Expression of T-bet and GATA-3 in peripheral blood mononuclear cells of patients with oral lichen planus

https://doi.org/10.1016/j.archoralbio.2010.11.006Get rights and content

Abstract

Objective

Oral lichen planus (OLP) is a T-cell-mediated chronic inflammatory oral disease of unknown aetiology. Imbalanced cytokine production by Th1 and Th2 probably contributes to the pathogenesis of OLP. Growing evidence has suggested that two Th1/Th2-specific transcription factors, T-bet and GATA-3, may play a critical role in the development of Th1 and Th2 immunity. The aim of the present study was to investigate the mRNA expressions of T-bet and GATA-3 in the peripheral blood mononuclear cells of OLP subjects, and their expression patterns in relation to several clinical features.

Design

Expressions of T-bet and GATA-3 mRNA in peripheral blood mononuclear cells isolated from twenty-eight OLP subjects and sixteen controls were detected by real-time reverse transcription-polymerase chain reaction.

Results

When OLP subjects were regarded as a whole group, T-bet mRNA level and the ratio of T-bet/GATA-3 mRNA in OLP subjects were significantly higher (P < 0.05) than those in controls. When the OLP subjects were divided according to different clinical forms, genders or age groups, T-bet, but not GATA-3, mRNA levels in reticular (P < 0.01), female (P < 0.05) and elder (age > 55, P < 0.05) OLP patients were significantly higher than those in control subjects. T-bet/GATA-3 mRNA ratio only in reticular (P < 0.05) OLP subjects was significantly higher than that in control subjects.

Conclusions

The results implicate a predominant role of Th1-type immune response in pathogenesis of OLP. Different gene expressions of T-bet in different clinical features may indicate different immunoregulatory mechanisms of OLP.

Introduction

Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa that affects from 0.1% to about 4% of the population.1 It is seen worldwide, mostly in the fifth to sixth decades of life, and is twice as common in women as in men.2 Varieties of clinical presentations of OLP have been recognized, mainly including reticular, atrophic/ulcerative lesions.1 Reticular OLP is the most common form, which presents as whitish, slightly raised lines arranged in a net-like pattern, and is often asymptomatic. The atrophic/ulcerative form of OLP often presents as thinning of the epithelium leading to poorly defined areas of erythema and shallow ulcerations, which cause some degree of pain. Once established, oral lesions of OLP are chronic, rarely undergoing spontaneous remission, and are potentially premalignant.3 Although the aetiology of OLP is still unclear, there is extensive evidence to suggest that T-cell-mediated immune response plays a key role in the onset and perpetuation of this disorder.4 Histochemical analysis of OLP lesions reveals a dense subepithelial inflammatory infiltrate consisting predominantly of T lymphocytes.1, 4 Whilst most intraepithelial lymphocytes in OLP are CD8+ T cells, lymphocytes in the lamina propria are mainly CD4+ T helper (Th) cells.1, 4

When activated, CD4+ T cells can differentiate into several functional subsets, the major two of which are Th1 and Th2 cells. Th1 cells produce IL-2 and IFN-γ, and are efficient in cellular immunity. Th2 cells secrete IL-4, IL-5 and IL-10, and have the helper function for the humoral immunity.5 These two Th subsets cross-regulate each other's function and determine to a great extent the characteristics of immune responses and developments. The balance between Th1/Th2 immune responses determines whether the immune response is appropriate for the organism homeostasis or will result in detrimental immunopathogenesis.6, 7 Several factors, such as the form and dose of antigens, types of antigen presenting cells, co-stimulatory molecules, and cytokines in the local environment, can influence the fate of activated T cells.7 Recent evidences have suggested that two transcription factors, T-box expressed in T cells (T-bet) and GATA-binding protein 3 (GATA-3), play a determining role in Th cell differentiation.5, 7 T-bet is a Th1 specific transcription factor, which promotes Th1 lineage commitment and maintains a Th1 immune response by an auto-regulatory positive feedback loop with interferon-gamma.8, 9, 10 On the other hand, GATA-3 is a member of the GATA family of zinc finger proteins, and plays a pivotal role in the Th2 development by inducing Th2 cytokine production.11, 12, 13 It is also demonstrated that changes in the ratio of T-bet and GATA-3 expressions reflected changes in the Th1- and Th2-specific cytokines in various immune conditions, thus could provide a useful surrogate marker to measure Th1/Th2 status.5, 7 The imbalanced expression pattern of T-bet and GATA-3, resulting in a swing of Th1/Th2 pendulum, has been implicated in the pathogenesis of different immunological diseases such as lupus nephritis, atopic dermatitis, Kawasaki disease, and rheumatoid arthritis.14, 15, 16, 17 Extensive studies have focused on Th cell-related cytokines and chemokines in cultured cells, lesion tissues, tissue transudate, saliva and serum from OLP patients, including IL-1, IL-2, IFN-γ, TNF-α, IL-6, IL-8, IL-4, IL-10.18, 19, 20, 21, 22 However, to the extension of our knowledge, there have been no reports on the expressions of T cell-specific transcription factors T-bet and GATA-3 in OLP.

Although OLP is an organ-specific immune disorder that mainly affects oral mucosa, some authors have investigated the alterations of lymphocytes subsets and functions in peripheral blood in patients with OLP.23, 24, 25, 26 A comprehensive study performed by Carrozzo et al. had revealed increased CD8+ proportion in the peripheral blood in OLP patients, whilst the proportion of CD4+ was slightly lower than in healthy subjects, leading to a reduction of CD4+/CD8+ ratio.23 A significantly higher ratio of memory (CD4+CD45RO+) to naïve (CD4+CD45RA+) T cells in peripheral blood in the OLP patients was also reported recently.24 These findings suggested that the pathogenesis of OLP involved specific migration of certain T cells from the bloodstream to the oral mucosa, which may due to alterations in lymphocyte subsets in peripheral blood.23 Besides, changes of peripheral blood lymphocytes can reflect the composition and cell function in the intraepithelial infiltration.25, 26 In addition, for the research related with lymphocyte phenotypes and functions, analysis of peripheral blood mononuclear cells has some obvious advantages compared with the lesional tissues, such as easier access, less invasion and safer. Thus, we chose the peripheral blood mononuclear cells (PBMC) as the research media in our study.

The aim of the present study was to investigate the gene expression patterns of T-bet and GATA-3, as well as the ratio of T-bet/GATA-3 mRNA expression, in PBMC from OLP patients and their association with clinical features.

Section snippets

Clinical features of subjects

Twenty-eight OLP patients were enrolled from Department of Oral Medicine, School and Hospital of Stomatology, Wuhan University. The patients were clinically diagnosed and histopathologically confirmed as OLP based on the modified WHO diagnostic criteria of OLP.27 Amongst these OLP subjects, 15 of them were classified as reticular form whilst the others were classified as atrophic/ulcerative form according to the clinical manifestation. Sixteen age–sex matched healthy individuals were also

Gene expressions of T-bet and GATA-3 in OLP and control subjects (Fig. 1)

When OLP subjects were regarded as a whole group, T-bet mRNA level in OLP subjects was significantly higher than that in controls (P < 0.01). On the other hand, there was no statistical difference in GATA-3 mRNA level between the OLP and the control subjects. Furthermore, the ratio of T-bet/GATA-3 mRNA expression in OLP subjects was significantly higher than that in healthy control subjects (P < 0.05).

Gene expressions of T-bet and GATA-3 in different clinical forms of OLP subjects (Fig. 2)

When OLP subjects were divided into reticular and atrophic/ulcerative groups according to their

Discussion

The role of Th1/Th2 polarization associated-cytokines and chemokines in OLP has been studied extensively in the past decades, but the Th1/Th2 balance pattern in OLP is still controversial. Khan et al. observed that the expressions of Th1 cytokines IFN-γ and TNF-α increased strongly in OLP lesions, which were also secreted by cultured OLP lesional T cells in vitro.18 These results indicated that OLP was characterized by a Th1 cytokine bias. However, Rhodus et al. and Liu et al. reported

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      T cells can differentiate into Th1, Th2, Th17, and Treg cells, all of which are involved in the pathogenesis of OLP (Wang et al., 2016). Our previous study showed that the T-bet/GATA3 ratio and IFN-γ increased in OLP patients, indicating Th1-predominant immunity in OLP (Hu et al., 2015; Khan et al., 2003; Lu et al., 2011). IFN-γ induced Th1 differentiation by upregulating T-bet expression and inhibited Th2 cell proliferation as well as cytokine secretion (Banerjee et al., 2010).

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    1

    These authors contributed equally to this work.

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