Serial analysis of the effects of methimazole therapy on circulating B cell subsets in Graves' disease

Abstract

The immunosuppressive effects of antithyroid drug therapy are well recognized; however, the cellular mechanisms underlying their action remain largely unknown. In the present paper we have prospectively analyzed the in vivo effects of methimazole treatment on a large number of circulating B cell subsets, involved in the effector phase of the immune response, in a group of 18 hyperthyroid patients with Graves' disease (GD). The patients were sequentially studied before (day 0) and 7, 14, 30, 90 and 180 days after methimazole therapy. The results were compared with both a group of 19 age- and sex-matched healthy controls and a group of 20 untreated/euthyroid GD patients in long-term remission. The combination of flow cytometry and three colour immunofluorescence revealed a clear increase (P < 0.001) in the numbers of circulating total B cells (CD19+) due to a significant increase (P < 0.001) in the CD5+, FMC7+, CD5+/ FMC7+ and CD23+ B cell subsets in hyperthyroid GD patients with respect to both healthy individuals and to GD patients in long-term remission. The absolute numbers of all these B cell subsets analyzed before treatment, although abnormal, were not statistically different from those observed during the whole period of therapy. When comparing the percentages of these B cell subsets during treatment, significant changes (P < 0.001) were only observed in the proportion of CD5+, CD5+/FMC7+ and CD5- B cells at the end of the follow-up period with respect to those found both before and during the first month of therapy. Whereas CD5+ and CD5+/FMC7+ B cells decreased (P < 0.001) after 3 months of therapy, CD5- B cells showed a significant increase (P < 0.001) at the end of therapy. It is remarkable that the percentage of CD5+, CD5+/FMC7+, CD5- and CD23+ B cell subsets were abnormal during the whole period of treatment and that they never reached normal values. These results show that, in vivo, GD patients treated with methimazole exhibited an abnormal but rather stable pattern of B cell distribution, similar to that present in hyperthyroid untreated GD patients, except for the CD5+ and CD5- B cell populations. Our findings suggest that in vivo methimazole therapy would not directly have an important influence on circulating B cell subsets.

The effects of CD40- and interleukin (IL-4)-activated CD23+ cells on the production of IL-10 by mononuclear cells in Graves’ disease: the role of CD8+ cells

“…+ CD29 + memory T cells helping to activate B cells account for a large fraction of the thyroid-infiltrating lymphocytes, which are counteracted by CD8 + T cells [5]; (3); CD23 + cells [6] and soluble CD23 [7] are increased in PBMC derived from Graves' disease patients; and (4) Th2 cells, by secreting IL-4, IL-5 and IL-6, provide more efficient help for B-cell activation, antibody production, and switching to the IgE and IgG1 isotypes [17,18]. Moreover, Graves' patients with high levels of serum IgE tend to resist antithyroid drug-mediated reductions in anti-TSH receptor antibody titres [19].…”

“…The augmented production of B cell growth factor (BCGF; IL-14) from peripheral and thyroid-infiltrating lymphocytes [5], increased numbers of CD23 + cells [6] and the secretion of sCD23 [7] may participate in B cell activation in Graves' disease. Activated B cells present antigens and interact with T cells by means of their expression of various co-stimulatory ligands such as CD80/CD86, which binds CD28/CTLA-4 (CD152) on T cells, and CD40 binding CD40 ligand (CD40L; CD154) on T cells [8].…”

Serial analysis of the effects of methimazole or radical therapy on circulating CD16/56 subpopulations in Graves' disease

“…Several abnormalities of the immune system have been described in GD patients, either within the thyroid gland (2,3) or in the peripheral blood (4)(5)(6)(7)(8)(9)(10)(11)(12). CD16/56þ cells have rarely been analyzed in GD patients (10)(11)(12)(13).…”

The expression of the beta 1 integrin CD29 and the beta 2 integrin CD11b is decreased in peripheral blood lymphocytes from Graves' disease patients

“…Although GD and HT are organ-specific autoimmune diseases, characterized by intrathyroidal lymphocytic infiltration (1), our studies were performed on peripheral blood. Nevertheless, disturbances in GD and HT are not solely limited to the thyroid gland (21). Moreover, data from thyroid tissue are representative of that group of GD patients who require surgical therapy because of either uncontrolled hyperthyroidism or a relapse of GD.…”