Journal List > Ann Dermatol > v.29(1) > 1095798

Li, Lu, Zhang, Zhou, and Chen: Increased Serum High Mobility Group Box 1 (HMGB1) Concentration and the Altered Expression of HMGB1 and Its Receptor Advanced Glycation Endproducts in Pemphigus
Dear Editor:
Pemphigus is an autoimmune mucocutaneous blistering disease induced by antibodiesbind to desmoglein (DSG) 3 and 1. Nevertheless, people's understanding towards molecular mechanisms underlying the progression of the disease is incomplete. High mobility group box 1 (HMGB1), a ubiquitous nuclear protein expressed in almost all cell types, could be translated to cytoplasma and released extracelluarly during sterile inflammation and infection. Extracellular HMGB1 contributes to inflammatory reaction and tissue damage through its receptor advanced glycation endproducts (RAGE). Moreover, neutralizing HMGB1 can attenuate inflammation and tissue damage in many types of inflammatory conditions including arthritis, colitis, sepsis and ischaemia reperfusion1. Thus, serum levels of HMGB1 and tissue expression of HMGB1 and its receptor RAGE in patients with pemphigus were investigated herein.
This study consisted of 27 patients with pemphigus, 22 with bullous pemphigoid and 32 age- and gender-matched healthy subjects. All patients were not on drugs 15 days before this study. Pemphigus patients were treated with systemic corticosteroids and intravenous immunoglobulin therapy. Their serum samples, collected before and after treatment, were examined by enzyme-linked immunosorbent assay (ELISA; RapidBio Laboratories, Calabasas, CA, USA) under instructions of the manufacturer. Skin expression of HMGB1 and RAGE were observed from 15 patients with pemphigus, 12 with bullous pemphigoid, as well as 15 age- and gender-matched healthy individuals. Immunohistochemistry were used to detect the expression of HMGB1 and its acceptor RAGE using antibodies against HMGB1 (clone EPR3507; Epitomics, Burlingame, CA, USA), RAGE (Boster Biological Technology Co., Ltd., Wuhan, China) and horseradish peroxidase-conjugated secondary antibodies.
As shown in Fig. 1A pemphigus patients had significantly higher serum HMGB1 levels than bullous pemphigoid patients, and healthy controls. As presented in Fig. 1B, serum HMGB1 levels in 16 pemphigus patients before treatment were significantly higher than those after treatment (p=0.008). As shown in Fig. 2, HMGB1 expression was found principally. Skin expression HMGB1 from healthy individuals and Bullous pemphigoid was nearly entirely confined to nucleus. In contrast, plentiful cytoplasmic of HMGB1 was detected in the epidermis of lesional skin in pemphigus patients. Besides, the skin expression of RAGE was negative in controls, strong positive in pemphigus patients and weak positive in bullous pemphigoid patients.
As we know, pro-inflammatory cytokines or cellura apoptosis is involved in HMGB1 release. In the pathogenesis of pemphigus, apoptosis promotes the separation of epidermal cells, which causes acantholysis of matrix cells, together with the stimulation from proinflammatory factors, abnormal expression of HMGB1 can be inferred23. Our previous work showed the existence of cytoplasmic expression of HMGB1 in lesional skin of psoriasis4. In this work, we indicated that HMGB1 serum levels were obviously increased in pemphigus patients. Furthermore, cytoplasmic expression of HMGB1 and overexpression of it receptor RAGE in the epidermis observed in pemphigus skin lesions. Therefore, we suggest that HMGB1/RAGE interaction may contribute to inflammatory reaction and tissue damage in pathogenesis of pemphigus. Further study is undergone to explore the function of HMGB1 in the pathogenesis of pemphigus, and achieve a new therapy method by inhibiting their interaction.

Figures and Tables

Fig. 1

Serum levels of high mobility group box 1 (HMGB1) were determined by enzyme-linked immunosorbent assay. (A) Serum levels of HMGB1 were obtained from 27 patients with pemphigus, 22 with bullous pemphigoid and 32 control subjects. Serum HMGB1 levels in patients with pemphigus were significantly higher than those in control subjects. p-values are based on the Mann-Whitney U test. (B) Wilcoxon signed ranks test for paired data showed that serum HMGB1 levels of 16 patients with pemphigus before treatment were significantly higher than those after treatment.

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Fig. 2

Tissue samples were obtained from 15 patients with pemphigus, 12 patients with bullous pemphigoid and 15 control subjects. The expression of high mobility group box 1 (HMGB1) and receptor advanced glycation endproducts (RAGE) in the skin was detected by immunohistochemistry. The skin expression of RAGE was negative in controls, was strong positive in pemphigus patients and weak positive in bullous pemphigoid patients. Inset: HMGB1 expressed in cytoplasm of patients with pemphigus. Scale bars=50 µm.

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ACKNOWLEDGMENT

This work was supported by Natural Science Foundation of China (No. 81470143).

References

1. Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011; 29:139–162.
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2. Lotti R, Marconi A, Pincelli C. Apoptotic pathways in the pathogenesis of pemphigus: targets for new therapies. Curr Pharm Biotechnol. 2012; 13:1877–1881.
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3. Chiapa-Labastida M, Zentella-Dehesa A, León-Dorantes G, Becker I. Pemphigus vulgaris: accumulation of apoptotic cells in dermis and epidermis possibly relates to pathophysiology through TNF-alpha production by phagocytes. Eur J Dermatol. 2011; 21:874–888.
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4. Chen T, Guo ZP, Li L, Wang L, Jia RZ, Cao N, et al. Increased HMGB1 serum levels and altered HMGB1 expression in patients with psoriasis vulgaris. Arch Dermatol Res. 2013; 305:263–267.
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