Elsevier

Human Immunology

Volume 65, Issue 7, July 2004, Pages 758-766
Human Immunology

Gene for the activating natural killer cell receptor, KIR2DS1, is associated with susceptibility to psoriasis vulgaris

https://doi.org/10.1016/j.humimm.2004.05.008Get rights and content

Abstract

Psoriasis vulgaris, particularly its juvenile form, is strongly associated with the HLA-Cw*06 allele encoding the HLA-Cw6 molecule. This molecule is recognized by the inhibitory receptor KIR2DL1 and the activatory receptor KIR2DS1, which are expressed on natural killer cells and subpopulations of T lymphocytes. Humans differ by the presence or absence of particular KIR genes. We hypothesized that either activatory KIR2DS1 or inhibitory KIR2DL1 gene frequencies might be different in psoriatic patients from a control population. Therefore, we compared the frequencies of KIR2D inhibitory (L) and activatory (S) genes in 116 psoriasis vulgaris patients and in 123 healthy controls. Fourteen novel gene combinations were found. KIR2DS1 was present in 85% of the patients, but only in 51% of the controls (corrected p [pc] < 0.0009). Similarly, HLA-Cw*06 was much more frequent in patients (77%) than in controls (17%; pc < 0.00002). Statistical analysis suggests that, although the contribution of these two factors to psoriasis is partially independent, they interact nevertheless. This result strongly speaks for a role of KIR2DS1 on recognition of HLA-Cw6 in susceptibility to psoriasis.

Introduction

Psoriasis vulgaris is a multifactorial human skin disease 1, 2, 3, 4. The strongest genetic association was found with a major histocompatibility complex allele, HLA-Cw*06 5, 6, 7, particularly in juvenile psoriasis 7, 8, 9. Human leukocyte antigen (HLA)-C molecules are recognized by natural killer (NK) cell immunoglobulin-like receptors, KIR, encoded in the leukocyte receptor complex on chromosome 19q13.4 10, 11, 12, 13, 14, and fall into two groups differing in amino acid positions 77 and 80 in the α1 domain. Group 1, or C1, HLA-C molecules (HLA-Cw1, 3, 7, 8, 12, 13, 14, 1507, 1601) are characterized by Ser77/Asn80, and group 2 (C2) molecules (HLA-Cw2, 4, 5, 6, 707, 12042, 15, 1602, 17) possess Asn77/Lys80. These two groups are distinguished by two groups of killer cell immunoglobulin-like receptors (KIRs): C1 molecules are ligands for KIR2DL2, KIR2DL3, and KIR2DS2, where C2 molecules are recognized by KIR2DL1 and KIR2DS1 ([11]; for KIR nomenclature, see [15]). KIR region exhibits a high level of haplotypic polymorphism (i.e., individuals differ remarkably in their repertoires of KIR genes 11, 12). Interaction of KIRs with HLA-C molecules affects effector-target cell adhesion, formation of the immune synapse, and signaling [16]. KIRs are expressed not only by NK cells, but also by subsets of activated T lymphocytes 17, 18. We reasoned, therefore, that because psoriasis vulgaris is associated with the C2 molecule HLA-Cw6 (see previous section) and presumably has an autoimmune component 2, 3, then the gene for the activatory KIR receptor KIR2DS1 that recognizes HLA-Cw6 might also be associated with this disease. Alternatively, the gene for the inhibitory receptor KIR2DL1 might be protective. The results presented here show an association of KIR2DS1, but not its inhibitory counterpart, with psoriasis.

Section snippets

Patients and controls

A total of 116 patients were diagnosed with psoriasis vulgaris in the Clinic of Venereology and Dermatology, and blood samples were collected. Diagnosis was based on the presence of both characteristic skin changes (macroscopic morphology) and typical course of the disease. Only patients with psoriasis vulgaris were included; those with other types of psoriasis were excluded from our study. Characteristics of the patients and their subgroups based on age at disease onset are shown in Table 1.

Results

One hundred sixteen patients diagnosed with psoriasis vulgaris and 123 healthy control individuals were typed for the presence or absence of KIR2DL1, KIR2DL2, KIR2DL3, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, and its partial deletant, KIR2DS4*003 (KIR1D), (although KIR2DS4*003 is official designation of partially deletant KIR2DS4 allele [15], its former name KIR1D will be used in following text for clarity), and KIR2DS5 genes by PCR using locus-specific primers. Altogether, 77 different KIR2D

Discussion

KIR2DS1 is the only activatory KIR known to bind the HLA-Cw6 molecule [11]. Our results show that individuals possessing both HLA-Cw*06 and KIR2DS1 genes may be more susceptible to psoriasis than those possessing only one or none of them, if other genetic and environmental factors contributing to this multifactorial condition are present.

The contribution of the KIR2DS gene to the susceptibility to HLA-associated disease, described here for KIR2DS1 and HLA-Cw*06, is not unprecedented. First,

Acknowledgment

We are grateful to Dr. Carlos Vilches for advice and sharing his unpublished data. We are also indebted to Dr. Ryszard Kozłowski, Director of the Regional Blood Transfusion Center in Wrocław, his staff, and all voluntary blood donors for their invaluable help in collecting blood samples, and to Mrs. Małgorzata Rąpała, M.S., Eng., for expert statistical analysis.

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    Supported by the Ministry of Scientific Research and Information Technology grant No. 3 P05B 141 25 and by the Ludwik Hirszfeld Institute of Immunology and Experimental Therapy grant No. 14/2004.

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