Role of B Cell-Activating Factor in Chronic Obstructive Pulmonary Disease.
BACKGROUND
B cell-activating factor (BAFF) plays a major role in activation of B cells and in adaptive humoral immune responses. In chronic obstructive pulmonary disease (COPD), lymphoid follicles have been associated with disease severity, and overexpression of BAFF has been demonstrated within lymphoid follicles of patients with severe COPD.


OBJECTIVE
To investigate expression and localization of BAFF in the lungs of patients with COPD and to study the role of BAFF in COPD by antagonizing BAFF in a mouse model of chronic cigarette smoke (CS) exposure.


METHODS
We quantified and localized BAFF expression in lungs of never-smokers, smokers without COPD, and patients with COPD and in lungs of air- or CS-exposed mice by reverse-transcriptase polymerase chain reaction, ELISA, immunohistochemistry, and confocal imaging. Next, to investigate the role of BAFF in COPD, we antagonized BAFF by prophylactic or therapeutic administration of a soluble fusion protein of the BAFF-receptor, BAFFR-Fc, in mice exposed to air or CS for 24 weeks and evaluated several hallmarks of COPD and polarization of lung macrophages.


RESULTS
BAFF expression was significantly increased in lungs of patients with COPD and CS-exposed mice. BAFF staining in lymphoid follicles was observed around B cells, CD4(+) cells, dendritic cells, follicular dendritic cells, and fibroblastic reticular cells. Prophylactic and therapeutic administration of BAFFR-Fc in mice reduced pulmonary B-cell numbers and prevented CS-induced formation of lymphoid follicles and increases in immunoglobulin levels. Interestingly, prophylactic BAFFR-Fc administration significantly attenuated pulmonary inflammation and destruction of alveolar walls. Moreover, antagonizing BAFF altered the phenotype of alveolar and interstitial macrophages.


CONCLUSIONS
BAFF is significantly increased in lungs of patients with COPD and is present around both immune and stromal cells within lymphoid follicles. Antagonizing BAFF in CS-exposed mice attenuates pulmonary inflammation and alveolar destruction.
1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
Leen J M
LJ
Seys
1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
Fien M
FM
Verhamme
2 AstraZeneca Respiratory, Inflammation and Autoimmune iMed, Molndal, Sweden.
Anja
A
Schinwald
3 Laboratory of Immunoregulation and Mucosal Immunity, Department for Molecular Biomedical Research, VIB, Ghent, Belgium.|4 Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
Hamida
H
Hammad
2 AstraZeneca Respiratory, Inflammation and Autoimmune iMed, Molndal, Sweden.
Danen Mootoosamy
DM
Cunoosamy
5 Department of Research, MedImmune, LLC, Gaithersburg, Maryland.
Claudie
C
Bantsimba-Malanda
6 AstraZeneca Cardiovascular and Metabolic Disease iMed, Molndal, Sweden; and.
Alan
A
Sabirsh
6 AstraZeneca Cardiovascular and Metabolic Disease iMed, Molndal, Sweden; and.
Eileen
E
McCall
7 AstraZeneca Discovery Sciences iMed, Alderley Park, United Kingdom.
Liz
L
Flavell
5 Department of Research, MedImmune, LLC, Gaithersburg, Maryland.
Ronald
R
Herbst
1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
Sharen
S
Provoost
3 Laboratory of Immunoregulation and Mucosal Immunity, Department for Molecular Biomedical Research, VIB, Ghent, Belgium.|4 Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
Bart N
BN
Lambrecht
1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
Guy F
GF
Joos
1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
Guy G
GG
Brusselle
1 Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
Ken R
KR
Bracke
D056704:Adaptive Immunity; D000368:Aged; D000818:Animals; D053264:B-Cell Activating Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D008221:Lymphoid Tissue / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects
D053264:B-Cell Activating Factor; D012906:Smoke; C505719:TNFSF13B protein, human
B cell–activating factor; B lymphocytes; COPD; lymphoid follicles