Dendritic cells in muscle lesions of sarcoidosis

Summary

Sarcoidosis is a chronic systemic granulomatous disorder of unknown etiology. The precise mechanism by which granulomatous lesions form is still obscure. Dendritic cells (DCs) are the most efficient antigen presenting cells; however, pathologic investigations of dendritic cells in the affected lesions of sarcoidosis are quite limited. We immunohistochemically examined the localization and phenotypes of dendritic cells and the expressions of CD40 and CD40L (CD154), which are key molecules in dendritic cell activation, in the muscles of 5 patients with muscular sarcoidosis, 8 patients with muscular disorders without inflammation, and 4 patients with histologically normal muscles as controls. In muscular sarcoidosis, CD1c-positive myeloid dendritic cells were scattered mainly in the lymphocyte layers of granulomas and the endomysium around the granulomas. Double immunostaining revealed that some CD1c-positive cells expressed the mature dendritic cell marker CD83, but immature dendritic cell marker CD1a-positive cells were not found. Smaller numbers of Blood dendritic cell antigen (BDCA)-2–positive plasmacytoid dendritic cells were found in the lymphocyte layers of granulomas. In the controls, small numbers of CD1c-positive cells were seen in the endomysium, whereas BDCA-2–positive cells were not observed except in 1 case. In muscular sarcoidosis, CD40 was expressed on mononuclear cells, on the interstitium around the muscle fibers and granulomas, and on the endothelium of vessels. CD40L was positive on mononuclear cells scattered within and around granulomas in 3 of 5 patients. In the controls, CD40 was expressed on the endothelium of the vessels and sparse mononuclear cells in the lesions of muscle fiber necrosis, whereas CD40L was not seen in any. In muscular sarcoidosis, recruitment of myeloid dendritic cells and less plasmacytoid dendritic cells and up-regulation of the CD40/CD40L system in affected muscles suggest that myeloid dendritic cells may be mainly involved in granulomatous inflammation through antigen presentation in a Th1 immune milieu.

Introduction

Sarcoidosis is a granulomatous disorder of unknown etiology in which a chronic evolution of granulomas through various phases, such as the early stage of cell aggregation shaping into granulomas, the subsequent stage of expansion and maturation of granulomas, and the late stage of resolution or fibrosis, occurs in susceptible organs. Granulomas mainly consist of macrophages, epitheloid cells which are believed to develop from macrophages, and CD4+ T cells as central cores. Around the central cores, CD4+ T cells, CD8+ T cells, and macrophages randomly distribute, constituting lymphocyte layers [1]. Although recruitment of these immune cells is thought to be controlled mainly by Th1cytokines, the detailed mechanism is still unknown [1], [2], [3].

Dendritic cells (DCs) play cardinal roles both in innate and adaptive immunity. Recent advances in investigations of the DC ontogeny and functions revealed 2 major phenotypes of DCs, myeloid DCs, and plasmacytoid DCs [4]. Myeloid DCs are characterized by a monocyte morphology and found in peripheral tissues, secondary lymphoid organs, and peripheral blood. They capture antigens in the peripheral tissues, carry them to the draining lymph nodes, and stimulate naive T cells [4]. They can present lipid antigens to T cells through the expression of major histocompatibility complex (MHC) class 1–like molecules CD1c [5]. Plasmacytoid DCs are derived from a lymphoid lineage. They can enter the lymph node at high endothelial venules during inflammation, where they are able to secrete large amounts of type 1 interferon in response to viral stimulation [6]. Plasmacytoid DCs express a unique lectin recognized by monoclonal antibody BDCA-2. Both myeloid DCs and plasmacytoid DCs are suggested to be involved in a variety of immunologic disorders [7]. They could be a potential target of immunotherapy in intractable immune-mediated disorders. In sarcoidosis, the possible involvement of DCs in the pathomechanism has been suggested, but there have been no reports of a phenotypic analysis of myeloid DCs and plasmacytoid DCs in the affected organs of sarcoidosis.

CD40, a member of the tumor necrosis factor receptor family, is a 48-kDa transmembrane glycoprotein surface receptor [8]. CD40 is expressed not only on immune cells such as B cells, T cells, and DCs, but also on endothelium and epithelial cells. The ligand for CD40 (CD40L, CD154) is a 34- to 39-kDa type 2 integral membrane protein that is expressed on activated CD4+ T cells, activated B cells, platelets, and smooth muscle cells. CD40L is also induced by DCs stimulated by CD40. Thus, CD40 and CD40L are both reciprocally expressed on activated DCs and lymphocytes and are profoundly involved in the interaction between DCs and T cells as costimulatory molecules. CD40L-activated myeloid DCs produce large amount of Th1 cytokine, interleukin (IL)-12 [9]. Nevertheless, the CD40/CD40L system in sarcoidosis has attracted little attention to date. There has been only one report documenting CD40 expression on alveolar macrophages in sarcoidosis [10].

To further understand the roles of DCs in the pathomechanism of sarcoidosis, we immunohistochemically studied the localization and phenotypes of DCs in muscular sarcoidosis. We also immunohistochemically examined CD40 and CD40L.