SLE patients usually have more activated peripheral blood mononuclear cells (PBMCs) in blood circulation than healthy individuals and there are numerous investigations demonstrating abnormalities in different subpopulations which illustrate the complexity of the pathogenesis in this disease. surface S100A8/A9 was detected TOK-8801 on all leukocyte subpopulations investigated except for T cells. By confocal microscopy, real-time PCR and activation assays, we could demonstrate that pDCs, monocytes and PMNs could synthesize S100A8/A9. Furthermore, pDC cell surface S100A8/A9 was higher in patients with active disease as compared to patients with inactive disease. Upon immune complex activation, pDCs up-regulated the cell surface S100A8/A9. SLE patients experienced also increased serum levels of S100A8/A9. Conclusions Patients with SLE experienced increased cell surface S100A8/A9, which could be important in amplification and persistence of inflammation. Importantly, pDCs were able to synthesize S100A8/A9 proteins and up-regulate the cell surface expression upon immune complex-stimulation. Thus, S100A8/A9 may be a potent target for treatment of inflammatory diseases such as SLE. Introduction Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation in several organ systems, B cell hyperactivity, autoantibodies, match consumption and an ongoing type I interferon (IFN) production [1,2]. SLE patients usually have more activated peripheral blood mononuclear cells (PBMCs) in blood circulation than healthy individuals and there are numerous investigations demonstrating abnormalities in different subpopulations which illustrate the complexity of the pathogenesis in this disease. Increased numbers of plasma cells [3,4], HLA-DR+ T cells [5,6] and decreased numbers of circulating dendritic cells [7,8] have been reported. Pro-inflammatory CD16+ monocytes have been described to be increased in rheumatoid arthritis but are so far not investigated in SLE [9]. The IFN-alpha (IFN) production in SLE is usually detectable in serum [10], and over-expression of IFN-regulated genes, termed the type I IFN signature, has also been exhibited in PBMCs [11-16] as well as in platelets [17]. In mice, type I IFNs induce lymphopenia through redistribution of the lymphocytes [18] and there is an inverse correlation between serum IFN and leukocyte count in humans [10]. SLE patients have circulating immune complexes (ICs), which often contain RNA or DNA [19,20]. ICs TOK-8801 could be endocytosed by the natural IFN generating cells, the plasmacytoid dendritic cells (pDCs) and induce IFN production through Toll-like receptor (TLR) 7 or TLR9 activation [21,22], which is considered to have a important role in the pathogenesis of SLE [23]. IFN has many immunomodulatory functions such as inducing monocyte maturation [24], increasing IFN production from NK cells [25], prolonging the survival of activated T cells [26] and differentiating B cells to plasma cells [27]. S100A8 and S100A9 are users of the calcium-binding S100-protein family and are released at inflammatory sites by phagocytes as a complex (S100A8/A9; also called calprotectin or MRP8/14) [28]. Several pro-inflammatory properties have been explained for the S100A8/A9 complex, such as activation of monocytes [29], amplification of cytokine production [30], regulation of migration of myeloid derived suppressor cells [31] and, as exhibited recently, a ligand for receptor for advanced glycation end products (RAGE) and TLR4 [32]. Patients with SLE have increased serum levels of S100A8/A9 [33,34] and the concentration correlates with disease activity. Here we have investigated the portion and activation status of several leukocyte subpopulations and measured cell surface S100A8/A9 on these cells, corresponding S100A8 and S100A9 mRNA expression as well as serum levels of S100A8/A9 in healthy controls and SLE patients to learn more about the role of these proteins in SLE. Materials and methods Patients SLE patients were recruited TOK-8801 from an ongoing prospective control program at the Department of Rheumatology, Sk?ne University or college Hospital, Lund, Sweden. Blood samples were taken at their regular visits. Healthy subjects, age-matched to the patients, were used as controls. An overview of clinical characteristics is offered in Tables ?Furniture11 and ?and2.2. Disease activity was assessed using SLEDAI-2K [35]. The following SLE treatments were used at the time point of blood sampling: hydroxychloroquine ( em Ppia n /em = 38), azathioprine ( em n /em = 17), mycophenolatmofetil ( em n /em = 11), rituximab (within the last 12 months, em n /em = 5), methotrexate ( em n /em = 4), cyclosporine A ( em n /em = 3), cyclophosphamide ( em n /em = 2), chloroquine phosphate ( em n /em = 1) and intravenous immunoglobulins ( em n /em = 1). All patients fulfilled at least four American College of Rheumatology (ACR) 1982 criteria for SLE [36]. The study was approved by the regional ethics table (LU 378-02). Informed consent was obtained from all participants. Table 1 Clinical characteristics of the SLE patients at the time point of blood sampling thead th align=”left” rowspan=”1″ colspan=”1″ Characteristics /th th align=”center” rowspan=”1″ colspan=”1″ SLE ( em n /em = 63) /th th align=”center” rowspan=”1″ colspan=”1″ Control ( em n /em = 33) /th /thead Age, median (range), years42 (19 to 81)45 (24.
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