Increased B Cell ADAM10 in Allergic Patients and Th2 Prone Mice

Abstract

ADAM10, as the sheddase of the low affinity IgE receptor (CD23), promotes IgE production and thus is a unique target for attenuating allergic disease. Herein, we describe that B cell levels of ADAM10, specifically, are increased in allergic patients and Th2 prone WT mouse strains (Balb/c and A/J). While T cell help augments ADAM10 expression, Balb WT B cells exhibit increased ADAM10 in the naïve state and even more dramatically increased ADAM10 after anti-CD40/IL4 stimulation compared C57 (Th1 prone) WT B cells. Furthermore, ADAM17 and TNF are reduced in allergic patients and Th2 prone mouse strains (Balb/c and A/J) compared to Th1 prone controls. To further understand this regulation, ADAM17 and TNF were studied in C57Bl/6 and Balb/c mice deficient in ADAM10. C57-ADAM10B-/- were more adept at increasing ADAM17 levels and thus TNF cleavage resulting in excess follicular TNF levels and abnormal secondary lymphoid tissue architecture not noted in Balb-ADAM10B-/-. Moreover, the level of B cell ADAM10 as well as Th context is critical for determining IgE production potential. Using a murine house dust mite airway hypersensitivity model, we describe that high B cell ADAM10 level in a Th2 context (Balb/c WT) is optimal for disease induction including bronchoconstriction, goblet cell metaplasia, mucus, inflammatory cellular infiltration, and IgE production. Balb/c mice deficient in B cell ADAM10 have attenuated lung and airway symptoms compared to Balb WT and are actually most similar to C57 WT (Th1 prone). C57-ADAM10B-/- have even further reduced symptomology. Taken together, it is critical to consider both innate B cell levels of ADAM10 and ADAM17 as well as Th context when determining host susceptibility to allergic disease. High B cell ADAM10 and low ADAM17 levels would help diagnostically in predicting Th2 disease susceptibility; and, we provide support for the use ADAM10 inhibitors in treating Th2 disease.

ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses

“…We have previously reported decreased T H 2 responses in ADAM10 B−/− mice (6). With the above results, we hypothesized that this defect in T H 2 responses may be a result of elevated ICOSL in these mice.…”

“…Defective humoral immune responses in ADAM10 B−/− mice (5, 6) and an earlier report of ADAM17 being important for ICOSL shedding (16) prompted us to examine whether ADAM10 was involved in the shedding of ICOSL. Our studies demonstrate a large increase in ICOSL surface expression on B cells from ADAM10 B−/− mice (Fig.…”

“…In these mice, the overexpression of surface ICOSL results in the internalization and degradation of T cell ICOS in the absence of T cell receptor (TCR) stimulation. As a result, the mice lack both proper T FH and T H 2 effector cell populations post immunization, explaining the defective humoral immunity previously reported in the ADAM10 B−/− mice (5, 6). In addition, increased ICOSL resulted in enhanced T H 1 and T H 17 T cell activation as demonstrated by a model of Experimental Autoimmune Encephalitis (EAE).…”

“…ADAM10 has been shown to act in many paracrine signaling mechanisms and is responsible for cleaving numerous substrates, including Notch receptors, Delta-like 1 (Dll1), IL-6R, CXCL16, and CD23 (3, 4). We have shown that loss of ADAM10 on B cells (ADAM10 B−/− ) results in loss of the marginal zone B cell compartment, disorganized secondary lymphoid architecture, decreased antigen-specific antibody (5), and decreased airway hyper-responsiveness and eosinophilic infiltration in two models of allergic airway disease (6, 7). …”

Allergen-dependent oxidant formation requires purinoceptor activation of ADAM 10 and prothrombin

“…It is also involved in stem cell factor-dependent mast cell migration. ADAM 10 expression is upregulated in a model of asthma and on B cells in patients with allergy and in T H 2-prone mice 8, 9. The combination of high ADAM 10 expression on B cells within a T H 2 cytokine environment causes mimicry of disease pathophysiology, namely, mucus cell hyperplasia, airway constriction, inflammation, and IgE production, whereas development of these is attenuated in mice deficient in ADAM 10 9 …”