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Wednesday, March 4, 2015

Role of siglecs and related glycan-binding proteins in immune responses and immunoregulation

Recent years have seen a tremendous acceleration of knowledge in the field of glycobiology, revealing many intricacies and functional contributions that were previously poorly appreciated or even unrecognized. This review by Bochner and Zimmermann highlights several topics relevant to glycoimmunology in which mammalian and pathogen-derived glycans displayed on glycoproteins and other scaffolds are recognized by specific glycan-binding proteins (GBPs), leading to a variety of proinflammatory and anti-inflammatory cellular responses (J Allergy Clin Immunol 2015; 135: 598-608). Their main focus is on 2 families of GBPs, sialic acid–binding immunoglobulin-like lectins (siglecs) and selectins, which are involved in multiple steps of the immune response, including distinguishing pathogens from self, cell trafficking to sites of inflammation, fine-tuning of immune responses leading to activation or tolerance, and regulation of cell survival. Importantly for the clinician, accelerated rates of discovery in the field of glycoimmunology are being translated into innovative medical approaches that harness the interaction of glycans and GBPs to the benefit of the host and might soon lead to novel diagnostics and therapeutics.

Lectins are members of families with carbohydrate recognition domains, and glycosaminoglycan-binding proteins, which bind mostly sulfated glycosaminoglycans. The authors focus mainly on sialic acid–binding immunoglobulin-like lectins (siglecs), which are I-type (immunoglobulin superfamily–type) lectins, and selectins, a subset of the C-type (calcium-dependent) lectin family, which collectively function in the immune system in processes such as pathogen recognition and cell adhesion, activation, signaling, and death. The inhibitory function of siglecs is being exploited for suppressing unwanted immune responses, such as autoimmunity, transplantation, allergic diseases, and others. Current therapeutic approaches mainly involve the use of immunosuppressive drugs; however, this compromises normal immunity and thus carries risks. Novel methods are being explored that would induce antigen-specific tolerance while preserving protective immunity.

Although there is great complexity in glycobiology and glycoimmunology, clear patterns for the role of glycans and GBPs in immune responses are emerging. Glycans are one part of the immune system’s ability to distinguish self from danger; however, pathogens can sometimes use their glycocalyx to evade immune recognition. Similarly, cancer cells can adapt their glycome as part of an evolutionary advantage to evade immune reactivity. Glycans and GBPs are part of the regulation of recruitment of immune cells to sites of inflammation, and defects in GPBs or their ligands can lead to immunodeficiencies. The level of immune response or tolerance is regulated in part by glycans and GBPs, and knowledge of this balance is guiding targeted therapy by using novel approaches involving glycans, including vaccination. Several tactics exploiting glycoimmunology have already or will soon make their way to the clinic, and it is anticipated that additional therapeutic approaches will emerge as our understanding of the glycome and its function in immune responses expands.

Question for the authors:
Preserving protective immunity while suppressing unwanted immune responses would have momentous outcomes. Based on current research, when can clinicians expect to see novel therapeutics utilizing glycobiology in clinical trials?

A company called Glycomimetics, Inc. is already in advanced stages of clinical trials with a pan-selectin antagonist (full disclosure:  Dr. Bochner has received shares of stock from them as a result of my consulting efforts with them a few years ago).  Another company, Sialix, is focusing on therapies targeting specific glycans on cancers and other inflammation-related glycans.  We should soon know whether glycan-based vaccines will prove useful, and glycan-based targeting via liposomal delivery of drug payloads shows exciting beneficial effects in pre-clinical testing in various disease models.  So several glycan and glycan-binding protein based therapies are, or will soon be, in clinical trials.

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