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Published in: Arthritis Research & Therapy 1/2012

Open Access 01-02-2012 | Research article

International cohort study of 73 anti-Ku-positive patients: association of p70/p80 anti-Ku antibodies with joint/bone features and differentiation of disease populations by using principal-components analysis

Authors: Katja Lakota, Gerhard G Thallinger, Snezna Sodin-Semrl, Blaz Rozman, Ales Ambrozic, Matija Tomsic, Sonja Praprotnik, Sasa Cucnik, Katjusa Mrak-Poljsak, Angela Ceribelli, Ilaria Cavazzana, Franco Franceschini, Jiri Vencovsky, Laszlo Czirják, Cecilia Varjú, Gunther Steiner, Martin Aringer, Bojana Stamenkovic, Oliver Distler, Marco Matucci-Cerinic, Tanja Kveder

Published in: Arthritis Research & Therapy | Issue 1/2012

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Abstract

Introduction

An international cohort study of 73 anti-Ku-positive patients with different connective tissue diseases was conducted to differentiate the anti-Ku-positive populations of patients based on their autoantibody profile and clinical signs/symptoms and to establish possible correlations between antibodies against Ku p70 and Ku p80 with autoimmune diseases.

Methods

Sera of anti-Ku-positive patients were collected from six European centers and were all secondarily tested (in the reference center); 73 were confirmed as positive. Anti-Ku antibodies were detected with counter-immunoelectrophoresis (CIE), line immunoassay (LIA), and immunoblot analyses. All clinical and laboratory data were follow-up cumulative data, except for anti-Ku antibodies. Statistical analyses were performed by using R (V 2.12.1). The Fisher Exact test was used to evaluate the association between anti-Ku antibodies and diagnosis, gender, clinical signs, and other observed antibodies. The P values were adjusted for multiple testing. Separation of disease populations based on the presence of antibodies and clinical signs was investigated by principal-components analysis, which was performed by using thr// R's prcomp function with standard parameters.

Results

A 16% higher prevalence of anti-Ku p70 was found over anti-Ku p80 antibodies. In 41 (57%) patients, a combination of both was detected. Five (7%) patients, who were CIE and/or LIA anti-Ku positive, were negative for both subsets, as detected with the immunoblot; 31% of the patients had undifferentiated connective tissue disease (UCTD); 29% had systemic sclerosis (SSc); 18% had systemic lupus erythematosus (SLE); 11% had rheumatoid arthritis; 7% had polymyositis; and 3% had Sjögren syndrome.

Conclusions

A significant positive association was found between female patients with anti-Ku p70 and joint/bone features, and a significant negative association was found between female patients with anti-Ku p80 only and joint/bone features (P = 0.05, respectively). By using the first and the third components of the principal-component analysis (PCA) with 29 parameters evaluated, we observed that the anti-Ku-positive population of UCTD patients had overlapping parameters, especially with SLE, as opposed to SSc, which could be helpful in delineating UCTD patients.
Appendix
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Literature
1.
go back to reference Featherstone C, Jackson SP: Ku, a DNA repair protein with multiple cellular functions?. Mutat Res. 1999, 434: 3-15.CrossRefPubMed Featherstone C, Jackson SP: Ku, a DNA repair protein with multiple cellular functions?. Mutat Res. 1999, 434: 3-15.CrossRefPubMed
2.
go back to reference Fisher TS, Zakian VA: Ku: a multifunctional protein involved in telomere maintenance. DNA Repair (Amst). 2005, 4: 1215-1226. 10.1016/j.dnarep.2005.04.021.CrossRef Fisher TS, Zakian VA: Ku: a multifunctional protein involved in telomere maintenance. DNA Repair (Amst). 2005, 4: 1215-1226. 10.1016/j.dnarep.2005.04.021.CrossRef
3.
go back to reference Tuteja R, Tuteja N: Ku autoantigen: a multifunctional DNA-binding protein. Crit Rev Biochem Mol Biol. 2000, 35: 1-33. 10.1080/10409230091169177.CrossRefPubMed Tuteja R, Tuteja N: Ku autoantigen: a multifunctional DNA-binding protein. Crit Rev Biochem Mol Biol. 2000, 35: 1-33. 10.1080/10409230091169177.CrossRefPubMed
4.
go back to reference Reeves WH: Antibodies to the p70/p80 (Ku) antigens in systemic lupus erythematosus. Rheum Dis Clin North Am. 1992, 18: 391-414.PubMed Reeves WH: Antibodies to the p70/p80 (Ku) antigens in systemic lupus erythematosus. Rheum Dis Clin North Am. 1992, 18: 391-414.PubMed
5.
go back to reference Nussenzweig A, Sokol K, Burgman P, Li L, Li GC: Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: the effects of ionizing radiation on growth, survival, and development. Proc Natl Acad Sci USA. 1997, 94: 13588-13593. 10.1073/pnas.94.25.13588.PubMedCentralCrossRefPubMed Nussenzweig A, Sokol K, Burgman P, Li L, Li GC: Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: the effects of ionizing radiation on growth, survival, and development. Proc Natl Acad Sci USA. 1997, 94: 13588-13593. 10.1073/pnas.94.25.13588.PubMedCentralCrossRefPubMed
6.
go back to reference Ouyang H, Nussenzweig A, Kurimasa A, Soares VC, Li X, Cordon-Cardo C, Li W, Cheong N, Nussenzweig M, Iliakis G, Chen DJ, Li GC: Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo. J Exp Med. 1997, 186: 921-929. 10.1084/jem.186.6.921.PubMedCentralCrossRefPubMed Ouyang H, Nussenzweig A, Kurimasa A, Soares VC, Li X, Cordon-Cardo C, Li W, Cheong N, Nussenzweig M, Iliakis G, Chen DJ, Li GC: Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo. J Exp Med. 1997, 186: 921-929. 10.1084/jem.186.6.921.PubMedCentralCrossRefPubMed
7.
go back to reference Cavazzana I, Ceribelli A, Quinzanini M, Scarsi M, Airo P, Cattaneo R, Franceschini F: Prevalence and clinical associations of anti-Ku antibodies in systemic autoimmune diseases. Lupus. 2008, 17: 727-732. 10.1177/0961203308089442.CrossRefPubMed Cavazzana I, Ceribelli A, Quinzanini M, Scarsi M, Airo P, Cattaneo R, Franceschini F: Prevalence and clinical associations of anti-Ku antibodies in systemic autoimmune diseases. Lupus. 2008, 17: 727-732. 10.1177/0961203308089442.CrossRefPubMed
8.
go back to reference Rozman B, Cucnik S, Sodin-Semrl S, Czirják L, Varjú C, Distler O, Huscher D, Aringer M, Steiner G, Matucci-Cerinic M, Guiducci S, Stamenkovic B, Stankovic A, Kveder T: Prevalence and clinical associations of anti-Ku antibodies in patients with systemic sclerosis: a European EUSTAR-initiated multi-centre case-control study. Ann Rheum Dis. 2008, 67: 1282-1286.CrossRefPubMed Rozman B, Cucnik S, Sodin-Semrl S, Czirják L, Varjú C, Distler O, Huscher D, Aringer M, Steiner G, Matucci-Cerinic M, Guiducci S, Stamenkovic B, Stankovic A, Kveder T: Prevalence and clinical associations of anti-Ku antibodies in patients with systemic sclerosis: a European EUSTAR-initiated multi-centre case-control study. Ann Rheum Dis. 2008, 67: 1282-1286.CrossRefPubMed
9.
go back to reference Reeves WH, Sthoeger ZM, Lahita RG: Role of antigen selectivity in autoimmune responses to the Ku (p70/p80) antigen. J Clin Invest. 1989, 84: 562-567. 10.1172/JCI114199.PubMedCentralCrossRefPubMed Reeves WH, Sthoeger ZM, Lahita RG: Role of antigen selectivity in autoimmune responses to the Ku (p70/p80) antigen. J Clin Invest. 1989, 84: 562-567. 10.1172/JCI114199.PubMedCentralCrossRefPubMed
10.
go back to reference Porges AJ, Ng T, Reeves WH: Antigenic determinants of the Ku (p70/p80) autoantigen are poorly conserved between species. J Immunol. 1990, 145: 4222-4228.PubMed Porges AJ, Ng T, Reeves WH: Antigenic determinants of the Ku (p70/p80) autoantigen are poorly conserved between species. J Immunol. 1990, 145: 4222-4228.PubMed
11.
go back to reference Reeves WH, Pierani A, Chou CH, Ng T, Nicastri C, Roeder RG, Sthoeger ZM: Epitopes of the p70 and p80 (Ku) lupus autoantigens. J Immunol. 1991, 146: 2678-2686.PubMed Reeves WH, Pierani A, Chou CH, Ng T, Nicastri C, Roeder RG, Sthoeger ZM: Epitopes of the p70 and p80 (Ku) lupus autoantigens. J Immunol. 1991, 146: 2678-2686.PubMed
12.
go back to reference Yaneva M, Arnett FC: Antibodies against Ku protein in sera from patients with autoimmune diseases. Clin Exp Immunol. 1989, 76: 366-372.PubMedCentralPubMed Yaneva M, Arnett FC: Antibodies against Ku protein in sera from patients with autoimmune diseases. Clin Exp Immunol. 1989, 76: 366-372.PubMedCentralPubMed
13.
go back to reference Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger , Michell DM, Neustadt DH, Pinals RS, Schaller JG, Sharp JT, Wilder RL, Hunder GG: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988, 31: 315-324. 10.1002/art.1780310302.CrossRefPubMed Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger , Michell DM, Neustadt DH, Pinals RS, Schaller JG, Sharp JT, Wilder RL, Hunder GG: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988, 31: 315-324. 10.1002/art.1780310302.CrossRefPubMed
14.
go back to reference Dalakas MC, Hohlfeld R: Polymyositis and dermatomyositis. Lancet. 2003, 362: 971-982. 10.1016/S0140-6736(03)14368-1.CrossRefPubMed Dalakas MC, Hohlfeld R: Polymyositis and dermatomyositis. Lancet. 2003, 362: 971-982. 10.1016/S0140-6736(03)14368-1.CrossRefPubMed
15.
go back to reference Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997, 40: 1725-CrossRefPubMed Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997, 40: 1725-CrossRefPubMed
16.
go back to reference LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, Rowell N, Wollheim F: Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988, 15: 202-205.PubMed LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, Rowell N, Wollheim F: Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988, 15: 202-205.PubMed
17.
go back to reference Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH, European Study Group on Classification Criteria for Sjögren's Syndrome: Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002, 61: 554-558. 10.1136/ard.61.6.554.PubMedCentralCrossRefPubMed Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH, European Study Group on Classification Criteria for Sjögren's Syndrome: Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002, 61: 554-558. 10.1136/ard.61.6.554.PubMedCentralCrossRefPubMed
18.
go back to reference Distler JHW, Kalden JR, Distler O: Undifferentiated connective tissue disease, overlap syndromes and mixed connective tissue disease. EULAR Compendium on Rheumatic Diseases. Edited by: Bijlsma JWJ. 2009, London: BMJ Publishing Group Ltd, 244-256. Distler JHW, Kalden JR, Distler O: Undifferentiated connective tissue disease, overlap syndromes and mixed connective tissue disease. EULAR Compendium on Rheumatic Diseases. Edited by: Bijlsma JWJ. 2009, London: BMJ Publishing Group Ltd, 244-256.
19.
go back to reference Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006, 4: 295-306. 10.1111/j.1538-7836.2006.01753.x.CrossRefPubMed Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006, 4: 295-306. 10.1111/j.1538-7836.2006.01753.x.CrossRefPubMed
20.
go back to reference Bunn C, Kveder T: Counterimmunoelectrophoresis and immunodiffusion for the detection of antibodies to soluble cellular antigens. Manual of Biological Markers of Disease. Edited by: Van Venrooij WJ, Maini RN. 1993, Nonvell, MA: Kluwer Academic Publishers, 1-12. Bunn C, Kveder T: Counterimmunoelectrophoresis and immunodiffusion for the detection of antibodies to soluble cellular antigens. Manual of Biological Markers of Disease. Edited by: Van Venrooij WJ, Maini RN. 1993, Nonvell, MA: Kluwer Academic Publishers, 1-12.
22.
go back to reference Benjamini Y, Hochberg Y: The adaptive control of the false discovery rate in multiple hypotheses testing. J Behav Educ Statist. 2000, 25: 60-83.CrossRef Benjamini Y, Hochberg Y: The adaptive control of the false discovery rate in multiple hypotheses testing. J Behav Educ Statist. 2000, 25: 60-83.CrossRef
23.
go back to reference Wang J, Dong X, Stojanov L, Kimpel D, Satoh M, Reeves WH: Human autoantibodies stabilize the quaternary structure of Ku antigen. Arthritis Rheum. 1997, 40: 1344-1353.CrossRefPubMed Wang J, Dong X, Stojanov L, Kimpel D, Satoh M, Reeves WH: Human autoantibodies stabilize the quaternary structure of Ku antigen. Arthritis Rheum. 1997, 40: 1344-1353.CrossRefPubMed
24.
go back to reference Li GC, Ouyang H, Li X, Nagasawa H, Little JB, Chen DJ, Ling CC, Fuks Z, Cordon-Cardo C: Ku70: a candidate tumor suppressor gene for murine T cell lymphoma. Mol Cell. 1998, 2: 1-8. 10.1016/S1097-2765(00)80108-2.CrossRefPubMed Li GC, Ouyang H, Li X, Nagasawa H, Little JB, Chen DJ, Ling CC, Fuks Z, Cordon-Cardo C: Ku70: a candidate tumor suppressor gene for murine T cell lymphoma. Mol Cell. 1998, 2: 1-8. 10.1016/S1097-2765(00)80108-2.CrossRefPubMed
25.
go back to reference Arrington ED, Caldwell MC, Kumaravel TS, Lohani A, Joshi A, Evans MK, Chen HT, Nussenzweig A, Holbrook NJ, Gorospe M: Enhanced sensitivity and long-term G2 arrest in hydrogen peroxide-treated Ku80-null cells are unrelated to DNA repair defects. Free Radic Biol Med. 2000, 29: 1166-1176. 10.1016/S0891-5849(00)00439-1.CrossRefPubMed Arrington ED, Caldwell MC, Kumaravel TS, Lohani A, Joshi A, Evans MK, Chen HT, Nussenzweig A, Holbrook NJ, Gorospe M: Enhanced sensitivity and long-term G2 arrest in hydrogen peroxide-treated Ku80-null cells are unrelated to DNA repair defects. Free Radic Biol Med. 2000, 29: 1166-1176. 10.1016/S0891-5849(00)00439-1.CrossRefPubMed
Metadata
Title
International cohort study of 73 anti-Ku-positive patients: association of p70/p80 anti-Ku antibodies with joint/bone features and differentiation of disease populations by using principal-components analysis
Authors
Katja Lakota
Gerhard G Thallinger
Snezna Sodin-Semrl
Blaz Rozman
Ales Ambrozic
Matija Tomsic
Sonja Praprotnik
Sasa Cucnik
Katjusa Mrak-Poljsak
Angela Ceribelli
Ilaria Cavazzana
Franco Franceschini
Jiri Vencovsky
Laszlo Czirják
Cecilia Varjú
Gunther Steiner
Martin Aringer
Bojana Stamenkovic
Oliver Distler
Marco Matucci-Cerinic
Tanja Kveder
Publication date
01-02-2012
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2012
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar3550

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