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

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BORDEAUX2-BU Santé (330632101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Analyse du transcriptome de poule (Gallus) ; profil d'expression des ARNm de différents tissus et analyse du métabolisme des lipides.

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Inhibition of <i>in vitro</i> and <i>in vivo</i> inflammatory responses in rats by p30A peptide.

<p>(A) Rat peritoneal macrophages were activated <i>via</i> CD23 antigens with/without p30A, L-NIL or pCtl. Cell supernatants were collected 48 h later and nitrite levels were quantified. Values are mean±s.d. of cells from 3 different rats. (B) Cumulative clinical score/rat obtained following 50 days post-immunization in all groups. AIA rats were treated either after or before (d0) the onset of symptoms. Treatment consisted of p30A, hydrocortisone (HC, 30 mg/rat)) or pCtl (100 mg/rat). Shown are means of cumulative score/rat±s.d. from 5 (HC) or 8 rats (other conditions). (C) Evolution of arthritis severity scores of adjuvant-induced arthritis (AIA) in rats treated with intracutaneous p30A or pCtl (100 mg/rat) or hydrocortisone (after the onset of clinical signs as illustrated by arrows (means from 8 rats, s.e.m.<20%). (D) Histopathologic analysis confirm p30A ability to decrease all components of AIA lesions: pannus formation and inflammation of the synovium (P), deformity of joint and bones (asterix), bone remodeling and destruction (arrowhead), bone neoformation (arrows) and cartilage destruction.</p

Inhibition of inflammatory mediator generation from healthy human PBL-derived macrophages by p30A.

<p>Decreased levels of TNF-α (A), IL-6 (B), IL-1β, IL-8 and IL-10 (C) were detected in CD23-activated cells after incubation with p30A. No effect was observed with control peptide (pCtl). Values are mean±s.d. of cells from 5 (IL-6, TNF-α) or 2 (IL-1β, IL-8, IL-10) different donors.</p

Inhibition of CD23-mediated activation of iNOS pathway in human macrophages by p30A.

<p>Human CD23⁺ monocyte-derived macrophages were incubated with cross-linking CD23-McAb (20 µg/ml) alone or following 1 h pre-incubation with 10 µg/ml of various peptides. (A) Inducible NO-synthase expression promoted by CD23-mediated activation is decreased in cells pre-incubated with p30A. Expression of iNOS mRNA was compared to HPRT mRNA levels. (B) Inhibition of NO generation from human activated macrophages by synthetic peptides. Cell supernatants were collected 72 h following cell cultures and levels of nitrites were determined. Dose-dependent reduction of nitrites was obtained with p30A synthetic, whereas control peptides (pCtl) had no effect. Results are expressed as mean of 3 distinct donor cell preparations (SEM<20%). (C) Inducible NOS-mediated NO generation in human macrophages is decreased following pre-incubation with p30A or L-NIL prior to CD23-mediated activation. Results are expressed as mean±s.d. of 7 distinct donor cell preparations.</p