Evidence for local dendritic cell activation in pulmonary sarcoidosis

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Sarcoidosis is a granulomatous disease characterized by a seemingly exaggerated immune response against a difficult to discern antigen. Dendritic cells (DCs) are pivotal antigen presenting cells thought to play an important role in the pathogenesis. Paradoxically, decreased DC immune reactivity was reported in blood samples from pulmonary sarcoidosis patients. However, functional data on lung DCs in sarcoidosis are lacking. We hypothesized that at the site of disease DCs are mature, immunocompetent and involved in granuloma formation. Methods We analyzed myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in broncho-alveolar lavage (BAL) and blood from newly diagnosed, untreated pulmonary sarcoidosis patients and healthy controls using 9-color flowcytometry. DCs, isolated from BAL using flowcytometric sorting (mDCs) or cultured from monocytes (mo-DCs), were functionally assessed in a mixed leukocyte reaction with naïve allogeneic CD4+ T cells. Using Immunohistochemistry, location and activation status of CD11c + DCs was assessed in mucosal airway biopsies. Results mDCs in BAL, but not in blood, from sarcoidosis patients were increased in number when compared with mDCs from healthy controls. mDCs purified from BAL of sarcoidosis patients induced T cell proliferation and differentiation and did not show diminished immune reactivity. Mo-DCs from patients induced increased TNFα release in co-cultures with naïve allogeneic CD4 + T cells. Finally, immunohistochemical analyses revealed increased numbers of mature CD86 + DCs in granuloma-containing airway mucosal biopsies from sarcoidosis patients. Conclusion Taken together, these finding implicate increased local DC activation in granuloma formation or maintenance in pulmonary sarcoidosis.

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Publié le 01 janvier 2012
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Berge et al . Respiratory Research 2012, 13 :33 http://respiratory-research.com/content/13/1/33
R E S E A R C H Open Access Evidence for local dendritic cell activation in pulmonary sarcoidosis Bregje Ten Berge 1 , Alex KleinJan 1 , Femke Muskens 1 , Hamida Hammad 2 , Henk C Hoogsteden 1 , Rudi W Hendriks 1 , Bart N Lambrecht 1,2 and Bernt Van den Blink 1*
Abstract Background: Sarcoidosis is a granulomatous disease characterized by a seemingly exaggerated immune response against a difficult to discern antigen. Dendritic cells (DCs) are pivotal antigen presenting cells thought to play an important role in the pathogenesis. Paradoxically, decreased DC immune reactivity was reported in blood samples from pulmonary sarcoidosis patients. However, functional data on lung DCs in sarcoidosis are lacking. We hypothesized that at the site of disease DCs are mature, immunocompetent and involved in granuloma formation. Methods: We analyzed myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in broncho-alveolar lavage (BAL) and blood from newly diagnosed, untreated pulmonary sarcoidosis patients and healthy controls using 9-color flowcytometry. DCs, isolated from BAL using flowcytometric sorting (mDCs) or cultured from monocytes (mo-DCs), were functionally assessed in a mixed leukocyte reaction with naïve allogeneic CD4+ T cells. Using Immunohistochemistry, location and activation status of CD11c + DCs was assessed in mucosal airway biopsies. Results: mDCs in BAL, but not in blood, from sarcoidosis patients were increased in number when compared with mDCs from healthy controls. mDCs purified from BAL of sarcoidosis patients induced T cell proliferation and differentiation and did not show diminished immune reactivity. Mo-DCs from patients induced increased TNF a release in co-cultures with naïve allogeneic CD4 + T cells. Finally, immunohistochemical analyses revealed increased numbers of mature CD86 + DCs in granuloma-containing airway mucosal biopsies from sarcoidosis patients. Conclusion: Taken together, these finding implicate increased local DC activation in granuloma formation or maintenance in pulmonary sarcoidosis. Keywords: Sarcoidosis, Dendritic cells, Bronchoalveolar lavage, Granuloma, TNF α
Background data are suggestive of airborne or infectious antigens, in Sarcoidosis is a systemic disease characterized by the pre- particular mycobacterial p eptides, but attempts to link sence of noncaseating granulomas in involved organs, sarcoidosis to a causative pathogen are difficult and affecting the lung in more than 90% of patients [1,2]. The remain controversial [5-7]. Increased numbers of CD4 + granulomatous reaction occurs in the absence of a clearly T cells in the broncho-alveolar lavage (BAL) fluid are a defined immunological target. However, a reaction to an further hallmark of disease [3 ,4]. Increased proportions unidentified antigen is suspe cted [3]. An antigen-driven of oligoclonal CD4 + T cells were found in the BAL from pathogenesis is supported by disease-associated poly- patients with sarcoidosis, consistent with a MHC-morphisms in genes encoding antigen recognizing or restricted antigen-driven process [8,9]. Both granuloma antigen presenting molecules such as Toll-like receptors formation and T cell alveolitis have been characterized as and MHC class II [4]. Epidemiological and experimental Th-1 responses [3,4,10-12]. These data have led to the hypothesis that sarcoidosis emerges from an exaggerated Th1 immune response upon presentation of an unidenti-* Correspondence: b.vandenblink@erasmusmc.nl fied antigen by an antigen presenting cell (APC). 1 DCeopnarttrimbuetnetdofeqPuulalmlyonaryMedicine,ErasmusMC,Dr.Molewaterplein50, Past studies on APCs involved in pulmonary sarcoido-3015, GE Rotterdam, The Netherlands sis focused on alveolar macrophages [8,9,13]. However, Full list of author information is available at the end of the article © 2012 Berge et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.