Original Article
 

Analysis of Killer Cell Immunoglobulin-like Receptor Genes and Their HLA Ligands in Iranian Patients with Ankylosing Spondylitis

Abstract

Ankylosing Spondylitis (AS) is a chronic rheumatic disease which mainly involves the axial skeleton. It seems that non-HLA genes, as well as HLA-B27 gene, are linked to the etiology of the disease. Recently, it has been documented that KIRs and their HLA ligands are contributed to the Ankylosing Spondylitis. The aim of this study was to evaluate the KIR genes and their HLA ligands in Iranian AS patients and healthy individuals. The present study includes 200 AS patient samples and 200 healthy control samples. KIR genotyping was performed using the polymerase chain reaction sequence-specific primer (PCR-SSP) method to type the presence or absence of the 16 KIR genes, 6 known specific HLA class I ligands and also, two pseudogenes. Two KIR genes (KIR-2DL3 and KIR2DL5), and among the HLA ligands, two HLA ligands (HLA-C2Lys80 and HLA-B27) genes were significantly different between case and control groups. In addition, we found some interesting KIR/HLA compound genotypes, which were associated with AS susceptibility. Our results suggest that the AS patients present more activating and less inhibitory KIR genes with combination of their HLA ligands than healthy controls. Once the balance of signal transduction between activating and inhibitory receptors is disturbed, the ability of NK cells to identify and lyse the targets in immune responses will be compromised. Accordingly, imbalance of activating and inhibitory KIR genes by up-regulating the activation and losing the inhibition of KIRs signaling or combination of both might be one of the important factors which underlying the pathogenesis of AS.

1. Gouveia EB, Elmann D, Morales MS. Ankylosing spondylitis and uveitis: overview. Revista brasileira de reumatologia. 2012;52(5):742-56.

2. Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A.Ankylosing spondylitis: an overview. Annals of the rheumatic diseases. 2002;61 Suppl 3:iii8-18.

3. McVeigh CM, Cairns AP. Diagnosis and management of ankylosing spondylitis. BMJ (Clinical research ed).2006;333(7568):581-5.

4. Haywood KL, Garratt AM, Dawes PT. Patient- assessed health in ankylosing spondylitis: a structured review. Rheumatology (Oxford, England).2005;44(5):577-86.

5. Smith JA. Update on ankylosing spondylitis: current concepts in pathogenesis. Current allergy and asthma reports. 2015;15(1):489.

6. Mahmoudi M, Jamshidi AR, Amirzargar AA, Farhadi E, Nourijelyani K, Fallahi S, et al. Association between endoplasmic reticulum aminopeptidase-1 (ERAP-1) and susceptibility to ankylosing spondylitis in Iran. Iranian journal of allergy, asthma, and immunology.2012;11(4):294-300.

7. Mahmoudi M, Amirzargar AA, Jamshidi AR, Farhadi E, Noori S, Avraee M, et al. Association of IL1R polymorphism with HLA-B27 positive in Iranian patients with ankylosing spondylitis. European cytokine network.2011;22(4):175-80.

8. Nicknam MH, Mahmoudi M, Amirzargar AA, Jamshidi AR, Rezaei N, Nikbin B. HLA-B27 subtypes and tumor necrosis factor alpha promoter region polymorphism in Iranian patients with ankylosing spondylitis. European cytokine network. 2009;20(1):17-20.

9. Khan MA, Ball EJ. Genetic aspects of ankylosing spondylitis. Best practice & research Clinical rheumatology. 2002;16(4):675-90.

10. Zhang G, Luo J, Bruckel J, Weisman MA, Schumacher HR, Khan MA, et al. Genetic studies in familial ankylosing spondylitis susceptibility. Arthritis and rheumatism. 2004;50(7):2246-54.

11. Conigliaro P, Scrivo R, Valesini G, Perricone R.Emerging role for NK cells in the pathogenesis of inflammatory arthropathies. Autoimmunity reviews.2011;10(10):577-81.

12. Reveille JD. Recent studies on the genetic basis of ankylosing spondylitis. Current rheumatology reports.2009;11(5):340-8.

13. Daryabor G, Mahmoudi M, Jamshidi A, Nourijelyani K, Amirzargar A, Ahmadzadeh N, et al. Determination of IL-23 receptor gene polymorphism in Iranian patients with ankylosing spondylitis. European cytokine network.2014;25(1):24-9.

14. Moretta A, Pende D, Locatelli F, Moretta L. Activating and inhibitory killer immunoglobulin-like receptors (KIR) in haploidentical haemopoietic stem cell transplantation to cure high-risk leukaemias. Clinical and experimental immunology. 2009;157(3):325-31.

15. Khakoo SI, Carrington M. KIR and disease: a model system or system of models? Immunological reviews.2006;214:186-201.

16. Alter G, Martin MP, Teigen N, Carr WH, Suscovich TJ, Schneidewind A, et al. Differential natural killer cell- mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes. The Journal of experimental medicine. 2007;204(12):3027-36.

17. Chewning JH, Gudme CN, Hsu KC, Selvakumar A, Dupont B. KIR2DS1-positive NK cells mediate alloresponse against the C2 HLA-KIR ligand group in vitro. Journal of immunology (Baltimore, Md : 1950).2007;179(2):854-68.

18. Diaz-Pena R, Blanco-Gelaz MA, Suarez-Alvarez B, Martinez-Borra J, Lopez-Vazquez A, Alonso-Arias R, et al. Activating KIR genes are associated with ankylosing spondylitis in Asian populations. Human immunology.2008;69(7):437-42.

19. Jiao YL, Zhang BC, You L, Li JF, Zhang J, Ma CY, et al.Polymorphisms of KIR gene and HLA-C alleles: possible association with susceptibility to HLA-B27-positive patients with ankylosing spondylitis. Journal of clinical immunology. 2010;30(6):840-4.

20. Lopez-Larrea C, Blanco-Gelaz MA, Torre-Alonso JC, Bruges Armas J, Suarez-Alvarez B, Pruneda L, et al. Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations. Arthritis research & therapy.2006;8(4):R101.

21. Tajik N, Shahsavar F, Poormoghim H, Radjabzadeh MF, Mousavi T, Jalali A. KIR3DL1+HLA-B Bw4Ile80 and KIR2DS1+HLA-C2 combinations are both associated with ankylosing spondylitis in the Iranian population. International journal of immunogenetics. 2011;38(5):403-9.

22. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. The Journal of Rheumatology. 1994;21(12):2286-91.

23. Calin A, Garrett S, Whitelock H, Kennedy L, O'hea J, Mallorie P, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. The Journal of rheumatology. 1994;21(12):2281-5.

24. Jenkinson TR, Mallorie PA, Whitelock H, Kennedy LG, Garrett S, Calin A. Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS Metrology Index. The Journal of Rheumatology. 1994;21(9):1694-8.

25. Roe BA, Crabtree J, Khan A. Methods for DNA isolation.Part III. Protocols for recombinant DNA isolation,cloning, and sequencing [Internet edition] Norman, OK: University of Oklahoma. 1995:2488-98.

26. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B (Methodological). 1995:289-300.

27. Single RM, Martin MP, Meyer D, Gao X, Carrington M.Methods for assessing gene content diversity of KIR with examples from a global set of populations. Immunogenetics. 2008;60(12):711-25.

28. Fauriat C, Ivarsson MA, Ljunggren HG, Malmberg KJ, Michaelsson J. Education of human natural killer cells by activating killer cell immunoglobulin-like receptors. Blood. 2010;115(6):1166-74.

29. Jiao YL, Ma CY, Wang LC, Cui B, Zhang J, You L, et al.Polymorphisms of KIRs gene and HLA-C alleles in patients with ankylosing spondylitis: possible association with susceptibility to the disease. Journal of clinical immunology. 2008;28(4):343-9.

30. Qin H, Wang Z, Du W, Lee WH, Wu X, Riggs AD, et al.Killer cell Ig-like receptor (KIR) 3DL1 down-regulation enhances inhibition of type 1 diabetes by autoantigen- specific regulatory T cells. Proceedings of the National Academy of Sciences of the United States of America.2011;108(5):2016-21.

31. Yen JH, Moore BE, Nakajima T, Scholl D, Schaid DJ, Weyand CM, et al. Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis. The Journal of experimental medicine. 2001;193(10):1159-67.

32. Shastry A, Sedimbi SK, Rajalingam R, Rumba I, Kanungo A, Sanjeevi CB. Different KIRs confer susceptibility and protection to adults with latent autoimmune diabetes in Latvian and Asian Indian populations. Annals of the New York Academy of Sciences. 2008;1150:133-8.

33. Ramirez-De los Santos S, Sanchez-Hernandez PE,Munoz-Valle JF, Palafox-Sanchez CA, Rosales-Rivera LY, Garcia-Iglesias T, et al. Associations of killer cell immunoglobulin- like receptor genes with rheumatoid arthritis. Disease markers. 2012;33(4):201-6.

34. Harvey D, Pointon J, Sleator C, Meenagh A, Farrar C, Sun J, et al. Analysis of killer immunoglobulin-like receptor genes in ankylosing spondylitis. Annals of the rheumatic diseases. 2009;68(4):595-8.

35. Jiao Y-L, Ma C-Y, Wang L-C, Cui B, Zhang J, You L, et al. Polymorphisms of KIRs gene and HLA-C alleles in patients with ankylosing spondylitis: possible association with susceptibility to the disease. Journal of clinical immunology. 2008;28(4):343-9.

36. Boyton RJ, Altmann DM. Natural killer cells, killer immunoglobulin-like receptors and human leucocyte antigen class I in disease. Clinical and experimental immunology. 2007;149(1):1-8.

37. Carter KW, Pluzhnikov A, Timms AE, Miceli-Richard C, Bourgain C, Wordsworth BP, et al. Combined analysis of three whole genome linkage scans for Ankylosing Spondylitis. Rheumatology (Oxford, England).2007;46(5):763-71.

38. Fang M, Chen R, Cai Q, Duan S, Lv K, Cheng N, et al.Association of HLA genes with ankylosing spondylitis in Han population of eastern China. Scandinavian journal of immunology. 2007;65(6):559-66.

39. Augusto DG, Lobo-Alves SC, Melo MF, Pereira NF, Petzl-Erler ML. Activating KIR and HLA Bw4 ligands are associated to decreased susceptibility to pemphigus foliaceus, an autoimmune blistering skin disease. PloS one. 2012;7(7):e39991.

40. Lorentzen AR, Karlsen TH, Olsson M, Smestad C, Mero IL, Woldseth B, et al. Killer immunoglobulin-like receptor ligand HLA-Bw4 protects against multiple sclerosis. Annals of neurology. 2009;65(6):658-66.

Files
IssueVol 15, No 1 (2016) QRcode
SectionOriginal Article(s)
Keywords
Ankylosing spondylitis HLA antigen KIR receptor Polymerase chain reaction

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Mahmoudi M, Jamshidi AR, Karami J, Mohseni A, Amirzargar AA, Farhadi E, Ahmadzadeh N, Nicknam MH. Analysis of Killer Cell Immunoglobulin-like Receptor Genes and Their HLA Ligands in Iranian Patients with Ankylosing Spondylitis. Iran J Allergy Asthma Immunol. 2016;15(1):27-38.