Glycobiology: Toward Understanding the Function of Sugars.

The concept of innate immunity refers to the first-line host defense that serves to limit infection in the early hours after exposure to microorganisms. Recent data have highlighted similarities between pathogen recognition, signaling pathways, and effector mechanisms of innate immunity in Drosophila and mammals, pointing to a common ancestry of these defenses. In addition to its role in the early phase of defense, innate immunity in mammals appears to play a key role in stimulating the subsequent, clonal response of adaptive immunity.

/pdf/phylogenetic-perspectives-in-innate-immunity-1u8kp8a668.pdf

Phylogenetic Perspectives in Innate Immunity

In addition to their role in binding antigen, antibodies can regulate immune responses through interacting with Fc receptors (FcRs). In recent years, significant progress has been made in understanding the mechanisms that regulate the activity of IgG antibodies in vivo. In this Review, we discuss recent studies addressing the multifaceted roles of FcRs for IgG (FcgammaRs) in the immune system and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases.

/pdf/fcg-receptors-as-regulators-of-immune-responses-46isonwygz.pdf

Fcγ receptors as regulators of immune responses

AdipoQ is a novel adipose-specific gene dysregulated in obesity.

Lack of Fucose on Human IgG1 N-Linked Oligosaccharide Improves Binding to Human FcγRIII and Antibody-dependent Cellular Toxicity

The glycosylation of the circulating immunoglobulin-gamma (IgG) antibody molecules changes in rheumatoid arthritis The extent of the changes correlates with the disease severity and reverses in remission We demonstrate here that the alteration in glycosylation associated with rheumatoid arthritis can create a new mode for the interaction of IgG with complement through binding to the collagenous lectin mannose-binding protein (MBP) Rheumatoid arthritis is associated with a marked increases in IgG glycoforms that lack galactose (referred to as G0 glycoforms) in the Fc region of the molecule and that terminate in N-acetyl glucosamine (GlcNAc) We show, using nuclear magnetic resonance (NMR) and X-ray data, that these terminal GlcNAc residues become accessible for MBP binding We further demonstrate that multiple presentation of IgG-G0 glycoforms to MBP results in activation of the complement This suggests that a contribution to the chronic inflammation of the synovial membrane could arise from the localization of the IgG-G0 glycoforms in the affected joint and from resulting activation of complement

Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein.

Collectins: collagenous C-type lectins of the innate immune defense system

A receptor binding to the C1q subcomponent of complement has been reported by many workers. In this paper we report for the first time that C1q receptor binds not only to C1q, but also to three other structurally similar ligands, namely mannan binding protein (MBP), conglutinin, and lung surfactant protein (SP-A). All these ligands have been reported to enhance removal of species bound to their globular domain from blood (MBP, conglutinin, C1q) or lung (SP-A) through phagocytosis. One of the possible roles for ligand-receptor binding may be initiation of phagocytosis.

https://rupress.org/jem/article-pdf/172/3/955/1100807/955.pdf

Human leukocyte C1q receptor binds other soluble proteins with collagen domains.

Isolation and characterisation of potential respiratory syncytial virus receptor(s) on epithelial cells.

Rituxan, a chimeric anti-CD20 antibody, is the first antibody approved for immunotherapy in non-Hodgkin's B-cell lymphoma and other B-cell lymphoproliferative disorders. Additionally, efficacy of Rituxan treatment has been reported in nonmalignant autoimmune diseases such as rheumatoid arthritis. Crosslinking of CD20 molecules by Rituxan induces therapeutic B-cell depletion. CD20 is a B-lymphocyte specific integral membrane protein, proposed to function as a store-operated calcium channel, which is activated upon receptor-stimulated calcium depletion of intracellular stores. Crosslinking of CD20 by antibodies has been reported to induce a redistribution of CD20 molecules to specialized microdomains at the plasma membrane known as lipid rafts. Here, we report that in the absence of Rituxan, CD20 exhibits a low affinity to lipid rafts. However, binding of Rituxan significantly increases the affinity of CD20 for lipid rafts resulting in its redistribution to a fraction resistant to Triton X-100 solubilization. Furthermore, we demonstrate that disturbing the raft integrity by cholesterol extraction results in dissociation of CD20 from a Triton X-100 resistant fraction followed by complete inhibition of Rituxan-induced calcium entry and apoptosis. The integrity of lipid rafts seems to play a crucial role for CD20-induced caspase activation. These data show, for the first time, that Rituxan-induced translocation of CD20 to lipid rafts is important for increased intracellular Ca(2+) levels and downstream apoptotic signalling.

Rajneesh Malhotra

Papers

Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein.

Collectins: collagenous C-type lectins of the innate immune defense system

Human leukocyte C1q receptor binds other soluble proteins with collagen domains.

Isolation and characterisation of potential respiratory syncytial virus receptor(s) on epithelial cells.

Rituxan (anti-CD20 antibody)-induced translocation of CD20 into lipid rafts is crucial for calcium influx and apoptosis.