Study On The Role Of Th22Cells And Its Functional Cytokine IL-22in Graves’ Diseases

Background: Graves’ disease (GD) is an organ-specific autoimmune diseasethat is attributed to overstimulation of the thyroid glands by agonistic anti-thyrotropinreceptor antibody (thyroid-stimulating antibody; TSAb), leading to hyperthyroidismand thyroid enlargement. GD occurs predominantly in women and its incidence isapproximately0.25–1.09%in the Chinese population. GD represents both the mostcommon cause of, hyperthyroidism and an archetypical example ofantibody-mediated organspecific autoimmunity. The pathogenesis of GD is complexand heterogeneous, and its etiology remains unclear. Since TSAb is a hallmark of GDT helper type2(Th2) responses have been associated with the pathogenesis of GD.Strikingly, recent studies have suggested that other types of functional T cells, such asTh17cells, also play an important role in the pathogenesis of GD. However, there islittle information available about the role of other types of immunocompetent cells inthe development and progression of GD.Antigen determinants activate naive CD4+T cells, which can differentiate intoTh17and Th22cells (besides Th1and Th2cells), which are regulated by RORct andaryl hydrocarbon receptor transcription factor, respectively. Th17cells predominantlyproduce IL-17A, while Th22cells secrete IL-22. Both IL-17A and IL-22have beenshown to be pro-inflammatory cytokines that participate in the pathogenesis ofautoimmune diseases, such as rheumatoid arthritis (RA), Crohn’s disease, systemiclupus erythematosus (SLE), and psoriasis. A previous study has shown that a highfrequency of Th17cells and high levels of IL-17are present in patients with severe GD and that Th17, together with Th1cells, may contribute to the development ofHashimoto’s thyroiditis. However, there is little information about whether higherfrequency of Th17and higher concentrations of IL-17A also exist in Chinese patientswith GD and how Th17responses are associated with the concentrations of TSAb andthyroid function in GD patients. Furthermore, it is unclear whether Th22and IL-22responses are associated with the development of GD. In addition, IL-22and IL-17can be secreted by some subsets of CD4+T cells. However, what the levels of thesecytokines are in GD patients and how they are related to the thyroid function have notbeen explored. At present, the pathogenesis of GD is still not completely clear,leading to the difficulty in treatment.Aim: To study the expressions of Th22cells and its functional cytokines IL-22inGD with new onset. And then explore its role in the pathogenesis of GD, provide newideas for the early diagnosis and treatment of the diseases.Method: Twenty seven patients with new onset GD were recruited from theoutpatient service of the First Hospital of Jilin University, Changchun, China betweenDecember2011and November2012. Twenty seven gender-and agematched healthyvolunteers without a family history of GD were recruited from the outpatient serviceof the same hospital and served as controls. Individual participants fasted overnight,and their peripheral venous blood samples were collected.The frequency of CD4+IFN-γ–IL17A–IL-22+Th22, CD4+IFN-γ–IL17A+IL-22–Th17, CD4+IFN-γ–IL17A+IL-22+Th17/Th22, CD4+IFN-γ+IL-17A–IL-22–Th1,and CD4+IFN-γ+IL17+Th1/Th17cells in individual samples were determined byflow cytometry following intracellular staining with anti-cytokine antibodies. Theconcentrations of serum TSH, FT3, and FT4in individual participants were examinedby chemiluminescent enzyme immunoassay using specific kits. The concentrations ofserum anti-TSH receptor antibodies (A-TSHR) in all participants were examined byradioimmunoassay using the specific kit, according to the manufacturers’ instruction. The concentrations of serum TSAb in individual participants were examined byenzyme linked immunosorbent assay.Results:1. A higher frequency of IL-17A+and IL-22+CD4+T cells in GDpatients.2. Higher concentrations of serum IL-17and IL-22are present in GD patients.3. The percentages of peripheral blood Th22and Th17cells are positivelycorrelated with the concentrations of serum TSAb in GD patients.Conclusions:1. The percentages of Th17, Th22, and the levels of plasma IL-17and IL-22were correlated positively with the levels of serum TSAb in those patients,suggesting that Th17and Th22cells and their cytokines may contribute to thepathogenesis of GD in Chinese, and as bio-indicators for monitoring disease severityand drug efficacy.2. There is a positive correlation between Th22and Th17cells in GD patients,suggesting that Th22and Th17cells may play a synergistic role in GD.