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Introduction: Despite considerable therapeutic advances in the last 20 years, metastatic cancers remain a major cause of death. We previously identified prominin‐2 (PROM2) as a biomarker predictive of distant metastases and decreased survival, thus providing a promising bio‐target. In this translational study, we set out to decipher the biological roles of PROM2 during the metastatic process and resistance to cell death, in particular for metastatic melanoma. Methods and results: Methods and results: We demonstrated that PROM2 overexpression was closely linked to an increased metastatic potential through the increase of epithelial‐to‐mesenchymal transition (EMT) marker expression and ferroptosis resistance. This was also found in renal cell carcinoma and triple negative breast cancer patient‐derived xenograft models. Using an oligonucleotide anti‐sense anti‐PROM2, we efficaciously decreased PROM2 expression and prevented metastases in melanoma xenografts. We also demonstrated that PROM2 was implicated in an aggravation loop, contributing to increase the metastatic burden both in murine metastatic models and in patients with metastatic melanoma. The metastatic burden is closely linked to PROM2 expression through the expression of EMT markers and ferroptosis cell death resistance in a deterioration loop. Conclusion: Our results open the way for further studies using PROM2 as a bio‐target in resort situations in human metastatic melanoma and also in other cancer types. [ABSTRACT FROM AUTHOR]

Objective: To describe the epidemiology of primary Sjögren's syndrome (SS) in a multiracial/multiethnic population.Methods: A cross-sectional study with 5 case-retrieval sources identified adults with primary SS living in the Greater Paris area (population 1,172,482 adults) in 2007. Diagnoses were verified by the American-European Consensus Group (AECG) criteria and study-specific enlarged criteria based on the presence of ≥3 of 4 AECG items among subjective oral or ocular dryness, anti-SSA/SSB positivity, and positive minor salivary gland biopsy results. Prevalence estimates were standardized to those for the world population and a 5-source capture-recapture analysis (CRA) was used. Racial/ethnic differences in primary SS features were evaluated.Results: In all, 133 subjects met the AECG criteria and 203 met the enlarged criteria. The 2007 prevalence of primary SS was 1.02 cases per 10,000 adults (95% confidence interval [95% CI] 0.85-1.22) for the AECG criteria and 1.52 cases per 10,000 adults (95% CI 1.30-1.76) for the enlarged criteria. The CRA indicated completeness of case findings of ∼90%. Compared to subjects with European backgrounds, those with non-European backgrounds had 2.1-2.3 times higher primary SS prevalence and were younger (P < 0.0001) and were more likely to have polyclonal hypergammaglobulinemia (P < 0.0001) and anti-SSA/SSB antibodies (P = 0.0005 and P < 0.0001 for the AECG and enlarged criteria, respectively).Conclusion: The figure of 1.02–1.52 cases per 10,000 adults we found and estimates from the few other population-based census surveys support that the prevalence of diagnosed primary SS is between 1 and 9 cases per 10,000 (0.01-0.09%) [corrected] in the general population. Non-European race/ethnicity may be associated with increased primary SS risk and a distinct disease profile. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) play a pivotal role in tolerance. Adrenomedullin (AM), a neuropeptide with anti-apoptotic and anti-inflammatory effects, may decrease T helper type 1 effector cells and induce regulatory T (Treg) cells. The aim of this study was to evaluate AM effects on murine dendritic cell (DC) maturation and functions. Bone marrow-derived DC were produced and stimulated with CpG motifs, lipopolysaccharide or AM for 24 hr. Then, DC maturation and expression of AM and AM receptors were evaluated. Compared with lipopolysaccharide-stimulated or CpG-stimulated DC, AM-stimulated DC had lower levels of co-stimulatory molecule expression and pro-inflammatory cytokine release. The AM induced high levels of interferon-γ but not of interleukin-10. Importantly, AM inhibited lipopolysaccharide-induced maturation of DC. However, allogeneic T-cell stimulation and endocytic capacity of AM-stimulated DC were comparable to those of semi-mature and mature DC. Moreover, DC expressed AM and its receptors at a basal level, and AM receptor expression increased with DC maturation. The AM stimulation induced indoleamine 2,3-dioxygenase (IDO) expression, promoting Treg cell expansion. For the first time, we describe the DC maturation phenotype by a neuropeptide (AM). We have demonstrated that AM and its receptors are expressed in DC and that exogenous AM can modify the DC phenotype and functions and can induce a semi-mature DC phenotype with IDO expression. These results indicate close interactions among immune system regulation mechanisms and calcitonin-like peptides. [ABSTRACT FROM AUTHOR]

Objective. Adrenomedullin22–52 is a truncated peptide derived from adrenomedullin, a growth factor with antiapoptotic and immunoregulatory properties. It can act as an agonist or an antagonist depending on cell type. Its in vivo effects are unknown, but adrenomedullin22–52 could possess immunomodulatory properties. This study was undertaken to evaluate the effect of adrenomedullin22–52 in a mouse model of arthritis. Methods. DBA/1 mice with collagen‐induced arthritis (CIA) were treated with 1.2 μg/gm adrenomedullin22–52, adrenomedullin, or saline at arthritis onset. Bone mineral density was measured at the beginning of the experiment and when mice were killed. Mouse joints were processed for histologic analysis and protein studies, and spleens were examined for Treg cell expression. Cytokine expression was studied in mouse joint tissue and serum. Results. In mice with CIA, adrenomedullin and adrenomedullin22–52 reduced clinical and histologic arthritis scores and shifted the pattern of articular and systemic cytokine expression from Th1 to Th2, as compared to untreated mice with CIA (controls). Tumor necrosis factor α, interleukin‐6 (IL‐6), and IL‐17A levels were significantly decreased in the joints of mice with CIA treated with adrenomedullin or adrenomedullin22–52 as compared to controls, whereas IL‐4 and IL‐10 levels were increased. Adrenomedullin22–52 was more effective than adrenomedullin in modulating cytokine content and enhanced Treg cell function without changing Treg cell expression compared to controls. Adrenomedullin receptor binding and transcriptional adrenomedullin receptor expression were markedly increased in joints from controls, whereas adrenomedullin receptor binding was considerably decreased in treated animals. Mice with CIA treated with adrenomedullin or adrenomedullin22–52 had considerably fewer apoptotic chondrocytes and diminished cartilage degradation. Adrenomedullin22–52 completely prevented systemic bone loss by preserving osteoblastic activity, but without changes in osteoclastic activity. Conclusion. Our findings indicate that adrenomedullin22–52, which has no vasoactive or tumor‐inducing effects, is a potent antiinflammatory and bone‐protective agent in this arthritis model. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) mediate interactions between innate and specific immunity and may induce regulatory mechanisms. We investigated the effects of modulated DCs in mice with collagen-induced arthritis (CIA) and tested the responses of cells to induced naturally occurring regulatory T cells. DCs were stimulated or not with DNA or lipopolysaccharide (LPS) for 24 hr. DC maturation was assayed, and then modulated DCs were intraperitoneally injected on day 14 into DBA/1 mice to treat CIA. In addition to arthritis scores and type 2 collagen (CII) response, the induction of CD4+ CD25+ T cells was analysed by flow cytometry in peripheral blood and the expression of Foxp3, transforming growth factor (TGF)-β, interleukin (IL)-10 and cytotoxic T-lymphocyte antigen (CTLA)-4 was quantified. Finally, the expression of indoleamine-2,3-dioxygenase (IDO) was assayed in DCs. In comparison with LPS-stimulated DCs, plasmid-stimulated DCs expressed lower levels of major histocompatibility complex (MHC) class II, CD40, CD80 and CD86 molecules and secreted less IL-12p70, interferon (IFN)-γ, IL-10 and TNF-α, displaying a semi-mature phenotype. Compared with non-stimulated DCs, stimulated DCs improved arthritis scores when injected after immunization, without modifying the T helper type 1 (Th1)/Th2 balance of the immune response against collagen. Stimulated DCs induced markers for regulatory T cells (Foxp3, TGF-β1 and CTLA-4) in vivo. Only LPS-stimulated DCs expressed IDO, which may explain their better therapeutic efficacy. Regulatory mechanisms were induced using DCs modulated by innate immunity stimulators. Innate immunity mechanisms do not require the presence of the disease-causing antigen, even in T- and B-cell specific diseases. Our results have implications for the treatment of rheumatoid arthritis, an autoimmune disease whose triggering antigen has not been identified, and substantially clarify the role of regulatory T cells in CIA. [ABSTRACT FROM AUTHOR]

Objective: Adrenomedullin(22-52) is a truncated peptide derived from adrenomedullin, a growth factor with antiapoptotic and immunoregulatory properties. It can act as an agonist or an antagonist depending on cell type. Its in vivo effects are unknown, but adrenomedullin(22-52) could possess immunomodulatory properties. This study was undertaken to evaluate the effect of adrenomedullin(22-52) in a mouse model of arthritis., Methods: DBA/1 mice with collagen-induced arthritis (CIA) were treated with 1.2 μg/gm adrenomedullin(22-52) , adrenomedullin, or saline at arthritis onset. Bone mineral density was measured at the beginning of the experiment and when mice were killed. Mouse joints were processed for histologic analysis and protein studies, and spleens were examined for Treg cell expression. Cytokine expression was studied in mouse joint tissue and serum., Results: In mice with CIA, adrenomedullin and adrenomedullin(22-52) reduced clinical and histologic arthritis scores and shifted the pattern of articular and systemic cytokine expression from Th1 to Th2, as compared to untreated mice with CIA (controls). Tumor necrosis factor α, interleukin-6 (IL-6), and IL-17A levels were significantly decreased in the joints of mice with CIA treated with adrenomedullin or adrenomedullin(22-52) as compared to controls, whereas IL-4 and IL-10 levels were increased. Adrenomedullin(22-52) was more effective than adrenomedullin in modulating cytokine content and enhanced Treg cell function without changing Treg cell expression compared to controls. Adrenomedullin receptor binding and transcriptional adrenomedullin receptor expression were markedly increased in joints from controls, whereas adrenomedullin receptor binding was considerably decreased in treated animals. Mice with CIA treated with adrenomedullin or adrenomedullin(22-52) had considerably fewer apoptotic chondrocytes and diminished cartilage degradation. Adrenomedullin(22-52) completely prevented systemic bone loss by preserving osteoblastic activity, but without changes in osteoclastic activity., Conclusion: Our findings indicate that adrenomedullin(22-52) , which has no vasoactive or tumor-inducing effects, is a potent antiinflammatory and bone-protective agent in this arthritis model., (Copyright © 2012 by the American College of Rheumatology.)

Objective: A disease resembling the human spondylarthropathies develops in HLA-B27-transgenic rats. This disease in rats is mediated by CD4+ T cells, but antigen-presenting cells (APCs) may also play a role. Dendritic cells (DCs) have been reported to be defective in allogeneic mixed lymphocyte culture in this model. Here, we further investigated the functional defect of APCs., Methods: DCs and B cells from nontransgenic, HLA-B27 (33-3)-transgenic, and HLA-B7 (120-4)-transgenic rats were used to stimulate T cells. Surface expression of HLA-B transgene and rat molecules on APCs and the formation of conjugates between DCs and T cells were monitored by flow cytometry., Results: We observed a strikingly defective stimulation of allogeneic and syngeneic T lymphocytes by APCs from HLA-B27 but not HLA-B7 rats, even if stimulation was driven in the presence of anti-T cell receptor (TCR) antibody. We found no evidence that HLA-B27 DCs were immature, lacked production of some diffusible factor, or produced an inhibitory factor for T cells. When comparing the levels of expression of class II major histocompatibility complex, CD2, intercellular adhesion molecule 1, lymphocyte function-associated antigen 1, B7, and CD40 molecules at the surface of DCs from 33-3, 120-4, and nontransgenic rats, we found little difference. However, HLA-B27-transgenic DCs formed fewer conjugates with T cells than did nontransgenic DCs. Furthermore, the proportion of conjugates formed between DCs and T cells, as well as the difference between nontransgenic and HLA-B27-transgenic DCs, were in large part reduced by blocking CD86 on DCs., Conclusion: We confirmed defective stimulation of T cells by APCs in HLA-B27 rats, the mechanism of which appears to implicate APC/T cell contact, independent of TCR engagement. In addition, decreased use of the CD86 costimulatory molecule by B27 DCs was observed. Impaired costimulatory function could result in a loss of tolerance toward microbial flora in this model.