Elsevier

Human Immunology

Volume 66, Issue 7, July 2005, Pages 836-841
Human Immunology

Activating Killer Cell Immunoglobulin-Like Receptor Gene KIR2DS1 Is Associated With Psoriatic Arthritis

https://doi.org/10.1016/j.humimm.2005.04.005Get rights and content

Abstract

Killer cell immunoglobulin-like receptor genotyping was performed on a cohort of American Caucasian patients with psoriasis to investigate any possible relationship between these chromosome 19 genes and autoimmune-linked disease. This patient cohort also contained a subgroup of patients who had been additionally diagnosed as positive for psoriatic arthritis (PsA). Because of the known association of human leucocyte antigen (HLA)-Cw*06 with psoriasis, the study concentrated on the five KIR genes that have HLA-C as their recognized ligand (i.e., KIR2DL1, -2DL2, -2DL3, -2DS1, and -2DS2). An increase in the frequency of the activating KIR2DS1 gene was detected in the PsA patients, compared with psoriasis patients negative for PsA and an unaffected American Caucasian control group.

Introduction

Psoriasis, an inflammatory skin disease affecting approximately 2%–3% of the Northern European population, is believed to be caused by a combination of genetic and environmental factors [1]. Of patients affected with psoriasis, approximately 10%–30% are also affected with psoriatic arthritis (PsA), an arthritic condition similar to rheumatoid arthritis with inflammation in the joints, but with no rheumatoid factor present in the blood [1, 2]. Although a person with psoriasis may not have PsA, it is rare for a PsA patient to be negative for psoriasis. Psoriasis is widely known to be associated with human leucocyte antigen (HLA) alleles, particularly HLA-Cw*0602 and -B*57, but association with other non–chromosome 6 markers has been recorded [2, 3, 4]. HLA-Cw*0602 has also been reported to increase susceptibility to PsA [5]. Tumor necrosis factor (TNF)-α is a prominent cytokine that is upregulated in psoriasis, and may mediate inflammation in lesions through the induction of increased production of interleukin (IL)-1, IL-6, IL-8, and nuclear transcription factor κB. Anti-TNF therapy is becoming a valuable research tool for psoriasis and PsA treatment [6, 7, 8].

Natural killer (NK) cells, a subset of large granular lymphocytes that mature in the bone marrow, circulate in the peripheral blood and constitute 10%–15% of blood cells. They are an important component of the immune response against infected and malignant cells [9]. During the progression of autoimmune diseases, NK cells are often present in many targeted organs [10]. In most cases, direct lysis of targeted organs by NK cells has not been found, suggesting that under these circumstances, the role of NK cells may be in the regulation of immune responses to autoantigens [10]. Decreased NK cell function has been reported in several autoimmune diseases [10, 11].

NK cell function is regulated by activating and inhibitory receptors, present on the cell surface [12]. Activating receptors engage various surface antigens on target cells, as well as certain major histocompatibility complex (MHC) class I molecules. The ligands for many of these receptors have yet to be identified. Inhibitory receptors mainly recognize MHC class I molecules. NK cells use two structurally distinct types of inhibitory receptors for their interaction with MHC class I molecules: the C-type lectins-like group (CD94/NKG2 heterodimers and Ly49), and the immunoglobulin-like superfamily (killer immunoglobulin-like receptors [KIR], leucocyte immunoglobulin-like receptor [LILR], and the leucocyte–associated inhibitory receptor LAIR]) [13, 14]. The KIR gene family is a highly polymorphic multigene family located on chromosome 19. These genes can either exhibit activating or inhibitory function. KIR genes, in particular the activating genes, have been implicated in autoimmune pathogenesis [15, 16, 17].

KIR genes possessing two extracellular domains are mainly specific for HLA-Cw specificities, which are categorized by dimorphisms at amino acid positions 77 and 80 of the HLA-C heavy chain [18] into group C1 and C2 molecules. Receptors KIR2DL2, -2DL3, and -2DS2 have as their ligands C1 molecules, which are defined by the presence of serine at amino acid position 77 and asparagine at position 80. Receptors KIR2DL1 and -2DS1 have C2 group ligands, which are defined by the presence of asparagine at amino acid position 77 and lysine at position 80 [18]. The binding affinity of the two domain inhibitory KIR (KIR2DL1, -2DL2, and -2DL3) with their HLA-C ligands, is greater than the binding affinity of the corresponding activating KIR (KIR2DS1 and -2DS2). Because of the importance of HLA-C, particularly HLA-Cw*0602, in psoriasis and related diseases, an investigation was performed to establish whether KIR receptors that use HLA-C molecules as their ligand have any importance in the autoimmune disorders psoriasis and PsA.

Section snippets

Samples Investigated

Patients positive for psoriasis vulgaris (n = 220) were available for study. Of these patients, 75 (34.1%) were also diagnosed as positive for PsA. The individuals were all Caucasian and have been previously described [19, 20]. They were collected from a variety of geographic locations throughout North America. Ninety normal Caucasian individuals, unrelated bone marrow donors from the Cleveland Clinic, Ohio, were used as a control group.

Polymerase Chain Reaction Amplification and Sequence-Specific Oligonucleotide Probe Analysis

To facilitate KIR gene identification, oligonucleotide

Results

The presence or absence of genes KIR2DL1, -2DL2, -2DL3, -2DS1, and -2DS2 were determined in the patient cohort and compared with KIR gene assignments of the control group (Table 3). The comparison with the controls was with the complete psoriasis group (n = 220), with patients who were PsA positive (n = 75) and with psoriasis patients who were PsA negative (n = 145). In addition, the PsA-positive group was compared with the PsA-negative group.

KIR2DS1 was significantly increased in the

Discussion

The aim of the study was to investigate the relationship between psoriasis and the chromosome 19 KIR genes. A positive association with KIR genes was not identified on examination of the total psoriasis-positive cohort. However, when we considered patients additionally affected with PsA, a positive association of the activating KIR2DS1 gene was identified, indicating a possible role for this gene in relation to susceptibility to PsA. This was an encouraging finding because KIR2DS1 has also

Acknowledgments

We thank Cindy Helms and Brandon Pierce, Department of Genetics, Washington School of Medicine, St. Louis, Missouri, for compilation of patient details. We are grateful to Dawn Thomas at the Cleveland Clinic, Cleveland, Ohio. This study was supported in part by NIH grants AR44577 and AR04904901 (AMB) and a grant from the National Psoriasis Foundation (AMB).

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