The role of KIR2DS1 in multiple sclerosis - KIR in Portuguese MS patients Andreia Bettencourt a, ⁎, Ana Martins Silva a,b , Cláudia Carvalho a , Bárbara Leal a , Ernestina Santos b , Paulo P. Costa a,c , Berta M. Silva a a UMIB — Instituto de Ciências Biomédicas Abel Salazar (ICBAS-UPorto), Porto Portugal b Neurology Department, Centro Hospitalar do Porto — Hospital de Santo António (CHP-HSA), Porto, Portugal c Instituto Nacional de Saúde Dr. Ricardo Jorge (INSA), Porto, Portugal abstract article info Article history: Received 23 September 2013 Received in revised form 16 January 2014 Accepted 21 January 2014 Keywords: Multiple Sclerosis KIR Natural killer cells Portugal Killer Immunoglobulin-like Receptor (KIR) genes may influence both resistance and susceptibility to different au- toimmune diseases, but their role in the pathogenesis of Multiple Sclerosis (MS) is still unclear. We investigated the influence of KIR genes on MS susceptibility in 447 MS Portuguese patients, and also whether genetic interac- tions between specific KIR genes and their HLA class I ligands could contribute to the pathogenesis of MS. We ob- served a negative association between the activating KIR2DS1 gene and MS (adjusted OR = 0.450, p = 0.030) independently from the presence of HLA-DRB1*15 allele. The activating KIR2DS1 receptor seems to confer pro- tection against MS most probably through modulation of autoreactive T cells by Natural Killer cells. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Multiple Sclerosis (MS) is the most common inflammatory demyelin- ating disease of the central nervous system (CNS) in young adults. The cause of MS is unknown, but it is widely believed to be an autoimmune disease occurring in genetically susceptible individuals after exposure to as-yet undefined environmental factors (Dyment et al., 2004). Although the nature of the environmental triggers remains undetermined, progress has been made in characterizing the genetic factors of MS susceptibility. The HLA class II allele DRB1*1501 is a well-established susceptibility fac- tor for this disease (Hafler et al., 2007; Silva et al., 2007), though recent studies reported a protective effect of some HLA class I alleles, such as the HLA-A*02 and Cw*05, independently of HLA-DRB1*1501 allele (Brynedal et al., 2007; Yeo et al., 2007; Silva et al., 2009) and there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex (Beecham et al., 2013). Natural killer (NK) cells contribute to both effector and regulatory functions of the innate immune system via their cytotoxic activity, mainly against viral infected cells or tumor cells, and also through their ability to secrete different cytokines (Moretta et al., 2008). These cells may play a regulatory role in MS by modulating the activation and the survival of autoreactive T cells, microglial cells and astrocytes that would otherwise cause inflammatory responses in CNS. Several experimental systems have provided evidence that NK cells have a suppressive role in autoim- munity. NK cells might kill dendritic cells (DC), or they might lyse T cells and silence antigen-specific response. In addition, NK cells might negatively affect T cell response by producing regulatory cytokines such as TGF-β or IL-10 (Shi and Van Kaer, 2006; Morandi et al., 2008). NK cells are normally restrained by inhibitory receptors that recognize target-cell-expressed MHC class I molecules; they recognize and interact with HLA class I antigens through killer cell immunoglobulin like recep- tors (KIR). These receptors are present on the cell membrane; it is the cytoplasmatic tail that defines their activating (short [S]) or inhibiting (long [L]) properties. The KIR gene cluster is located on chromosome 19q13 and consists of several genes and pseudogenes, exhibiting con- siderable structural variation, resulting in all genes rarely being con- comitantly present in one given individual. Known ligands include HLA-C, HLA-A, HLA-G and Bw04 molecules. HLA-C alleles can be defined as either ‘group 1’ or ‘group 2’. In group 1 [C1 epitope (Serine at pos 77, Asparagine at pos 80)] are the 2DL2, 2DL3, and 2DS2 binders, Cw*01, Cw*03, Cw*07, Cw*08, Cw*13, Cw*14 and Cw*16. In group 2 [C2 epitope (Asparagine at pos 77, Lysine at pos 80)] are the 2DL1 and 2DS1 binders, Cw*02, Cw*04, Cw*05, Cw*06, Cw*17 and Cw*18. In addition, it was re- ported ligand for 2DL4 as HLA-G, for 3DL1 (and 3DS1) as HLA-Bw4 motif, for3DL2 as HLA-A3 and -A11, and for 2DS4 as HLA-Cw*04; ligands for the other KIRs are still unknown (Boyton and Altmann, 2007). The interaction KIR/HLA results in either activation or inhibitory signals (Biassoni et al., 2009). Triggering of NK cells occurs only when activating signals overcome inhibitory signals. Genetic associ- ation studies suggest that KIR receptors may play beneficial roles in viral infections, such as in HIV or HCV and may also modulate Journal of Neuroimmunology 269 (2014) 52–55 ⁎ Corresponding author at: UMIB — Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Rua de Jorge Viterbo Ferreira no. 228, 4050-313 Porto, Portugal. Tel.: +351 220 428 271; fax: +351 226 066 106. E-mail address: ambettencourt@icbas.up.pt (A. Bettencourt). 0165-5728/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jneuroim.2014.01.009 Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim