Increased B Cell ADAM10 in Allergic Patients and Th2 Prone Mice.
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.
Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, Virginia, United States of America; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Lauren Folgosa
LF
Cooley
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Rebecca K
RK
Martin
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Hannah B
HB
Zellner
Department of Pediatrics, Division of Allergy and Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Anne-Marie
AM
Irani
Department of Pathology, Division of Anatomic Pathology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Cora
C
Uram-Tuculescu
Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.
Mohey Eldin
ME
El Shikh
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Daniel H
DH
Conrad
D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D016084:Bronchoconstriction; D017353:Gene Deletion; D020397:Goblet Cells / Q000473:pathology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007073:Immunoglobulin E / Q000276:immunology; D008221:Lymphoid Tissue / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008679:Metaplasia; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009093:Mucus / Q000378:metabolism; D039981:Pyroglyphidae; D017455:Receptors, IgE / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008565:Membrane Proteins; D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha; D007073:Immunoglobulin E; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse