Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations

Arthritis Research & Therapy, Jun 2006

Killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) loci are both highly polymorphic, and some HLA class I molecules bind and trigger cell-surface receptors specified by KIR genes. We examined whether the combination of KIR3DS1/3DL1 genes in concert with HLA-B27 genotypes is associated with susceptibility to ankylosing spondylitis (AS). Two HLA-B27-positive Caucasian populations were selected, one from Spain (71 patients and 105 controls) and another from the Azores (Portugal) (55 patients and 75 controls). All were typed for HLA-B and KIR (3DS1 and 3DL1) genes. Our results show that in addition to B27, the allele 3DS1 is associated with AS compared with B27 controls (p < 0.0001 and p < 0.003 in the Spanish population and Azoreans, respectively). We also observed that the association of KIR3DS1 to AS was found in combination with HLA-B alleles carrying Bw4-I80 in trans position in the Spanish population (30.9% in AS versus 15.2% in B27 controls, p = 0.02, odds ratio (OR) = 2.49) and in Azoreans (27.2% in AS versus 8.7% in B27 controls, p = 0.01, OR = 4.4 in Azoreans). On the other hand, 3DL1 was decreased in patients compared with B27 controls (p < 0.0001 in the Spanish population and p < 0.003 in Azoreans). The presence of this allele in combination with Bw4-I80 had a protective effect against the development of AS in the Spanish population (19.7% in AS, 35.2% in B27 controls; p = 0.03, OR = 0.45). The presence of KIR3DS1 or KIR3DL1 in combination with HLA-B*27s/HLA-B Bw4-I80 genotypes may modulate the development of AS. The susceptibility to AS could be determined by the overall balance of activating and inhibitory composite KIR-HLA genotypes.

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Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations

Arthritis Research & Therapy 0 Immunogenetic Service, Hospital de Santo Espirito de Angra do Heroismo , Vinha Brava. 9700 Angra do Heroismo, Azores , Portugal 1 Rheumatology Unit, Hospital Monte Naranco , Avda Dres Fernandez Vega 107. 33012 Oviedo, Asturias , Spain 2 Histocompatibility and Transplantation Unit, Hospital Universtario Central de Asturias , Celestino Villamil s/n. 33006 Oviedo, Asturias , Spain 3 Functional Biology Department, University of Oviedo , Avda Julian Claveria s/n. 33006 Oviedo, Asturias , Spain Killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) loci are both highly polymorphic, and some HLA class I molecules bind and trigger cell-surface receptors specified by KIR genes. We examined whether the combination of KIR3DS1/3DL1 genes in concert with HLA-B27 genotypes is associated with susceptibility to ankylosing spondylitis (AS). Two HLA-B27-positive Caucasian populations were selected, one from Spain (71 patients and 105 controls) and another from the Azores (Portugal) (55 patients and 75 controls). All were typed for HLA-B and KIR (3DS1 and 3DL1) genes. Our results show that in addition to B27, the allele 3DS1 is associated with AS compared with B27 controls (p < 0.0001 and p < 0.003 in the Spanish population and Azoreans, respectively). We also observed that the association of KIR3DS1 to AS was found in combination with HLA-B alleles - carrying Bw4-I80 in trans position in the Spanish population (30.9% in AS versus 15.2% in B27 controls, p = 0.02, odds ratio (OR) = 2.49) and in Azoreans (27.2% in AS versus 8.7% in B27 controls, p = 0.01, OR = 4.4 in Azoreans). On the other hand, 3DL1 was decreased in patients compared with B27 controls (p < 0.0001 in the Spanish population and p < 0.003 in Azoreans). The presence of this allele in combination with Bw4-I80 had a protective effect against the development of AS in the Spanish population (19.7% in AS, 35.2% in B27 controls; p = 0.03, OR = 0.45). The presence of KIR3DS1 or KIR3DL1 in combination with HLA-B*27s/HLA-B Bw4-I80 genotypes may modulate the development of AS. The susceptibility to AS could be determined by the overall balance of activating and inhibitory composite KIR-HLA genotypes. Introduction The association of ankylosing spondylitis (AS) with human leukocyte antigen (HLA)-B27 has been demonstrated worldwide, and evidence for the role of HLA-B27 in AS comes from linkage and association studies in humans and transgenic animal models. However, twin studies indicate that HLA-B27 contributes only 16% of the total genetic risk for disease [1]. Genome-wide scans have implicated regions on chromosomes 2q, 6p, 6q, 10q, 11q, 16q, 17q, and 19q in AS [2,3]. The killer immunoglobulin-like receptor (KIR) genes encode a group of proteins that are expressed on natural killer (NK) cells and in some T cells that are located on chromosome 19q13.4 in the leukocyte receptor complex (reviewed in [4]). KIR proteins act as receptors that recognise major histocompatibility complex (MHC) class I molecules and are directly involved in the activation and inhibition of NK and possibly also in CD8+ T cells [5,6]. Given the receptor-ligand relationship between certain combinations of KIR and HLA class I molecules, it is reasonable to AS = ankylosing spondylitis; HC = heavy chain; HLA = human leukocyte antigen; HWE = Hardy-Weinberg equilibrium; ILT = immunoglobulin-like lymphocyte T receptors; KIR = killer cell immunoglobulin-like receptor; MHC = major histocompatibility complex; NK = natural killer; NKR = natural killer receptor; OR = odds ratio; PCR = polymerase chain reaction; SSO = sequence-specific oligoprobe; SSP = sequence-specific primer; TCR = T-cell receptor. hypothesise a synergistic relationship between these polymorphic loci. This could be the case of the KIR3DL1 inhibitory receptor, the only KIR known to recognise HLA-B alleles. It binds to HLA-B with serological-defined epitope Bw4 (determined by amino acid positions 7983 of the molecule) [7] with an isoleucine at position 80 (Bw4-I80) [8]. The interaction of KIR3DL1 and Bw4-I80 has an inhibitory effect on the cytotoxic capacity of NK cells. All HLA-B27 subtypes carry Bw4 epitope, with the exception of B*2708 and other related subtypes, which carry Bw6. From those with Bw4, B*2702 is the only subtype with an isoleucine at position 80 (Bw4-I80). The differences between the activating receptor KIR3DS1 and the inhibitory 3DL1 are located in the intracytoplasmic tail. The inhibitory receptor has a long tail containing immunoreceptor tyrosine inhibitory motifs, whereas the activating receptor has a short tail without this motif but with the capacity to interact with activating adaptor proteins such as DAP12 [9]. The ligand for KIR3DS1 has not been determined, although it has been shown that the KIR3DS1 activating receptor in combination with HLA-B alleles that encode molecules with isoleucine at position 80 (HLA-B Bw4-I80) results in delayed progression to (...truncated)


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Carlos Lopez-Larrea, Miguel Blanco-Gelaz, Juan Torre-Alonso, Jacome Armas, Beatriz Suarez-Alvarez, Laura Pruneda, Ana Couto, Segundo Gonzalez, Antonio Lopez-Vázquez, Jesus Martinez-Borra. Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations, Arthritis Research & Therapy, 2006, pp. R101, 8, DOI: 10.1186/ar1988