Basophils and allergic inflammation

Abstract

Basophils were discovered by Paul Ehrlich in 1879 and represent the least abundant granulocyte population in mammals. The relative rarity of basophils and their phenotypic similarities with mast cells resulted in this cell lineage being historically overlooked, both clinically and experimentally. However, recent studies in human subjects and murine systems have shown that basophils perform nonredundant effector functions and significantly contribute to the development and progression of TH2 cytokine-mediated inflammation. Although the potential functions of murine and human basophils have provoked some controversy, recent genetic approaches indicate that basophils can migrate into lymphoid tissues and, in some circumstances, cooperate with other immune cells to promote optimal TH2 cytokine responses in vivo. This article provides a brief historical perspective on basophil-related research and discusses recent studies that have identified previously unappreciated molecules and pathways that regulate basophil development, activation, and function in the context of allergic inflammation. Furthermore, we highlight the unique effector functions of basophils and discuss their contributions to the development and pathogenesis of allergic inflammation in human disease. Finally, we discuss the therapeutic potential of targeting basophils in preventing or alleviating the development and progression of allergic inflammation.

Keywords: AD; APC; AR; Allergic rhinitis; Antigen-presenting cell; Atopic dermatitis; BAT; BaP; Basophil; Basophil activation test; Basophil precursor; CIU; Chronic idiopathic urticaria; EMH; EoE; Eosinophilic esophagitis; Extramedullary hematopoiesis; FDA; GMP; Granulocyte-monocyte progenitor; HDM; HSC; Hematopoietic stem cell; House dust mite; IgE; LTC(4); Leukotriene C(4); MCP; Mast cell precursor; MyD88; Myeloid differentiation primary response gene (88); T(H)2 cytokine; TSLP; Thymic stromal lymphopoietin; US Food and Drug Administration; allergic rhinitis; allergy; asthma; atopic dermatitis; eosinophilic esophagitis; food allergy; thymic stromal lymphopoietin; urticaria.

Figure 1. The clinical relevance of basophils

Basophils have been shown to contribute to many human disease states. Including allergic disease (contact dermatitis, atopic dermatitis, hypersensitivity responses and asthma), autoimmunity (bullous pemphigoid and lupus nephritis), inflammatory disorders (Crohn’s disease) and cancer (acute and chronic myelogenous leukemia). This article will focus on the contribution of basophils to allergic disease.

Figure 2. Basophil development

Murine basophils develop from hematopoietic stem cell (HSC) populations that reside in the bone marrow. As HSCs mature, they become granulocyte monocyte precursors (GMPs), basophils mast cell precursors (BMCPs) and basophil precursors (BaPs). To date 2 cytokines, T cell-derived IL-3 and epithelial cell-derived TSLP, have been shown to promote distinct phases of basophil development. After fully maturing in the bone marrow, basophils can enter the periphery and contribute to inflammation.

Figure 3. Heterogeneous effector functions of basophil populations

Recent studies have demonstrated that IL-3-elicited basophils are highly responsive to FcεRI crosslinking via IgE-antigen complexes. After encountering antigen, IL-3-elicited basophils release multiple effector molecules that can contribute to allergic inflammation. TSLP-elicited basophils are non-responsive to IgE-antigen complexes but produce multiple effector molecules following stimulation with cytokines such as IL-33 and IL-18. The observed functional heterogeneity between IL-3-elicited and TSLP-elicited basophils may allow IL-3-elciteid basophils and TSLP-elicited basophils to contribute to various allergic disorders that are associated with IgE responses and/or TSLP production.

Figure 4. The contributions of IgE and TSLP to allergic disease

Allergic disease states appear to separate into three separate categories, those that are highly IgE-dependent (urticarial and food allergy), those that are partially IgE-dependent (asthma and atopic dermatitis) and those that are IgE-independent (eosinophil esophagitis). Critically, allergic diseases that are only partially dependent on IgE, or independent of IgE are highly associated with TSLP production. Therefore, it is likely that IL-3-elicited basophils that are highly responsive to IgE-antigen complexes contribute to IgE-mediated allergic disorders, while TSLP-elicited basophils contribute to IgE-independent disorders.