Journal of Reproductive Immunology 103 (2014) 59–66 Contents lists available at ScienceDirect Journal of Reproductive Immunology j o ur na l ho me pag e: www.elsevier.com/locate/ jreprimm Anti-tissue transglutaminase antibody inhibits apoptotic cell clearance by macrophages in pregnant NOD mice Cecilia Só˜ nora a,b,∗ , Gustavo Mourglia-Ettlin a , Guillermina Calo c , Vanesa Hauk c , Rosanna Ramhorst c , Ana Hernández a , Claudia Pérez Leirós c a Cátedra de Inmunología, Facultad de Ciencias/Facultad de Química, Universidad de la República, Montevideo, Uruguay b Escuela Universitaria de Tecnología Médica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay c Laboratorio de Inmunofarmacología, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina a r t i c l e i n f o Article history: Received 13 July 2013 Received in revised form 23 October 2013 Accepted 12 November 2013 Keywords: Anti-tissue transglutaminase antibodies Celiac disease NOD mice a b s t r a c t Autoimmunity is a feature of celiac disease (CD) with tissue transglutaminase (tTG) as a major autoantigen. A correlation between gynecological-obstetric disorders in CD patients and the presence of circulating antibodies anti-tTG that inhibited tTG activity was reported. Serum anti-tTG antibodies were detected in a non-obese diabetic (NOD) mouse model of type I insulin-dependent diabetes mellitus and Sjögren’s syndrome, two comorbid states with CD. Since pregnancy complications have been described in NOD mice, we evaluated the ability of anti-tTG antibodies to affect the functions of tTG relevant to the normal course of an early pregnancy like extracellular matrix assembling and apoptotic cell phagocytosis by macrophages. Circulating IgG antibodies against tTG were detected in NOD mice with titers that decreased at early pregnancy; interestingly, the in vitro transamidating activity of tTG was reduced by NOD serum samples. Particularly, anti-tTG antibody inhibited apoptotic cell phagocytosis by peritoneal macrophages from pregnant NOD mice that express the enzyme on surface. Evidence provided support for a role for anti-tTG antibodies through reduced transamidating activity and reduced apoptotic cell clearance by the macrophages of pregnant NOD mice. © 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Pregnancy is a tightly regulated process, where sys- temic and local mechanisms act in synchronicity to allow the maternal immune system to tolerate the fetus. Espe- cially at the early post-implantation stage, intense tissue remodeling and apoptosis of trophoblast cells occur in a homeostatic immunosuppressant microenvironment. Various immune cell populations contribute to this anti- inflammatory milieu, with macrophages taking center stage owing to their high functional plasticity (Mosser and ∗ Corresponding author at: Cátedra de Inmunología, Facultad de Ciencias/Facultad de Química, Universidad de la República, Instituto de Higiene, Alfredo Navarro 3051, CP 11600, Montevideo, Uruguay. Tel.: +598 24801196. E-mail address: csonora@fmed.edu.uy (C. Só˜ nora). Edwards, 2008; Nagamatsu and Schust, 2010). In partic- ular, macrophages bearing an alternative activated profile participate in wound healing processes and the silent clear- ance of apoptotic cells (Abrahams et al., 2004; Fest et al., 2007; Straszewski-Chavez et al., 2005). The outcome of pregnancy may be impaired by several autoimmune conditions; celiac disease (CD) is a multifacto- rial disease (Garrote et al., 2008) with an incidence reaching 1% in western countries (Fasano et al., 2003; Dube et al., 2005) and increasing in prevalence worldwide (Cataldo and Montalto, 2007). Women appear to be preferentially affected (Bardella et al., 2005) and associated reproduc- tive disorders have been extensively reported (Ozgor and Selimoglu, 2010; Soni and Badawy, 2010); however, the molecular mechanisms involved remain unknown. Tissue transglutaminase (tTG; EC 2.3.2.13) is the spe- cific autoantigen in CD (Dieterich et al., 1997) and specific 0165-0378/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jri.2013.11.001