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

Realism and the logic of conceivability

On their alethic reading, formulas (T), (D), and (K) codify three of the most basic principles of possibility and its dual (necessity). This paper discusses these formulas on a broadly epistemic reading, and in particular as candidate principles about conceivability and its dual (inconceivability of the opposite). As will be shown, the question whether (T) and its classical dual equivalent, as well as (D) and (K) hold on this reading is not only a logical one but involves a distinctively metaphysical controversy between realist and antirealist views on the relation between truth on the one hand and various cognitive conditions such as knowability, conceivability, and thinkability on the other. It will be argued that the stance we take with regard to the metaphysical dispute has consequences for our assessment of the plausibility not only of (T) and its classical equivalent, but also of (D) and—when that stance is combined with a structural account of propositions—potentially of (K) as well; with all four taken in the above epistemic sense. A second upshot will be that the same sensitivity to metaphysical background commitment also applies to our view as to whether or not inconceivability of the opposite coincides with, or even entails, apriority

Context-sensitivity and the Preface Paradox for credence

It’s intuitively plausible to suppose that there are many things that we can be rationally certain of, at least in many contexts. The present paper argues that, given this principle of Abundancy, there is a Preface Paradox for (rational) credence. Section 1 gives a statement of the paradox, discusses its relation to its familiar counterpart for (rational) belief, and points out the congeniality between Abundancy and broadly contextualist trends in epistemology. This leads to the question whether considerations of context-sensitivity might lend themselves to solving the Preface for credence. Sections 2 and 3 scrutinize two approaches in this spirit—one mimicking Hawthorne’s (2002) Semantic Contextualist approach to an epistemic version of the Preface, the other one analogous to Clarke’s (2015) Sensitivist approach to the doxastic version—arguing that neither approach succeeds as it stands