Molecular Blocking of CD23 Supports Its Role in the Pathogenesis of Arthritis

BACKGROUND: CD23 is a differentiation/activation antigen expressed by a variety of hematopoietic and epithelial cells. It can also be detected in soluble forms in biological fluids. Initially known as the low-affinity receptor for immunoglobulin E (Fc epsilonRII), CD23 displays various other physiologic ligands such as CD21, CD11b/c, CD47-vitronectin, and mannose-containing proteins. CD23 mediates numerous immune responses by enhancing IgE-specific antigen presentation, regulating IgE synthesis, influencing cell differentiation and growth of both B- and T-cells. CD23-crosslinking promotes the secretion of pro-inflammatory mediators from human monocytes/macrophages, eosinophils and epithelial cells. Increased CD23 expression is found in patients during allergic reactions and rheumatoid arthritis while its physiopathologic role in these diseases remains to be clarified. METHODOLOGY/PRINCIPAL FINDINGS: We previously generated heptapeptidic countrestructures of human CD23. Based on in vitro studies on healthy and arthritic patients' cells, we showed that CD23-specific peptide addition to human macrophages greatly diminished the transcription of genes encoding inflammatory cytokines. This was also confirmed by significant reduction of mediator levels in cell supernatants. We also show that CD23 peptide decreased IgE-mediated activation of both human and rat CD23(+) macrophages. In vivo studies in rat model of arthritis showed that CD23-blocking peptide ameliorates clinical scores and prevent bone destruction in a dose dependent manner. Ex-vivo analysis of rat macrophages further confirmed the inhibitory effect of peptides on their activation. Taken together our results support the role of CD23 activation and subsequent inflammatory response in arthritis. CONCLUSION: CD23-blocking peptide (p30A) prevents the activation of monocytes/macrophages without cell toxicity. Thus, targeting CD23 by antagonistic peptide decreases inflammatory markers and may have clinical value in the treatment of human arthritis and allergic reactions involving CD23

Destructive arthritis in a patient with chikungunya virus infection with persistent specific IgM antibodies

<p>Abstract</p> <p>Background</p> <p>Chikungunya fever is an emerging arboviral disease characterized by an algo-eruptive syndrome, inflammatory polyarthralgias, or tenosynovitis that can last for months to years. Up to now, the pathophysiology of the chronic stage is poorly understood.</p> <p>Case presentation</p> <p>We report the first case of CHIKV infection with chronic associated rheumatism in a patient who developed progressive erosive arthritis with expression of inflammatory mediators and persistence of specific IgM antibodies over 24 months following infection.</p> <p>Conclusions</p> <p>Understanding the specific features of chikungunya virus as well as how the virus interacts with its host are essential for the prevention, treatment or cure of chikungunya disease.</p

IL-17 in the Rheumatologist’s Line of Sight

Over the past decades, the identification of several new cytokines, including interleukin (IL)-17 and IL-23, and of new T helper cell subsets, including Th17 cells, has changed the vision of immunological processes. The IL-17/Th17 pathway plays a critical role during the development of inflammation and autoimmunity, and targeting this pathway has become an attractive strategy for a number of diseases. This review aims to describe the effects of IL-17 in the joint and its roles in the development of autoimmune and inflammatory arthritis. Furthermore, biotherapies targeting directly or indirectly IL-17 in inflammatory rheumatisms will be developed

IgE mediates killing of intracellular Toxoplasma gondii by human macrophages through CD23-dependent, interleukin-10 sensitive pathway.

BACKGROUND: In addition to helminthic infections, elevated serum IgE levels were observed in many protozoal infections, while their contribution during immune response to these pathogens remained unclear. As IgE/antigen immune complexes (IgE-IC) bind to human cells through FcεRI or FcεRII/CD23 surface molecules, the present study aimed to identify which functional receptor may be involved in IgE-IC interaction with human macrophages, the major effector cell during parasite infection. METHODOLOGY/PRINCIPAL FINDINGS: Human monocyte-derived macrophages were infected with Toxoplasma gondii before being incubated with IgE-IC. IgE receptors were then identified using appropriate blocking antibodies. The activation of cells and parasiticidal activity were evaluated by mediator quantification and direct counting of infected macrophages. RNAs were extracted and cell supernatants were also collected for their content in tumor necrosis factor (TNF)-α, interleukin-10 (IL-10) and nitrites. Sera from symptomatic infected patients were also tested for their content of IgE, IL-10 and nitrites, and compared to values found in healthy donors. Results showed that IgE-IC induced intracellular elimination of parasites by human macrophages. IgE-mediated effect was FcεRI-independent, but required cross-linking of surface FcεRII/CD23, cell activation and the generation of nitric oxide (NO). Although TNF-α was shown to be produced during cell activation, this cytokine had minor contribution in this phenomenon while endogenous and exogenous IL-10 down-regulated parasite killing. Inverse relationship was found between IL-10 and NO expression by infected human macrophages at both mRNA and mediator levels. The relationship between these in vitro data and in vivo levels of various factors in T. gondii infected patients supports the involvement of CD23 antigen and IL-10 expression in disease control. CONCLUSION: Thus, IgE may be considered as immune mediator during antiprotozoal activity of human macrophages through its ability to trigger CD23 signaling. Increased cell activation by IgE-IC may also account for chronic inflammatory diseases observed in some patients

Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis

BACKGROUND: Dietary flavonols may play an important role in the adjunct therapy of chronic inflammation. The availability of therapeutic formulations of pentahydroxyflavone glycoside, rutoside (RU), led us to investigate the ability of this molecule to modulate the release of various proinflammatory mediators from human activated macrophages in vitro and to ameliorate arthritic markers in a rat model. METHODS: RU was added simultaneously to human macrophages during their activation. Cells were then analyzed for inflammation-related gene expression using a specific array, and cell supernatants were collected to measure inflammatory mediators. RU was also injected into adjuvant-induced arthritic rats, and disease progression and body weight were evaluated until 50 days after injection. Sera and peritoneal macrophages were also collected to quantify the RU effect on various inflammatory markers. RESULTS: RU inhibited inflammation-related gene expression in activated human macrophages and the release of nitric oxide, tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6 from these cells. In a rat model, RU inhibited clinical signs of chronic arthritis, correlating with decreased levels of inflammatory cytokines detected in rat sera and macrophage supernatants. CONCLUSION: Thus, RU may have clinical value in reducing inflammatory manifestations in human arthritis and other inflammatory diseases

The presence of IL-10, IgE and nitrites in sera from patients infected with <i>T. gondii</i>.

<p>Freshly isolated <b>s</b>era from 18 <i>T. gondii</i> infected patients or 11–18 uninfected controls were tested for the levels of IL-10, IgE and nitrites. (<b>A</b>) Infected patients have significantly high serum levels of IL-10 compared to controls. (<b>B</b>) Elevated IgE levels were detected in infected patients compared to controls, while concentrations of serum nitrites were close to normal values except to 6/8 patients with high IgE (>200 IU) levels (p<0.018).</p

Involvement of iNOS pathway during IgE-IC-mediated activation of <i>T. gondii</i> killing by human macrophages.

<p>Infected cells were incubated in the presence of IL-4, IgE-IC or anti-CD23 McAb. (<b>A</b>) Cells were then collected (24 h) for iNOS-mRNA quantification and cell supernatants were harvested (72 h) to assess the levels of nitrites. Both conditions induced iNOS mRNA expression and consequent NO generation. (<b>B</b>) Cells were also incubated with an iNOS inhibitor (L-NMMA), a negative control (D-NMMA), or chemical NO-donor (SNAP). Following 72 h incubation, the percentage of infected macrophages was assessed. Addition of L-NMMA inhibited IgE-IC- or CD23-mediated parasiticidal activity (p<0.0008) and was reversed by L-arginine supplementation. Addition of chemical NO completely destroyed parasites without cell toxicity (>75% viable cells found in control cultures). Results show mean±SD for data from 3 distinct macrophage preparations, each done in duplicates.</p