Basophil effector function and homeostasis during helminth infection

Abstract

IntroductionBasophil development and function is poorly understood, although this rare cell type was identified by Paul Ehrlich in 1879. 1 Basophils constitute less than 0.3% of leukocytes in the peripheral blood. They are functionally closely related to mast cells, since both cell types express the high-affinity receptor for IgE and produce similar effector molecules, including histamine, lipid mediators (eg, leukotrienes and prostaglandins), serine proteases, and interleukins (eg, IL-4, IL-13, and IL-6). 2 However, the developmental and functional relationship of basophils to other cell types is not clearly established. Helminth infections of mice cause a dramatic increase in basophil numbers, which is thought to be mediated by However, naive IL-3-deficient mice have normal levels of basophils, indicating that IL-3 promotes basophil development and/or survival but is not essential for the basophil lineage. 3 Increased numbers of basophils are found in the skin during the late-phase response of contact dermatitis 4 or atopic dermatitis. 5 Basophils are found in the lungs of patients with allergic asthma, and probably contribute to pathogenesis during fatal asthma. 6,7 On the other hand, they might contribute to protective immunity against helminths since basophils are an important source for IL-4 and IL-13. 8 Recently, basophils have been shown to be implicated in polarization of T-helper 2 (Th2) cells by allergens with protease activity 9 and IgG1-mediated anaphylaxis, 10 which further demonstrates their important functions during type 2 immune responses.The turnover of basophils has not yet been described, and their localization in tissues is essentially unknown. Basophils could enhance Th2-associated immune responses since they release IL-4 within minutes of activation. 11,12 Activation can occur by crosslinking of surface-bound IgE molecules or by a large variety of substances in an antigen-unspecific manner (reviewed in Falcone et al 2 ). Mast cells and basophils express constitutively low levels of IL-4, which can be visualized by using sensitive IL-4 reporter mice expressing enhanced green fluorescent protein (eGFP) under control of regulatory elements of IL-4 (4get mice 13 ). Infection of 4get mice with the helminth Nippostrongylus brasiliensis causes massive type 2 immune responses in the lung and small intestine, providing a valuable model to study basophil function during parasitic infections in vivo.Here, we analyzed basophil development and turnover by flow cytometry, BrdU incorporation, and adoptive transfer. We determined the localization of basophils in the spleen, lung, and small intestine of N brasiliensis-infected mice by immunofluorescence staining of tissue sections. Basophils were found to promote differentiation of alternatively activated macrophages in the lung, induce systemic eosinophilia, and contribute to worm expulsion in N brasiliensis-infected mice, demonstrating their central role during the effector phase of a type 2 immune response against helminths. MethodsMice IL-4 reporter ...

Basophils Protect against Reinfection with Hookworms Independently of Mast Cells and Memory Th2 Cells

“…Mice were infected with L3 larvae of N. brasiliensis, as described previously (16). Mice were reinfected 4-5 wk after the first infection for analysis of the memory response.…”

“…Furthermore, several recent publications demonstrated that basophils are important APCs driving the differentiation of Th2 cells in allergy models (13)(14)(15). Recently, we demonstrated that basophils contribute to the efficient expulsion of N. brasiliensis after a primary infection in the absence of Th2 cells (16). In addition, it was shown that basophils are equally important for resolving Trichuris muris infection (14).…”

Basophils and IgE: Linking the Allergic Environment to Autoimmunity

“…Like mast cells, the basophils role in the immune system has been mainly focused on its role in acute models of allergic reactions or on chronic models of parasitic infection where they appear to be important upon a second infection with the parasite [46]. However, if the basophil functions as an immunomodulatory cell, one might predict that there would be instances where the basophil might play an important role in immune diseases other than allergic disease.…”

Unraveling ALK signaling through phosphoproteomics

“…In this issue, Ohnmacht and Voehringer address the development and lifespan of basophils and further investigate their role in helminth infections. 5 In addressing these issues, they first identified the expression of the Thy1 antigen on the surface of IL-4 -expressing cells, which were defined by expression of green fluorescent protein in the 4get transgenic mouse. The basophils were distinguished from the other IL-4 ϩ , FceRI ϩ cell type, the mast cell, by the lack of the mast cell marker c-kit.…”

“…Advances in liquid chromatography-tandem mass spectrometry-driven proteomics have shifted the paradigm of translational cancer research that enables fast and reliable large scale study of proteins involved in many disease models. 4 It follows that identifying the ALK-regulated proteome 5,6 and phosphoproteome would lead to key insights into the signaling pathways important for the pathogenesis of ALCL.…”