Eosinophil is an important therapeutic target in the management of asthma due to their important role in airway inflammation, induction of airway hyperresponsiveness and their recently described role in airway remodeling. One such strategy targeting eosinophils is to target receptors expressed by eosinophils that might mediate the resolution of eosinophilic inflammation. One candidate receptor expressed by eosinophils is Siglec-8. Siglec-8 belongs to the CD33-related Siglec (CD33rSiglec) family, which are a subclass of Siglecs defined by their mutual sequence similarity (share about 50-80% sequence similarity), and clustered gene localization (chromosome 19q in humans). The cytoplasmic domain of the Siglec-8 contains immunoreceptor tyrosine-based inhibition motifs (ITIMs), suggesting that this molecule possesses inhibitory functions. In vitro studies demonstrated that cross-linking Siglec-8 receptors on eosinophils induced an apoptotic signal through the sequential production of reactive oxygen species (ROS), followed by induction of mitochondrial injury and caspase cleavage. In vivo studies using Siglec-F (functional paralog of Siglec-8) deficient mice demonstrated that Siglec-F deficient mice challenged with inhaled allergen significantly enhanced levels of eosinophilic airway inflammation as well as delayed resolution of eosinophilic inflammation. Administration of an anti-Siglec-F antibody significantly reduced levels of allergen induced eosinophilic airway inflammation and features of airway remodeling by reducing the production and increasing the clearance of eosinophils in murine model of asthma. Although further studies are needed to elucidate the precise role of Siglec-8, the results of these studies suggest that targeting of Siglec-8 may be a novel therapeutic approach for asthma and other allergic disease.
Airway Remodeling ; Animals ; Asthma ; Cytoplasm ; Eosinophils ; Humans ; Immunoreceptor Tyrosine-Based Inhibition Motif ; Inflammation ; Mice ; Reactive Oxygen Species ; Sialic Acid Binding Immunoglobulin-like Lectins

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease characterized by production of autoantibodies to various nuclear antigens and overexpression of genes regulated by IFN-I called IFN signature. Genetic studies on SLE patients and mutational analyses of mouse models demonstrate crucial roles of nucleic acid (NA) sensors in development of SLE. Although NA sensors are involved in induction of anti-microbial immune responses by recognizing microbial NAs, recognition of self NAs by NA sensors induces production of autoantibodies to NAs in B cells and production of IFN-I in plasmacytoid dendritic cells. Among various NA sensors, the endosomal RNA sensor TLR7 plays an essential role in development of SLE at least in mouse models. CD72 is an inhibitory B cell co-receptor containing an immunoreceptor tyrosine-based inhibition motif (ITIM) in the cytoplasmic region and a C-type lectin like-domain (CTLD) in the extracellular region. CD72 is known to regulate development of SLE because CD72 polymorphisms associate with SLE in both human and mice and CD72−/− mice develop relatively severe lupus-like disease. CD72 specifically recognizes the RNA-containing endogenous TLR7 ligand Sm/RNP by its extracellular CTLD, and inhibits B cell responses to Sm/RNP by ITIM-mediated signal inhibition. These findings indicate that CD72 inhibits development of SLE by suppressing TLR7-dependent B cell response to self NAs. CD72 is thus involved in discrimination of self-NAs from microbial NAs by specifically suppressing autoimmune responses to self-NAs.
Animals ; Antigens, Nuclear ; Autoantibodies ; Autoantigens ; Autoimmune Diseases ; Autoimmunity ; B-Lymphocytes ; Cytoplasm ; Dendritic Cells ; Discrimination (Psychology) ; Humans ; Immunoreceptor Tyrosine-Based Inhibition Motif ; Lectins, C-Type ; Lupus Erythematosus, Systemic ; Mice ; RNA