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Biomedical subjects

Jack R Wall

Publications and source records attributed to Jack R Wall.

10 recordsLinked to original sources
PubMed2006

Study of serum antibodies against three eye muscle antigens and the connective tissue antigen collagen XIII in patients with Graves' disease with and without ophthalmopathy: correlation with clinical features.

OBJECTIVE: The extraocular muscles are one of the primary tissues implicated in the autoimmune-mediated inflammation of thyroid-associated ophthalmopathy (TAO). Our aim was to determine the prevalence and level of antibodies against three candidate eye muscle antigens and the orbital fibroblast membrane antigen collagen XIII, in well-characterized patient groups. STUDY DESIGN AND PATIENTS: The study cohort consisted of patients with Graves' hyperthyroidism with and without ophthalmopathy, controls patients with other thyroid or other autoimmune disorders and healthy subjects. The presence of eye muscle antibodies was determined using an optimized and standardized enzyme-linked immunosorbent assay. We measured antibodies against (i) the 67-kDa flavoprotein (Fp) subunit of the mitochondrial enzyme succinate dehydrogenase; (ii) G2s, a 141 amino acid fragment of the winged-helix transcription factor FOXP1; (iii) calsequestrin, a 63-kDa calcium-binding protein; and (iv) collagen XIII, a connective tissue protein that is closely linked to the congestive ophthalmopathy subtype of TAO. Eye muscle antibody levels were correlated with clinical diagnosis and presence or not of ophthalmopathy. RESULTS: Prevalences of positive antibody tests to calsequestrin (75.0%) and collagen XIII (43.8%) were significantly greater in Graves' disease (GD) patients with ophthalmopathy than in healthy subjects, whereas modest significance was demonstrated with antibodies against Fp, but not G2s. Significantly greater serum levels of antibodies against calsequestrin, G2s, and collagen XIII, but not Fp, were found in GD patients with ophthalmopathy compared to control patients without eye disease and healthy subjects. CONCLUSIONS: Calsequestrin and collagen XIII antibodies are the most specific to TAO, whereas antibodies against G2s, and to a lesser extent Fp, are also markers of ophthalmopathy, but less reliable. These results are unique in that it is the first time the significance of a panel of three candidate eye muscle antibodies and a connective tissue antibody have been evaluated in the same patients with ophthalmopathy.

Adult↗
PubMed2005

Acute delirium in the setting of primary hypothyroidism: the role of thyroid hormone replacement therapy.

Psychiatric illness, mostly mania and psychosis, are reported to occur after rapid normalization of thyroid function in patients with primary hypothyroidism. It is generally believed that the gradual restoration of thyroid function may reduce the risk of psychiatric complications. This case report describes the occurrence of acute delirium in a 67-year-old man with primary hypothyroidism shortly after the initiation of thyroid hormone replacement. The use of low-dose thyroxine initially and persistent severe biochemical hypothyroidism on presentation with psychiatric symptoms illustrate that psychiatric illness can still occur despite unaggressive thyroid hormone replacement. A temporal relationship with the initiation of thyroxine and rapid recovery of mental state over 1 to 2 weeks differentiate this condition from hypothyroidism-related psychopathology, which tends to have a more prolonged course.

Aged↗
PubMed2004

Stress and thyroid autoimmunity.

While many studies have shown a connection between stress and autoimmune disease, most of the evidence for stress contributing to the onset and course of autoimmune disease is circumstantial and the mechanisms by which stress affects autoimmune disease are not fully understood. The best circumstantial evidence for an effect of stress on autoimmune thyroid disease is the well-known relationship between the onset of Graves' hyperthyroidism and major stress but even this is debated. However, most of the recent case-control studies have supported stress as a factor that affects the onset and clinical course of Graves' disease. On the other hand, there have been few reports concerning the possible relationship between stress and Hashimoto's thyroiditis. Because the onset and course of Hashimoto's thyroiditis is generally insidious, the effect of stress on Hashimoto's thyroiditis might be overlooked. Numerous human and animal studies have demonstrated that psychological and physiologic stressors induce various immunologic changes. Stress affects the immune system either directly or indirectly through the nervous and endocrine systems. These immune modulations may contribute to the development of autoimmunity as well as the susceptibility to autoimmune disease in genetically predisposed individuals. Stress can be one of the environmental factors for thyroid autoimmunity.

Animals↗
PubMed2003

Relationship between longitudinal behaviour of some markers of eye autoimmunity and changes in ocular findings in patients with Graves' ophthalmopathy receiving corticosteroid therapy.

OBJECTIVE: To investigate whether variations over time of TSH-receptor antibodies (TRAb) and antibodies against G2s (G2sAb) and extraocular muscles (EMAb) can predict worsening of ophthalmopathy in Graves' patients treated with intravenous glucocorticoid (IVGC) therapy. PATIENTS: Of 65 consecutive patients with treated Graves' disease and severe and active ophthalmopathy (GO) chosen to undergo IVGC treatment, only 57 patients, persistently euthyroid under methimazole therapy, were studied longitudinally for ocular parameters, TRAb, G2sAb and EMAb before therapy, at the end of therapy and, subsequently, every month for 21 months. MEASUREMENTS: TRAb was detected by radioimmunoassay (RIA), G2sAb by enzyme-linked immunosorbent assay (ELISA) and EMAb by indirect immunofluorescence. RESULTS: Forty-three out of 57 patients (75.4%, group 1) responded positively to therapy [improvement in diplopia and decrease in proptosis and clinical activity score (CAS)] but 14 (24.6%) did not (group 2). During follow-up after IVGC therapy, 12 out of 43 patients in group 1 (28%) showed a worsening in GO (group 1a), while 31 (72%) had stable ocular conditions or further improvement (group 1b). At the start of the study, TRAb, G2sAb and EMAb were not significantly different among the three groups. At the end of IVGC therapy TRAb levels decreased significantly with respect to starting values in all three groups of patients, whereas G2sAb and EMAb decreased significantly in groups 1a and 1b but not in group 2. During the subsequent follow-up, 10 patients in group 1a one/two months before and all 12 patients at the time of GO worsening showed an increase in G2sAb and EMAb but not in TRAb, which were consistently absent or present at low titre in all patients in this group. In group 1b TRAb, G2sAb and EMAb further decreased or became negative during the follow-up period. In all patients, TRAb were positively correlated with both CAS and proptosis only at the start of the study; by contrast, a significant correlation between both G2sAb and EMAb and diplopia was observed in groups 1a and 1b at all the times during the study, except one/two months before the worsening of GO in group 1a. CONCLUSIONS: Our results indicate that TRAb, G2sAb and EMAb can be considered sensitive markers of Graves' ophthalmopathy during the initial stages of ophthalmopathy, but that only G2sAb and EMAb seem to be good predictive markers of the outcome in patients after corticosteroid therapy. Thus, taking into account the cost/benefit ratio, a longitudinal evaluation of either EMAb or G2sAb could be useful in monitoring the intravenous glucocorticoid therapy in patients with severe and active ophthalmopathy to predict a possible worsening of Graves' ophthalmopathy.

Adult↗
PubMed2002

Classification and prediction of the progression of thyroid-associated ophthalmopathy by an artificial neural network.

OBJECTIVE: We have used an artificial neural network in an attempt to classify and predict the progression of thyroid-associated ophthalmopathy (TAO) at the first clinical examination. DESIGN: This retrospective comparative case series included a group of patients examined by the ophthalmologist only once because of the absence of signs of progressive disease (GR1), as subsequently monitored by an endocrinologist, and a group of patients on follow-up because of progressive disease (GR2). PARTICIPANTS AND METHODS: We examined 242 patients, of whom 207 were women and 35 were men. GR1 included 129 patients (257 eyes) who, on ophthalmologic assessment, were further classified as having no TAO (n = 53; GR1a) and only lid signs or inactive, stable TAO (n = 76; GR1b). GR2 included 113 patients (219 eyes). One hundred three normal subjects (205 eyes), 50 women and 53 men, were tested to provide normal ranges for proptosis values. We applied a model of back propagation neural network with 17 input variables, a training matrix of 414 observations, a randomly selected test group of 115 observations, and, as output, the progression of disease. The ophthalmologic assessment included (1) lid fissure measurement, (2) Hertel, (3) color vision, (4) cover test and Hess screen, (5) visual acuity, (6) tonometry, (7) fundus examination, (8) visual field, and (9) orbital computed tomography scan or ultrasonography. Other parameters included in the neural analysis were gender and age of the patients, their cigarette smoking, and the interval between follow-up visits. RESULTS: The prevalence of smokers among patients without TAO was significantly lower than that among those with TAO (P < 0.03). Mean proptosis values (Hertel) were significantly different in GR1, in GR2, and in a group of normal eyes (P < 0.0001), and the changes of values in consecutive measurements were associated with progression of the disease (P < 0.01). Differences of the proptosis values in the two groups of patients were not related to smoking. The neural network correctly classified 78.3% of 115 eyes (87 patients) and predicted TAO progression in 69.2% of 39 eyes (28 patients). CONCLUSIONS: In our opinion, neural network analysis can be successfully applied for classifying TAO and predicting progression at the first clinical examination.

Adolescent↗
PubMed2002

Experimental model for ophthalmopathy in BALB/c and outbred (CD-1) mice genetically immunized with G2s and the thyrotropin receptor.

In an attempt to develop an animal model for thyroid-associated ophthalmopathy (TAO) we have genetically immunized BALB/c and outbred (CD-1) mice with cDNAs encoding the thyroid and eye muscle shared protein G2s and full length human thyrotropin receptor (TSHr). Firstly, BALB/c mice were immunized with cDNAs for G2s and the TSHr, alone or in tandem with cDNAs for interleukin (IL)4 or IL12. Control mice were immunized with empty vehicle only. Sera from the great majority of experimental mice contained antibodies against a G2s fusion protein and the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase, the "64 kDa protein", with the greatest levels being found at sacrifice (17 wk). Antibody levels in mice immunized with G2s + TSHr or G2s + IL12 were generally higher than those in mice immunized with G2s only. TSHr antibodies (TRAb), measured as TSH binding inhibition, were detected in only two mice. On histological examination of the orbits, mild edema, eye muscle fiber separation and mast cell infiltration in and around the eye muscles were found in the majority of experimental mice, but not in control mice. Splenocytes were transferred from selected G2s-immunized mice to normal syngeneic litter mates. None of the transfer mice had serum antibodies against G2s, Fp or TSHr but their orbital tissue showed the same degree of mast cell infiltration as primary mice. No major histological changes were observed in the thyroid or other skeletal muscle in either primary or transfer mice. Similar results were observed in CD-1 mice although, overall, the model was better expressed than in BALB/c mice. In these mice, serum anti-G2s antibody levels were not significantly different between the various experimental groups except at 16 wk, when they were slightly greater than in control animals. Anti-Fp antibodies were detected at 12, 14 and 16 wk, in all experimental groups, including those immunized with G2s only, and were greatest in mice immunized with TSHr alone. TRAb levels were greatest in mice immunized with both G2s and the TSHr in the presence of TL4, but not IL12. The finding of negative anti-G2s but positive anti-Fp antibodies in some CD-1 mice suggests that eye muscle damage and Fp release must have been mediated by T lymphocytes, rather than antibodies, targeting G2s or some other as yet unidentified cell membrane antigen. Histological changes in the orbit were similar to those observed in BALB/c mice although mast cell numbers were greater, in both primary and transfer mice. Overall, the greatest histological changes were observed in CD-1 mice immunized with both G2s + TSHr + IL4. None of the animals became overtly hyperthyroid or hypothyroid during the course of the study although several of the CD-1 mice had abnormal TSH or T4 levels. These results indicate that we have established a valid model for human ophthalmopathy using the novel thyroid and eye muscle expressed protein G2s, now recognized as a fragment of the winged-helix transcription factor Foxp1, and TSHr, and that G2s and the TSHr are both primary antigens in TAO. Reactivity against a TSHr-like protein may be the first event leading to ophthalmopathy in humans with TAO and experimental mice and eye muscle damage may result from autoimmunity against G2s and Fp as a result of "antigen spreading".

Animals↗
PubMed2002

T-cell-mediated immunity in thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is considered to be an autoimmune inflammatory disorder of the extraocular muscles and the orbital fat/connective tissue. Recent studies analyzing T cells infiltrating retrobulbar tissues generated important insights into the immunopathogenesis of TAO. The present review focuses on advances in our understanding of mechanisms responsible for the autoimmune inflammation in TAO, especially T cell migration to the inflammatory site, T cell activation by autoantigens and costimulatory signals and their cytokine profile. The elucidation of these processes might lead to the development of novel therapeutic strategies directed against autoreactive T cells.

Graves Disease↗