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Lymphoid Follicle Cells in Chronic Obstructive Pulmonary Disease Overexpress the Chemokine Receptor CXCR3

¹ Department of Medicine and ² Department of Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Steven G. Kelsen, M.D., 761 Parkinson Pavilion, Temple University Hospital, 3401 N. Broad St., Philadelphia, PA 19140. E-mail: kelsen{at}temple.edu.

Rationale: The mechanisms underlying formation of lung lymphoid follicles (LF) in chronic obstructive pulmonary disease (COPD) are unknown. The chemokine receptor CXCR3 regulates immune responses in secondary lymphoid structures elsewhere in the body and is highly expressed by Th1 lymphocytes in the airway in COPD. Because chemokine receptors control inflammatory cell homing to inflamed tissue, we reasoned that CXCR3 may contribute to LF formation in COPD.

Objectives: We assessed the expression of CXCR3 and its ligands (IP-10/CXCL10, Mig/CXCL9, and ITAC/CXCL11) by LF cells in never-smokers, smokers without COPD, and subjects with COPD.

Methods: CXCR3, IP-10, Mig, and ITAC expression were assessed in lung sections from 46 subjects (never-smokers, smokers without COPD [S], and subjects with COPD in GOLD stages 1–4) by immunohistochemistry.

Measurements and Main Results: CXCR3-expressing T cells (CD8⁺ or CD4⁺) and B cells (CD20⁺) were topographically distributed at the follicle periphery and center, respectively. The percentage of immunohistochemically identified CXCR3⁺ cells increased progressively while proceeding from S through GOLD 3–4 (P < 0.01 for GOLD 3–4 vs. S). Moreover, the number of CXCR3⁺ follicular cells correlated inversely with FEV₁ (r = 0.60). The CXCR3 ligands IP-10 and Mig were expressed by several cell types in and around the follicle, including CD68⁺ dendritic cells/ macrophages, airway epithelial cells, endothelial cells, and T and B cells.

Conclusions: These results suggest that LF form in the COPD lung by recruitment and/or retention of CXCR3-expressing T and B lymphocytes, which are attracted to the region through production of CXCR3 ligands IP-10 and Mig by lung structural and follicular cells.

Key Words: lung inflammation • chemokines • cell recruitment

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The chemokine receptor CXCR3 regulates immune responses in secondary lymphoid structures and is highly expressed by Th1 lymphocytes in the airway in chronic obstructive pulmonary disease (COPD). In contrast, the mechanisms underlying formation of lung lymphoid follicles in COPD are unknown. What This Study Adds to the Field We report that the chemokine receptor CXCR3 and its ligands Mig/CXCL9 and IP-10/CXCL10 are highly expressed by cells in and around lymphoid follicles in COPD. These findings suggest that CXCR3 contributes to follicle formation in COPD.

 

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