Objective. To assess the efficacy of rituximab (RTX) in SSc.Methods. Fourteen patients with SSc were evaluated. Eight patients were randomized to receive two cycles of RTX at baseline and 24 weeks [each cycle consisted of four weekly RTX infusions (375 mg/m2)] in addition to standard treatment, whereas six patients (control group) received standard treatment alone. Lung involvement was assessed by pulmonary function tests (PFTs) and chest high-resolution CT (HRCT). Skin involvement was assessed both clinically and histologically.Results. There was a significant increase of forced vital capacity (FVC) in the RTX group compared with baseline (mean ± s.d.: 68.13 ± 19.69 vs 75.63 ± 19.73, at baseline vs 1-year, respectively, P = 0.0018). The median percentage of improvement of FVC in the RTX group was 10.25%, whereas that of deterioration in the controls was 5.04% (P = 0.002). Similarly, diffusing capacity of carbon monoxide (DLCO) increased significantly in the RTX group compared with baseline (mean ± s.d.: 52.25 ± 20.71 vs 62 ± 23.21, at baseline vs 1-year respectively, P = 0.017). The median percentage of improvement of DLCO in the RTX group was 19.46%, whereas that of deterioration in the control group was 7.5% (P = 0.023). Skin thickening, assessed with the Modified Rodnan Skin Score (MRSS), improved significantly in the RTX group compared with the baseline score (mean ± s.d.: 13.5 ± 6.84 vs 8.37 ± 6.45 at baseline vs 1-year, respectively, P < 0.001).Conclusion. Our results indicate that RTX may improve lung function in patients with SSc. To confirm our encouraging results we propose that larger scale, multicentre studies with longer evaluation periods are needed.

Objective. Dkk-1 is an inhibitory molecule that regulates the Wnt pathway, which controls osteoblastogenesis. This study was undertaken to explore the potential role of Dkk-1 in ankylosing spondylitis (AS), a prototypical bone-forming disease.Methods. Serum Dkk-1 levels were measured in 45 patients with AS, 45 patients with rheumatoid arthritis (RA), 15 patients with psoriatic arthritis (PsA), and 50 healthy subjects by sandwich enzyme-linked immunosorbent assay (ELISA). A functional ELISA was used to assess the binding of Dkk-1 to its receptor (lowdensity lipoprotein receptor-related protein 6). Furthermore, we studied the effect of sera from patients with AS and healthy subjects on the activity of the Wnt pathway in the Jurkat T cell model, with and without a neutralizing anti-Dkk-1 monoclonal antibody, by Western immunoblotting.Results. Serum Dkk-1 levels were significantly increased in patients with AS (mean ؎ SEM 2,730 ؎ 135.1 pg/ml) as compared with normal subjects (P ‫؍‬ 0.040), patients with RA (P ‫؍‬ 0.020), and patients with PsA (P ‫؍‬ 0.049). Patients with AS receiving anti-tumor necrosis factor ␣ (anti-TNF␣) treatment had significantly higher serum Dkk-1 levels than patients with AS not receiving such treatment (P ‫؍‬ 0.007). Patients with AS studied serially prior to and following anti-TNF␣ administration exhibited a significant increase in serum Dkk-1 levels (P ‫؍‬ 0.020), in contrast to patients with RA, who exhibited a dramatic decrease (P < 0.001). Jurkat cells treated with serum from AS patients exhibited increased Wnt signaling compared with cells treated with control serum. In that system, Dkk-1 blockade significantly enhanced Wnt signaling in control serum-treated, but not AS serum-treated, Jurkat T cells.Conclusion. Our findings indicate that in patients with AS, circulating bone formation-promoting factors functionally prevail. This can be at least partially attributed to decreased Dkk-1-mediated inhibition.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by a loss of tolerance to multiple endogenous antigens. SLE etiology remains largely unknown, despite recent insight into the immunopathogenesis of the disease. T cells are important in the development of the disease by amplifying the immune response and contributing to organ damage. Aberrant signaling, cytokine secretion and tissue homing displayed by SLE T cells have been extensively studied and the underlying pathogenic molecular mechanisms are starting to be elucidated. T-cell targeted treatments are being explored in SLE patients. This review is an update on the T-cell abnormalities and related therapeutic options in SLE.

Objective Effector CD8+ T cell function is impaired in SLE and associated with compromised ability to fight infections. SLAMF7 engagement has been shown to enhance NK cell degranulation. Thus, we characterized the expression and function of SLAMF7 on CD8+ T cells subsets isolated from peripheral blood of SLE patients and healthy subjects. Methods CD8+ T cell subset distribution, SLAMF7 expression and cytolytic enzyme expression (perforin, GzmA, GzmB) were monitored on cells isolated from SLE patients and healthy controls by flow cytometry. CD107a expression and IFNγ production in response to viral antigenic stimulation were assessed by flow cytometry in the presence or absence of an anti-SLAMF7 antibody. The antiviral cytotoxic activity in response to SLAMF7 engagement was determined using a flow cytometry-based assay. Results The distribution of CD8+ T cell subsets is altered in the peripheral blood of SLE patients with decreased effector cell subpopulation. Memory CD8+ T cells from SLE patients display decreased amounts of SLAMF7, a surface receptor that characterizes effector CD8+ T cells. Ligation of SLAMF7 increases CD8+ T cell degranulation capacity and the percentage of IFNγ-producing cell in response to antigen challenge in SLE and healthy controls. Moreover, SLAMF7 engagement promotes cytotoxic lysis of target cells in response to viral antigenic stimulation. Conclusion Activation of SLAMF7 through a specific mAb restores defective SLE effector CD8+ T cells function in response to viral antigens and represents a potential therapeutic option in SLE.

Objective Engagement of signaling lymphocytic activation molecule family member 4 (SLAMF4, CD244, 2B4) by its ligand SLAMF2 (CD48) modulates function and expansion of both NK cells and a subset of cytotoxic CD8+ T cells. As the cytotoxicity of CD8+ T lymphocytes isolated from systemic lupus erythematosus (SLE) patients is known to be impaired, we assess here whether expression and function of the checkpoint regulator SLAMF4 is altered on SLE CD8+ T cells. Methods Expression of SLAMF4 by healthy and SLE T cells was determined by Q-PCR and flow cytometry. T cells were activated with anti-CD3 antibody and degranulation activity was monitored by the surface expression of LAMP-1 (CD107a). The SLAMF4+ and SLAMF4− CD8 T cell subpopulations were characterized by LAMP-1, perforin and granzyme B expression and viral peptide-induced proliferation. Results SLAMF4 gene and surface protein expression is downregulated in CD8+ T cells from SLE patients as compared to cells obtained from healthy donors. Importantly, SLE patients have significantly fewer SLAMF4+ CD8+ T cells compared to healthy subjects. SLAMF4− CD8+ T cells from SLE patients have a decreased cytotoxic capacity and proliferative responses to viral peptides. The loss of memory SLAMF4+ CD8+ T cells in SLE patients is linked to the fact that they lose CD8 expression and become double negative T cells. Conclusion A selective loss of SLAMF4+ CD8+ T cells contributes to the compromised ability of SLE T cells to fight against infections.

Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM). Here we report that ICER is predominantly expressed in Th17 cells through the IL-6–STAT3 pathway and binds to the Il17a promoter, where it facilitates the accumulation of the canonical enhancer RORγt. In vitro differentiation from naive ICER/CREM-deficient CD4+ T cells to Th17 cells is impaired but can be rescued by forced overexpression of ICER. Consistent with a role of Th17 cells in autoimmune and inflammatory diseases, ICER/CREM-deficient B6.lpr mice are protected from developing autoimmunity. Similarly, both anti-glomerular basement membrane-induced glomerulonephritis and experimental encephalomyelitis are attenuated in ICER/CREM-deficient mice compared with their ICER/CREM-sufficient littermates. Importantly, we find ICER overexpressed in CD4+ T cells from patients with systemic lupus erythematosus. Collectively, our findings identify a unique role for ICER, which affects both organ-specific and systemic autoimmunity in a Th17-dependent manner.

Tumour necrosis factor alpha (TNF-α) is a key molecule of the inflammatory response and data derived from studies in experimental animal models and humans suggest that TNF-α may be implicated in the pathogenesis of various autoimmune and non-infectious inflammatory conditions. Over the past decade pharmaceutical agents directed against TNF-α (infliximab, adalimumab and etanercept) have been widely and successfully employed for the management of rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis, psoriatic arthritis, juvenile idiopathic arthritis and inflammatory bowel disease, whereas two novel anti-TNF-α agents, golimumab and certolimumab pegol, recently entered the market for the treatment of RA, AS, Crohn's disease and psoriasis. Encouraged by the positive results obtained from the use of TNF-α antagonists in terms of efficacy and safety and due to the increasingly accumulating evidence regarding the implication of TNF-α in the pathogenesis of numerous disorders, anti-TNF-α agents have been considered for the management of diseases other than the ones they were initially approved for. Although in the case of multiple sclerosis and chronic heart failure the outcome from the administration of TNF-α blockers had been less than favourable, in other cases of non-infectious inflammatory conditions the response to TNF-α inhibition had been fairly beneficial. More specifically, according to well-documented clinical trials, anti-TNF-α agents exhibited favourable results in Behçet's disease, non-infectious ocular inflammation, pyoderma gangrenosum and hidradenitis suppurativa. In this review we discuss the successful outcomes as well as the prospects for the future from the off-label use of TNF-α antagonists.

Genome-wide linkage analysis studies (GWAS) studies in systemic lupus erythematosus (SLE) identified the 1q23 region on human chromosome 1, containing the Signaling Lymphocytic Activation Molecule Family (SLAMF) cluster of genes, as a lupus susceptibility locus. The SLAMF molecules (SLAMF1-7) are immunoregulatory receptors expressed predominantly on hematopoietic cells. Activation of cells of the adaptive immune system is aberrant in SLE and dysregulated expression of certain SLAMF molecules has been reported. We examined the expression of SLAMF1-7 on peripheral blood T cells, B cells, monocytes, and their respective differentiated subsets, in patients with SLE and healthy controls in a systematic manner. SLAMF1 levels were increased on both T cell and B cells and their differentiated subpopulations in patients with SLE. SLAMF2 was increased on SLE CD4+ and CD8+ T cells. The frequency of SLAMF4+ and SLAMF7+ central memory and effector memory CD8+ T cells was reduced in SLE patients. Naïve CD4+ and CD8+ SLE T cells showed a slight increase in SLAMF3 levels. No differences were seen in the expression of SLAMF5 and SLAMF6 among SLE patients and healthy controls. Overall, the expression of various SLAMF receptors is dysregulated in SLE and may contribute to the immunopathogenesis of the disease.