Killer immunoglobulin-like receptor and their HLA ligands in Guillain–Barré Syndrome Stefan Blum a,b, ⁎, Peter Csurhes b , Stephen Reddel c , Judy Spies d , Pamela McCombe a,b a Royal Brisbane and Women's Hospital, Department of Neurology, Herston, QLD 4029, Australia b University of Queensland, Centre of Clinical Research, Herston Campus, Herston, QLD 4029, Australia c Concord Repatriation General Hospital, Concord, NSW 2139, Australia d Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia abstract article info Article history: Received 28 July 2013 Received in revised form 1 November 2013 Accepted 4 December 2013 Keywords: Guillain-Barré syndrome Receptors, KIR Histocompatibility antigens, Class I Killer cells, Natural Gene frequency Guillain–Barré Syndrome (GBS) is an inflammatory neuropathy that occurs in some individuals after exposure to an infectious illness. We investigated the role of Killer-immunoglobulin-like receptors (KIR) and their HLA li- gands as potential genetic factors in the pathogenesis of GBS. These receptors are involved in the innate immune response to infections. Whilst no significant differences in the frequencies KIR genes were found, HLA-C2 and HLA-B Bw4-T were more frequent in subjects with GBS than controls (p b 0.001). The inhibitory pairs KIR-2DL2/HLA-C2 and KIR-3DL1/ HLA-B Bw4-T were more frequent in GBS than controls (all p b 0.005). We propose that NK cell inhibition is an important factor in the pathogenesis of GBS. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Guillain–Barré syndrome (GBS) is an acquired neuropathy characterised by inflammation of peripheral nerve. It has clinical sub- groups, including Acute Motor Axonal Neuropathy (AMAN), which is an antibody mediated disease, and Acute Inflammatory Demyelinating Polyradiculopathy (AIDP) where there is inflammation in the peripheral nerve with macrophages and T cells (Asbury et al., 1969). Whilst in- creased T cell reactivity against myelin antigens has been found in some studies, the specific target antigen in GBS remains unknown (Csurhes et al., 2005a,b). GBS frequently occurs after infections (Winer, 2001). This has led to the suggestion that GBS is due to molec- ular mimicry, where there is cross-reactivity between antigens on path- ogens and those expressed on peripheral nerve (Ang et al., 2004). The best evidence for molecular mimicry is found with the AMAN variant where there is an immune response to Campylobacter jejuni. However, a wide variety of infectious agents and physical stressors have been re- ported to trigger GBS. As well as Campylobacter, these include, Haemophilus influenza, Helicobacter pylori, Herpes viridae, vaccinations and mechanical injury, like surgery or trauma. All these triggers lead to a relatively stereotyped illness course and pathological picture (van Doorn et al., 2008; Blum et al., in press). Particularly for AIDP, this suggests that GBS could be due to a non-specific activation of the im- mune system by infection or other triggers. Such a non-specific activa- tion could stimulate APCs to present antigen to pre-existing autoreactive T cells (Ichikawa et al., 2002). The genetic predisposition to GBS is not known. HLA associations are frequently described in human autoimmune diseases (Rose and Bona, 1993). However, in GBS, HLA has been studied in a number of cohorts of different genetic backgrounds with conflicting results and no con- firmed association (Gorodezky et al., 1983; Piradov et al., 1995; Koga et al., 1998; Li et al., 2000; Geleijns et al., 2005). These results might have been hampered by imprecise definitions of GBS, the conflation of subjects with different subtypes of disease and the limited numbers of subjects studied. Natural killer cells (NK cells) are lymphocytes that share common progenitor cells with T lymphocytes (Vivier et al., 2011). NK cells are crucial components of the early innate immune response, due to their ability to produce cytokines and chemokines and lyse target cells (Middleton and Gonzelez, 2010). They also have important roles in the regulation of the subsequent immune response against the patho- gen via production of cytokines and chemokines (Vivier et al., 2011). Killer immunoglobulin-like receptors (KIRs) constitute the largest family of human NK receptors, with multiple inhibitory and activating members showing extensive polymorphisms (Middleton and Gonzelez, 2010). Generally, KIR with a long cytoplasmic tail (i.e. KIR 2DL1) are in- hibitory, whereas KIR with a short tail are activating (i.e. KIR 2DS1). KIRs are found on NK cells, but also on subgroups of CD4+ and CD8+ T lymphocytes (van Bergen et al., 2004). For a functional interaction Journal of Neuroimmunology 267 (2014) 92–96 ⁎ Corresponding author at: Royal Brisbane and Women's Hospital, Department of Neurology, Butterfield St., Herston, QLD 4029, Australia. Tel.: +61 7 36468111; fax: +61 7 36467675. E-mail address: stefan_blum@health.qld.gov.au (S. Blum). 0165-5728/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jneuroim.2013.12.007 Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim