Elsevier

Immunology Letters

Volume 152, Issue 2, May 2013, Pages 121-125
Immunology Letters

The expression of human leukocyte antigen G (HLA-G) is associated with sacroiliitis stages of ankylosing spondylitis

https://doi.org/10.1016/j.imlet.2013.04.006Get rights and content

Abstract

Recent studies have demonstrated that human leukocyte antigen G (HLA-G) may play an important role in autoimmune diseases. The present study is to investigate whether or not HLA-G is associated with sacroiliitis stages of ankylosing spondylitis (AS), a systemic autoimmune disease. Plasma levels of soluble HLA-G (sHLA-G) and HLA-G expression on the surface of peripheral blood mononuclear cells (PBMCs) were measured in 55 AS patients and 49 healthy controls by using a specific HLA-G ELISA and flow cytometric (FCM) analysis, respectively. Association of HLA-G expression with sacroiliitis stages of the patients was statistically analyzed. The plasma sHLA-G concentrations were noticeably lower in the AS patients when compared to the healthy controls while the mean fluorescence intensity (MFI) of the HLA-G expression on the surface of PBMCs was significantly higher in the AS patients than in the healthy controls (both P < 0.0001). The HLA-G expression on the surface of PBMCs, plasma sHLA-G levels and HLA-B27 expression were significantly correlated to each other. Moreover, the plasma sHLA-G was inversely associated with the sacroiliitis stages (P = 0.008), while the HLA-G expression on the surface of PBMCs increased from stage 0 to II but decreased in stage III (P = 0.001). The significant association of HLA-G expressions with AS sacroiliitis stages suggests that HLA-G is possibly involved in the pathology of the disease. The detection of HLA-G expression may therefore be a useful laboratory test to reveal disease process in AS patients.

Introduction

Ankylosing spondylitis (AS) is a systemic rheumatic disease with inflammatory back pains as the major clinical symptom. Its etiology and pathogenesis are not yet fully understood although there is a strong association with HLA-B27, a classical HLA class I molecule [1], [2]. Since HLA-B27 interacts with CD8 T cells, AS is claimed to be an autoimmune disease and several theories have been proposed to explain the various mechanisms in which HLA-B27 might predispose spondyloarthritis [3]. However, the exact mechanisms underlying the pathogenesis of AS remain unknown.

Autoimmune diseases are disorders in which the immune system mistakenly recognizes and responds against its own cells and tissues. The major cause of the aberrant immune response is the loss of immune tolerance, which is the ability of the normal immune system to recognize and respond to foreign antigens, but not self antigens. Several mechanisms act together to ensure self tolerance, including clonal deletion, anergy ignorance and exhaustion, effector T-cell and regulatory T-cell balance, and cytokine deviation [4], [5]. In addition, numerous studies have recently demonstrated that human leukocyte antigen G (HLA-G) plays an essential role in the mechanisms of immune tolerance [6].

HLA-G is a non-classical major histocompatibility complex (HMC) class I antigen characterized by a low allelic polymorphism, a limited tissue distribution and the presence of membrane bound and soluble isoforms [6]. HLA-G was initially described as a molecule expressed by fetal tissues, and played a role in maternal–fetal tolerance [7]. Later, HLA-G was found to be involved in the mechanisms of immune tolerance in several areas including pregnancy, organ transplantation, oncology, autoimmune and inflammatory diseases by way of inhibiting cytolytic functions of natural killer cells, cytotoxic T-lymphocytes, and T-cell alloproliferative responses [6], [8].

With regard to autoimmune diseases, some studies have been carried out and found that plasma soluble HLA-G (sHLA-G) levels or HLA-G expression by monocytes were reduced in patients suffering from rheumatoid arthritis [9], asthma [10], and multiple sclerosis [11], [12] when compared to healthy controls. Low HLA-G surface expressions were also described in the type I diabetes [13], and postpartum activation of multiple sclerosis was associated with HLA-G down regulation [14]. A recent report showed that sHLA-G serum levels were significantly lower in AS, and the levels were associated with poor spinal mobility while the expression of HLA-G on surface of peripheral blood mononuclear cells (PBMCs) was higher in AS, which may reflect the disease activity of AS [15].

Since AS is a chronic disease with a wide variety of clinical presentations and outcomes, one or more bio-markers that may reflect or predict disease process seem to be important. Although physical tests of the Bath AS Disease Activity Index (BASDAI) and the Bath AS Functional Index (BASFI) are easy to perform, and represented reliable and sensitivity tools in defining disease status [16], currently there is no laboratory test to identify disease activity. Further, only 50–70% of patients with the active disease may have an increased level of C reactive protein (CRP) and a raised erythrocyte sedimentation rate (ESR). However, there lacks correlation between clinical signs of the disease activity and CRP and ESR [17], [18].

Based-upon the function of immune tolerance of HLA-G, we assume that HLA-G may not only be involved in the pathogenesis of AS, but can also reflect the disease process. To test our hypothesis, we compared HLA-G expression on surface of PBMCs and sHLA-G plasma levels between AS patients and healthy controls, and patients with various sacroiliitis stages defined by radiography because sacroiliitis is the main radiological criterion for disease diagnosis and reflects the disease process.

Section snippets

Study population and blood specimens

From September 2010 to August 2012, 55 patients diagnosed with AS diagnosed according to the 1984 modified New York criteria [19] were enrolled in this study at the Department of Rheumatology at the Sichuan Provincial People's Hospital. All patients were HLA-B27 positive. Forty-nine age- and sex-matched healthy volunteers were used as controls. Before entering into the study, informed consent was obtained from all the participants, while this study was approved by the ethics committee at the

HLA-G expression in healthy controls and AS patients

The plasma levels of sHLA-G were detected to range from 0.96 to 92.4 U/ml with a mean of 46.31 U/ml while the MFI values of HLA-G expression on PBMCs were detected to range from 0.1 to 3.9 with a mean of 1.06 in healthy controls. There was no significant difference between age ≤40 and >40 years old or between the male and female subgroups in either the plasma sHLA-G or HLA-G expression on PBMCs (Table 2).

The plasma concentrations of sHLA-G were detected to range from 2.73 to 68.4 with a mean of

Discussion

In the present study, firstly, we found that plasma sHLA-G levels were significantly lower while the HLA-G expression on the surface of PBMCs was notably higher in AS patients than that in healthy controls. Secondly, we found that plasma sHLA-G concentrations were inversely correlated with sacroiliitis stages of the disease, although HLA-G expression on the surface of PBMCs increased from sacroiliitis stage 0 to stage II, but decreased in stage III. Thirdly, we found that plasma sHLA-G and

Conclusion

In conclusion, we found a strongly correlation between plasma sHLA-G and sacroiliitis stages in AS patients, as well as a high correlation between HLA-G expression on the surface of PBMCs and HLA-B27 expression. These results suggest that the HLA-G molecule may be involved in the pathogenesis and disease course of AS. The detection of plasma sHLA-G levels may be a useful laboratory test for that reflects the disease process in AS patients, but further investigations with a larger patient

Conflict of interests

The authors declare that there are no conflicts of interest.

Ethical approval

The Ethics Committees at the Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital approved the study protocol.

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