- Email: [email protected]
Reply to Xie et al. about the article “Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis”
Correspondence / Joint Bone Spine 80 (2013) 115–119
medicine, Arisaema rhizomatum C.E.C. Fischer (ARCF), which has been used to alleviate pain and inflammation for patients suffering from rheumatism can lower the serum IL-33 levels in CIA mice [10]. Collectively, these findings may give therapeutic potential for RA, and suggest a valuable role for IL-33 in the development of RA. However, further studies are still needed to clarify the role of IL-33 in RA. Therefore, therapeutic agents targeting IL-33 might result in important new, innovative therapies for RA.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgement This work was not supported by any grants.
References [1] Talabot-Ayer D, McKee T, Gindre P, et al. Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Joint Bone Spine 2012;79:32–7. [2] Hong YS, Moon SJ, Joo YB, et al. Measurement of interleukin-33 (IL-33) and IL-33 receptors (sST2 and ST2L) in patients with rheumatoid arthritis. J Korean Med Sci 2011;26:1132–9. [3] Kageyama Y, Torikai E, Tsujimura K, et al. Involvement of IL-33 in the pathogenesis of rheumatoid arthritis: the effect of etanercept on the serum levels of IL-33. Mod Rheumatol 2012;22:89–93. [4] Xiangyang Z, Lutian Y, Lin Z, et al. Increased levels of interleukin-33 associated with bone erosion and interstitial lung diseases in patients with rheumatoid arthritis. Cytokine 2012;58:6–9. [5] Mu R, Huang HQ, Li YH, et al. Elevated serum interleukin-33 is associated with autoantibody production in patients with rheumatoid arthritis. J Rheumatol 2010;37:2006–13. [6] Kunisch E, Chakilam S, Gandesiri M, et al. IL-33 regulates TNF-a dependent effects in synovial fibroblasts. Int J Mol Med 2012;29: 530–40. [7] Jiang D, Liang J, Noble PW. Hyaluronan in tissue injury and repair. Annu Rev Cell Dev Biol 2007;23:435–61. [8] Campo GM, Avenoso A, D’Ascola A, et al. 6-Mer hyaluronan oligosaccharides increase IL-18 and IL-33 production in mouse synovial fibroblasts subjected to collagen-induced arthritis. Innate Immun 2012, doi:10.1177/1753425911435953. [9] Campo GM, Avenoso A, D’Ascola A, et al. Inhibition of hyaluronan synthesis reduced inflammatory response in mouse synovial fibroblasts subjected to collagen-induced arthritis. Arch Biochem Biophys 2012;518:42– 52. [10] Chunxia C, Peng Z, Huifang P, et al. Extracts of Arisaema rhizomatum C.E.C. Fischer attenuate inflammatory response on collagen-induced arthritis in BALB/c mice. J Ethnopharmacol 2011;133:573–82.
Qiang Xie a,b Shi-Cun Wang b Jian Zhong a Jun Li a,∗ a School of Pharmacy, Anhui Medical University, 81, Meishan Road, Hefei, 230032 Anhui, PR China b PET/CT center, Anhui Provincial Hospital, 17, Lujiang Road, Hefei, 230001 Anhui, PR China ∗ Corresponding
author. Tel.: +86 551 516 1001; fax: +86 551 516 1001. E-mail address: [email protected] (J. Li) Accepted 10 October 2012 Available online 11 December 2012
doi:10.1016/j.jbspin.2012.10.014
117
Reply to Xie et al. about the article “Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis”
a r t i c l e
i n f o
Keywords: Arthritis Biomarker Disease activity IL-33 Serum Synovial fluid
In this commentary, the authors discuss the potential value of interleukin (IL)-33 as a biomarker and therapeutic target in rheumatoid arthritis (RA). This view is certainly interesting. Concerning the usefulness of IL-33 as a biomarker, in our study, we were intrigued by the apparent specificity of IL-33 for RA, since we could not detect IL-33 in serum and SF samples of patients with psoriatic arthritis or non-psoriatic spondyloarthropathies. However, our study included a limited number of patients and this observation was not confirmed in another study, involving a larger cohort of patients, which described elevated IL-33 levels in ankylosing spondylitis patients as compared to healthy controls [1]. Xie et al. further mention that correlations were observed between the levels of IL-33 and IL-1 [2,3], IL-6 [2], C-reactive protein (CRP) [4] (although not confirmed in [5]), disease activity, respectively Disease Activity Score (DAS28-CRP) [4,6] (although not confirmed in [5]), the presence of rheumatoid factor (RF) [5] and anti-cyclic citrullinated peptide (anti-CCP) antibodies [5]. It has to be stressed though that this list is a summary of correlations found across different studies, which sometimes correspond to a single observation, and which, in some instances, were not confirmed in other studies. It is thus still early to draw definitive conclusions concerning the involvement of IL-33 in RA. Some important issues are still unclear such as the correlation of IL-33 levels with disease activity. The usefulness of IL-33 as a biomarker thus awaits clarification. In addition, we fully agree that further studies, both in human RA and in animal models, are necessary to confirm a potential interest for this molecule as a target for therapy. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Han GW, Zeng LW, Liang CX, et al. Serum levels of IL-33 is increased in patients with ankylosing spondylitis. Clin Rheumatol 2011;30:1583–8. [2] Hong YS, Moon SJ, Joo YB, et al. Measurement of interleukin-33 (IL-33) and IL-33 receptors (sST2 and ST2L) in patients with rheumatoid arthritis. J Korean Med Sci 2011;26:1132–9. [3] Matsuyama Y, Okazaki H, Hoshino M, et al. Sustained elevation of interleukin33 in sera and synovial fluids from patients with rheumatoid arthritis non-responsive to anti-tumor necrosis factor: possible association with persistent IL-1beta signaling and a poor clinical response. Rheumatol Int 2012;32:1397–401. [4] Kageyama Y, Torikai E, Tsujimura K, et al. Involvement of IL-33 in the pathogenesis of rheumatoid arthritis: the effect of etanercept on the serum levels of IL-33. Mod Rheumatol 2012;22:89–93. [5] Mu R, Huang HQ, Li YH, et al. Elevated serum interleukin 33 is associated with autoantibody production in patients with rheumatoid arthritis. J Rheumatol 2010;37:2006–13. [6] Matsuyama Y, Okazaki H, Tamemoto H, et al. Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritis. J Rheumatol 2010;37:18–25.
118
Correspondence / Joint Bone Spine 80 (2013) 115–119
Dominique Talabot-Ayer a,b Cem Gabay a,b Gaby Palmer a,b,∗ a Division of Rheumatology, Department of Internal Medicine, University Hospital, Geneva, Switzerland b Department of Pathology-Immunology, University of Geneva School of Medicine, 1, rue Michel-Servet, 1211 Geneva 4, Switzerland ∗ Corresponding
author. Tel.: +41 22 379 57 68; fax: +41 22 379 57 46. E-mail address: [email protected] (G. Palmer) Accepted 10 October 2012 Available online 20 November 2012 doi:10.1016/j.jbspin.2012.10.007
Comment about the article by Bisson-Vaivre et al.: “The role of HLA and KIR in anti-TNF therapy”
a r t i c l e
References [1] Bisson-Vaivre A, Alcaix D, Zarnitsky C, et al. Efficacy of anti-TNF in patients with spondyloarthritis in absence of any imaging sign. Joint Bone Spine 2012, doi:10.1016/j.jbspin.2012.08.003. [2] Carmona L, Descalzo MA, Perez-Pampin E, et al. All-cause and cause-specific mortality in rheumatoid arthritis are not greater than expected when treated with tumour necrosis factor antagonists. Ann Rheum Dis 2007;66:880–5. [3] Herrinton LJ, Liu L, Chen L, et al. Association between anti-TNF-␣ therapy and all-cause mortality. Pharmacoepidemiol Drug Saf 2012, doi:10.1002/pds.3354. [4] Grijalva CG, Chen L, Delzell E, et al. Initiation of tumor necrosis factor-␣ antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA 2011;306:2331–9. [5] Picascia A, Grimaldi V, Zullo A, et al. Current concepts in histocompatibility during heart transplant. Exp Clin Transplant 2012;10:209–18. [6] Jiao YL, Zhang BC, You L, et al. Polymorphisms of KIR gene and HLA-C alleles: possible association with susceptibility to HLA-B27-positive patients with ankylosing spondylitis. J Clin Immunol 2010;30:840–4. [7] McGeough CM, Berrar D, Wright G, et al. Killer immunoglobulin-like receptor and human leukocyte antigen-C genotypes in rheumatoid arthritis primary responders and non-responders to anti-TNF-␣ therapy. Rheumatol Int 2012;32:1647–53.
Vincenzo Grimaldi a,∗ Maria Lourdes Montesano a Teresa Infante b Claudio Napoli a,b a Department of General Pathology and U.O.C. Immunohematology, Transfusion Medicine and Transplant Immunology (SIMT), Regional Reference Laboratory of Transplant Immunology (LIT), Azienda Universitaria Policlinico (AOU), Second University of Naples, Piazza Miraglia 2, 80138 Naples, Italy b SDN Foundation, IRCCS, 80143 Naples, Italy
i n f o
Keywords: Anti-tumor necrosis factor (TNF) Human leukocyte antigen (HLA) Spondyloarthritis Rheumatoid arthritis
We have read the interesting paper of Bisson-Vaivre et al. [1] reporting the incidence of human leukocyte antigen (HLA) B27 carriers with imaging sings in 385 patients with spondyloarthritis (SpA). The efficacy of anti-tumor necrosis factor (TNF) therapy was also evaluated [1]. They concluded that 257 patients with imaging sings had significantly more frequent therapeutic responses to anti-TNF therapy and this phenomenon was associated with significantly higher frequency of HLA B27. Until now, studies of potential risk of anti-TNF therapy on mortality have provided conflicting results [2–4]. Anti-TNF therapy is not associated with increased mortality among patients with autoimmune diseases [3] nor with infection risk [4]. A more detailed HLA analysis [5] and anti-TNF therapy should be carried in SpA patients. Indeed, several studies have shown the role of killer cell immunoglobulin-like receptor (KIR) and their corresponding specific HLA-C ligands to the pathogenesis of some autoimmune diseases [6]. Moreover, it was investigated the correlation of KIR gene polymorphisms and HLA-C ligands with anti-TNF therapy in rheumatoid arthritis (RA) patients. McGeough et al. [7] have shown that RA patients responding to therapy have a significantly higher frequency of KIR2DS2/KIR2DL2. A positive response was associated with an activating KIR-HLA genotype, KIR2S2(+)HLA-C group 1/2 homozygous [7]. Therefore, it would be interesting to test also in SpA patients, with and without imaging sings (analyzed by BissonVaivre et al. in 2012) whether genetic polymorphisms of KIR and HLA-C might have influenced the effectiveness of anti-TNF therapy. This would allow the early identification of patients that may benefit of TNF therapy.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
∗ Corresponding
author. E-mail address: [email protected] (V. Grimaldi) Accepted 21 November 2012 Available online 31 December 2012 doi:10.1016/j.jbspin.2012.11.007
Reply to Grimaldi et al. about the article “The role of HLA and KIR in anti-TNF therapy”
a r t i c l e
i n f o
Keywords: Spondyloarthritis HLA KIR Anti-TNF
We really want to thank Grimaldi et al. [1] for their interesting comment upon our article about the efficacy of anti-TNF in patients with spondyloarthritis in absence of any imaging sign [2], recently published in Joint Bone Spine. Our results showed that the percentage of patients with exclusively clinical signs of spondyloarthritis who responded to anti-TNF was far from negligible (nearly 40%) and that anti-TNF efficacy was significantly higher in the HLA-B27 carriers with initial imaging signs rather than in the other patients (P = 0.028). The killer cell immunoglobulin-like receptors (KIR) are mainly expressed on the surface of the natural-killer cells. Their close interaction with the HLA system is well established in the pathogenesis of several autoimmune diseases, rheumatoid arthritis notably [3], as well as in the preservation of the immunological tolerance [4]. The interaction of specific sub-types of KIR and HLA alleles may thus
medicine, Arisaema rhizomatum C.E.C. Fischer (ARCF), which has been used to alleviate pain and inflammation for patients suffering from rheumatism can lower the serum IL-33 levels in CIA mice [10]. Collectively, these findings may give therapeutic potential for RA, and suggest a valuable role for IL-33 in the development of RA. However, further studies are still needed to clarify the role of IL-33 in RA. Therefore, therapeutic agents targeting IL-33 might result in important new, innovative therapies for RA.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgement This work was not supported by any grants.
References [1] Talabot-Ayer D, McKee T, Gindre P, et al. Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Joint Bone Spine 2012;79:32–7. [2] Hong YS, Moon SJ, Joo YB, et al. Measurement of interleukin-33 (IL-33) and IL-33 receptors (sST2 and ST2L) in patients with rheumatoid arthritis. J Korean Med Sci 2011;26:1132–9. [3] Kageyama Y, Torikai E, Tsujimura K, et al. Involvement of IL-33 in the pathogenesis of rheumatoid arthritis: the effect of etanercept on the serum levels of IL-33. Mod Rheumatol 2012;22:89–93. [4] Xiangyang Z, Lutian Y, Lin Z, et al. Increased levels of interleukin-33 associated with bone erosion and interstitial lung diseases in patients with rheumatoid arthritis. Cytokine 2012;58:6–9. [5] Mu R, Huang HQ, Li YH, et al. Elevated serum interleukin-33 is associated with autoantibody production in patients with rheumatoid arthritis. J Rheumatol 2010;37:2006–13. [6] Kunisch E, Chakilam S, Gandesiri M, et al. IL-33 regulates TNF-a dependent effects in synovial fibroblasts. Int J Mol Med 2012;29: 530–40. [7] Jiang D, Liang J, Noble PW. Hyaluronan in tissue injury and repair. Annu Rev Cell Dev Biol 2007;23:435–61. [8] Campo GM, Avenoso A, D’Ascola A, et al. 6-Mer hyaluronan oligosaccharides increase IL-18 and IL-33 production in mouse synovial fibroblasts subjected to collagen-induced arthritis. Innate Immun 2012, doi:10.1177/1753425911435953. [9] Campo GM, Avenoso A, D’Ascola A, et al. Inhibition of hyaluronan synthesis reduced inflammatory response in mouse synovial fibroblasts subjected to collagen-induced arthritis. Arch Biochem Biophys 2012;518:42– 52. [10] Chunxia C, Peng Z, Huifang P, et al. Extracts of Arisaema rhizomatum C.E.C. Fischer attenuate inflammatory response on collagen-induced arthritis in BALB/c mice. J Ethnopharmacol 2011;133:573–82.
Qiang Xie a,b Shi-Cun Wang b Jian Zhong a Jun Li a,∗ a School of Pharmacy, Anhui Medical University, 81, Meishan Road, Hefei, 230032 Anhui, PR China b PET/CT center, Anhui Provincial Hospital, 17, Lujiang Road, Hefei, 230001 Anhui, PR China ∗ Corresponding
author. Tel.: +86 551 516 1001; fax: +86 551 516 1001. E-mail address: [email protected] (J. Li) Accepted 10 October 2012 Available online 11 December 2012
doi:10.1016/j.jbspin.2012.10.014
117
Reply to Xie et al. about the article “Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis”
a r t i c l e
i n f o
Keywords: Arthritis Biomarker Disease activity IL-33 Serum Synovial fluid
In this commentary, the authors discuss the potential value of interleukin (IL)-33 as a biomarker and therapeutic target in rheumatoid arthritis (RA). This view is certainly interesting. Concerning the usefulness of IL-33 as a biomarker, in our study, we were intrigued by the apparent specificity of IL-33 for RA, since we could not detect IL-33 in serum and SF samples of patients with psoriatic arthritis or non-psoriatic spondyloarthropathies. However, our study included a limited number of patients and this observation was not confirmed in another study, involving a larger cohort of patients, which described elevated IL-33 levels in ankylosing spondylitis patients as compared to healthy controls [1]. Xie et al. further mention that correlations were observed between the levels of IL-33 and IL-1 [2,3], IL-6 [2], C-reactive protein (CRP) [4] (although not confirmed in [5]), disease activity, respectively Disease Activity Score (DAS28-CRP) [4,6] (although not confirmed in [5]), the presence of rheumatoid factor (RF) [5] and anti-cyclic citrullinated peptide (anti-CCP) antibodies [5]. It has to be stressed though that this list is a summary of correlations found across different studies, which sometimes correspond to a single observation, and which, in some instances, were not confirmed in other studies. It is thus still early to draw definitive conclusions concerning the involvement of IL-33 in RA. Some important issues are still unclear such as the correlation of IL-33 levels with disease activity. The usefulness of IL-33 as a biomarker thus awaits clarification. In addition, we fully agree that further studies, both in human RA and in animal models, are necessary to confirm a potential interest for this molecule as a target for therapy. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Han GW, Zeng LW, Liang CX, et al. Serum levels of IL-33 is increased in patients with ankylosing spondylitis. Clin Rheumatol 2011;30:1583–8. [2] Hong YS, Moon SJ, Joo YB, et al. Measurement of interleukin-33 (IL-33) and IL-33 receptors (sST2 and ST2L) in patients with rheumatoid arthritis. J Korean Med Sci 2011;26:1132–9. [3] Matsuyama Y, Okazaki H, Hoshino M, et al. Sustained elevation of interleukin33 in sera and synovial fluids from patients with rheumatoid arthritis non-responsive to anti-tumor necrosis factor: possible association with persistent IL-1beta signaling and a poor clinical response. Rheumatol Int 2012;32:1397–401. [4] Kageyama Y, Torikai E, Tsujimura K, et al. Involvement of IL-33 in the pathogenesis of rheumatoid arthritis: the effect of etanercept on the serum levels of IL-33. Mod Rheumatol 2012;22:89–93. [5] Mu R, Huang HQ, Li YH, et al. Elevated serum interleukin 33 is associated with autoantibody production in patients with rheumatoid arthritis. J Rheumatol 2010;37:2006–13. [6] Matsuyama Y, Okazaki H, Tamemoto H, et al. Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritis. J Rheumatol 2010;37:18–25.
118
Correspondence / Joint Bone Spine 80 (2013) 115–119
Dominique Talabot-Ayer a,b Cem Gabay a,b Gaby Palmer a,b,∗ a Division of Rheumatology, Department of Internal Medicine, University Hospital, Geneva, Switzerland b Department of Pathology-Immunology, University of Geneva School of Medicine, 1, rue Michel-Servet, 1211 Geneva 4, Switzerland ∗ Corresponding
author. Tel.: +41 22 379 57 68; fax: +41 22 379 57 46. E-mail address: [email protected] (G. Palmer) Accepted 10 October 2012 Available online 20 November 2012 doi:10.1016/j.jbspin.2012.10.007
Comment about the article by Bisson-Vaivre et al.: “The role of HLA and KIR in anti-TNF therapy”
a r t i c l e
References [1] Bisson-Vaivre A, Alcaix D, Zarnitsky C, et al. Efficacy of anti-TNF in patients with spondyloarthritis in absence of any imaging sign. Joint Bone Spine 2012, doi:10.1016/j.jbspin.2012.08.003. [2] Carmona L, Descalzo MA, Perez-Pampin E, et al. All-cause and cause-specific mortality in rheumatoid arthritis are not greater than expected when treated with tumour necrosis factor antagonists. Ann Rheum Dis 2007;66:880–5. [3] Herrinton LJ, Liu L, Chen L, et al. Association between anti-TNF-␣ therapy and all-cause mortality. Pharmacoepidemiol Drug Saf 2012, doi:10.1002/pds.3354. [4] Grijalva CG, Chen L, Delzell E, et al. Initiation of tumor necrosis factor-␣ antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA 2011;306:2331–9. [5] Picascia A, Grimaldi V, Zullo A, et al. Current concepts in histocompatibility during heart transplant. Exp Clin Transplant 2012;10:209–18. [6] Jiao YL, Zhang BC, You L, et al. Polymorphisms of KIR gene and HLA-C alleles: possible association with susceptibility to HLA-B27-positive patients with ankylosing spondylitis. J Clin Immunol 2010;30:840–4. [7] McGeough CM, Berrar D, Wright G, et al. Killer immunoglobulin-like receptor and human leukocyte antigen-C genotypes in rheumatoid arthritis primary responders and non-responders to anti-TNF-␣ therapy. Rheumatol Int 2012;32:1647–53.
Vincenzo Grimaldi a,∗ Maria Lourdes Montesano a Teresa Infante b Claudio Napoli a,b a Department of General Pathology and U.O.C. Immunohematology, Transfusion Medicine and Transplant Immunology (SIMT), Regional Reference Laboratory of Transplant Immunology (LIT), Azienda Universitaria Policlinico (AOU), Second University of Naples, Piazza Miraglia 2, 80138 Naples, Italy b SDN Foundation, IRCCS, 80143 Naples, Italy
i n f o
Keywords: Anti-tumor necrosis factor (TNF) Human leukocyte antigen (HLA) Spondyloarthritis Rheumatoid arthritis
We have read the interesting paper of Bisson-Vaivre et al. [1] reporting the incidence of human leukocyte antigen (HLA) B27 carriers with imaging sings in 385 patients with spondyloarthritis (SpA). The efficacy of anti-tumor necrosis factor (TNF) therapy was also evaluated [1]. They concluded that 257 patients with imaging sings had significantly more frequent therapeutic responses to anti-TNF therapy and this phenomenon was associated with significantly higher frequency of HLA B27. Until now, studies of potential risk of anti-TNF therapy on mortality have provided conflicting results [2–4]. Anti-TNF therapy is not associated with increased mortality among patients with autoimmune diseases [3] nor with infection risk [4]. A more detailed HLA analysis [5] and anti-TNF therapy should be carried in SpA patients. Indeed, several studies have shown the role of killer cell immunoglobulin-like receptor (KIR) and their corresponding specific HLA-C ligands to the pathogenesis of some autoimmune diseases [6]. Moreover, it was investigated the correlation of KIR gene polymorphisms and HLA-C ligands with anti-TNF therapy in rheumatoid arthritis (RA) patients. McGeough et al. [7] have shown that RA patients responding to therapy have a significantly higher frequency of KIR2DS2/KIR2DL2. A positive response was associated with an activating KIR-HLA genotype, KIR2S2(+)HLA-C group 1/2 homozygous [7]. Therefore, it would be interesting to test also in SpA patients, with and without imaging sings (analyzed by BissonVaivre et al. in 2012) whether genetic polymorphisms of KIR and HLA-C might have influenced the effectiveness of anti-TNF therapy. This would allow the early identification of patients that may benefit of TNF therapy.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
∗ Corresponding
author. E-mail address: [email protected] (V. Grimaldi) Accepted 21 November 2012 Available online 31 December 2012 doi:10.1016/j.jbspin.2012.11.007
Reply to Grimaldi et al. about the article “The role of HLA and KIR in anti-TNF therapy”
a r t i c l e
i n f o
Keywords: Spondyloarthritis HLA KIR Anti-TNF
We really want to thank Grimaldi et al. [1] for their interesting comment upon our article about the efficacy of anti-TNF in patients with spondyloarthritis in absence of any imaging sign [2], recently published in Joint Bone Spine. Our results showed that the percentage of patients with exclusively clinical signs of spondyloarthritis who responded to anti-TNF was far from negligible (nearly 40%) and that anti-TNF efficacy was significantly higher in the HLA-B27 carriers with initial imaging signs rather than in the other patients (P = 0.028). The killer cell immunoglobulin-like receptors (KIR) are mainly expressed on the surface of the natural-killer cells. Their close interaction with the HLA system is well established in the pathogenesis of several autoimmune diseases, rheumatoid arthritis notably [3], as well as in the preservation of the immunological tolerance [4]. The interaction of specific sub-types of KIR and HLA alleles may thus