Eun Sook Kim; Hyo Won Jung; Il Sung Nam-Goong; Soon Joo Woo; Jung Il Choi; Young Il Kim

doi:10.3803/jkse.2006.21.2.116

Journal List > J Korean Soc Endocrinol > v.21(2) > 1063845

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Kim, Jung, Nam-Goong, Woo, Choi, and Kim: Expression of 4-1BB and 4-1BBL in Graves’ Disease

Original Article

J Korean Soc Echocardiogr 2006;21(2):116-124.

Published online: 9 January 2006

DOI: https://doi.org/10.3803/jkse.2006.21.2.116

Expression of 4-1BB and 4-1BBL in Graves’ Disease

Eun Sook Kim, Hyo Won Jung¹, Il Sung Nam-Goong, Soon Joo Woo, Jung Il Choi¹, Young Il Kim

Department of Internal Medicine, Ulsan University Hospital, College of Medicine

¹Biomedical Research Center, Ulsan University Hospital

Received 5 July 2005 Accepted 7 November 2005

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Background:

4-1BB mediated costimulatory signal is a recently identified immunotherapeutic strategy for treating autoimmune diseases without depressing the immune response. In this study, we investigated the expression of 4-1BB and 4-1BBL on the peripheral blood mononuclear cells (PBMC) and we assessed whether the serum levels of soluble (s) 4-1BB and s4-1BBL in the patients with Graves’ disease (GD) and compared them with normal subjects.

Methods:

Expression of 4-1BB and 4-1BBL on PBMC of GD patients was determined by flow cytometry. The concentrations of s4-1BB and s4-1BBL were assessed in the sera of GD patients by performing ELISA.

Results:

4-1BB was constitutively expressed on naive CD4⁺ and CD8⁺ T cells of the GD patients and this was increased by stimulation. 4-1BBL was also expressed on the antigen-presenting cells such as CD19⁺ B cells, monocytes and dendritic cells in GD patients. The serum levels of s4-1BB and s4-1BBL were significantly higher in GD patients than those in controls, and these levels were significantly correlated with the serum levels of thyroid-binding inhibitory immunoglobulin and free T4.

Conclusion:

These results indicate that effector T cells of GD patients can be activated through the 4-1BB-mediated costimulatory signal. Elevated s4-1BB and s4-1BBL levels in the sera of GD patients may affect modulation of the clinical course in GD patients. (J Kor Soc Endocrinol 21:116~124, 2006)

Keywords: Costimulatory molecule, Graves’ disease, 4-1BB, 4-1BBL

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Fig. 1.

Expression levels of 4-1BB and 4-1BBL on PBMC of the patients with Graves’ disease (GD). Naïve PBMC were activated with 1 μg/mL of anti-CD3 mAb and 5 μg/mL of LPS for 24 hr. Expression levels of 4-1BB (A) and 4-1BBL (B) on PBMC of patients with GD were analyzed by flow cytometry compared with control group.

Fig. 2.

Expression patterns of 4-1BB and 4-1BBL on PBMC of the patients with Graves’ disease. A and C, PE conjugated CD4⁺/CD8⁺ T cells with FITC conjugated 4-1BB/4-1BBL fluorescence dot plots in the lymphocytes population of PBMC with healthy subject (A) and GD patient (C) by two-color cytometry. Square box presents double-positive cell population. B and D, 4-1BBL expression on primary monocytes (Mo) and monocyte-derived dendritic cells (DCs) of healthy subject (B) and GD patient (D) by single-color flow cytometric histogram. The thick lines represent 4-1BBL⁺ cells and the thin lines represent isotype-matched mAb as a control.

Fig. 3.

Serum levels of s4-1BB and s4-1BBL in the patients with Graves’ disease. s4-1BB (A) and s4-1BBL (B) were assessed in sera of the patients with Graves’ disease by ELISA and compared with normal subjects as a control.

Fig. 4.

Correlation between s4-1BB and s4-1BBL levels in sera of the patients with Graves’ disease. The concentrations of s4-1BB and s4-1BBL were measured in sera of the same patients by ELISA.

Fig. 5.

Correlation between s4-1BB/s4-1BBL and clinical parameters of the patients with Graves’ disease (GD). A, Correlation between s4-1BB and TBII (%) levels in sera of the patients with GD. B, Correlation between s4-1BB and free T4 (ng/mL) levels in sera of GD patients. C, Correlation between s4-1BBL and TBII levels in sera of GD patients. D, Correlation between s4-1BBL and free T4 levels in sera of GD patients.

Table 1.

Clinical characteristics of each study group

		Age (years)		Gender		TBII (%)	free T4 (ng/dL)	TSH (μU/mL)	TPOAb (IU/mL)	TgAb (IU/mL)
Reference	Value	N		F	M	0-15.0	0.89-1.81	0.35-5.50	0-25	0-40
Graves’	Disease	20	36 ± 11	16	4	40.9 ± 17.3^*	6.43 ±2.39^*	0.01 ± 0.00^*	466 ±358^*	304 ±683
Control		20	42 ± 8	20	0	3.8 ± 2.1	1.4 ±1.06	0.58 ± 0.68	12 ±11.3	2.6 ±3.4

TBII, thyroid binding inhibitory immunoglobulin; TgAb, antibodies to thyroglobulin; TPOAb, antibodies to thyroid peroxidase.

^* P < 0.05 vs. control.

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