Experimental Gerontology 39 (2004) 801–805

www.elsevier.com/locate/expgero

Hypothetical soluble KIR2DS4 natural killer cell receptor molecule does not associate with successful ageing in the Irish

Owen A. Ross , Lynn D. Maxwell , I. Maeve Rea , Martin D. Curran

aSchool of Biology and Biochemistry, Queens University of Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK bNorthern Ireland Regional Histocompatibility and Immunogenetics Laboratory, City Hospital, Belfast, Northern Ireland, UK cDepartment of Geriatric Medicine, Queens University of Belfast, Belfast, Northern Ireland, UK

Received 27 November 2003; received in revised form 14 January 2004; accepted 6 February 2004

Abstract

The identification of immunogenetic longevity markers is a major area of molecular gerontological research. A number of genetic loci have been examined, e.g. the HLA and cytokine networks. This study investigated a genetic marker within the highly polymorphic KIR gene system with successful ageing in the Irish population. A 22 bp deletion was identified in the KIR2DS4 gene that predicts a truncated soluble KIR molecule with one intact Ig-like domain. The frequency of this variant was determined using a specific-primer PCR methodology. There was no observed association between this common polymorphic variation within this activatory KIR gene and the aged Irish population. This is the first study of KIR polymorphism in ageing and although no association was identified, the importance of the KIR network in the immune response and its polymorphic nature warrants more detailed analysis to ascertain its role in immunosenescence.

Keywords: KIR; 2DS4 deletion; Polymorphism; Ageing

1. Introduction

elderly, an overall cytotoxic activity is maintained even though there are increased numbers of mature NK cells observed (Di Lorenzo et al., 1999; Solana et al., 1999; Miyaji et al., 2000). NK cells lyse abnormal cells that either lack the expression, or express diminished amounts, of human leukocyte antigen (HLA) class I molecules. The ability of NK cells to discriminate between normal and HLA class I-deficient cells is due to the expression of clonally distri- buted HLA class I inhibitory receptors (Biassoni et al., 2000).

with optimal functioning of the immune system, suggesting that specific genetic determinants may reside in poly- morphic loci that regulate the immune response. Dysregula- tion of immune function accompanying ageing (immunosenescence) is postulated to contribute to morbid- ity and mortality in the aged via an increased risk of disease, infection, tumours, and autoimmune disorders (Franceschi et al., 1995, 2000; Solana and Pawelec, 1998; Malaguarnera et al., 2001).

Human NK cells express two structurally distinct receptor families that mediate their interactions; the c-type lectin-like heterodimer receptors and the immunoglobulin- like (Ig-like) receptors (Lopez-Botet et al., 2000). In contrast to the relatively conserved CD94/NKG2 lectin- like receptors, the Ig-like receptors display considerable variation, particularly the killer cell immunoglobulin-like receptors (KIR). NK cells are known to clonally express KIR genes and whilst it is unclear how the repertoire of receptors expressed by NK cells is created, recent studies on the NK cell expression of KIR in different individuals imply that the repertoire is dependent on the presence of different genes in an individuals genome (Uhrberg et al., 1997;

Natural killer (NK) cells play a crucial role in the innate immune response and a hypothesis was proposed that a well-preserved NK cell activity is important for successful ageing (Sansoni et al., 1993; Franceschi et al., 1995;

* Corresponding author. Address: School of Biology and Biochemistry, Queens University of Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK. Tel.: þ44-2890263979; fax: þ44- 2890263880.

E-mail address: owenaross@hotmail.com (O.A. Ross). 1 Present address: Public Health and Clinical Microbiology Laboratory, Addenbrooke’s Hospital, Cambridge, England.

O.A. Ross et al. / Experimental Gerontology 39 (2004) 801–805

Shilling et al., 2002). The KIR gene family represents a highly polymorphic class of receptor-encoding genes, which to date have displayed considerable allelic diversity and it is postulated that KIR polymorphism arises from both the occurrence of random point mutations and recombination between homologous KIR genes (Shilling et al., 1998; Witt

to ascertain whether this polymorphism within the KIR region was associated with successful ageing.

2. Materials and methods

2.1. Subjects

Recently, our laboratory reported the presence of a common 22 bp deletion in the activatory KIR2DS4 gene that predicts a soluble KIR molecule (Maxwell et al., 2002). The deletion causes a frameshift predicting a truncated KIR2DS4 protein with a significantly altered D2 domain, which would be secreted due to the loss of the transmem- brane/cytoplasmic domains. A representative KIR2DS4 deletion allele sequence (KIR2DS4*003; available under accession number AJ417554) containing the 22 bp deletion in exon 5, is aligned against a non-deleted allele (KIR2DS4*00102) sequence in Fig. 1 (Dohring et al., 1996;