Am J Respir Crit Care Med. 2012 Feb 1;185(3):311-21. Epub 2011 Nov 22.
Pulmonary Lymphoid Neogenesis in Idiopathic Pulmonary Arterial Hypertension.
Perros F, Dorfmüller P, Montani D, Hammad H, Waelput W, Girerd B, Raymond N, Mercier O, Mussot S, Cohen-Kaminsky S, Humbert M, Lambrecht BN.
Service de Pneumologie et Reanimation Respiratoire, HOPITAL ANTOINE BECLERE, 157 rue de la Porte de Trivaux, Clamart, 92140, France.
Abstract
RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) patients present circulating autoantibodies against vascular wall components. Pathogenic antibodies may be generated in tertiary (ectopic) lymphoid tissues (tLTs).
OBJECTIVES: To assess how frequent are tLTs in IPAH lungs, as compared to controls and flow-induced PAH in patients with Eisenmenger syndrome, and to identify local mechanisms responsible for their formation, perpetuation and function.
METHODS: tLTs composition and structure were studied by multiple immunostainings. Cytokines/chemokines and growth factors expression was quantified by real-time PCR and localized by immunofluoresence. The systemic mark of pulmonary lymphoid neogenesis was investigated by flow cytometry analyses of circulating lymphocytes. MEASUREMENTS AND MAIN RESULTS: As opposed to lungs from controls and Eisenmenger syndrome, IPAH lungs contained perivascular tLTs, comprising B and T cell areas with high endothelial venules and dendritic cells. Lymphocyte survival factors, such as IL-7 and PDGF-A, were expressed in tLTs as well as the lymphorganogenic cytokines/chemokines, lymphotoxin-α/-β, CCL19, CCL20, CCL21 and CXCL13, which might explain depletion of circulating CCR6+ and CXCR5+ lymphocytes. tLTs were connected to remodeled vessels via an ER-TR7+ stromal network and supplied by lymphatic channels. The presence of germinal center centroblasts, follicular dendritic cells, activation-induced cytidine deaminase and IL21+PD1+ T follicular helper cells in tLTs together with CD138+ plasma cells accumulation around remodeled vessels in areas of immunoglobulin deposition argued for local immunoglobulin class switching and ongoing production.
CONCLUSIONS: We highlight the main features of lymphoid neogenesis specifically in the lungs of patients with IPAH providing new evidence of immunological mechanisms in this severe condition.
PMID:22108206