Models to study the pathogenesis of thyroid autoimmunity.

In vitro and in vivo models to study the pathogenesis of thyroid autoimmunity are reviewed. Animal models with experimentally induced or spontaneously developed autoimmune thyroid disease as well as transplantation models have been used extensively in these studies, but also the use of thyroid cell cultures from both humans and animals has contributed to the present state of knowledge. Cytokines may play a role in the pathogenic mechanism in thyroid autoimmunity. The major in vitro and in vivo effects of for example interleukin-1, tumour necrosis factor and gamma-interferon on differentiated thyroid cell functions are inhibitory. The advantage of using cell cultures has been the possibility of studying an influence on thyrocytes from a single agent individually, such as cytokines, hormones or growth factors. The disadvantage is that an organism is under the influence of a multitude of factors that can only be investigated in vivo in intact organisms. Both types of models have therefore been important in the understanding of thyroid autoimmunity.     

New ideas in thyroid autoimmunity

Endocrine epithelial cells do not normally express human leukocyte antigen (HLA) class II molecules, but do so in a variety of autoimmune diseases. This finding suggests the hypothesis that such inappropriate class II-positive expression may enable these cells to present autoantigens and thus contribute to autoimmune pathogenesis. Indeed, class II-positive thyrocytes can present both exogenous antigenic peptides and intrinsic autoantigens to the appropriate T cells. Class II expression by thyrocytes can be induced by interferon-gamma, and is positively and negatively regulated by thyroid-stimulating hormone and epidermal growth factor, respectively. Furthermore, heterogeneity of thyrocyte class II subregion expression appears to be related to the nature of the inducing stimulus. The complexity of regulatory signals is underlined by findings in type I diabetes: islet beta cells aberrantly express class II in this disease, but class II cannot be induced in normal beta cells by interferon-gamma.     

Developmental profiles of TSH, sex steroids, and their receptors in the thyroid and their relevance to thyroid growth in immature rats.

Sex steroids are reported to influence thyroid pathogenesis in human and experimental animals. However, there is no report on this phenomenon during the early developmental period. The mitotic activity of thyrocytes in rats reaches its peak by day 10 postpartum. Thyrocytes actively proliferate in immature rats during the first three postnatal weeks, during which the pre-pubertal rise in serum titers of testosterone and estradiol has been recorded. The aim of the present study was to analyze whether there is a physiological relevance between thyroid growth and sex steroids during the postnatal period. Serum and thyroid tissue hormones (TSH, testosterone, and estradiol) were assayed by liquid phase RIA, and receptors for these hormones were also quantified. The peak rate of thyrocyte proliferation was observed during the second postnatal week in rats. Since the concentrations of sex steroids and their receptors also reached a peak around this period, it is suggested that elevated sex steroids and their receptors in the thyroid might enhance thyrocyte proliferation. A positive correlation between thyroid growth indices and sex steroids and their receptors further strengthens this suggestion. This is a preliminary study, and further experimental study may strengthen this proposal. This is the first report to show the availability of sex steroids and their receptors in the thyroid glands of immature rats under normal conditions.     

Genetic factors in the etiology and pathogenesis of autoimmunity.

Family and population studies indicate that several different genes can increase susceptibility to autoimmune diseases. Established genetic risk factors include genes encoding histocompatibility molecules, complement proteins, immunoglobulins, peptide transporter proteins, and genes controlling the production of sex hormones. Each factor may independently enhance the immunogenicity of autoantigens, either by increasing their processing and presentation by B lymphocytes and macrophages or by increasing the chance for recognition by autoreactive T and B lymphocytes. Genetic factors may also influence immune responses to infectious agents that can trigger autoimmunity. Because of the somatic generation of immune diversity, genetically identical individuals have different immune systems. The ability of genetic diagnosis to predict autoimmune disease in outbred populations cannot easily exceed the disease concordance rates in monozygotic twins, which usually are less than 50%. However, genetic diagnosis can target populations that should be monitored for serologic evidence of autoimmunity, which may precede clinical signs and symptoms. In the future, it may be possible to match different forms of immunotherapy with specific genetic defects.     

Views on the autoimmunity hypothesis for Chagas disease pathogenesis

Initially, the notion that the pathogenesis of Chagas disease has an autoimmune component was based on the finding that sera from Trypanosoma cruzi-infected patients or laboratory animals contain antibodies that recognize both parasite and host tissue antigens. Subsequent work suggested that T lymphocytes from chagasic patients and animals also displayed such cross-reactivity. However, the autoimmunity hypothesis has remained controversial because of experimental pitfalls, incomplete or inadequate controls, difficulties in reproducing some key results, and a lack of persuasive evidence that the cross-reactive antibodies or lymphocytes can truly effect the multifaceted pathological features of Chagas disease. Whether the immunologic autoreactivities described to date cause chagasic pathology or result from it is another unresolved question. Discussed herein are the most recent contributions to this topic and the reservations they have raised.     

Most nuclear systemic autoantigens are extremely disordered proteins: implications for the etiology of systemic autoimmunity

Patients with systemic autoimmune diseases usually produce high levels of antibodies to self-antigens (autoantigens). The repertoire of common autoantigens is remarkably limited, yet no readily understandable shared thread links these apparently diverse proteins. Using computer prediction algorithms, we have found that most nuclear systemic autoantigens are predicted to contain long regions of extreme structural disorder. Such disordered regions would generally make poor B cell epitopes and are predicted to be under-represented as potential T cell epitopes. Consideration of the potential role of protein disorder may give novel insights into the possible role of molecular mimicry in the pathogenesis of autoimmunity. The recognition of extreme autoantigen protein disorder has led us to an explicit model of epitope spreading that explains many of the paradoxical aspects of autoimmunity – in particular, the difficulty in identifying autoantigen-specific helper T cells that might collaborate with the B cells activated in systemic autoimmunity. The model also explains the experimentally observed breakdown of major histocompatibility complex (MHC) class specificity in peptides associated with the MHC II proteins of activated autoimmune B cells, and sheds light on the selection of particular T cell epitopes in autoimmunity. Finally, the model helps to rationalize the relative rarity of clinically significant autoimmunity despite the prevalence of low specificity/low avidity autoantibodies in normal individuals.     

The relevance of iron in the pathogenesis of Parkinson's disease

Alterations of iron levels in the brain has been observed and documented in a number of neurodegenerative disorders including Parkinson's disease (PD). The elevated nigral iron levels observed in PD may reflect a dysfunction of brain iron homeostasis. Under normal physiological conditions excess iron can be sequestrated in ferritin and neuromelanin. Alternatively, the excess iron may represent a component of brain iron deposition associated with ageing. The aetiology of idiopathic PD largely remains an enigma. However, intensive investigations have provided a host of putative mechanisms that might contribute to the pathogenesis underlying the characteristic degeneration of the dopaminergic neurons in the substantia nigra (SN). The mechanisms proposed include oxidative (and nitrative) stress, inflammation, excitotoxicity, mitochondrial dysfunction, altered proteolysis and finally apoptotic induced cell death. Iron-mediated cellular destruction is mediated primarily via reactive oxygen or/and nitrogen species induced oxidative stress. Furthermore, these pathogenic mechanisms appear to be closely interlinked to the cascade of events leading to cellular death. There are conflicting reports about the stage during disease progression at which nigral iron change occurs in PD. Some have found that there are no changes in iron content SN in asymptomatic incidental Lewy body disease, suggesting it may represent a secondary event in the cascade of neuronal degeneration. In contrast, others have found an elevation of iron in SN in pre-clinical stages. These discrepancies may be attributed to the occurrence of different sub-groups of the disease. This concurs with the notion that PD represents a group of related diseases with a number of potential pathogenic pathways.     

The relevance of apoptosis to AIDS pathogenesis

Several recent experimental findings support the hypothesis that apoptosis induced by human immune deficiency virus (HIV) is important in the pathogenesis of acquired immune deficiency syndrome (AIDS). Thus, one potential therapeutic strategy against AIDS may be to block the HIV-mediated apoptosis signal transduction pathway. Induction of apoptosis by HIV infection may prove a useful paradigm for the pathogenesis of a wide range of diseases that involve cell depletion and tissue atrophy.     

Prevalence of coeliac disease in patients with thyroid autoimmunity.

The occurrence of autoimmune thyroid disorders among patients with coeliac disease (CD) is well documented, but the exact prevalence of CD among patients with autoimmune thyroid diseases (ATD) is as yet unclear. We screened 150 newly diagnosed patients with ATD by serum endomysial antibody detection (EmA). In 5 subjects (3.3%) EmA positivity was found; all underwent jejunal biopsy. On gluten-free diet an excellent clinical and histological response was recorded with an improvement of hypothyroidism and reduction of the thyroxine dosage. Our data suggest a significant high prevalence (3.3%) of CD in patients with ATD, in particular with Hashimoto's thyroiditis.     

Neuroses and their pathogenesis

History and current state of the problem of experimental neuroses are reviewed in this article. The presented results of neurochemical, structural, and electroencephalographic investigations unravel earlier unknown aspects of the disease. Thus, circulatory cerebral hypoxia, as a principally new stage discovered for the first time in the development of an experimental neurosis allows the pathogenetically substantiated treatment with antioxidants to be applied in animal experiments and in clinical therapy of neurotic patients.     

Mechanisms and pathogenesis of thyroid cancer in animals and man

The transformation of the normal fully differentiated thyroid follicular cell to the rapidly growing undifferentiated anaplastic thyroid carcinoma cell involves a number of stages which have been defined morphologically and are now being related to various growth pathways and to molecular biological defects. The two main factors involved in this transformation are growth stimulation and mutagenesis. Growth stimulation alone, through elevated TSH, can lead to the development of thyroid tumours, usually benign, and retaining TSH dependency in some cases. Mutagens alone, if growth is suppressed, do not produce tumours, the combination of mutagens and increased growth is a potent carcinogenic regime. Non-genotoxic carcinogenesis in the thyroid involves growth, without mutagenesis the agent often causes this through affecting one component of thyroid hormone synthesis or metabolism, leading to a fall in thyroid hormone levels and a rise in TSH. Growth stimulation increases the rate of cell division, and therefore increases the chance of a mutation. Continued growth increases the change of subsequent events, in particular loss of heterozygosity in a tumour suppressor gene. The main oncogenes involved in human thyroid carcinogens are ras in the follicular tumour pathway, and ret in the papillary carcinoma pathway. p53 is involved in the progression of either papillary or follicular adenoma to an undifferentiated carcinoma. In experimental thyroid carcinogenesis, ras is again involved, with a link between the mutagenic agent used and the type of ras gene showing mutation. Analysis of the involvement of different growth factors and oncogenes in thyroid carcinogenesis suggests that genes related to the two receptors concerned with normal TSH stimulated growth, TSH receptor and the IGF1 recpptor may be involved in the progression of thyroid tumours of follicular pathology. Several tyrosine kinase receptors with unknown ligands or of uncertain physiological function are linked to papillary carcinoma. The recent large increase in papillary carcinoma of the thyroid in children exposed to fallout from the Chernobyl nuclear accident underlines the importance of understanding the pathobiology of thyroid neoplasia.