Alteration of the surface glycosylation pattern on malignant cells potentially affects tumor immunity by directly influencing interactions with glycan-binding proteins (lectins) on the surface of immunomodulatory cells. The sialic acid-binding Ig-like lectins Siglec-7 and -9 are MHC class I-independent inhibitory receptors on human NK cells that recognize sialic acid-containing carbohydrates. Here, we found that the presence of Siglec-9 defined a subset of cytotoxic NK cells with a mature phenotype and enhanced chemotactic potential. Interestingly, this Siglec-9 + NK cell population was reduced in the peripheral blood of cancer patients. Broad analysis of primary tumor samples revealed that ligands of Siglec-7 and -9 were expressed on human cancer cells of different histological types. Expression of Siglec-7 and -9 ligands was associated with susceptibility of NK cell-sensitive tumor cells and, unexpectedly, of presumably NK cell-resistant tumor cells to NK cellmediated cytotoxicity. Together, these observations have direct implications for NK cell-based therapies and highlight the requirement to consider both MHC class I haplotype and tumor-specific glycosylation.

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We report about new apoptotic and nonapoptotic death pathways in neutrophils that are initiated via the surface molecule sialic acid-binding immunoglobulin-like lectin (Siglec)-9. In normal neutrophils, Siglec-9 ligation induced apoptosis. Inflammatory neutrophils obtained from patients with acute septic shock or rheumatoid arthritis demonstrated increased Siglec-9, but normal Fas receptor-mediated cytotoxic responses when compared with normal blood neutrophils. The increased Siglec-9-mediated death was mimicked in vitro by short-term preincubation of normal neutrophils with proinflammatory cytokines, such as granulocyte/macrophage colony-stimulating factor (GM-CSF), interferon-␣ (IFN-␣), and IFN-␥, and was demonstrated to be caspase independent. Experiments using scavengers of reactive oxygen species (ROS) or neutrophils unable to generate ROS indicated that both Siglec-9-mediated caspase-dependent and caspase-independent forms of neutrophil death depend on ROS. Interestingly, the caspaseindependent form of neutrophil death was characterized by cytoplasmic vacuolization and several other nonapoptotic morphologic features, which were also seen in neutrophils present in joint fluids from rheumatoid arthritis patients. Taken together, these data suggest that apoptotic (ROS-and caspasedependent) and nonapoptotic (ROSdependent) death pathways are initiated in neutrophils via Siglec-9. The new insights have important implications for the pathogenesis, diagnosis, and treatment of inflammatory diseases such as sepsis and rheumatoid arthritis. IntroductionNeutrophils are important effector cells in inflammation. Delayed neutrophil apoptosis has been associated with several acute and chronic inflammatory diseases and appears to be mediated, at least partially, by the overexpression of neutrophil survival cytokines such as granulocyte-colony-stimulating factor (G-CSF), 1-3 granulocyte/macrophage colony-stimulating factor (GM-CSF), 1,2,4,5 and macrophage migration inhibitory factor (MIF). 6 Any failure in the process of neutrophil apoptosis likely results in the initiation of an inflammatory response and/or in the maintenance of an already existing inflammation. Therefore, studying neutrophil apoptosis under normal and inflammatory conditions seems to be important.The induction of neutrophil apoptosis during the resolution of a neutrophilic inflammatory response can be mimicked by culturing the cells with insufficient amounts of survival factors, a process, which is called spontaneous apoptosis. Spontaneous neutrophil apoptosis can be enhanced by Fas receptor stimulation. 7 Similar observations have been made in eosinophil in vitro cultures. Eosinophils undergo spontaneous apoptosis, which can be inhibited by survival cytokines such as interleukin 5 (IL-5) or GM-CSF. 8 Eosinophils also express functional Fas receptors that accelerate in vitro cell death. 9,10 Sialic acid-binding immunoglobulin-like lectins (Siglecs) belong to the immunoglobulin (Ig) supergene family and are characterized by the presence of an N-terminal V...

Genomic approaches continue to provide unprecedented insight into the microbiome, yet host immune interactions with diverse microbiota can be difficult to study. We therefore generated a microbial microarray containing defined antigens isolated from a broad range of microbial flora to examine adaptive and innate immunity. Serological studies with this microarray show that immunoglobulins from multiple mammalian species exhibit unique patterns of reactivity, while exposure of animals to distinct microbes induces specific serological recognition. While adaptive immunity exhibited plasticity toward microbial antigens, immunological tolerance limits reactivity toward self. We discovered that several innate immune galectins exhibit specific recognition of microbes that express self-like antigens, leading to direct killing of a broad range of gram negative and positive microbes. Thus, host protection against microbes appears to represent a balance between adaptive and innate immunity to defend against evolving antigenic determinants while protecting against molecular mimicry.

Siglecs are cell-surface proteins found primarily on hematopoietic cells. By definition, they are members of the immunoglobulin gene super-family and bind sialic acid. Most contain cytoplasmic tyrosine motifs implicated in cell signaling. This review will first summarize characteristics common and unique to Siglecs, followed by a discussion of each human Siglec in numerical order, mentioning in turn its closest murine ortholog or paralog. Each section will describe its pattern of cellular expression, latest known immune functions, ligands, and signaling pathways, with the focus being predominantly on CD33-related Siglecs. Potential clinical and therapeutic implications of each Siglec will also be covered.