1)
1). primarily done in mice, have shown that some IgE antibodies can be generated in peripheral tissues [2]; in contrast to IgG antibodies. Antibodies generated in peripheral tissues undergo direct class switching rather than a sequential class switch through an IgG intermediate and thus do not undergo an extensive process of affinity maturation through somatic hypermutation [3]. Such IgE antibodies are thought to be of lower affinity, whereas high affinity IgE antibodies are thought to be produced in germinal centers through a IgG1 intermediate that undergoes affinity maturation before sequential switching to the IgE subclass [4,5]. IgE antibody production in peripheral tissue may not be unusual, as it has been demonstrated that the majority of allergen-specific IgE in the blood of allergic patients is not derived from blood-derived B cells or plasma cells [6]. Recent work has also exhibited that IgE antibodies can be found in various diseases with inflammatory components [7] arguing that dysregulation of IgE production occurs in many inflammatory diseases and may have (patho)physiological consequences. Such findings suggest that differences in the affinity of IgE antibody interactions with an antigen are likely to affect immunological responses. Thus, multiple questions arise: 1. How are differences in the affinity of IgE antibody and antigen interactions interpreted? Does the FcRI sense these differences? 2. How do these differences influence the molecular signals generated upon FcRI activation? 3. What are the consequences of these affinity differences at the cellular level? 4. Are there differences in the physiological outcome when the affinity of IgE and antigen interactions differ? 5. Does this suggest a role for IgE antibodies beyond allergic disease? On mast cells and basophils, the FcRI consist of an IgE-binding chain [8], a chain that serves to amplify signaling [9,10], and two homodimeric chains that are essential for the signaling capability of this receptor. The FcRI’s ability to interpret its engagement by IgE and antigen is usually encoded in immunoreceptor tyrosine-based activation motifs (ITAMs) found in the and chains (fig.1). Phosphorylation of the FcRI and subsequent phosphorylation of other molecules requires aggregation of FcRI by IgE-antigen interactions. This allows the appropriate proximity of receptors with the associated Src family protein tyrosine kinase (SrcPTK), Lyn resulting ACY-1215 (Rocilinostat) in transphosphorylation [11,12]. The phosphorylation of tyrosine ACY-1215 (Rocilinostat) residues found in the ITAMs by Lyn results in the formation of novel docking sites for multiple signaling proteins that become activated and amplify signaling; the most notable example being that of Syk kinase [13,14]. Downstream of these events a plethora of molecular ACY-1215 (Rocilinostat) signals in the regulation of FcRI-dependent effector responses have been uncovered. These events include phosphorylation of scaffold adaptors, like the linker for activation of T cells (LAT) 1 and subsequent association and phosphorylation of phopholipsae C, molecules that Rabbit polyclonal to ARG1 serve to organize and promote calcium responses and degranulation in mast cells (fig. 1) [15]. The topic of FcRI signaling has been extensively covered over the years [16, 17] and will not be detailed herein. However, it has been proposed [18,19] that this ACY-1215 (Rocilinostat) occurrence of such downstream signaling events leading to a productive effector response requires that this FcRI remain in an aggregated (or clustered) state for sufficient time to allow such signals to be successfully propagated downstream. This kinetic proofreading hypothesis [18] argues that poor or low affinity stimuli.