Patients affected by Sjögren’s syndrome and systemic lupus erythematosus (SLE) carry autoantibodies to an intracellular protein denoted Ro52. Although the serologic presence of Ro52 autoantibodies is used clinically for diagnostic purposes, the function of the protein or why it is targeted as an autoantigen in several rheumatic conditions has not been elucidated. In this study, we show that the expression of Ro52 is significantly increased in PBMC of patients with Sjögren’s syndrome and SLE, and demonstrate that Ro52 is a RING-dependent E3 ligase involved in ubiquitination. Overexpression of Ro52, but not of Ro52 lacking the RING domain, in a mouse B cell line lead to decreased growth in steady state and increased cell death after activation via the CD40 pathway. The role of Ro52 in activation-mediated cell death was further confirmed as a reduction in Ro52 expression restored cell viability. These findings suggest that the increased expression of the Ro52 autoantigen in patients may be directly involved in the reduced cellular proliferation and increased apoptotic cell death observed in Sjögren’s syndrome and SLE, and may thus contribute to the autoantigenic load and induction of autoimmune B and T cell responses observed in rheumatic patients.

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-

The increased amount of extracellular HMGB-1 observed in salivary glands of patients with SS indicates that HMGB-1 is involved in the inflammatory process of the disease. This cytokine, along with TNF and IL-1beta, may form a proinflammatory loop that promotes the chronic features of the glandular inflammation in SS.

HMGB1 is a pro-inflammatory cytokine that together with TNF-alpha and IL-1beta is involved in the pathogenesis of spontaneously occurring skin lesions in lupus erythematosus. The purpose of the present study was to explore the sequence of events in HMGB1, TNF-alpha and IL-1beta expression under development and resolution of experimentally induced CLE lesions. The study involved investigation of 38 serial skin biopsies acquired from photoprovoked skin lesions of nine CLE patients, using immunohistochemical staining of tissue sections. In biopsies from the clinically most active phase of skin involvement extracellular, secreted HMGB1 and increased cytoplasmic HMGB1 were found, as compared with the late and fading lesions or non-lesional skin. Besides HMGB1, increased expression of TNF-alpha and IL-1beta was observed in dermal infiltrates of the induced CLE lesions. These cytokines were however not upregulated in all lesions, and increased expression of IL-1beta was seen predominantly in late biopsies.In conclusion, extracellular and cytoplasmic HMGB1 coincides with the clinically most active phase of photoinduced lesions of cutaneous lupus, and suggests that HMGB1 is an important factor in the inflammatory autoimmune process of CLE. HMGB1 can induce expression of TNF-alpha and IL-1beta, and formation of a pro-inflammatory loop between HMGB1, TNF-alpha, and IL-1beta may be responsible for the prolonged and sustained inflammation in CLE.

The incidence of Ro/SSA-positive SCLE in Stockholm County, Sweden is estimated to be 0.7 per 100,000 persons per year as compared with an incidence of SLE in Sweden of 4.8 per 100,000 persons per year. The prevalence is estimated to be 6.2-14 in 100,000 persons. Self-reported photosensitivity commonly corresponds to a history of PLE in Ro/SSA-positive patients, even when the clinical profile of SCLE is absent. Photoprotection should therefore be included in the treatment recommendations for these patients.