title: Loss of pro-apoptotic Bim promotes accumulation of pulmonary T lymphocytes and enhances allergen-induced goblet cell metaplasia.
abstract: Immunological tolerance during prolonged exposure to allergen is accompanied by a shift in the lymphocyte content and a reduction of goblet cell metaplasia (GCM). Bim initiates negative selection of autoreactive T and B cells and shut down of T cell immune responses in vivo. The present study investigated whether Bim plays a role in the resolution of GCM during prolonged exposure to allergen. Loss of Bim increased T lymphocyte numbers in the bronchoalveolar lavage at 4 and 15 days of allergen exposure. The numbers of pulmonary CD4(+)8(-), CD4(-)8(+), and gammadelta T cells were significantly higher in naive and allergen-challenged bim(-/-) mice compared with wild-type (WT) littermates. When activated, pulmonary bim(-/-) T cells produced increased levels of IFNgamma compared with bim(+/+) T cells. No differences were noted in the total numbers of epithelial cells per millimeter of basal lamina between bim(+/+) and bim(-/-) mice, and the rate of resolution over 15 days of exposure was similar in both groups of mice. However, GCM was significantly enhanced and expression of IL-13Ralpha2 was reduced in bim(-/-) mice compared with WT mice at 4 days. Furthermore, treatment of bronchiolar explant cultures with increasing IFNgamma levels reduced immunostaining for IL-13Ralpha2. Collectively, these studies suggest that, during prolonged exposure to allergen, Bim plays no role in the resolution of GCM, but increased IFNgamma levels in bim(-/-) mice may be responsible for reduced expression of IL-13Ralpha2 and enhanced GCM despite similar levels of IL-13 in bim(+/+) and bim(-/-) mice.
authors.affiliation: Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr., SE, Albuquerque, NM 87108, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Pierce
authors.forename: Jules
authors.initials: J
authors.lastname: Rir-Sima-Ah
authors.forename: Isaac
authors.initials: I
authors.lastname: Estrada
authors.forename: Julie
authors.initials: J
authors.lastname: Wilder
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
mesh_terms: D000485:Allergens / Q000276:immunology / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D020397:Goblet Cells / Q000276:immunology / Q000473:pathology*; D007371:Interferon-gamma / Q000378:metabolism; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008679:Metaplasia / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D000485:Allergens; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D053663:Interleukin-13 Receptor alpha2 Subunit; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma; D010047:Ovalbumin