Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus

Abstract

Objective. To investigate the role of the novel cytokine high mobility group box chromosomal protein 1 (HMGB-1) in the pathogenesis of cutaneous lupus erythematosus (CLE).Methods. Punch biopsy specimens of lesional and unaffected skin from 10 patients with CLE and 3 healthy control subjects were investigated. Immunohistochemical staining for HMGB-1, tumor necrosis factor ␣ (TNF␣), and interleukin-1␤ (IL-1␤) was performed on consecutive sections. Analysis of single-nucleotide polymorphisms of ؊308 TNF was performed on DNA extracted from peripheral blood mononuclear cells.Results. An altered expression of HMGB-1 was observed both in the epidermis and in the dermal infiltrates of lesional skin. Expression of HMGB-1 in the epidermis and dermis was increased (P < 0.01 and P < 0.001, respectively, versus unaffected skin), and translocation to the cytoplasm as well as the extracellular presence of secreted HMGB-1 were found. Increased levels of TNF␣ and IL-1␤ were also observed in the dermal infiltrates of lesional skin (P < 0.01 and P < 0.05, respectively, versus unaffected skin). The carrier frequency of the ؊308A TNF polymorphism was 80% in patients with subacute CLE, but this was not related to higher expression of TNF␣ in biopsy specimens from the CLE group.Conclusion. The high amount of extracellular HMGB-1 observed in skin lesions indicates that HMGB-1 is involved in the inflammatory process of CLE. TNF␣ and IL-1␤ may form a proinflammatory loop with HMGB-1, since they can induce the release of each other. The extracellular HMGB-1 observed by immunostaining of the epidermis indicates that keratinocytes may be an as yet unrecognized source of secreted HMGB-1, underscoring the role of the target organ in the rheumatoid autoimmune inflammatory process.The pathogenesis of cutaneous lupus erythematosus (CLE) remains to be fully understood, but ultraviolet (UV) radiation can trigger this autoimmune reaction in the skin. The different subsets of CLE include the acute, subacute, and chronic forms, and an individual patient may have more than 1 subset of CLE according to the currently accepted classifications (1). The lesions of subacute CLE have papulosquamous or annular features and are most commonly distributed on sunexposed areas of the skin, whereas the dermal manifestations of chronic CLE most often consist of coin-shaped scarring plaques, referred to as discoid lupus erythematosus (DLE). DLE lesions can, however, also occur in the skin of patients with systemic lupus erythematosus (SLE) and patients with subacute CLE (1). Subacute CLE is also frequently associated with the serologic presence of Ro/SSA autoantibodies (2-4).The diagnosis of different forms of CLE is confirmed histologically by the presence of epidermal hyperkeratosis, follicular plugging, and hydropic degeneration of the basal cell layer and a dermal lichenoid or patchy mononuclear infiltrate with perifollicular accen-

High Mobility Group Box Protein-1 Correlates with Renal Function in Chronic Kidney Disease (CKD)

“…Human atherosclerotic plaques, but not normal arteries, have been shown to produce extracellular HMGB-1 (29,30). Furthermore, in recent studies of autoimmune inflammatory conditions, increased expression of HMGB-1 was detected by immunohistochemical staining in skin lesions of patients with lupus erythematosus, and in the salivary glands of patients with Sjogren's syndromeindicating that HMGB-1 is involved in the inflammatory process of these diseases (31,32). Further studies, including tissue studies and HMGB-1 expression in urine may, therefore, clarify the role of HMGB-1, its significance in CKD, and whether its biological activity is also a marker of disease severity.…”

α-Actinin Immunization Elicits Anti-Chromatin Autoimmunity in Nonautoimmune Mice

“…Interestingly, it was recently shown that HMGB1 and RAGE mediate TLR9-dependent activation of plasmacytoid dendritic cells by DNA-containing immune complexes (41). Anti-HMGB1 Abs are found in SLE patients (42), whereas increased extracellular expression of HMGB1 is present in lupus skin lesions (43). Importantly, nephritogenic anti-dsDNA inducing Th cell lines derived from patients with active lupus nephritis proliferate in response to HMGB.…”

The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases

“…Melinda Magna 1 and David S Pisetsky of characteristic tissue pathology (for example, arthritis) or functional disturbance (for example, muscle weakness in myositis) by HMGB1 in in vitro or in vivo models; and (d) effectiveness of agents directed at HMGB1 in animal models (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Table 1 lists diseases in which studies implicate a role of HMGB1 in pathogenesis.…”