RATIONALE: Patients with idiopathic pulmonary arterial hypertension (IPAH) present circulating autoantibodies against vascular wall components. Pathogenic antibodies may be generated in tertiary (ectopic) lymphoid tissues (tLTs). OBJECTIVES: To assess the frequency of tLTs in IPAH lungs, as compared with control subjects and flow-induced PAH in patients with Eisenmenger syndrome, and to identify local mechanisms responsible for their formation, perpetuation, and function. METHODS: tLT composition and structure were studied by multiple immunostainings. Cytokine/chemokine and growth factor expression was quantified by real-time polymerase chain reaction and localized by immunofluorescence. 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 control subjects and patients with 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 platelet-derived growth factor-A, were expressed in tLTs as well as the lymphorganogenic cytokines/chemokines, lymphotoxin-α/-β, CCL19, CCL20, CCL21, and CXCL13, which might explain the depletion of circulating CCR6(+) and CXCR5(+) lymphocytes. tLTs were connected with 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 IL-21(+)PD1(+) follicular helper T cells in tLTs together with CD138(+) plasma cell 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.
RATIONALE: Patients with idiopathic pulmonary arterial hypertension (IPAH) present circulating autoantibodies against vascular wall components. Pathogenic antibodies may be generated in tertiary (ectopic) lymphoid tissues (tLTs). OBJECTIVES: To assess the frequency of tLTs in IPAH lungs, as compared with control subjects and flow-induced PAH in patients with Eisenmenger syndrome, and to identify local mechanisms responsible for their formation, perpetuation, and function. METHODS: tLT composition and structure were studied by multiple immunostainings. Cytokine/chemokine and growth factor expression was quantified by real-time polymerase chain reaction and localized by immunofluorescence. 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 control subjects and patients with 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 platelet-derived growth factor-A, were expressed in tLTs as well as the lymphorganogenic cytokines/chemokines, lymphotoxin-α/-β, CCL19, CCL20, CCL21, and CXCL13, which might explain the depletion of circulating CCR6(+) and CXCR5(+) lymphocytes. tLTs were connected with 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 IL-21(+)PD1(+) follicular helper T cells in tLTs together with CD138(+) plasma cell 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.
Authors: Elvira Stacher; Brian B Graham; James M Hunt; Aneta Gandjeva; Steve D Groshong; Vallerie V McLaughlin; Marsha Jessup; William E Grizzle; Michaela A Aldred; Carlyne D Cool; Rubin M Tuder Journal: Am J Respir Crit Care Med Date: 2012-06-07 Impact factor: 21.405
Authors: Norbert F Voelkel; Jose Gomez-Arroyo; Antonio Abbate; Harm J Bogaard; Mark R Nicolls Journal: Eur Respir J Date: 2012-06-27 Impact factor: 16.671
Authors: Daniela Farkas; Aysar A Alhussaini; Donatas Kraskauskas; Vita Kraskauskiene; Carlyne D Cool; Mark R Nicolls; Ramesh Natarajan; Laszlo Farkas Journal: Am J Respir Cell Mol Biol Date: 2014-09 Impact factor: 6.914
Authors: Kelley L Colvin; Patrick J Cripe; D Dunbar Ivy; Kurt R Stenmark; Michael E Yeager Journal: Am J Respir Crit Care Med Date: 2013-11-01 Impact factor: 21.405
Authors: C A Huppé; P Blais Lecours; A Lechasseur; D R Gendron; A M Lemay; E Y Bissonnette; M R Blanchet; C Duchaine; M C Morissette; H Rosen; D Marsolais Journal: Mucosal Immunol Date: 2017-04-19 Impact factor: 7.313
Authors: Wen Tian; Xinguo Jiang; Yon K Sung; Eric Shuffle; Ting-Hsuan Wu; Peter N Kao; Allen B Tu; Peter Dorfmüller; Aiqin Cao; Lingli Wang; Gongyong Peng; Yesl Kim; Patrick Zhang; James Chappell; Shravani Pasupneti; Petra Dahms; Peter Maguire; Hassan Chaib; Roham Zamanian; Marc Peters-Golden; Michael P Snyder; Norbert F Voelkel; Marc Humbert; Marlene Rabinovitch; Mark R Nicolls Journal: Circulation Date: 2019-08-29 Impact factor: 29.690