In 1991, Lynne Burek published a brief commentary in the 75th anniversary issue of the American Journal of Epidemiology entitled, “The Interaction of Basic Science and Population-Based Research: Autoimmune Thyroiditis as a Case History” (1). He traced the pathways that led us from fundamental investigations in the laboratory to population studies designed to determine the factors that predict the risk of autoimmune thyroid disease before the onset of diagnostic clinical signs. In the present article, He will especially comment on the changes in the field that mark the transition into the 21st century, which reflect a combination of broadly based systematic research.
The autoimmune diseases, which collectively affect more than 20 million Americans, are clinically diverse but share a fundamental etiology: a self-reactive adaptive immune response. By definition, these diseases are distinguished by the presence of B cells and T cells that recognize antigens present in the body of the host, in the form of self-reactive antibodies or T cells. In recent years, a related group of diseases has been described as sharing many of the same inflammatory mediators but lacking self-reactive lymphocytes, which are often to referred as “auto-inflammatory responses,” and these disorders usually have a clear genetic component and evidence of activation of innate immune system. According to epidemiologic studies, the incidence rates of autoimmune disorders is increasing in industrialized countries, which probably reflects some environmental changes. In addition, greater attention has been directed to these diseases because of improved diagnostic procedures and therapeutic interventions. However, for any of them, there is essentially no definitive cure. A common feature of most autoimmune diseases, is that they develop gradually, so serious tissue damage might occur before the clinical diagnosis diseases. This observation strengthens the efforts to diagnose autoimmune diseases earlier in their courses before irreversible damage occurs. These studies are interdisciplinary in nature and require the combined efforts of immunologists, epidemiologists, environmental scientists, geneticists, and clinicians. In the past decades, such collaborative teams have conducted many researches on autoimmune diseases.
The primary early risk factors for induction of an autoimmune response have been identified in the genes of the major histocompatibility complex (MHC) (2). Heightened susceptibility depends on potent activation of self-antigen–specific T lymphocytes by antigen-presenting cells bearing the same MHC. In sub-sequent studies of thyroiditis in humans, an autoimmune response to particular epitopes of the thyroglobulin molecule predicted progression of disease. Other genes, inside and outside of the MHC, modify the initial autoimmune response. These immune-regulatory genes are often expressed through particular cytokines and other inflammatory media- tors and enhance or limit the disease of genetically susceptible animals selected on the basis of their MHC haplotype (3). Beyond these genetic risk factors, many internal variables can shift autoimmune responses to clinical disease that are less likely to occur. These variables include such factors as gender, age, pregnancy, and even neurologic and emotional signals. Combined with genetic factors, characteristic autoimmune antibodies are the best predictors of impending autoimmune diseases. On the basis of the earlier decades of fundamental research, the practical application of this knowledge in human susceptibility predictors is described. Because of the high genetic susceptibility of thyroiditis in their family members, children with high genetic predisposition to thyroiditis were studied, and the onset of autoantibody formation and occurrence of clinical signs in normal children were tracked. Through years of follow-up research, children with a high risk of autoimmune thyroiditis can be identified. For example, among the 19 siblings who share the MHC haplotypes with a brother or sister who has been clinically diagnosed with autoimmune thyroiditis, 17 (89%) have thyroid antibodies, and 6 of these 17 (35%) showed biochemical or physical evidence of thyroid dysfunction during the first decade of observation. Since the beginning of this study, researchers have revisited these children in disease- susceptible families on several occasions and have proposed a gradual “natural history” of autoimmune thyroiditis. The step 1 in the "natural history" begins with a combination of genetic traits, and then the step 2 is environmental exposure, such as excessive dietary iodine (5). Step 3 is marked by the production of characteristic autoantibodies to specific determinants of thyroglobulin, as well as the production of antibodies against additional thyroid-specific antigens, such as thyroid peroxidase. In step 4, subclinical thyroiditis is evidenced by a decrease in thyroxine levels. Then in step 5, thyroid-stimulating hormone is compensatoryly increased, and thyroxine is rised to normal level. Finally, step 6 is characterized by overt hypothyroidism in which the thyroxine level cannot rise, the level of thyroid-stimulating hormone is increased, and there is pathologic and clinical evidence of thyroid goiter or an atrophic thyroid gland. Because this series of steps can take many months or years, there is an opportunity to identify individuals at highest risk of developing autoimmune disorders by using genetic and functional markers and to intervene with preventive measures.
The Autoimmune disease model
- Childhood Asthma
Asthma is a chronic airway inflammatory disease. Due to the persistence of this chronic inflammatory reaction, the airway is highly reactive, and the symptoms recur when exposed to the cause. The study of the pathogenesis of asthma has evolved from the theory of sputum to the theory of chronic inflammation of the airways, and has now developed into a parallel theory of smooth muscle dysfunction and airway inflammation. Clinical treatment can also be done by repeated treatment, with emphasis on anti-inflammatory and relief of smooth muscle spasm. In the 1950s, non-selective adrenaline was used as an antispasmodic agent to treat asthma. In 1956, a selective strong short-acting β2 agonist (Short Acting Beta 2 Agonist, SABA) was introduced. In 1971, a β2 agonist (Long Acting Beta2 Agonist, LABA) came out. Oral glucocorticoids were used in the 1960s to antagonize airway inflammation, which is effective but has many side effects. In 1972, beclomethasone dipropionate (BDP) was successfully developed. In the 1980s, budesonide (BUD) and fluticasone propionate (FP) were developed. By analogy, these inhaled corticosteroids have a stronger anti-inflammatory effect on the airway, and their side effects are significantly reduced.
When children are stimulated by allergens, cold air or other incentives, they often first manifest as symptoms of upper respiratory tract allergy, such as itchy eyes, itchy nose, sneezing, etc. Because infants and young children are difficult to express itching, their symptoms often only express as blinking, blowing nose, etc, and further manifest as itching, dry cough and expectoration. These symptoms usually last for hours or days before the onset of asthma. Sudden onset of wheezing is a major feature of childhood asthma. The wheezing symptoms of asthma in children vary greatly depending on the severity of asthma. Children may have high-pitched wheezing that can be heard without a stethoscope or at a distance. Due to frequent breathing or difficulty breathing, asthma symptoms in infants and young children can be expressed as mouth breathing and nose flapping, and many children may be accompanied by a cough. Under normal circumstances, dry cough will appear at the beginning of the disease. When the seizure subsides, a white mucus-like phlegm will be coughed out. In severe cases, the symptoms of asthma can be expressed as irritability, purpura, pale, and cold sweat. Physical examination revealed an increase in heart rate and wheezing in both lungs. Symptoms of heart failure may be further aggravated with jugular vein engorgement, edema, middle lung, small blisters, and enlarged liver. Signs of emphysema can be seen in children with chronic asthma, such as barrel chest and chest percussion. In the remission period, children with asthma may have no symptoms or signs, have no effect on activities, or only manifest as symptoms of allergic rhinitis and pharyngitis. A small number of children may have chest discomfort, with or without wheezing in the lungs.
To be continued in Part II…