The Immunomodulatory Role of Melatonin in Promoting the Progression of Graves' Disease

Project: A - Government Institutionb - Ministry of Science and Technology

Project Details

Description

Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disease, with a prevalence of 1-5% in normal population. Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are two major types of AITDs. GD is mainly resulted from antibody-mediated response and leads to thyroid follicular cell hyperplasia and ultimately evolve into hyperthyrodisim. In clinical settings, GD is the most common etiology of hyperthyroidism. It has been well documented that the occurrence of GD is derived from the formation of thyroid-stimulating hormone receptor antibody (TSHRAb) targeting thyroid-stimulating hormone receptor. Melatonin (MLT) is secreted from pineal gland and is inhibited by light to the retina and promoted by darkness. MLT has several biological functions, including the control of the circadian and seasonal rhythm, the anti-oxidant, the elimination of free radicals and timing control of puberty, etc. The relationship between MLT and hypothalamus-pituitary-thyroid axis remains controversial. One animals study showed that thyroid-stimulating hormone was higher in MLT treated group than control group while there was no significant difference in peripheral thyroid function. In contrast, other study demonstrated that MLT could inhibit TSH secretion and directly inhibit the secretion of T4. In addition to its endocrinological activity, MLT also performed strong immunoregulatory functions. MLT has been investigated in the therapy of several autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, type 1 diabetes mellitus, rheumatoid arthritis and inflammatory bowel disease and the response varied. However, the impact of MLT on AITD, including GD and HT has never been examined so far. Recently, we investigated the possible associations of single-nucleotide polymorphisms (SNPs) of melatonin receptor type 1A (MTNR1A) and 1B (MTNR1B), with AITD in an ethnic Chinese population. We found only genetic variants of MTNR1A but not MTNR1B were associated with a susceptibility to GD. Moreover, we had established a GD mouse model by immunization with human thyroglobulin (TG) to a MLT-synthesizing strain (CBA mouse), which was characterized by profound hyperthyroidism, the presence of circulating TSHRAb and hyperplastic thyroid follicle cells. We also demonstrated that administration of MLT in GD animal models could increase spleen weight and elevation of TSHRAb. In the meanwhile, there was no significant change in pathological features in only MLT-treated mice compared to control groups, which suggested MLT alone could play a very limited role in thyroid function and thyroid immunity in the normal thyroid. In the study, we will use this GD model to investigative the immunological profiles of GD and MLT. By harvesting T and B lymphocytes from full-blown GD and MLT-treated GD animals, we will further perform the adoptive cell transfer assay to elucidate whether T or B cells dominates in the occurrence of these animal models. Finally, we will assess the immunomodulatory effects and the pathological features in two MLT-deficient mouse strains (BALB/c and C56BL/6) after TG immunization and MLT administration.
StatusFinished
Effective start/end date8/1/177/31/18

Keywords

  • Melatonin
  • Graves' disease
  • thyroglobulin