Highlights
- •β-glucans are biological response modifiers with rich sources and diverse structures.
- •Extensive studies of β-glucan have been carried out to demonstrate its adjuvant activity on anti-infection vaccination and anti-tumor therapy.
- •The immunoadjuvant effects of β-glucans are mainly depending on the recognition of specific receptors such as dectin-1 and CR3.
Abstract
β-glucans, a group of polysaccharides exist in many organism species such as mushrooms, yeasts, oats, barley, seaweed, but not mammalians, have a variety of biological activities and applications in drugs and other healthcare products. In recent years, β-glucans have been studied as adjuvants in anti-infection vaccines as well as immunomodulators in anti-cancer immunotherapy. β-glucans can regulate immune responses when administered alone and can connect innate and adaptive immunity to improve immunogenicity of vaccines. When β-glucans act as immunostimulants or adjuvants, a set of receptors have been revealed to recognize β-glucans, including dectin-1, complement receptor 3 (CR3), CD5, lactosylceramide, and so on. Therefore, this review is mainly focused on the application of β-glucans as immune adjuvants, the receptors of β-glucans, as well as their structure and activity relationship which will benefit future research of β-glucans.
Introduction
The term adjuvant was first used to refer to the substances combined with vaccines to improve the intensity and longevity of immune response or to change the type of response, with low toxicity and weak immunogenicity [1], [2]. Traditionally, according to the roles that adjuvants play in vaccination, adjuvants were divided into three types, namely, vehicle, storage and immune stimulant [3]. Vehicle adjuvant can take vaccine to specific tissues or to antigen presenting cells (APCs) directly. Storage adjuvant can extend the duration of immune reaction to antigen, whereas immune stimulant adjuvant can enhance the sensitivity of immune system to antigen. Nowadays, the definition of adjuvant has been expanded. Adjuvants are not merely used in prophylactic vaccine formulation, but also used in therapeutic formulation and used alone for immunomodulatory purpose. Hence, these adjuvants can be collectively referred to as immunoadjuvants [4]. More recently, extensive research on immunomodulatory activities of these immunoadjuvants demonstrates the relationship and mechanisms between adjuvants and immune system [5], [6]. The general mechanism is that immunoadjuvants can be recognized as pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), which present on the surface of immune cells, and then initiate a series of effects such as signaling pathways activation, gene expression, cytokines secretion, cells maturation and differentiation and lead to the activation of adaptive immune response [3]. Thus, substances that have immunomodulatory effects or PRR binding capabilities are studied for their potential use as adjuvants.
Many polysaccharides that can bind to PRRs and stimulate immune system, such as α-glucans (modified dextran), β-glucans (yeast polysaccharides and lentinan), β-fructans (inulin), mannan and chitosan, have the potential to be used as immunoadjuvants [7], [8]. Among these polysaccharides, β-glucans are components of fungal cell wall and have lots of immunomodulatory properties [9], [10]. β-glucans are β-linked homopolysaccharides composed of D-glucopyranosyl residues and can be extracted from mushrooms, yeasts, oats, barley, seaweed, algae, fungi and bacterial cell walls [11], [12], [13]. However, the structures of β-glucans are diverse. For example, β-glucan from microorganism is mainly constituted by β (1 → 3) linked glucose with several (1 → 6) linked branches, while β-glucan from plant is mainly constituted by β (1 → 3) and β (1 → 4) linked glucose without branch. Besides, curdlan, one type of β-glucans from bacteria, is assembled only with a β (1 → 3) glucose molecule without any branches [14]. Based on the β-linked backbones, β-glucans can be recognized and captured mainly by specific receptors, such as dectin-1 on dendritic cells (DCs) and macrophages. Their recognitions initiate signal cascade to promote cytokine production, cell maturation and migration and the sensitivity to antigen, then induce or reinforce Th1 cells biased adaptive immune response so as to exert adjuvant effects [15], [16], [17]. Consequently, immunomodulatory activities and receptors of β-glucans are investigated comprehensively and have been developed in anti-infection vaccine as well as anti-tumor therapy.
Section snippets
Immunomodulatory activity
The immunomodulatory activities of β-glucans have been studied for decades [13], [18], [19], and the investigations have been mainly focused on their effects on cytokines secretion, function changes of immune cells and shift of Th1/Th2 response bias [20] (shown in Table 1). To the effect on cytokine secretion of immunocytes, β-glucans present both pro- and anti-inflammatory activities. For example, in human monocytes and macrophages, β-glucan extracted from mushroom had a distinct stimulating
Effects of structure on the bioactivity of β-glucans
β-glucans obtained from different sources often have different primary structures and conformations. The primary structure of β-glucans is defined by glucosidic bond type, as well as degrees of branching and polymerization, while the conformation of β-glucans often presents as random coil, single helix and triple helix and is affected by the primary structure, inter-molecular force, temperature and solvent [82]. Both primary structure and conformation of β-glucans play a crucial role on their
Dectin-1
Among the PRRs, toll-like receptors (TLRs) and C-type lectin receptors (CLRs) are two representative types on the surface of APCs such as DCs [88]. Dectin-1 is a well-researched CLR that is responsible for β-glucan recognition and plays an important role in anti-fungal infection [89]. It recognizes β-(1 → 3) and/or β-(1 → 6) linked glucans and the binding strength depends on the size, linkage type and branching degrees of the β-glucans [90], [91]. Though, there are larger number of studies
Problems and future perspectives
Although immunomodulatory activities of β-glucan were reported very early, research on its immune regulation, adjuvant effect and its receptor interactions is still at the primary stage [13], [19]. Furthermore, though the adjuvanticity of β-glucans is generally accepted there are also some studies that have reported the opposite results and conclusions. In one such study, when administered β-glucan or particle β-glucan adjuvant together with influenza vaccine to mice, there appeared no
Acknowledgments
This work was supported by the National Natural Science Foundation of China (NO. 81603011).
Author contributions
YimingJin was involved with project concept development, performed the literature search and prepared the manuscript. PingliLi assisted with project concept development and reviewed the manuscript. FengshanWang reviewed and revised the manuscript.
Conflict of interest
All authors have no conflicts to declare.
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