The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Martin, M. P.
Right arrow Articles by Carrington, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Martin, M. P.
Right arrow Articles by Carrington, M.
The Journal of Immunology, 2002, 169: 2818-2822.
Copyright © 2002 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Susceptibility to Psoriatic Arthritis: Influence of Activating Killer Ig-Like Receptor Genes in the Absence of Specific HLA-C Alleles1

Maureen P. Martin*, George Nelson*, Jeong-Hee Lee2,{dagger}, Fawnda Pellett{ddagger}, Xiaojiang Gao*, Judith Wade§, Michael J. Wilson3,¶, John Trowsdale, Dafna Gladman{ddagger} and Mary Carrington4,*

* Basic Research Program, SAIC-Frederick, and {dagger} Laboratory of Genomic Diversity, National Cancer Institute, Frederick, MD 21702; {ddagger} Toronto Western Research Institute and Center for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, and § Regional HLA Laboratory, University Health Network, Toronto, Ontario, Canada; and Immunology Division, Department of Pathology, University of Cambridge, Cambridge, United Kingdom


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
NK cell activity is partially controlled through interactions between killer Ig-like receptors (KIR) on NK cells and their respective HLA class I ligands. Independent segregation of HLA and KIR genes, along with KIR specificity for particular HLA allotypes, raises the possibility that any given individual may express KIR molecules for which no ligand is present. Inhibitory receptor genes KIR2DL2/3 and KIR2DL1 were present in nearly all subjects sampled in this study, whereas their respective activating homologs, KIR2DS2 and KIR2DS1, are each present in about half of the subjects. In this work we report that subjects with activating KIR2DS1 and/or KIR2DS2 genes are susceptible to developing psoriatic arthritis, but only when HLA ligands for their homologous inhibitory receptors, KIR2DL1 and KIR2DL2/3, are missing. Absence of ligands for inhibitory KIRs could potentially lower the threshold for NK (and/or T) cell activation mediated through activating receptors, thereby contributing to pathogenesis of psoriatic arthritis.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Killer Ig-like receptor (KIR)5 recognition of HLA class I molecules contributes to the array of receptor-ligand interactions that determines NK cell response to its target (reviewed in Ref. 1). Binding of inhibitory KIR (designated 2DL and 3DL) to specific HLA molecules has been clearly demonstrated (reviewed in Ref. 2) and correlates well with their ability to inhibit NK cytolysis of target cells bearing those HLA allotypes. Specificity of inhibitory KIR for HLA-C allotypes is dictated to a large extent by the presence of asparagine or lysine at position 80 of the HLA-C molecule (3). KIR2DL1 recognizes group 2 HLA-C molecules, which have Lys80, whereas KIR2DL2 and KIR2DL3 prefer group 1 HLA-C molecules containing Asn80 (3). Studies performed in vitro indicate that this division of specificity is not necessarily strict and may depend to some extent on bound peptide (4, 5). However, the crystal structures of KIR2DL2-Cw*0301 and KIR2DL1-Cw*0401 suggest greater specificity in ligand binding than do the in vitro studies (6, 7).

Based on assays measuring target cell killing, activating KIR (designated 2DS and 3DS) can mediate NK cell activity through recognition of HLA ligands under some circumstances (8), but little if any direct binding of activating KIR molecules to their putative HLA ligands has been detected. Thus, the ligands for KIR2DS1 and KIR2DS2 (which exhibit high homology to the inhibitory KIR2DL1 and KIR2DL2/3, respectively) are not known, but candidate ligands include non-MHC molecules, such as foreign or microbial Ags expressed on infected cells, normal cell surface proteins that are aberrantly expressed, or complexes of pathogen-derived peptides bound to MHC class I molecules. Strong support for the possibility that non-HLA molecules behave as ligands for activating KIR derives from the recent identification of the mouse CMV m157 gene product as the ligand for the mouse activating NK cell receptor Ly49H, an interaction that leads to NK cell killing of the infected targets (9, 10, 11, 12, 13, 14). The Ly49 family in mice is considered to be functionally equivalent to the KIRs (15).

KIR3DL1 binds HLA-B allotypes that have the Bw4 epitope (determined by amino acid positions 79–83 of the molecule) (16), and HLA-B Bw4 molecules with isoleucine at position 80 (Bw4-80I) may be better ligands than those containing threonine at position 80 (17). The ligand for KIR3DS1 has not been determined, although the presence of this gene along with alleles encoding Bw4-80I has an epistatic protective effect on AIDS progression (18), suggesting that, like KIR3DL1, KIR3DS1 recognizes at least some of the Bw4 allotypes in HIV-positive individuals.

Diversity at the KIR locus has been generated by an evolutionary history of expansion and contraction, presumably due to combinations of duplication and unequal crossing over within the locus (19, 20). Up to 12 KIR genes appear to be expressed, and KIR haplotypes consist of various combinations of KIR genes (19, 21). The number of putatively expressed KIR genes present on a single haplotype ranges from 7 to 11, depending primarily on the presence or absence of activating KIR loci (19, 21, 22). The most common Caucasian haplotype, the "A" haplotype (frequency of ~50%), contains only a single activating KIR gene, KIR2DS4, and six inhibitory KIR loci (21). The remaining "B" haplotypes are very diverse and contain two to five activating KIR loci. Diversity in KIR gene content, KIR specificity for particular HLA allotypes, and the unlinked physical location of the KIR loci (19q13.4) relative to the HLA loci (6p21) give rise to the possibility that, for some KIR loci, any given individual may encode receptor only, ligand only, both receptor and ligand, or neither one.

NK cells have been implicated in the defense against infectious diseases through mechanisms involving cytotoxicity and cytokine production (reviewed in Ref. 23), presumably mediated in part by activating KIR molecules. As in other limbs of the innate and acquired immune response, the benefits of such a defense system may be coupled to certain risks resulting in a situation whereby KIR genes conferring protection against one disease may predispose to another, perhaps less deadly, disease. NK cells may accumulate in target organs of certain autoimmune diseases, and loss of NK cell inhibition may exacerbate damage to the tissue. Recent evidence suggests that a subset of T cells expressing KIR2DS2 may mediate vascular damage in patients with rheumatoid arthritis (24), implicating a role for activating KIR in autoimmune pathogenesis.

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis and is classified among the rheumatoid factor-negative, HLA-B*27-associated spondyloarthropathies (25). Among those who develop the disease, PsA usually follows onset of psoriasis, and genetic effects predisposing to psoriasis have been observed in individuals with PsA, including HLA-Cw*0602 (26). However, progression to PsA after development of psoriasis may involve additional disease loci that are not associated with psoriasis alone. Given the strong HLA-B and -C associations with PsA and the ligand-receptor relationship between HLA class I and KIR molecules, we tested whether the presence or absence of KIR loci might influence susceptibility to PsA. The data indicate that the activating genes KIR2DS1 and KIR2DS2 associate with disease, but only when the HLA ligands for the closely related inhibitory KIRs, KIR2DL1 and KIR2DL2/3, are absent. We propose that, in the absence of ligands for the KIR2DL1 and KIR2DL2/3 molecules, both of which are present in nearly all individuals, the threshold for NK cell activation is lowered, thereby allowing NK cell activation mediated by KIR2DS1 and KIR2DS2.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Study population

Three hundred sixty-six patients with PsA attending the University of Toronto Psoriatic Arthritis Clinic at the Toronto Western Hospital were studied after informed consent and approval by the Research Ethics Board of the University Health Network. Patients are registered in the clinic if they have an inflammatory arthritis associated with psoriasis. Two hundred ninety-nine controls from the Regional HLA Laboratory (University Health Network) were also studied. The majority were cadaveric donors and the remainder were normal healthy volunteers.

HLA class I genotyping

Genomic DNA was amplified using locus-specific primers flanking exons 2 and 3. The PCR products were blotted on nylon membranes and hybridized with a panel of sequence-specific oligonucleotide probes (see http://www.ihwg.org/protocols/protocol.htm). Alleles were assigned by the reaction patterns of the sequence-specific oligonucleotide probes. Ambiguous typing results were resolved by sequence analysis.

KIR genotyping

Genomic DNA from patients and controls was genotyped for presence or absence of the following KIR genes: 2DL1, 2DL2, 2DL3, 2DL4, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DL1, 3DL2, 3DL3, and 3DS1. Genotyping was performed using PCR amplification with primers specific for each locus (PCR-SSP). Internal control primers for a 796-bp fragment of the third intron of DRB1 were also included in each PCR. Two sets of primers were designed for each locus (see supplemental material6 for details of the KIR typing method and primer sequences).

Statistical analysis

Frequency differences between PsA and control groups were tested for significance by a two-sided Fisher’s exact test. Multifactorial analysis was performed by logistic regression (27) (PROC LOGISTIC, the SAS system; SAS Institute, Cary, NC). Due to the number of alternate factors being considered, an automatic stepwise selection was used to determine significant factors (p < 0.05).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Increased frequencies of both HLA-Cw*0602 and -B*27 among individuals with PsA have been observed previously (26, 28). The frequencies of individuals with at least one copy of these alleles were also more common among the PsA samples studied here relative to individuals without PsA from the same demographic area (B*27, 19.4 vs 9.7%; Cw*0602, 31 vs 18.3%, respectively; Table IGo). Phenotypic KIR gene frequencies (i.e., the presence of at least one copy of each gene per individual) among the two groups indicated consistently higher frequencies of activating KIR in the PsA group relative to controls, except for KIR2DS4, which is the only activating KIR present on the common A haplotype (21). The presence of multiple activating KIR genes is characteristic of the B haplotypes, and certain pairs of activating KIR genes are known to be in linkage disequilibrium with one another (20). Thus, the increased frequency of most activating KIR among individuals with PsA could be due to hitchhiking of these genes with a single activating KIR that confers disease susceptibility.


View this table:
[in this window]
[in a new window]
  		Table I. HLA allele and KIR gene frequencies in PsA and controls

 
The inhibitory KIR2DL2 and KIR2DL3 segregate as alleles of a single locus, which was present in all individuals tested, and KIR2DL1 was observed in nearly all individuals. In contrast, their activating counterparts, KIR2DS2 and KIR2DS1, were observed in only a fraction of all samples tested (35–56.4%). KIR2DS1 was more frequent in the disease group (46.3%) than in the control group (35%) and represented the greatest gene frequency difference between the two groups.

Because KIR2DL1 interaction with group 2 HLA-C molecules on target cells would theoretically inhibit an activating signal mediated by KIR2DS1, we hypothesized that an effect of KIR2DS1 would be greatest among individuals who are missing group 2 HLA-C ligands for KIR2DL1. Therefore, we determined the various combinatorial frequencies of KIR2DS1 with Cw*0602 (a group 2 HLA-C allele that is strongly associated with PsA) or other group 2 HLA-C alleles (Fig. 1GoA). Individuals with no Cw*0602 and no KIR2DS1 appeared to be relatively protected (55% in controls vs 38% in PsA), corresponding with an increased frequency of individuals with KIR2DS1 plus Cw*0602 in the PsA group (14%) relative to controls (8%). The frequency of individuals with HLA-Cw*0602 but without KIR2DS1 was increased by ~6% in the PsA group relative to controls. KIR2DS1 was increased by 5% in the disease group when group 2 HLA-C alleles (including Cw*0602) were missing. However, in the presence of group 2 HLA-C alleles (excluding Cw*0602), KIR2DS1 frequencies were nearly identical in the disease and control groups. A significant difference (p = 0.001) between the PsA and control groups was observed in a trend test of protective to susceptible genotype frequencies (i.e., frequencies of Cw*0602-negative individuals with 1) no KIR2DS1, 2) KIR2DS1 with group 2 Cw alleles, and 3) KIR2DS1 without group 2 Cw alleles). These data suggested that KIR2DS1 might contribute to the pathogenesis of PsA by influencing NK or T cell activity when ligands for KIR2DL1 are absent, a situation whereby a dominant KIR2DL1-mediated inhibitory signal cannot occur. A virtually identical pattern of HLA-C/KIR2DS1 genotype frequencies was observed when individuals with HLA-B*27 were removed from the analysis (p = 0.002, Fig. 1GoB).



View larger version (18K):
[in this window]
[in a new window]
  		FIGURE 1. Influence of KIR2DS1 and HLA-C on PsA. Frequency of combinations of KIR2DS1, HLA Cw group 2 alleles, and Cw*0602 in PsA (black bars) and control (gray bars) groups for all subjects (A) and for subjects lacking B*27 (B). Percentages for the factors are shown above the bars. On the left, three groups of subjects without HLA-Cw*0602 are shown, divided into subjects with no KIR2DS1, with KIR2DS1 and HLA Cw group 2 (the ligand for KIR2DL1), and with KIR2DS1 but lacking Cw group 2. Values of p were determined using the Mantel-Haenszel test for trend. On the right, subjects with Cw*0602, with or without KIR2DS1, are shown.

 
Due to apparent effects of multiple variables at the HLA and KIR loci on risk of developing PsA, a multivariate regression analysis was used to test more rigorously for statistical significance of genotype frequency differences between the PsA and control groups. Variables tested in the analysis included HLA alleles shown previously to associate with PsA (HLA-B*27 and -Cw*0602) and the three activating KIR genes (KIR2DS1, KIR2DS2, and KIR3DS1) that have inhibitory KIR homologs with known HLA ligands. Additionally, these three KIR genes in the absence of HLA ligands for their inhibitory counterparts (i.e., KIR2DS1 with no group 2 HLA-C alleles, KIR2DS2 with no group 1 HLA-C alleles, and KIR3DS1 with no HLA-B Bw4-80I alleles) were also used as covariates in the model. Significant effects were observed for both HLA-B*27 and -Cw*0602, confirming previous reports (26, 28) (Table IIGo). Furthermore, in the absence of group 2 HLA-C alleles, KIR2DS1 was significantly associated with PsA (odds ratio (OR) = 2.2, p = 0.0025), as initially suggested by the frequencies shown in Fig. 1Go. A marginally significant effect of KIR2DS2 in the absence of group 1 alleles was also observed (OR = 2.3, p = 0.023), supporting the hypothesis that activating KIR may enhance development of PsA when ligands for the corresponding inhibitory KIR are missing. KIR3DS1 in the absence of HLA-B Bw4-80I alleles showed no significant effect. As indicated by the multivariate regression analysis, the entire effect of KIR2DS1 and KIR2DS2 is attributable to having these alleles when ligands for the corresponding inhibitory KIRs are missing, and their effects are independent of HLA-B*27 and -Cw*0602.


View this table:
[in this window]
[in a new window]
  		Table II. ORs for individual and combinations of HLA and KIR typesa

 
The joint effect of the two activating genes KIR2DS1 and KIR2DS2 on PsA susceptibility is illustrated in Fig. 2Go. Individuals without either KIR2DS1 or KIR2DS2 are relatively protected against development of PsA (27% in PsA vs 40% in controls), whereas the frequency of individuals with KIR2DS1 and/or KIR2DS2 necessarily with the corresponding inhibitory KIR ligand is similar in patients and controls (45 vs 47%, respectively) (Fig. 2GoA). However, as indicated from the multivariate analysis, individuals who have KIR2DS1 and/or KIR2DS2 without the corresponding inhibitory KIR ligand are susceptible to PsA (27% in PsA vs 15% in controls; p = 1 x 10-5). The effect is similar when subjects with HLA-B*27 and/or Cw*0602 are omitted from the analysis (Fig. 2GoB; p = 2 x 10-5).



View larger version (22K):
[in this window]
[in a new window]
  		FIGURE 2. Influence on PsA of activating KIRs in the presence and absence of ligands for their inhibitory counterpart. Frequency of individuals missing both KIR2DS1 and KIR2DS2 (left) in PsA (black bars) and control (gray bars) groups; presence of KIR2DS1 and/or KIR2DS2, necessarily with HLA ligand for the corresponding inhibitory KIR (middle); and presence of KIR2DS1 and/or KIR2DS2, with one or both lacking ligand for the corresponding inhibitory KIR (right). Thus, individuals carrying both KIR2DS1 and KIR2DS2, with ligand present for only one of the two corresponding inhibitory receptors, are included in the right group. Percentages for the factors are shown above the bars. Significance was determined from the Mantel-Haenszel test for trend, for a progressive difference in frequencies between groups in the three comparisons. A, All subjects. B, Subjects lacking both HLA-B*27 and Cw*0602.

 
Absence of KIR2DS1 and KIR2DS2 was associated with protection against PsA, whereas these receptors conferred susceptibility to disease when HLA ligands for the corresponding inhibitory KIRs were missing. The presence of KIR2DS1 and/or KIR2DS2 along with HLA alleles encoding ligands for KIR2DL1 and KIR2DL2/3, genes that were present in nearly all individuals sampled, was neutral (Fig. 2Go). These data suggest that, in the presence of their HLA ligands, corresponding inhibitory KIR may neutralize the effect of the activating KIR. KIR2DS2 has been implicated in the pathogenesis of vascular damage among individuals with rheumatoid arthritis (24), and it would be of interest to determine whether this effect could be attributed to KIR2DS2 in the absence of alleles encoding HLA ligands for KIR2DL2/3.

Activating KIR molecules are known to bind poorly to HLA molecules compared with that observed for inhibitory KIR (29, 30), perhaps explaining the observed dominance of inhibition over activation of NK cells. The susceptibility effect of KIR2DS1 and KIR2DS2 in the absence of group 2 and group 1 HLA-C alleles, respectively, suggests that ligands for the KIR2DS molecules are not the same HLA molecules recognized by homologous KIR2DL receptors. Data from mice indicate that viral proteins structurally similar to class I molecules serve as ligands for activating receptors on NK cells (9, 10, 11, 12, 13, 14), raising the possibility that activating receptors in humans may also recognize foreign molecules on target cells as opposed to recognition of self class I molecules.

The KIR locus appears to be particularly prone to molecular genetic mechanisms that result in dynamic fluctuation of gene content and allelic variation (19, 21). The potentially deleterious effects of activating KIR are certainly not lethal; therefore, these genes may remain and continue to induce or exacerbate pathogenesis of low mortality diseases such as PsA. Several HLA class I alleles are known to have either beneficial or deleterious consequences, depending on the type of disease. An example is the contribution of B*5301 to susceptibility in AIDS progression while protecting against severe malaria (31, 32). We recently reported an epistatic interaction between genes encoding the activating receptor KIR3DS1 and HLA-B molecules bearing a subset of Bw4 epitopes in protection against AIDS progression (18). Thus, KIR genes are likely to undergo opposing selection processes in a manner similar to that proposed for the HLA loci, ensuring persistence and perhaps expansion of genetic diversity at the KIR locus.


   Acknowledgments
 
We thank Drs. William Klitz, Michael Dean, and Lewis Lanier for helpful comments.


   Footnotes
 
1 This work was supported with federal funds from the National Cancer Institute, National Institutes of Health (under Contract No. NO1-CO-12400), the Arthritis Society, and the Canadian Institutes for Health Research. M.J.W. and J.T. were supported by grants from the Medical Research Council and the Wellcome Trust. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Back

2 Current address: Department of Pathology, College of Medicine, GyeonSang National University, Chinju, South Korea. Back

3 Current address: GlaxoSmithKline, Stevenage, U.K. Back

4 Address correspondence and reprint requests to Dr. Mary Carrington, Basic Research Program, SAIC-Frederick, P.O. Box B, National Cancer Institute, Frederick, MD 21702. E-mail address: carringt{at}ncifcrf.gov Back

5 Abbreviations used in this paper: KIR, killer Ig-like receptor; PsA, psoriatic arthritis; OR, odds ratio. Back

6 The on-line version of this article contains supplemental material. Back

Received for publication June 19, 2002. Accepted for publication July 26, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Lanier, L. L.. 1998. NK cell receptors. Annu. Rev. Immunol. 16:359.[Medline]
  2. Long, E. O., S. Rajagopalan. 2000. HLA class I recognition by killer cell Ig-like receptors. Semin. Immunol. 12:101.[Medline]
  3. Moretta, A., M. Vitale, C. Bottino, A. M. Orengo, L. Morelli, R. Augugliaro, M. Barbaresi, E. Ciccone, L. Moretta. 1993. P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells: anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities. J. Exp. Med. 178:597.[Abstract/Free Full Text]
  4. Kim, J., Y. J. Chwae, M. Y. Kim, I. H. Choi, J. H. Park, S. J. Kim. 1997. Molecular basis of HLA-C recognition by p58 natural killer cell inhibitory receptors. J. Immunol. 159:3875.[Abstract]
  5. Maenaka, K., T. Juji, T. Nakayama, J. R. Wyer, G. F. Gao, T. Maenaka, N. R. Zaccai, A. Kikuchi, T. Yabe, K. Tokunaga, et al 1999. Killer cell immunoglobulin receptors and T cell receptors bind peptide-major histocompatibility complex class I with distinct thermodynamic and kinetic properties. J. Biol. Chem. 274:28329.[Abstract/Free Full Text]
  6. Boyington, J. C., S. A. Motyka, P. Schuck, A. G. Brooks, P. D. Sun. 2000. Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405:537.[Medline]
  7. Fan, Q. R., E. O. Long, D. C. Wiley. 2001. Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1-HLA-Cw4 complex. Nat. Immunol. 2:452.[Medline]
  8. Moretta, A., S. Sivori, M. Vitale, D. Pende, L. Morelli, R. Augugliaro, C. Bottino, L. Moretta. 1995. Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. J. Exp. Med. 182:875.[Abstract/Free Full Text]
  9. Arase, H., E. S. Mocarski, A. E. Campbell, A. B. Hill, L. L. Lanier. 2002. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296:1323.[Abstract/Free Full Text]
  10. Brown, M. G., A. O. Dokun, J. W. Heusel, H. R. Smith, D. L. Beckman, E. A. Blattenberger, C. E. Dubbelde, L. R. Stone, A. A. Scalzo, W. M. Yokoyama. 2001. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292:934.[Abstract/Free Full Text]
  11. Lee, S. H., S. Girard, D. Macina, M. Busa, A. Zafer, A. Belouchi, P. Gros, S. M. Vidal. 2001. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nat. Genet. 28:42.[Medline]
  12. Daniels, K. A., G. Devora, W. C. Lai, C. L. O’Donnell, M. Bennett, R. M. Welsh. 2001. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J. Exp. Med. 194:29.[Abstract/Free Full Text]
  13. Smith, H. R., J. W. Heusel, I. K. Mehta, S. Kim, B. G. Dorner, O. V. Naidenko, K. Iizuka, H. Furukawa, D. L. Beckman, J. T. Pingelet al. 2002. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl. Acad. Sci. USA 99:8826.[Abstract/Free Full Text]
  14. Vivier, E., C. A. Biron. 2002. Immunology: a pathogen receptor on natural killer cells. Science 296:1248.[Abstract/Free Full Text]
  15. Hanke, T., H. Takizawa, C. W. McMahon, D. H. Busch, E. G. Pamer, J. D. Miller, J. D. Altman, Y. Liu, D. Cado, F. A. Lemonnier, et al 1999. Direct assessment of MHC class I binding by seven Ly49 inhibitory NK cell receptors. Immunity 11:67.[Medline]
  16. Barnstable, C. J., D. Snary, M. J. Crumpton, W. F. Bodmer. 1979. The structure and evolution of the HLA-Bw4 and Bw6 antigens. Tissue Antigens 13:334.[Medline]
  17. Cella, M., A. Longo, G. B. Ferrara, J. L. Strominger, M. Colonna. 1994. NK3-specific natural killer cells are selectively inhibited by Bw4-positive HLA alleles with isoleucine 80. J. Exp. Med. 180:1235.[Abstract/Free Full Text]
  18. Martin, M. P., X. Gao, J.-H. Lee, G. W. Nelson, R. Detels, J. J. Goedert, S. Buchbinder, K. Hoots, D. Vlahov, J. Trowsdale, et al 2002. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat. Genet. 31:429.[Medline]
  19. Wilson, M. J., M. Torkar, A. Haude, S. Milne, T. Jones, D. Sheer, S. Beck, J. Trowsdale. 2000. Plasticity in the organization and sequences of human KIR/ILT gene families. Proc. Natl. Acad. Sci. USA 97:4778.[Abstract/Free Full Text]
  20. Vilches, C., P. Parham. 2002. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu. Rev. Immunol. 20:217.[Medline]
  21. Uhrberg, M., N. M. Valiante, B. P. Shum, H. G. Shilling, K. Lienert-Weidenbach, B. Corliss, D. Tyan, L. L. Lanier, P. Parham. 1997. Human diversity in killer cell inhibitory receptor genes. Immunity 7:753.[Medline]
  22. Witt, C. S., C. Dewing, D. C. Sayer, M. Uhrberg, P. Parham, F. T. Christiansen. 1999. Population frequencies and putative haplotypes of the killer cell immunoglobulin-like receptor sequences and evidence for recombination. Transplantation 68:1784.[Medline]
  23. Biron, C. A., K. B. Nguyen, G. C. Pien, L. P. Cousens, T. P. Salazar-Mather. 1999. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17:189.[Medline]
  24. Yen, J. H., B. E. Moore, T. Nakajima, D. Scholl, D. J. Schaid, C. M. Weyand, J. J. Goronzy. 2001. Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis. J. Exp. Med. 193:1159.[Abstract/Free Full Text]
  25. Gladman, D. D., P. Rahman. 2001. Psoriatic arthritis. S. Ruddy, and E. D. Harris, and C. B. Sledge, and R. C. Budd, and J. S. Sergent, eds. Kelly’s Textbook of Rheumatology 1071. Saunders, Philadelphia.
  26. Gladman, D. D., C. Cheung, C. M. Ng, J. A. Wade. 1999. HLA-C locus alleles in patients with psoriatic arthritis (PsA). Hum. Immunol. 60:259.[Medline]
  27. Cox, D. R., E. J. Snell. 1989. The Analysis of Binary Data Chapman and Hall, London.
  28. Barton, A. C., I. N. Bruce, A. J. Silman. 2001. Genetic studies of psoriatic arthritis: dissecting joints and skin. J. Rheumatol. 28:3.[Free Full Text]
  29. Biassoni, R., A. Pessino, A. Malaspina, C. Cantoni, C. Bottino, S. Sivori, L. Moretta, A. Moretta. 1997. Role of amino acid position 70 in the binding affinity of p50.1 and p58.1 receptors for HLA-Cw4 molecules. Eur. J. Immunol. 27:3095.[Medline]
  30. Vales-Gomez, M., H. T. Reyburn, R. A. Erskine, J. Strominger. 1998. Differential binding to HLA-C of p50-activating and p58-inhibitory natural killer cell receptors. Proc. Natl. Acad. Sci. USA 95:14326.[Abstract/Free Full Text]
  31. Gao, X., G. W. Nelson, P. Karacki, M. P. Martin, J. Phair, R. Kaslow, J. J. Goedert, S. Buchbinder, K. Hoots, D. Vlahov, et al 2001. Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N. Engl. J. Med. 344:1668.[Abstract/Free Full Text]
  32. Hill, A. V., C. E. Allsopp, D. Kwiatkowski, N. M. Anstey, P. Twumasi, P. A. Rowe, S. Bennett, D. Brewster, A. J. McMichael, B. M. Greenwood. 1991. Common west African HLA antigens are associated with protection from severe malaria. Nature 352:595.[Medline]



This article has been cited by other articles:


Home page
 Rheumatology (Oxford)Home page
D. P. Lowe, M. A. Cook, S. J. Bowman, D. C. Briggs, and the UK Sjogren's Interest Group
Association of killer cell immunoglobulin-like receptors with primary Sjogren's syndrome
Rheumatology, April 1, 2009; 48(4): 359 - 362.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
N. Fodil-Cornu, S.-H. Lee, S. Belanger, A. P. Makrigiannis, C. A. Biron, R. M. Buller, and S. M. Vidal
Ly49h-Deficient C57BL/6 Mice: A New Mouse Cytomegalovirus-Susceptible Model Remains Resistant to Unrelated Pathogens Controlled by the NK Gene Complex
J. Immunol., November 1, 2008; 181(9): 6394 - 6405.
[Abstract] [Full Text] [PDF]

Home page
 LupusHome page
S. Toloza, F. Pellett, V Chandran, D Ibanez, M. Urowitz, and D. Gladman
Association of killer cell immunoglobulin-like receptor genotypes with vascular arterial events and anticardiolipin antibodies in patients with lupus
Lupus, September 1, 2008; 17(9): 793 - 798.
[Abstract] [PDF]

Home page
 J. Immunol.Home page
L. A. Guethlein, A. M. Older Aguilar, L. Abi-Rached, and P. Parham
Evolution of Killer Cell Ig-Like Receptor (KIR) Genes: Definition of an Orangutan KIR Haplotype Reveals Expansion of Lineage III KIR Associated with the Emergence of MHC-C
J. Immunol., July 1, 2007; 179(1): 491 - 504.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
O. A. Huynh, T. Hampartzoumian, J. P. Arm, J. Hunt, L. Borges, M. Ahern, M. Smith, C. L. Geczy, H. P. McNeil, and N. Tedla
Down-regulation of leucocyte immunoglobulin-like receptor expression in the synovium of rheumatoid arthritis patients after treatment with disease-modifying anti-rheumatic drugs
Rheumatology, May 1, 2007; 46(5): 742 - 751.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A. Mullally and J. Ritz
Beyond HLA: the significance of genomic variation for allogeneic hematopoietic stem cell transplantation
Blood, February 15, 2007; 109(4): 1355 - 1362.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. A. Campillo, J. A. Martinez-Escribano, M. R. Moya-Quiles, L. A. Marin, M. Muro, N. Guerra, A. Parrado, M. Campos, J. F. Frias, A. Minguela, et al.
Natural Killer Receptors on CD8 T Cells and Natural Killer Cells from Different HLA-C Phenotypes in Melanoma Patients.
Clin. Cancer Res., August 15, 2006; 12(16): 4822 - 4831.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
R. J. Boyton, J. Smith, R. Ward, M. Jones, L. Ozerovitch, R. Wilson, M. Rose, J. Trowsdale, and D. M. Altmann
HLA-C and Killer Cell Immunoglobulin-like Receptor Genes in Idiopathic Bronchiectasis
Am. J. Respir. Crit. Care Med., February 1, 2006; 173(3): 327 - 333.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Cook, D. Briggs, C. Craddock, P. Mahendra, D. Milligan, C. Fegan, P. Darbyshire, S. Lawson, E. Boxall, and P. Moss
Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation
Blood, February 1, 2006; 107(3): 1230 - 1232.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
T. Hayashi, K. Imai, Y. Morishita, I. Hayashi, Y. Kusunoki, and K. Nakachi
Identification of the NKG2D Haplotypes Associated with Natural Cytotoxic Activity of Peripheral Blood Lymphocytes and Cancer Immunosurveillance
Cancer Res., January 1, 2006; 66(1): 563 - 570.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
M. Butsch Kovacic, M. Martin, X. Gao, T. Fuksenko, C.-J. Chen, Y.-J. Cheng, J.-Y. Chen, R. Apple, A. Hildesheim, and M. Carrington
Variation of the Killer Cell Immunoglobulin-Like Receptors and HLA-C Genes in Nasopharyngeal Carcinoma
Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2673 - 2677.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
K. Kuroki, N. Tsuchiya, M. Shiroishi, L. Rasubala, Y. Yamashita, K. Matsuta, T. Fukazawa, M. Kusaoi, Y. Murakami, M. Takiguchi, et al.
Extensive polymorphisms of LILRB1 (ILT2, LIR1) and their association with HLA-DRB1 shared epitope negative rheumatoid arthritis
Hum. Mol. Genet., August 15, 2005; 14(16): 2469 - 2480.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
N. Azuz-Lieberman, G. Markel, S. Mizrahi, R. Gazit, J. Hanna, H. Achdout, R. Gruda, G. Katz, T. I. Arnon, S. Battat, et al.
The involvement of NK cells in ankylosing spondylitis
Int. Immunol., July 1, 2005; 17(7): 837 - 845.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Xu, A. N. Vallejo, Y. Jiang, C. M. Weyand, and J. J. Goronzy
Distinct Transcriptional Control Mechanisms of Killer Immunoglobulin-like Receptors in Natural Killer (NK) and in T Cells
J. Biol. Chem., June 24, 2005; 280(25): 24277 - 24285.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
L. Abi-Rached and P. Parham
Natural selection drives recurrent formation of activating killer cell immunoglobulin-like receptor and Ly49 from inhibitory homologues
J. Exp. Med., April 18, 2005; 201(8): 1319 - 1332.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
M. Carrington, S. Wang, M. P. Martin, X. Gao, M. Schiffman, J. Cheng, R. Herrero, A. C. Rodriguez, R. Kurman, R. Mortel, et al.
Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci
J. Exp. Med., April 4, 2005; 201(7): 1069 - 1075.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. van Bergen, A. Thompson, A. van der Slik, T. H. M. Ottenhoff, J. Gussekloo, and F. Koning
Phenotypic and Functional Characterization of CD4 T Cells Expressing Killer Ig-Like Receptors
J. Immunol., December 1, 2004; 173(11): 6719 - 6726.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
S. E. Hiby, J. J. Walker, K. M. O'Shaughnessy, C. W.G. Redman, M. Carrington, J. Trowsdale, and A. Moffett
Combinations of Maternal KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success
J. Exp. Med., October 18, 2004; 200(8): 957 - 965.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
G. W. Nelson, M. P. Martin, D. Gladman, J. Wade, J. Trowsdale, and M. Carrington
Cutting Edge: Heterozygote Advantage in Autoimmune Disease: Hierarchy of Protection/Susceptibility Conferred by HLA and Killer Ig-Like Receptor Combinations in Psoriatic Arthritis
J. Immunol., October 1, 2004; 173(7): 4273 - 4276.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. R. Snyder, T. Nakajima, P. J. Leibson, C. M. Weyand, and J. J. Goronzy
Stimulatory Killer Ig-Like Receptors Modulate T Cell Activation through DAP12-Dependent and DAP12-Independent Mechanisms
J. Immunol., September 15, 2004; 173(6): 3725 - 3731.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
S. I. Khakoo, C. L. Thio, M. P. Martin, C. R. Brooks, X. Gao, J. Astemborski, J. Cheng, J. J. Goedert, D. Vlahov, M. Hilgartner, et al.
HLA and NK Cell Inhibitory Receptor Genes in Resolving Hepatitis C Virus Infection
Science, August 6, 2004; 305(5685): 872 - 874.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
G. Katz, R. Gazit, T. I. Arnon, T. Gonen-Gross, G. Tarcic, G. Markel, R. Gruda, H. Achdout, O. Drize, S. Merims, et al.
MHC Class I-Independent Recognition of NK-Activating Receptor KIR2DS4
J. Immunol., August 1, 2004; 173(3): 1819 - 1825.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
G. Saruhan-Direskeneli, F. A. Uyar, A. Cefle, S. C. Onder, E. Eksioglu-Demiralp, S. Kamali, M. Inanc, L. Ocal, and A. Gul
Expression of KIR and C-type lectin receptors in Behcet's disease
Rheumatology, April 1, 2004; 43(4): 423 - 427.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. A. Cook, D. W. Milligan, C. D. Fegan, P. J. Darbyshire, P. Mahendra, C. F. Craddock, P. A. H. Moss, and D. C. Briggs
The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell transplantation for myeloid leukemia
Blood, February 15, 2004; 103(4): 1521 - 1526.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
R. Rajalingam, P. Parham, and L. Abi-Rached
Domain Shuffling Has Been the Main Mechanism Forming New Hominoid Killer Cell Ig-Like Receptors
J. Immunol., January 1, 2004; 172(1): 356 - 369.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
A. R. van der Slik, B. P.C. Koeleman, W. Verduijn, G. J. Bruining, B. O. Roep, and M. J. Giphart
KIR in Type 1 Diabetes: Disparate Distribution of Activating and Inhibitory Natural Killer Cell Receptors in Patients Versus HLA-Matched Control Subjects
Diabetes, October 1, 2003; 52(10): 2639 - 2642.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. P. Martin, A. Bashirova, J. Traherne, J. Trowsdale, and M. Carrington
Cutting Edge: Expansion of the KIR Locus by Unequal Crossing Over
J. Immunol., September 1, 2003; 171(5): 2192 - 2195.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
X. Saulquin, L. N. Gastinel, and E. Vivier
Crystal Structure of the Human Natural Killer Cell Activating Receptor KIR2DS2 (CD158j)
J. Exp. Med., April 7, 2003; 197(7): 933 - 938.
[Abstract] [Full Text] [PDF]

Home page
 ASH Education BookHome page
M. D. Cooper, L. L. Lanier, M. E. Conley, and J. M. Puck
Immunodeficiency Disorders
Hematology, January 1, 2003; 2003(1): 314 - 330.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Martin, M. P.
Right arrow Articles by Carrington, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Martin, M. P.
Right arrow Articles by Carrington, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS