系统性红斑狼疮血清抗核小体抗体水平及意义的探讨
摘要
背景：抗核小体抗体（Antinucleosome antibody ，AnuA ）被认为与系统性红斑狼疮（SLE）相关，其出现提示狼疮肾炎（LN）的发生。
目的：研究AnuA在SLE患者血清中的水平及其相关影响因素，探讨AnuA在SLE发病中的作用机制，为临床治疗、预后判断提供新的理论依据。
方法：酶联免疫吸附实验（ELISA）测定120例初诊SLE患者、55例其他风湿性疾病和30名健康对照血清中AnuA水平。同时记录各种临床表现，测定其治疗前的其他自身抗体（抗核抗体、抗dsDNA、抗Sm、抗组蛋白抗体、抗磷脂抗体）和实验室指标（血细胞计数、尿蛋白、血沉、补体、循环免疫复合物、肝肾功能）。分析各指标之间的关系。疾病活动性根据系统性红斑狼疮疾病活动指数（SLEDAI）进行评分。
结果：自身抗体在SLE及对照组的阳性率分别为AnuA 56和7%，抗dsDNA 35% 和1%，抗Sm 24% 和0%。AnuA与患者性别、年龄、病程无相关性，敏感性和特异性分别为55.83%、 95.29%。AnuA参与SLE的发病，与肾脏损害有关。血清AnuA水平与肝细胞损害的程度可能存在一定关系。血清中AnuA与SLE特异性诊断指标抗dsDNA抗体相关，水平与SLE活动性指标补体C3C4(AnuA阳性组比AnuA 阴性组， C3： 0.53 +/- 0.24 g/L vs 0.79 +/- 0.23 g/L， p < 0.001； C4： 0.10 +/- 0.04 g/L vs 0.18 +/- 0.04 g/L， p < 0.001)、白细胞计数、血小板计数呈负相关，与SLEDAI呈正相关(t = 2.171, P < 0.05)。AnuA阳性组关节炎、口腔溃疡、蛋白尿发生率明显高于阴性组。AnuA分别与抗Sm、抗dsDNA联合诊断SLE时敏感性显著提高（p =0.0001）。
结论：AnuA在SLE血清中高水平存在，血清AnuA测定是诊断和治疗SLE中实验室检查的有益补充，与抗dsDNA联合诊断SLE、LN时敏感而且特异，但尚不能认为是LN的标记性抗体，不能预告肾损害危险度增加。
BACKGROUND: Antinucleosome antibody (AnuA) has recently heen described in patients with systemic lupus erythematosus (SLE) and it has been suggested that its presence is associated with lupus nephritis(LN).
OBJECTIVE: To study the frequency and disease specificity of AnuA reactivity in diverse connective tissue diseases (CTD). To assess the prevalence and clinical associations of AnuA in SLE. To compare the utility of auto-antibodies for the diagnosis of SLE.
METHODS: We included 120 consecutive patients (107 female) with SLE (four or more ACR criteria). As control groups we included 30 healthy blood donors and 55 patients with 7 other CTD. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). A venous blood sample was drawn to measure AnuA by enzyme-linked immunosorbent assay (ELISA). The groups were evaluated for AnuA and for clinical, humoral parameters (hemoglobin, blood cell count, urinanalysis, ESR, ANA, CIC, ALT, C3C4, ALB) and other auto-antibodies [anti-double-stranded DNA (anti-dsDNA), anti-Smith (anti-Sm), anti-nuclear (ANA), anti-histones (AHA), anti-cardiolipin (ACL)].
RESULTS: The prevalence of AnuA in SLE patients and controls was 55.83% and 4.71% respectively, 35% and 1.18% for anti-dsDNA, and 24.17% and 0% for anti-Sm. AnuA had a sensitivity of 55.83% and specificity of 95.29% for SLE diagnosis. AnuA showed the highest correlation with disease activity, especially in patients negative for anti-dsDNA antibodies. The levels of AnuA strongly correlated with SLEDAI (t = 2.171, P < 0.05), but inversely correlated
with serum complement (C3, C4) levels in anti-dsDNA negative SLE patients (in AnuA positive group than (vs) AnuA negative group, C3: 0.53 +/- 0.24 g/L vs 0.79 +/- 0.23 g/L, p < 0.001; C4: 0.10 +/- 0.04 g/L vs 0.18 +/- 0.04 g/L, p < 0.001). Arthritis, ulceration and albuminuria were more altered in AnuA positive group than (vs) AnuA negative group. AnuA also showed strong association with renal and liver damage.
CONCLUSION: The measurement of AnuA appears to be a useful addition to the laboratory tests that can help in the diagnosis and treatment of SLE, especially in patients who are negative for anti-dsDNA antibodies. Our data suggest that the AnuA may be a sensitive and specific for SLE, but isn’t a marker for an increased risk of lupus nephritis. Simultaneous detection of AnuA, anti-dsDNA, anti-Sm and ANA can notably improve the specificity.
目的：研究AnuA在SLE患者血清中的水平及其相关影响因素，探讨AnuA在SLE发病中的作用机制，为临床治疗、预后判断提供新的理论依据。
方法：酶联免疫吸附实验（ELISA）测定120例初诊SLE患者、55例其他风湿性疾病和30名健康对照血清中AnuA水平。同时记录各种临床表现，测定其治疗前的其他自身抗体（抗核抗体、抗dsDNA、抗Sm、抗组蛋白抗体、抗磷脂抗体）和实验室指标（血细胞计数、尿蛋白、血沉、补体、循环免疫复合物、肝肾功能）。分析各指标之间的关系。疾病活动性根据系统性红斑狼疮疾病活动指数（SLEDAI）进行评分。
结果：自身抗体在SLE及对照组的阳性率分别为AnuA 56和7%，抗dsDNA 35% 和1%，抗Sm 24% 和0%。AnuA与患者性别、年龄、病程无相关性，敏感性和特异性分别为55.83%、 95.29%。AnuA参与SLE的发病，与肾脏损害有关。血清AnuA水平与肝细胞损害的程度可能存在一定关系。血清中AnuA与SLE特异性诊断指标抗dsDNA抗体相关，水平与SLE活动性指标补体C3C4(AnuA阳性组比AnuA 阴性组， C3： 0.53 +/- 0.24 g/L vs 0.79 +/- 0.23 g/L， p < 0.001； C4： 0.10 +/- 0.04 g/L vs 0.18 +/- 0.04 g/L， p < 0.001)、白细胞计数、血小板计数呈负相关，与SLEDAI呈正相关(t = 2.171, P < 0.05)。AnuA阳性组关节炎、口腔溃疡、蛋白尿发生率明显高于阴性组。AnuA分别与抗Sm、抗dsDNA联合诊断SLE时敏感性显著提高（p =0.0001）。
结论：AnuA在SLE血清中高水平存在，血清AnuA测定是诊断和治疗SLE中实验室检查的有益补充，与抗dsDNA联合诊断SLE、LN时敏感而且特异，但尚不能认为是LN的标记性抗体，不能预告肾损害危险度增加。
BACKGROUND: Antinucleosome antibody (AnuA) has recently heen described in patients with systemic lupus erythematosus (SLE) and it has been suggested that its presence is associated with lupus nephritis(LN).
OBJECTIVE: To study the frequency and disease specificity of AnuA reactivity in diverse connective tissue diseases (CTD). To assess the prevalence and clinical associations of AnuA in SLE. To compare the utility of auto-antibodies for the diagnosis of SLE.
METHODS: We included 120 consecutive patients (107 female) with SLE (four or more ACR criteria). As control groups we included 30 healthy blood donors and 55 patients with 7 other CTD. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). A venous blood sample was drawn to measure AnuA by enzyme-linked immunosorbent assay (ELISA). The groups were evaluated for AnuA and for clinical, humoral parameters (hemoglobin, blood cell count, urinanalysis, ESR, ANA, CIC, ALT, C3C4, ALB) and other auto-antibodies [anti-double-stranded DNA (anti-dsDNA), anti-Smith (anti-Sm), anti-nuclear (ANA), anti-histones (AHA), anti-cardiolipin (ACL)].
RESULTS: The prevalence of AnuA in SLE patients and controls was 55.83% and 4.71% respectively, 35% and 1.18% for anti-dsDNA, and 24.17% and 0% for anti-Sm. AnuA had a sensitivity of 55.83% and specificity of 95.29% for SLE diagnosis. AnuA showed the highest correlation with disease activity, especially in patients negative for anti-dsDNA antibodies. The levels of AnuA strongly correlated with SLEDAI (t = 2.171, P < 0.05), but inversely correlated
with serum complement (C3, C4) levels in anti-dsDNA negative SLE patients (in AnuA positive group than (vs) AnuA negative group, C3: 0.53 +/- 0.24 g/L vs 0.79 +/- 0.23 g/L, p < 0.001; C4: 0.10 +/- 0.04 g/L vs 0.18 +/- 0.04 g/L, p < 0.001). Arthritis, ulceration and albuminuria were more altered in AnuA positive group than (vs) AnuA negative group. AnuA also showed strong association with renal and liver damage.
CONCLUSION: The measurement of AnuA appears to be a useful addition to the laboratory tests that can help in the diagnosis and treatment of SLE, especially in patients who are negative for anti-dsDNA antibodies. Our data suggest that the AnuA may be a sensitive and specific for SLE, but isn’t a marker for an increased risk of lupus nephritis. Simultaneous detection of AnuA, anti-dsDNA, anti-Sm and ANA can notably improve the specificity.
引文
Madaio MP, Hodder S, Schuarz RS, et al. Responsiveness of autoimmune and normal mice to nucleic acid autoantigens. J Immunol 1984;132:872-882
Berden JH. Lupus nephritis. Nephrology Forum. Kidney Int.1997;52:538-58.
Burlingame RW, Boey ML, Starkebaum G, et al. The central to histones and DNA in systemic Lupus erythematosus. J clin Invest 1994;94:184-92.
Amoura Z, Piette J-C, BachJ-F, et al. The key role of nucleosomes in lupus. Arthritis Rheum 1999;42:833-43.
Bruns A, Blass S, Hausdorf G, et al. Nucleosomes are major T and B cell autoantigens in systemic lupus erythematosus. Arthritis Rheum. 2000 Oct;43(10):2307-15
Lugher K, Macler AW, Richmond RK. Cristal structure of the nucleosome core particle at 2.8 resolution. Nature,1997;389:251-261.
Hannestad K, Stollar BD. Certain rheumatoid factor react with nucleosomes. Nature,1978;275:671-673.
Berden JH. Lupus nephritis: consequence of disturbed removal of apoptotic cells? Neth J Med. 2003 Aug; 61(8): 233-8.
Decker P, Wolburg H, Rammensee HG. Nucleosomes induce lymphocyte necrosis.Eur J Immunol. 2003 Jul; 33(7): 1978-87.
Berden JH, light R, van Bruggen MC, et al. Role of nucleosomes for induction and glomerulur binding of autoantibodies in lupus nephritis. Curr opin Nephrol Hypertens,1999,8(3):299-306.
Monestier M. Autoantibodies to nucleosomes and histone-DNA complexes. Methods, 1997;11:36-43.
Berden JH, Grootscholten C, Jurgen WC, et al. Lupus nephritis: a nucleosome waste disposal defect? J Nephrol. 2002 Nov-Dec; 15 Suppl 6: S1-10.
Amoura Z, Piette JC. Role of the nucleosome in the physiopathology of systemic lupus erythematosus Ann Med Interne (Paris). 2003 Feb;154(1):25-32.
Ravirajan CT, Rowse L, MacGowan JR, et al. An analysis of clinical disease activity and nephritis-associated serum autoantibody profiles in patients with systemic lupus erythematosus: a cross-sectional study. Rheumatology (Oxford). 2001 Dec;40(12):1405-12.
Simon JA, Cabiedes J, Ortiz E, et al. Anti-nucleosome antibodies in patients with systemic lupus erythematosus of recent onset. Potential utility as a diagnostic tool and disease activity marker. Rheumatology (Oxford). 2004 Feb; 43(2): 220-4. Epub 2003 Sep 16.
Ghillani-Dalbin P, Amoura Z, Cacoub P, et al. Testing for anti-nucleosome antibodies in daily practice: a mono centric evaluation in 1696 patients. Lupus. 2003; 12(11): 833-7.
Chairns AP, McMillan SA, Crtckard AD, et al. Antinucleosome antibodies in the dianosis of systemic lupus erythematosus. Ann Rheum Dis,2003,62:272-273.
苏茵,韩蕾,栗占国等. 抗核小体抗体测定在系统性红斑狼疮诊断中的意义.中华风湿病学杂志,2003,7:474-477.
Rahman A, Hiepe F. Anti-DNA antibodies--overview of assays and clinical correlations. Lupus. 2002;11(12):770-3.
CerveraR, khamashta, MA, Font J. Prospective (Morbidity and mortality in systemic lupus erythematosus. A multicenter prospective study of 1000 patients. Medicine (Baltimore) 1999;78:167-75.
Grootscholten C, van Bruggen MC, van der Pijl JW, et al. Deposition of nucleosomal antigens (histones and DNA) in the epidermal basement membrane in human lupus nephritis. Arthritis Rheum. 2003 May; 48(5): 1355-62.
Coritsidis GN, Lombardo F, Rumore P, et al. Nucleosome effects on mesangial cell matrix and proliferation: a possible role in early lupus
nephritis.Exp Nephrol. 2002;10(3):216-26.
Morel L, Crober BP, Blenman KR, et al. Genetic reconstitution of systemic lupus erythemtosus immunopathology with polycongenic murine strains. Proc Natl Acad USA 2000,97:6670-5.
R Cervera, O Vinas, M Ramos-Casals, et al. Anti-chromatin antibodies in systemic lupus erythematosus: a useful marter for lupus nephritis. Ann Rheum Dis 2003;62:431-434.
Kewalramani R, Singh AK. Immunopathogenesis of lupus and lupus nephritis: recent insights. Curr Opin Nephrol Hypertens. 2002 May; 11(3): 273-7.
Chabre H, Amoura Z, Piette JC, Presence of nucleosome-restricted antibodies in patients with systemic lupus erythematosus. Arthritis Rheum. 1995 Oct; 38(10): 1485-91.
Laderach D, Koutouzov S, Bach JF, Yamamoto AM. Concomitant early appearance of anti-ribonucleoprotein and anti-nucleosome antibodies in lupus prone mice.J Autoimmun. 2003 Mar;20(2):161-70.
Shi Y., A.Kaliyaperumal, L.Lu, t al. Promiscuous presentation and recognition of nucleosomal autoepitopes in lupus: role of autoimmune Tcell receptor αchain. J.Exp. Med. 1998,187:367.
Kaliyperumal A, Michaels MA, Datta SK. Antigen-specfic therapy of murine lupus nephritis using nucleosomal peptide: tolerance spreading impairs pathogenic function of autoimmune T and B cells. J Immunol,1999,162:5775-5783.
Berden JH. Lupus nephritis. Nephrology Forum. Kidney Int.1997;52:538-58.
Burlingame RW, Boey ML, Starkebaum G, et al. The central to histones and DNA in systemic Lupus erythematosus. J clin Invest 1994;94:184-92.
Amoura Z, Piette J-C, BachJ-F, et al. The key role of nucleosomes in lupus. Arthritis Rheum 1999;42:833-43.
Bruns A, Blass S, Hausdorf G, et al. Nucleosomes are major T and B cell autoantigens in systemic lupus erythematosus. Arthritis Rheum. 2000 Oct;43(10):2307-15
Lugher K, Macler AW, Richmond RK. Cristal structure of the nucleosome core particle at 2.8 resolution. Nature,1997;389:251-261.
Hannestad K, Stollar BD. Certain rheumatoid factor react with nucleosomes. Nature,1978;275:671-673.
Berden JH. Lupus nephritis: consequence of disturbed removal of apoptotic cells? Neth J Med. 2003 Aug; 61(8): 233-8.
Decker P, Wolburg H, Rammensee HG. Nucleosomes induce lymphocyte necrosis.Eur J Immunol. 2003 Jul; 33(7): 1978-87.
Berden JH, light R, van Bruggen MC, et al. Role of nucleosomes for induction and glomerulur binding of autoantibodies in lupus nephritis. Curr opin Nephrol Hypertens,1999,8(3):299-306.
Monestier M. Autoantibodies to nucleosomes and histone-DNA complexes. Methods, 1997;11:36-43.
Berden JH, Grootscholten C, Jurgen WC, et al. Lupus nephritis: a nucleosome waste disposal defect? J Nephrol. 2002 Nov-Dec; 15 Suppl 6: S1-10.
Amoura Z, Piette JC. Role of the nucleosome in the physiopathology of systemic lupus erythematosus Ann Med Interne (Paris). 2003 Feb;154(1):25-32.
Ravirajan CT, Rowse L, MacGowan JR, et al. An analysis of clinical disease activity and nephritis-associated serum autoantibody profiles in patients with systemic lupus erythematosus: a cross-sectional study. Rheumatology (Oxford). 2001 Dec;40(12):1405-12.
Simon JA, Cabiedes J, Ortiz E, et al. Anti-nucleosome antibodies in patients with systemic lupus erythematosus of recent onset. Potential utility as a diagnostic tool and disease activity marker. Rheumatology (Oxford). 2004 Feb; 43(2): 220-4. Epub 2003 Sep 16.
Ghillani-Dalbin P, Amoura Z, Cacoub P, et al. Testing for anti-nucleosome antibodies in daily practice: a mono centric evaluation in 1696 patients. Lupus. 2003; 12(11): 833-7.
Chairns AP, McMillan SA, Crtckard AD, et al. Antinucleosome antibodies in the dianosis of systemic lupus erythematosus. Ann Rheum Dis,2003,62:272-273.
苏茵,韩蕾,栗占国等. 抗核小体抗体测定在系统性红斑狼疮诊断中的意义.中华风湿病学杂志,2003,7:474-477.
Rahman A, Hiepe F. Anti-DNA antibodies--overview of assays and clinical correlations. Lupus. 2002;11(12):770-3.
CerveraR, khamashta, MA, Font J. Prospective (Morbidity and mortality in systemic lupus erythematosus. A multicenter prospective study of 1000 patients. Medicine (Baltimore) 1999;78:167-75.
Grootscholten C, van Bruggen MC, van der Pijl JW, et al. Deposition of nucleosomal antigens (histones and DNA) in the epidermal basement membrane in human lupus nephritis. Arthritis Rheum. 2003 May; 48(5): 1355-62.
Coritsidis GN, Lombardo F, Rumore P, et al. Nucleosome effects on mesangial cell matrix and proliferation: a possible role in early lupus
nephritis.Exp Nephrol. 2002;10(3):216-26.
Morel L, Crober BP, Blenman KR, et al. Genetic reconstitution of systemic lupus erythemtosus immunopathology with polycongenic murine strains. Proc Natl Acad USA 2000,97:6670-5.
R Cervera, O Vinas, M Ramos-Casals, et al. Anti-chromatin antibodies in systemic lupus erythematosus: a useful marter for lupus nephritis. Ann Rheum Dis 2003;62:431-434.
Kewalramani R, Singh AK. Immunopathogenesis of lupus and lupus nephritis: recent insights. Curr Opin Nephrol Hypertens. 2002 May; 11(3): 273-7.
Chabre H, Amoura Z, Piette JC, Presence of nucleosome-restricted antibodies in patients with systemic lupus erythematosus. Arthritis Rheum. 1995 Oct; 38(10): 1485-91.
Laderach D, Koutouzov S, Bach JF, Yamamoto AM. Concomitant early appearance of anti-ribonucleoprotein and anti-nucleosome antibodies in lupus prone mice.J Autoimmun. 2003 Mar;20(2):161-70.
Shi Y., A.Kaliyaperumal, L.Lu, t al. Promiscuous presentation and recognition of nucleosomal autoepitopes in lupus: role of autoimmune Tcell receptor αchain. J.Exp. Med. 1998,187:367.
Kaliyperumal A, Michaels MA, Datta SK. Antigen-specfic therapy of murine lupus nephritis using nucleosomal peptide: tolerance spreading impairs pathogenic function of autoimmune T and B cells. J Immunol,1999,162:5775-5783.