Asthma is a chronic airway disease characterized by wheezing, cough, shortness of breath, chest tightness, and “asthma attacks” caused by obstruction in airflow. In the United States, prevalence has increased since 2001 with children and African Americans having the highest incidence . Asthma-related medical costs are $3,300 per diagnosed individual including missed school and work days and asthma-related deaths totaled 3,404 in 2010 [2;3]. Worldwide, 300 million people are diagnosed with asthma and 70% of those suffer from other allergies as well . Helminth infection, however, is considered a disease of developing countries and is rarely concomitant with allergies . The World Health Organization estimates that 1.5 billion people, or 24% of the world’s population, is infected by soil transmitted helminthes, with the majority of cases occurring in east Asia, China, and Sub-Saharan Africa . Allergy, asthma, and helminth infection are considered classic Th2 diseases with immunoglobulin E (IgE) as the predominant antibody class coordinating the response. IgE levels are tightly regulated, being the antibody with the lowest levels
IgE regulates the immune response in one of three ways. First, antigen specific IgE binds the high affinity IgE receptor, FcεRI, on mast cells (MCs) or basophils where it can persist for up to 21 days waiting to bind to antigen, cross-link the FcεRI and degranulate the cell . Degranulation results in release of vasoactive mediators such as histamine, leukotrienes, prostaglandins, and other biologically active products, inducing the classic symptoms of allergic diseases (e.g. wheal and flare or urticaria) depending upon the location of the reaction, while additionally activating the MC or basophil to induce late stage cytokine production . Second, circulating IgE can bind to its antigen creating an IgE-immune complex. IgE immune complexes are picked up by circulating follicular (FO) B cells by binding to CD23, the low affinity IgE receptor (FcεRII). These CD23+B cells then traffic to the splenic follicles where antigen transfer occurs followed by rapid increases in antigen-specific CD4+T cell proliferation and IgG responses . Third, circulating IgE can bind to CD23 on B cells, inducing a negative regulatory response to shut down and control excessive IgE synthesis .
Enzymatic regulation of CD23 and downstream IgE synthesis was initially how a disintegrin and metalloproteinase (ADAM) 10 (ADAM10) became an important topic in Th2 mediated disease responses . ADAMs are a family of zinc dependent proteases involved in ectodomain cleavage of transmembrane proteins and regulated intramembrane proteolysis. Of all the ADAMs, ADAM10 and ADAM17, also known as tumor necrosis factor alpha (TNF) converting enzyme (TACE), are most closely related with regards to structure and share many overlapping substrates [13;14]. Structurally, they contain a zinc dependent metalloproteinase domain, disintegrin and cysteine rich ligand binding domain, transmembrane domain, and cytoplasmic domain . ADAM10 is widely expressed in many cells types and is a highly investigated target in disease processes ranging from cancer and Alzheimer’s disease to asthma . Since its discovery, many ADAM10 substrates have been identified including CD23, Notch1, TNF, amyloid precursor protein (APP) and epidermal growth factor (EGF), further supporting its ability to participate in an array of pathologic processes . ADAM10 has been of much interest in allergic and other Th2 mediated diseases as it is the principle sheddase of the low affinity IgE receptor, CD23. Through an unknown mechanism, soluble CD23 (sCD23) negatively regulates IgE production, meaning increased ADAM10 and thus sCD23 production leads to enhanced IgE production [12;17]. Furthermore, increased sCD23 is seen in sera of allergic patients in active allergy season, which corresponds with increased circulating IgE . Increased cleavage of CD23 leaves less membrane bound CD23 (mCD23) to negatively regulate IgE production as well as increased sCD23 to interact with other pro-inflammatory receptors such as CD11b-CD18 on monocytes [19;20]. Therefore, blocking cleavage of CD23 could be an important target in regulating IgE synthesis and thus the first step in the allergic cascade.
ADAM17, the principal protease of membrane TNF (mTNF), epidermal growth factor receptor (EGFR) ligands, and other vasoactive mediators, has been classically studied in inflammatory syndromes and cancer, with less emphasis on its role in allergy . While ADAM17 is the principle sheddase of mTNF, ADAM10 can cleave TNF albeit to a lesser extent . Dysregulation of TNF is critical for the pathologic characteristics underlying many disease states including cancer, type 2 diabetes, and rheumatoid arthritis . Furthermore, increased TNF production is a key factor implicated in B cell aging, which ultimately curtails class-switched antibody production . B cell TNF is, further, required for maintaining proper secondary lymphoid tissue architecture and antibody production and in its absence severe defects are seen [24;25]. ADAM17 is potentially a new target for diagnostic and/or therapeutic intervention in Th2 mediated diseases, as it and TNF are reduced in B cells of allergic patients [23;26;27].
Herein, the role of ADAM10 and ADAM17 in B cell responses, maintenance of secondary lymphoid tissue architecture, and Th2 mediated diseases, such as allergic rhinitis, asthma, and helminth infection is explored.
2. ADAM10 in B cell development and function
Through their cleaved substrates, members of the ADAM family regulate a wide range of functions, including cell migration, proliferation, and adhesion . With regards to B cell development and function, ADAM10 and ADAM17 have both been extensively studied with respect to lymphocyte development through initiation of the canonical Notch signaling pathway, germinal center responses, and plasma cell function [17;23;26;29;30]. Four Notch receptors exist in humans and rodents, which can interact with five different ligands . Upon ligand-receptor interaction, ADAM10 initiates S2 cleavage followed by S3 cleavage by y secretase, effectively releasing the Notch intracellular domain (NICD), which translocates to the nucleus leading to altered gene expression [32;33]. The role of ADAM10 in Notch signaling has been extensively studied as ADAM10 deficient embryos are similar to those of Notch 1-4 deficient embryos  and Notch 1 signaling is impaired in ADAM10 deficient thymocytes . Furthermore, ADAM10 but not ADAM17 is required for Notch 1 rate-limiting, S2 cleavage, which has important implications in novel approaches to targeting Notch 1 signaling in cancer . B lymphocytes, however, preferentially express Notch 2  and Notch 2 signaling is noted in pre, pro, immature, follicular and marginal zone (MZ) B cells. MZBs are unique B cells, which behave in a T independent manner and are critical for early antibody production against blood borne pathogens . Interestingly, their development is dependent on ADAM10 as it is critical for initiation of Notch 2 signaling . B cell ADAM10, furthermore, has been shown to be critical for antibody production by follicular B2 cells. While the role of ADAM10 in IgE production is discussed below,
3. ADAM10 and ADAM17 in germinal center formation and secondary lymphoid tissue architecture
TNF and its closely related family members have been extensively studied in the development and maintenance of secondary lymphoid tissue architecture. Because ADAM10 and ADAM17 are closely related ADAMs, many questions have been raised about their functional redundancy under physiologic as well as in various genetically manipulated animal models. While ADAM17 is the principle sheddase of TNF, ADAM10 is known to cleave TNF, especially in the absence of ADAM17 . In addition to TNF,
4. ADAM10 and ADAM17 in murine and human allergic airway disease
4.1. ADAM10 is the principle sheddase of CD23
CD23 is a unique Fc receptor as it is a type 2 transmembrane protein and a member of the calcium dependent (C type) lectin family. It exists in two isoforms, CD23a and CD23b, and has three domains: (1) IgE interacting carboxy terminal domain, (2) stalk regions, and (3) a short cytoplasmic tail . Surface CD23 levels can be increased in an IL-4 or IL-13 dependent manner . In humans, peripheral blood mononuclear cells stimulated with IL-4 exhibit increased CD23 shedding and IgE production whereas treatment with anti-CD23, which prevents its cleavage, inhibits IgE production . Several enzymes have been implicated in the cleavage of CD23 including ADAM8  and other hydroxymate sensitive metalloproteinases , but ADAM10 was determined by
4.2. ADAM10, ADAM17, and their substrates in murine and human airway hypersensitivity
Mouse models of airway hypersensitivity are classically used to model asthma in humans. The role of ADAM10 and ADAM17 and their substrates has been widely studied in lung inflammation models used to simulate upper and lower airway disease. First, as described herein, ADAM10 is critical in the regulation of IgE production through its substrate, CD23. Transgenic mice overexpressing CD23 (CD23Tg) had been shown previously to have reduced IgE and lung inflammation [44;45]. In a OVA-induced lung inflammation model,
Lastly, while glutamate is classically known for its role as an excitatory neurotransmitter, glutamate receptors have been found on T cells , macrophages , and human B cells . The kainate receptor is a multi-subunit, ionotropic glutamate receptor.
In addition to B cells, neutrophils or leukocytes and their respective ADAM10 and ADAM17 levels have also been described in lung inflammation models. Neutrophils recruitment occurs early during inflammation and their mediators affect the activity and recruitment of many other immune cells. The number of neutrophils in sputum was seen to be elevated in patients with both acute and chronic asthma and especially those with lower eosinophil numbers and those unresponsive to corticosteroid treatment [53-55]. Both ADAM10 and ADAM17, with some conflicting reports, have been described to be important for leukocyte migration to the airway in lung inflammation models. In leukocyte specific ADAM17 deficient mice,
Epidermal growth factor receptor (EGFR) signaling is reported to be integral in tissue repair, airway remodeling in asthma, and MUC5AC mucin production in lung inflammation models [58-60]. ADAM17 is responsible for the processing of epidermal growth factor receptor ligands including transforming growth factor alpha (TGFα) . In normal human bronchial epithelial (NHBE) cells,
5. ADAM10, CD23 and MDSCs in helminth infection
In industrialized countries, incidence of helminth infection is greatly reduced and when observed it is commonly associated with a reduced parasite burden . Worldwide, over one billion individuals are heavily infected with helminth and are rarely affected by allergic disease , a correlation demonstrated by many epidemiological studies [65;66]. Allergic diseases share many factors with helminth infections, including a similar cytokine milieu (e.g. IL-13, IL-4, IL-5) and most importantly up-regulation of IgE [65;66]. These factors contribute to the symptomology of allergic disease, yet in helminth infected individuals, are protective [65;66]. This is despite helminth being the strongest natural promoter of IgE synthesis . It is well established that parasite-specific IgE is important for anti-helminth immunity, but helminthes are also known to elicit large amounts of polyclonal or non-specific IgE in the sera of infected individuals. This finding has been thought to be a protective response by the parasite . Helminth evolution has selected for this trait that benefits parasite life and reproduction, assisting the helminth in immune evasion .
In both allergy and helminth infection, IgE responses have been associated with CD23 expression and thus ADAM10 enzymatic activity [68-70]. The product, sCD23, has been a diagnostic indicator in many different diseases [69;71]. In an epidemiological study of individuals infected with the helminth
Mast cells (MCs), which are important in mediating response to helminth infection, have been shown to express ADAM10 . ADAM10 deletion results in reduced proliferation and migration of bone marrow derived masts cells
ADAM10Tg mice, generated by injection of ADAM10 cDNA under control of the H-2Kb promoter and the IgH enhancer, overexpress murine ADAM10 and were initially made to study the role of ADAM10 in lymphocyte development [76-78]. Inclusion of the IgH enhancer results in preferential expression on B lineage cells. This overexpression of ADAM10 was observed on bone marrow (BM) cells and markedly reduced the numbers of pro, pre, and immature B cells in the BM resulting in an almost complete loss of peripheral B2 B cells due to improper Notch cleavage and signaling . The only B cell population unaltered by ADAM10 overexpression was B1a and B1b cells, which typically reside in the peritoneal and pleural cavities . ADAM10Tg animals also exhibit significant myeloid accumulation. In the BM of these mice, CD11b+Gr-1+cells constitute over 90% of total BM cells. These cells leave the BM and migrate to all secondary lymphoid organs, where they are defined as myeloid derived suppressor cells (MDSCs). Recent work has shown a similar scenario exists in human disease, with defects in Notch signaling driving MDSC accumulation .
MDSCs accumulate in a spectrum of disease states including cancer, the natural aging process, solid organ transplantation, parasitic infections, sepsis, autoimmune disease, trauma, and burns [80-83]. MDSCs are classified as either monocytic (CD11b+Ly6C+Ly6G-) or granulocytic (CD11b+Ly6CintLy6G+) subsets . This heterogeneous population was observed within the MDSCs in the ADAM10Tg . Although MDSC accumulation is a byproduct of ADAM10 overexpression in early hematopoietic progenitors, ADAM10 expression is not altered in these cells. ADAM10Tg mice, therefore, could be exploited to study MDSC-mediated immune regulation in an environment devoid of confounding factors.
While MDSCs are most well-defined for their immunosuppressive role in cancer, a new role for accumulation of MDSCs in Th2-driven parasitic infection, such as
Recent evidence is beginning to suggest that mast cells (MCs) contribute to the recruitment and activity of these MDSCs [86;88;89]. While MCs have been well documented to mediate allergic inflammation, new evidence is emerging to define the novel interaction between the MDSC and the MC. In MC-deficient mice, MDSC enhanced parasitic clearance is completely reversed. Additionally, co-culture of MCs and MDSCs results in enhanced IgE-mediated cytokine production by the MC . Without MCs, MDSCs fail to migrate to the liver. This is thought to be through MC mediators such as histamine and IL-13 [86;87]. Histamine has been shown to induce MDSC proliferation, migration and activation (Figure 2) . This is reflected in humans as reported by
6. ADAM10, CD23 and IgE immune complexes
Antibody, in complex with its antigen, provides the immune system with a feedback response against the complexed antigen. This feedback mechanism results in immune stimulation or suppression depending upon the antibody class . IgE, complexed with antigen, has long been shown to induce a significantly increased immune response over antigen alone. This response results in increased antigen specific T cell proliferation and antigen specific IgG
Exosomes are defined as tiny membrane bound particles ranging from 30-150nm. Although originally discovered in the 1980s and thought to be primarily for cellular waste , exosomal research has undergone a resurgence given the protein and micro-RNA cargo that is packed into these particles . In a previous publication,
ADAM 10 and 17 proteases have been widely studied in Th2 mediated disease responses including allergic rhinitis, asthma, and helminth infection. Enzymatic regulation of ADAM10 and 17 substrates as well as the relative amount of ADAM10 and 17 on immune cells is critical for preventing Th2 mediated disease as well as maintenance of normal antibody production, germinal center formation, and secondary lymphoid tissue architecture. While the role of ADAM10 in Th2 diseases is classically recognized for its regulation of IgE synthesis by CD23 cleavage, predisposition to asthma as well as severity of disease appears to be in part controlled by a tight regulation of ADAM10 and ADAM17 proteolytic activity, which in turn controls the cleavage of key substrates such as CD23, TNF, TGFα, and TGFβ1. These substrates ultimately effect IgE production, airway remodeling, inflammatory cell infiltration, and airway responsiveness.
Attenuation of MC degranulation and neutralization of MC mediators such as histamine and leukotrienes are common targets of therapeutic interventions used in asthma and allergic airway disease. MC histamine release is critical, however, for function, migration, and activation of MDSCs, which have been shown to alleviate helminth infection by decreasing parasite burden. This finding was studied using a unique model of MDSC accumulation in a mouse model that overexpresses ADAM10. Therefore, while MDSCs is could be considered harmful in severe allergy, they may also be essential for protection against helminth infection.
This review has demonstrated the essential role of ADAM10 and 17 and their substrates in Th2 mediated disease and provided a review of evidence supporting the continued exploration of ADAM10 and ADAM17 as potential therapeutic and diagnostic targets.
Work discussed in this review, which is from the author’s laboratory is supported by grant RO1AI18697 from NIAID/NIH, American Asthma Foundation 11-0094 AAF, and a bridge grant from the VCU School of Medicine.
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