International Journal of Hygiene and Environmental Health 217 (2014) 586–591 Contents lists available at ScienceDirect International Journal of Hygiene and Environmental Health jou rn al hom ep age: www.elsevier.com/locate/ijheh Lymphocyte activation in silica-exposed workers Michelle Rocha-Parise a , Leonilda M.B. Santos b , Jan G.M.C. Damoiseaux c , Ericson Bagatin d , Alessandro V. Lido d , Cristiane Okuda Torello a , Jan W. Cohen Tervaert e,f , Mary L.S. Queiroz a,∗ a Department of Pharmacology and Hemocenter, Faculty of Medical Sciences, FCM, State University of Campinas—UNICAMP, Campinas, SP, Brazil b Department of Genetics, Neuroimmunology Unit, Evolution and Bioagents, Institute of Biology, State University of Campinas—UNICAMP, Campinas, SP, Brazil c Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands d Department of Preventive and Social Medicine, Occupational Medicine Area, Faculty of Medical Sciences, FCM, State University of Campinas—UNICAMP, Campinas, SP, Brazil e Maastricht University, Maastricht, The Netherlands f Sint Franciscus Gasthuis, Rotterdam, The Netherlands a r t i c l e i n f o Article history: Received 11 June 2013 Received in revised form 17 November 2013 Accepted 19 November 2013 Keywords: Lymphocytes Soluble IL-2 receptor alpha Interleukin-2 Silica Cytokines Autoimmunity a b s t r a c t Exposure to silica dust has been examined as a possible risk factor for autoimmune diseases, including systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and ANCA-associated vasculitis. However, the underlying cellular and molecular mechanisms resulting in the increased prevalence of autoimmunity remain elusive. To clarify these mechanisms, we studied various markers of immune activation in individuals occupationally exposed to silica dust, i.e., serum levels of soluble IL-2 receptor (sIL-2R), levels of IL-2, other pro- and anti-inflammatory cytokines and lymphoproliferation. Our results demonstrate that silica-exposed individuals present important alterations in their immune response when compared to controls, as shown by increased serum sIL-2R levels, decreased production of IL-2 and increased levels of the pro-inflammatory (IFN-, IL-1, TNF-, IL-6) as well as anti-inflammatory (IL-10 and TGF-) cytokines. Furthermore, silica-exposed individuals presented enhanced lymphoproliferative responses. Our findings provide evidence that the maintenance of immune homeostasis may be disturbed in silica-exposed individuals, possibly resulting in autoimmune disorders. © 2013 Elsevier GmbH. All rights reserved. Introduction Studies demonstrate that silica can act as an adjuvant to nonspecifically enhance the immune response. Many cases of autoimmune diseases in silica-exposed individuals have been iden- tified in patients with silicosis and the risk of developing clinical connective tissue diseases has been reported to be greater among individuals with either silicosis or silica exposure (Rosenman and Moore-Fuller, 1999). In fact, silica dust exposure may be associated with a wide range of autoimmune diseases and abnormalities (as reviewed by Parks et al., 1999). However, the underlying mecha- nisms resulting in increased prevalence of autoimmunity remain ∗ Corresponding author at: Department of Pharmacology and Hemocenter, Faculty of Medical Sciences, FCM, State University of Campinas—UNICAMP, Carlos Chagas st. 480, Zip code 13083-878, Campinas, SP, Brazil. Tel.: +55 19 3521 8751; fax: +55 19 3289 2968. E-mail addresses: mlsq@fcm.unicamp.br, microcha123@yahoo.com.br (M.L.S. Queiroz). elusive (Cohen Tervaert et al., 1998; Steenland and Goldsmith, 1995). Peripheral mechanisms of self tolerance and immune homeo- stasis are essential to control self-reactive cells and the loss or reduction of these mechanisms may result in autoimmune dis- ease. In particular, leukocytes may play a role in the generation of autoimmune diseases in silica-exposed individuals based on their involvement in the processing and presentation of silica particles (Pernis, 2005). Stimulation of lymphocytes is observed in human and experimental silicosis, as demonstrated by increased levels of autoantibodies (Conrad and Mehlhorn, 2000; Subra et al., 2001), immunoglobulins and immune complexes (Doll et al., 1981). Fur- thermore, silica was shown to stimulate the polyclonal activation of human T cells in vitro (Ueki et al., 1994). After activation, both T and B lymphocytes express in their membranes specific recep- tors for interleukin (IL)-2 (Loughnan et al., 1988). This membrane receptor is important for cell stimulation with interleukin-2 (IL- 2) (O’Shea et al., 2002), a potent T cell growth factor. Besides the membrane IL-2 receptor expression, the release of these receptors in a soluble form takes place after leukocyte stimulation and the soluble alpha subunit of IL-2 receptor (sIL-2R) appears to possess 1438-4639/$ – see front matter © 2013 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.ijheh.2013.11.002