Activation of human basophils by combined toll‐like receptor‐ and FcεRI‐triggering can promote Th2 skewing of naive T helper cells

Abstract

Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionBasophils are circulating granulocytes that can migrate to tissues when inflammation or other triggers are present locally. Activation of basophils through crosslinking of FcεRI via antigen-specific IgE causes the release of granule contents (histamine, proteoglycans), lipid-derived mediators (leukotrienes), and cytokines. Due to their potent activation via IgE-bound antigens and their production of T helper 2 (Th2) type cytokines such as IL-4 and IL-13, Correspondence: Jolien Suurmond e-mail: j.suurmond@lumc.nl basophils are often considered important innate effector cells in IgE-mediated immune responses. Besides activation through IgE, several other pathways have been described to activate basophils, including activation through complement receptors and toll-like receptors (TLR). Although information about TLR protein expression and the response of basophils to TLR ligands is scarce, human basophils express mRNA of several TLRs, and protein of TLR-2 and -4. However, the functional response of basophils to ligation of most TLRs is unknown [1][2][3][4].Basophil responses to TLR ligands may be important, as it is not understood how pathogens and allergens may lead to induction of Th2 responses. As TLR ligation of dendritic cells most often induces type 1 responses through production of IL-12, it is not understood whether and how Th2 cells can be induced via TLR. Since basophils are a known early source of IL-4 and other cytokines associated with Th2 responses, they have been proposed to play a prominent role in the induction of such responses [8]. In mice, it was suggested that basophils play a crucial role in responses against Th2-associated helminth parasites and in protease allergens [9][10][11]. Basophils were proposed to function as APCs in these studies and were also shown to be present in LNs in models of allergy and helminth infection [12][13][14]. However, the function of basophils as APCs during the priming phase of Th2 responses in mice has been challenged by others [13,15,16], and human basophils could not present antigens to CD4 + T cells [17,18]. Therefore, it seems unlikely that human basophils function as APCs. However, by providing an early IL-4 signal that facilitates Th2 skewing after T-cell activation by APCs, basophils could play an important role in skewing of Th2 responses as accessory cells. Indeed, in a mouse model for papain-induced Th2 responses, both DCs and basophils were important for Th2 skewing [19].Since several allergens and helminth parasites can activate TLRs [20][21][22], it would be of high importance to know whether human basophils can be activated via TLR triggering, and if so, which cytokines are released. Until now, little information on these aspects is available for human basophils. Furthermore, as allergic responses and helminth infections may induce IgE responses [23], it would be important to know whether these pathways would interact and prom...

Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity

“…This process causes a vicious cycle wherein each disease flare can initiate further autoantibody production and tissue injury (107)(108)(109). Furthermore, combined TLR-and Fc receptor-mediated activation of myeloid cells often leads to an enhanced inflammatory response that is thought to contribute to the chronicity of inflammation (51,94,110,111). Therefore, those self-antigens that can most potently activate B cells because they are TLR ligands may also potently enhance pathogenic inflammatory responses (Figure 3).…”

IgE and IL‐33−mediated triggering of human basophils inhibits TLR4−induced monocyte activation

“…Even though the role of the sialylated fraction of IVIG or basophils in the immunomodulatory effects of IVIG therapy has recently been challenged [9], another study using an experimental model of IgE-mediated chronic allergic inflammation, showed that mouse basophils, through IL-4, drive the differentiation of monocytes into anti-inflammatory macrophages, thereby regulating chronic allergic skin inflammation in vivo [10]. Human basophils, which can significantly differ from their mouse counterparts [1,3,11], have been known for a long time to produce , and have been recently shown to induce Th2 skewing of naïve helper T cells in vitro [13,14]. On the other hand, the function as antigen presenting cells, still debated in mice, has been ruled-out for human basophils by several groups [15][16][17].…”

“…Human basophils, which can significantly differ from their mouse counterparts [1,3,11], have been known for a long time to produce IL-4 [12], and have been recently shown to induce Th2 skewing of naïve helper T cells in vitro [13,14]. On the other hand, the function as antigen presenting cells, still debated in mice, has been ruled-out for human basophils by several groups [15][16][17].…”

Demystification of enigma on antigen-presenting cell features of human basophils: data from secondary lymphoid organs

“…13 Therefore, we stimulated basophils with lipopolysaccharide from E. coli (LPS, TLR4 agonist), FSL-1 (Pam2CGDPKHPKSF, TLR2/6 agonist), or CpG ODN (TLR9 agonist). Furthermore, we also used papain as a model allergen in our experiments, and this cysteine protease allergen can directly activate basophils and promote murine basophil-mediated Th2 responses.…”

“…Furthermore, we also used papain as a model allergen in our experiments, and this cysteine protease allergen can directly activate basophils and promote murine basophil-mediated Th2 responses. 4 Since, IgEbound antigens/allergens provide the most-potent activation signal for basophils, 13,14 this stimulation condition was mimicked by crosslinking of surface FcεRI-bound IgE by using anti-IgE antibodies (See Online Supplementary Methods).…”