune thyroid disease in Britain is influenced by the pattern of iodine intake, the prevalence of subclinical disease (detectable antithyroid antibodies in biochemically euthyroid individuals) has been measured in female blood donors from seven towns in England and Wales previously characterised in terms of past and present iodine intake. Thyroglobulin antibody and thyroid peroxidase antibody were measured by highly sensitive assays which are based on the direct interaction between antibody and radiolabelled antigen. Excluding cases of overt thyroid disease (biochemically hypo- or hyperthyroid with thyroid antibodies), the overall prevalences of the antibodies in sera from the 698 female blood donors were 17.8% for thyroglobulin antibody and 17.8% for thyroid peroxidase antibody. Both antibodies were found in 12.3% of the female blood donors. In contrast, the prevalences of thyroglobulin antibody and thyroid peroxidase antibody were 41 and 43%, respectively, in the 117 female relatives of 18 probands with autoimmune thyroid disease, but the highest prevalences were observed in groups of women patients with Graves' disease (N = 39) or Hashimoto's disease (N = 39) (51, and 97% for thyroglobulin antibody, respectively, and 72 and 97% for thyroid peroxidase antibody, respectively). Antibody prevalence increased with age in the female blood donors rising from 10.6% at age 18-24 to 30.3% at age 55-64 for thyroglobulin antibody and from 14.9% at age 18-24 to 24.2% at age 55-64 for thyroid peroxidase antibody. Geographical differences in the prevalences of both antibodies were not significant and did not correlate with either the previous goitre prevalence or with current differences in iodine intake.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Potential role of PHA in producing human monoclonal thyroid autoantibodies of different subclasses.
A human monoclonal autoantibody to thyroglobulin (Tg) of subclass IgG2 was developed by fusing a mouse myeloma with Tg antibody secreting Epstein-Barr virus (EBV)-infected B lymphocytes from a Hashimoto patient. Subsequent studies showed that EBV-infected B lymphocytes from this patient synthesized IgG2 Tg antibody while unfractionated blood lymphocytes cultured with pokeweed mitogen secreted IgG1, IgG2, and IgG4 Tg antibodies in amounts proportional to those present in the patient's serum. To investigate this discrepancy further, we cultured EBV-infected lymphocytes from blood, lymph nodes, and thyroid tissue in medium alone and with increasing concentrations of PHA. In individuals with thyroid autoantibodies predominantly of subclass IgG1, PHA enhanced the levels of total Tg antibody synthesis without affecting the IgG subclass distribution. However, in patients with serum autoantibodies of subclasses IgG1, 2, and 4, the increased levels of total Tg antibody synthesis were associated with increased amounts of thyroid autoantibodies of all of these subclasses; in some instances IgG1 and IgG4 autoantibodies were only synthesized in cultures containing PHA. These observations suggest that addition of the T-cell mitogen PHA to cultures of EBV-infected lymphocytes may ensure activation of B-cell precursors committed to synthesizing the IgG subclasses characteristic of serum antibody in the lymphocyte donor. Since Tg antibodies of subclasses IgG2 and IgG4 recognize different epitopes on Tg, the ability to produce human monoclonal antibodies of different IgG subclasses may simultaneously ensure the development of antibodies to different epitopes on the same antigen.
Animals↗
Autoantibodies to thyroglobulin and thyroid peroxidase in blood spots measured with a sensitive, direct radioimmunoassay.
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Autoantibodies↗
Iodine supplementation with oral or intramuscular iodized oil. A two-year follow-up of a comparative trial.
A controlled trial of iodine supplementation comparing oral with intramuscular iodized oil has been carried out in an iodine deficient area of Zaire. Two years after the administration of 2 ml of oral iodized oil to the population of four villages the overall goitre prevalence had fallen from 64 to 54%. In a further two villages given 2 ml of intramuscular oil the prevalence fell from 65 to 50%. The effectiveness of supplementation was also assessed by measuring changes in thyroid function in women of reproductive age. Among women in the villages given oral iodized oil, the geometric mean thyroxine concentration, measured in dried bloodspots, rose from 27.2 to 52.6 nmol/L at the two-year follow-up. This was similar to the response of the intramuscularly treated villages in which thyroxine levels rose from 32.1 to 65.4 nmol/L. There was no change in goitre prevalence or thyroid function in two control villages. Oral iodized oil is a cheaper and simpler alternative to the injected form providing effective iodine prophylaxis for up to two years after a single dose.
Administration, Oral↗
The influence of T cell depletion on recovery of T cell proliferation to herpesviruses and Candida after allogeneic bone marrow transplantation.
To test the influence of T cell depletion of the marrow in allogeneic bone marrow transplantation on functional T cell recovery, in vitro lymphocyte proliferation tests (LPTs) to microbial antigens were regularly performed in 23 recipients of normal BM and in 25 patients receiving BM with a fixed low number of T cells (1 x 10(5) T cells/kg body weight; recipients of T-depleted BM). The long-term recovery of positive LPT to at least 1 of the 4 tested microbial antigens--Candida, herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus--was nearly similar in both groups: 16/23 versus 18/25. Recovery of LPT to Candida and HSV in the first 3 months appeared to be greatly influenced by prophylactic measures; only 2/23 recipients of normal BM, receiving amphotericin B, showed a positive LPT to Candida versus 13/25 recipients of T-depleted BM (P less than 0.01). In contrast, only 1/23 seropositive recipients of T-depleted BM, receiving acyclovir, showed a positive LPT to HSV versus 9/22 recipients of normal BM (P less than 0.05). A positive LPT to CMV in the first 3 months was found in 9/9 seropositive recipients of normal BM, versus in 5/11 seropositive recipients of T-depleted BM (P less than 0.05). Five of the 6 patients with a negative LPT died of CMV-interstitial pneumonia versus 1/14 with positive LPT (P less than 0.01). We conclude that in CMV-seropositive recipients of allogeneic BM, T cell depletion of the graft affects the early recovery of T cell proliferation to CMV, which is associated with a higher risk of fatal CMV-interstitial pneumonia.
Antigens, Fungal↗
The effect of theophylline on thyrotoxic tremor.
1. The effect of intravenous aminophylline on theophylline-induced tremor were studied in six hyperthyroid patients before and after treatment to euthyroidism. 2. Baseline tremor power was significantly greater in the hyperthyroid compared with the euthyroid state (P less than 0.05). 3. Aminophylline produced a significantly greater increase in tremor power in the hyperthyroid compared with euthyroid state. 4. There was a significant increase in plasma theophylline clearance and reduction in t1/2 elimination when patients were hyperthyroid but volume of distribution did not change. 5. Intravenous aminophylline potentiates the tremor produced in hyperthyroidism despite an increase in plasma theophylline clearance. A pharmacodynamic mechanism is therefore likely.
Aged↗
Does infection initiate Graves disease? A population based 10 year study.
In order to detect whether micro-organisms could initiate the autoimmune process in Graves' disease we have studied the temporal and spatial distribution of 857 cases of hyperthyroidism occurring in a community over ten years. Cases were identified through biochemistry laboratory records and following the exclusion of patients with toxic nodular goitre or with insufficient clinical data there were 599 with Graves' disease--an average annual incidence of 15.9 per 100,000. There was a tendency for cases to present in the summer months. The reported onset of symptoms, however, peaked in December and June. There was no evidence of clustering of cases in space and time using two different statistical methods. Incidence rates doubled between 1976 and 1980 and then declined--a trend that could neither be explained by changes in laboratory or clinical diagnosis nor did it correlate with any pattern of microbial disease in the area. We conclude that it is unlikely that infections that behave in an epidemic manner have a causative role in triggering Graves' disease.
Adolescent↗
A human-mouse hybridoma which secretes monoclonal thyroglobulin autoantibody with properties similar to those of the donor patient's serum autoantibody.
Human monoclonal antibodies produced by Epstein Barr (EB) virus transformation and/or cell fusion are frequently IgM antibodies which tend to cross react with a range of antigens and often bear little relationship to the highly specific IgG antibodies associated with human autoimmune disease. By fusing EB virus transformed B lymphocytes from a Hashimoto patient with a mouse myeloma line and selecting for synthesis of IgG class thyroglobulin (Tg) antibody, we have developed a hybridoma (VB/5) secreting Tg antibody of IgG2 subclass and lambda light chain type which has the characteristics of a monoclonal antibody on isoelectric focussing. The antibody has a high affinity for human Tg and recognises Tg from other primates but not non-primate Tg. However, it does not react with human thyroid peroxidase or a panel of other autoantigens. In terms of affinity constant, functional affinity and affinity heterogeneity, the antibody closely resembles the IgG2 lambda Tg antibody present in the serum of the Hashimoto patient whose B lymphocytes were used to develop the hybridoma. In addition to providing a useful reference standard for Tg antibody IgG subclass assays, VB/5 antibody and the hybridoma line provide a valuable starting point for detailed studies of Tg autoantibodies and the genes coding for the variable regions of their heavy and light chains.
Animals↗
A clinical evaluation of the Accutracker--a lightweight ambulatory blood pressure monitor.
An evaluation of the 'Accutracker', a new lightweight ambulatory blood pressure monitor, has been carried out in 14 subjects. Using a cross-over study design, BP readings obtained by the monitor were compared with BP measurements carried out in the opposite arm by a random zero sphygmomanometer. Both the systolic and diastolic blood pressures obtained by the 'Accutracker' were lower than the corresponding mercury sphygmomanometer readings (mean bias -5.6 and -7.0 mmHg respectively). The reproducibility of the monitor readings was significantly and substantially poorer than those obtained with the sphygmomanometer even when machine-flagged suspect values were excluded from the analysis. The results suggest that the data obtained from this device should be interpreted with caution.
Adult↗
Endemic goitre and iodine deficiency disorders--aetiology, epidemiology and treatment.
Disorders caused by iodine deficiency continue to be a major health problem in many underdeveloped areas of the world. The most significant is the impaired mental and physical development which occurs as a result of iodine deprivation early in life. Individuals in affected communities show a spectrum of abnormalities which can be attributed to two interacting pathological processes. Fetal hypothyroidism in the first and early second trimester predominantly affects the developing nervous system causing deaf-mutism and mental retardation. If hypothyroidism occurs in the early postnatal period the main abnormalities are growth stunting and related somatic abnormalities. Subclinical deficits of intellectual and motor development may also be found in apparently normal individuals living in affected areas. Although dietary iodine deficiency is clearly the major aetiological factor in both endemic goitre and cretinism, cofactors such as goitrogens, other trace element deficiencies and immunological mechanisms may greatly modify the expression of these disorders. Iodine supplementation programmes form the basis of the public health strategy in combatting these disorders. Where the iodization of foodstuffs is not feasible, an alternative is the use of iodine containing oil which can be given orally or intramuscularly to provide a long-lasting supply of iodine.
Goiter, Endemic↗