ログイン
ランキング
お知らせ
ログイン
文献詳細
増大特集 Antibody Update
文献概要
はじめに
膠原病では自己抗体の出現が大きな特徴であり，それが自己免疫疾患という概念に分類される大きな根拠にもなっている。膠原病における自己抗体の多くは，核内や細胞内に存在する（細胞表面や体液中には通常は存在しない）分子を抗原とするため，その病因的意義はいまだに明らかではない。しかしながら，多くの自己抗体は疾患特異性が高く，さらに病型や臨床症状とも密接に相関することから，膠原病の診断・分類・治療において重要な役割を持っている。
関節リウマチ，全身性エリテマトーデス，全身性強皮症においては，疾患特異的自己抗体が大多数（80％以上）の例で陽性になる。ところが，多発筋炎（polymyositis：PM）や皮膚筋炎（dermatomyositis：DM）では，従来は自己抗体検査があまり有用でないと考えられていた。実際に，筋炎に特異的な自己抗体として日常診療で測定可能である抗Jo-1抗体は，PMでは20～30％，DMでは約5％にしか検出されない。さらに，蛍光抗体間接法による抗核抗体も陰性だったり低力価だったりすることが多く，これは全身性エリテマトーデスや全身性強皮症で高力価の抗核抗体が高率に陽性となるのと対照的である。
しかしながら，近年になって，PM/DMに特異性の高い新たな自己抗体が同定され，臨床的意義の解析も進んできた。このような筋炎特異自己抗体として，抗アミノアシルtRNA合成酵素（aminoacyl-tRNA synthetase：ARS）抗体，抗Mi-2抗体，抗MDA5抗体（抗CADM140抗体），抗TIF1抗体（抗155/140抗体），抗SRP抗体，抗NXP-2抗体（抗MJ抗体），抗SAE抗体などが挙げられる（Table1)1-3)。これらの抗体を合わせるとPM/DMの多くの症例で特異抗体が陽性になることになり，特にDMでは全身性エリテマトーデスや全身性強皮症と比べても遜色のない陽性率となることが明らかになった。
炎症性ミオパチーは，多様性のあるカテゴリーであり，PMとDMでは異なる発症機序が想定されている。筋症状もさまざまであり，DMの中には筋症状を欠くclinically amyopathic DM（CADM）の病型もある。また，発症年齢をとっても小児に発症するタイプと成人に発症するタイプがある。さらに，「皮膚」と「筋」以外に，悪性腫瘍と間質性肺炎という二大合併症が大きな意味を持っている。筋炎特異自己抗体は，臨床症状や合併症と密接に相関することが明らかになってきたため，このようなPM/DMの分類を考えるうえで，「自己抗体によるPM/DMのサブセット分類」が極めて有用な手段となることが明らかになってきた。すなわち，筋炎特異抗体の同定は，単に診断のみならず経過の予測や治療方針の決定においても有用であり，また，一部の抗体では抗体価が疾患活動性を反映する可能性もある。
膠原病では自己抗体の出現が大きな特徴であり，それが自己免疫疾患という概念に分類される大きな根拠にもなっている。膠原病における自己抗体の多くは，核内や細胞内に存在する（細胞表面や体液中には通常は存在しない）分子を抗原とするため，その病因的意義はいまだに明らかではない。しかしながら，多くの自己抗体は疾患特異性が高く，さらに病型や臨床症状とも密接に相関することから，膠原病の診断・分類・治療において重要な役割を持っている。
関節リウマチ，全身性エリテマトーデス，全身性強皮症においては，疾患特異的自己抗体が大多数（80％以上）の例で陽性になる。ところが，多発筋炎（polymyositis：PM）や皮膚筋炎（dermatomyositis：DM）では，従来は自己抗体検査があまり有用でないと考えられていた。実際に，筋炎に特異的な自己抗体として日常診療で測定可能である抗Jo-1抗体は，PMでは20～30％，DMでは約5％にしか検出されない。さらに，蛍光抗体間接法による抗核抗体も陰性だったり低力価だったりすることが多く，これは全身性エリテマトーデスや全身性強皮症で高力価の抗核抗体が高率に陽性となるのと対照的である。
しかしながら，近年になって，PM/DMに特異性の高い新たな自己抗体が同定され，臨床的意義の解析も進んできた。このような筋炎特異自己抗体として，抗アミノアシルtRNA合成酵素（aminoacyl-tRNA synthetase：ARS）抗体，抗Mi-2抗体，抗MDA5抗体（抗CADM140抗体），抗TIF1抗体（抗155/140抗体），抗SRP抗体，抗NXP-2抗体（抗MJ抗体），抗SAE抗体などが挙げられる（Table1)1-3)。これらの抗体を合わせるとPM/DMの多くの症例で特異抗体が陽性になることになり，特にDMでは全身性エリテマトーデスや全身性強皮症と比べても遜色のない陽性率となることが明らかになった。
炎症性ミオパチーは，多様性のあるカテゴリーであり，PMとDMでは異なる発症機序が想定されている。筋症状もさまざまであり，DMの中には筋症状を欠くclinically amyopathic DM（CADM）の病型もある。また，発症年齢をとっても小児に発症するタイプと成人に発症するタイプがある。さらに，「皮膚」と「筋」以外に，悪性腫瘍と間質性肺炎という二大合併症が大きな意味を持っている。筋炎特異自己抗体は，臨床症状や合併症と密接に相関することが明らかになってきたため，このようなPM/DMの分類を考えるうえで，「自己抗体によるPM/DMのサブセット分類」が極めて有用な手段となることが明らかになってきた。すなわち，筋炎特異抗体の同定は，単に診断のみならず経過の予測や治療方針の決定においても有用であり，また，一部の抗体では抗体価が疾患活動性を反映する可能性もある。
参考文献
1) Fujimoto M: Dermatomyositis: myositis-specific autoantibodies and skin manifestations. Clin Exp Neuroimmunol 3: 74-84, 2012
2) Gunawardena H, Betteridge ZE, McHugh NJ: Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression. Rheumatology (Oxford) 48: 607-612, 2009
3) Mammen AL: Autoimmune myopathies: autoantibodies, phenotypes and pathogenesis. Nat Rev Neurol 7: 343-354, 2011
4) Nishikai M, Reichlin M: Heterogeneity of precipitating antibodies in polymyositis and dermatomyositis: characterization of the Jo-1 antibody system. Arthritis Rheum 23: 881-888, 1980
5) Mathews MB, Bernstein RM: Myositis autoantibody inhibits histidyl-tRNA synthetase: a model for autoimmunity. Nature 304: 177-179, 1983
6) Rosa MD, Hendrick JP Jr, Lerner MR, Steitz JA, Reichlin M: A mammalian tRNAHis-containing antigen is recognized by the polymyositis-specific antibody anti-Jo-1．Nucleic Acids Res 11: 853-870, 1983
7) Targoff IN: Laboratory testing in the diagnosis and management of idiopathic inflammatory myopathies. Rheum Dis Clin North Am 28: 859-890, viii, 2002
8) Connors GR, Christopher-Stine L, Oddis CV, Danoff SK: Interstitial lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past 35 years? Chest 138: 1464-1474, 2010
9) Hirakata M, Nagai S: Interstitial lung disease in polymyositis and dermatomyositis. Curr Opin Rheumatol 12: 501-508, 2000
10) Casciola-Rosen L, Andrade F, Ulanet D, Wong WB, Rosen A: Cleavage by granzyme B is strongly predictive of autoantigen status: implications for initiation of autoimmunity. J Exp Med 190: 815-826, 1999
11) Howard OMZ, Dong HF, Yang D, Raben N, Nagaraju K, et al: Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells. J Exp Med 196: 781-791, 2002
12) Levine SM, Raben N, Xie D, Askin FB, Tuder R, et al: Novel conformation of histidyl-transfer RNA synthetase in the lung: the target tissue in Jo-1 autoantibody-associated myositis. Arthritis Rheum 56: 2729-2739, 2007
13) Reichlin M, Mattioli M: Description of a serological reaction characteristic of polymyositis. Clin Immunol Immunopathol 5: 12-20, 1976
14) Targoff IN, Reichlin M: The association between Mi-2 antibodies and dermatomyositis. Arthritis Rheum 28: 796-803, 1985
15) Komura K, Fujimoto M, Matsushita T, Kaji K, Kondo M, et al: Prevalence and clinical characteristics of anti-Mi-2 antibodies in Japanese patients with dermatomyositis. J Dermatol Sci 40: 215-217, 2005
16) Hamaguchi Y, Kuwana M, Hoshino K, Hasegawa M, Kaji K, et al: Clinical correlations with dermatomyositis-specific autoantibodies in adult Japanese patients with dermatomyositis: a multicenter cross-sectional study. Arch Dermatol 147: 391-398, 2011
17) Okada S, Weatherhead E, Targoff IN, Wesley R, Miller FW: Global surface ultraviolet radiation intensity may modulate the clinical and immunologic expression of autoimmune muscle disease. Arthritis Rheum 48: 2285-2293, 2003
18) Love LA, Weinberg CR, McConnaughey DR, Oddis CV, Medsger TA Jr, et al: Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women. Arthritis Rheum 60: 2499-2504, 2009
19) Burd CJ, Kinyamu HK, Miller FW, Archer TK: UV radiation regulates Mi-2 through protein translation and stability. J Biol Chem 283: 34976-34982, 2008
20) Kashiwagi M, Morgan BA, Georgopoulos K: The chromatin remodeler Mi-2beta is required for establishment of the basal epidermis and normal differentiation of its progeny. Development 134: 1571-1582, 2007
21) Casciola-Rosen L, Nagaraju K, Plotz P, Wang K, Levine S, et al: Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy. J Exp Med 201: 591-601, 2005
22) Mammen AL, Casciola-Rosen LA, Hall JC, Christopher-Stine L, Corse AM, et al: Expression of the dermatomyositis autoantigen Mi-2 in regenerating muscle. Arthritis Rheum 60: 3784-3793, 2009
23) Sato S, Hirakata M, Kuwana M, Suwa A, Inada S, et al: Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis. Arthritis Rheum 52: 1571-1576, 2005
24) Sato S, Hoshino K, Satoh T, Fujita T, Kawakami Y, et al: RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: association with rapidly progressive interstitial lung disease. Arthritis Rheum 60: 2193-2200, 2009
25) Nakashima R, Imura Y, Kobayashi S, Yukawa N, Yoshifuji H, et al: The RIG-I-like receptor IFIH1/MDA5 is a dermatomyositis-specific autoantigen identified by the anti-CADM-140 antibody. Rheumatology (Oxford) 49: 433-440, 2010
26) Hoshino K, Muro Y, Sugiura K, Tomita Y, Nakashima R, et al: Anti-MDA5 and anti-TIF1-gamma antibodies have clinical significance for patients with dermatomyositis. Rheumatology (Oxford) 49: 1726-1733, 2010
27) Koga T, Fujikawa K, Horai Y, Okada A, Kawashiri SY, et al: The diagnostic utility of anti-melanoma differentiation-associated gene 5 antibody testing for predicting the prognosis of Japanese patients with DM. Rheumatology (Oxford) 51: 1278-1284, 2012
28) Kang EH, Nakashima R, Mimori T, Kim J, Lee YJ, et al: Myositis autoantibodies in Korean patients with inflammatory myositis: anti-140-kDa polypeptide antibody is primarily associated with rapidly progressive interstitial lung disease independent of clinically amyopathic dermatomyositis. BMC Musculoskelet Disord 11: 223, 2010
29) Chen F, Wang D, Shu X, Nakashima R, Wang G: Anti-MDA5 antibody is associated with A/SIP and decreased T cells in peripheral blood and predicts poor prognosis of ILD in Chinese patients with dermatomyositis. Rheumatol Int 32: 3909-3915, 2012
30) Fiorentino D, Chung L, Zwerner J, Rosen A, Casciola-Rosen L: The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study. J Am Acad Dermatol 65: 25-34, 2011
0405 with susceptibility to anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis in the Japanese population. Arthritis Rheum 64: 3736-3740, 2012
32) Gono T, Sato S, Kawaguchi Y, Kuwana M, Hanaoka M, et al: Anti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis. Rheumatology (Oxford) 51: 1563-1570, 2012
33) Muro Y, Sugiura K, Hoshino K, Akiyama M: Disappearance of anti-MDA-5 autoantibodies in clinically amyopathic DM/interstitial lung disease during disease remission. Rheumatology (Oxford) 51: 800-804, 2012
34) Kobayashi I, Okura Y, Yamada M, Kawamura N, Kuwana M, et al: Anti-melanoma differentiation-associated gene 5 antibody is a diagnostic and predictive marker for interstitial lung diseases associated with juvenile dermatomyositis. J Pediatr 158: 675-677, 2011
35) Kaji K, Fujimoto M, Hasegawa M, Kondo M, Saito Y, et al: Identification of a novel autoantibody reactive with 155 and 140 kDa nuclear proteins in patients with dermatomyositis: an association with malignancy. Rheumatology (Oxford) 46: 25-28, 2007
36) Targoff IN, Mamyrova G, Trieu EP, Perurena O, Koneru B, et al: A novel autoantibody to a 155-kd protein is associated with dermatomyositis. Arthritis Rheum 54: 3682-3689, 2006
37) Fujimoto M, Hamaguchi Y, Kaji K, Matsushita T, Ichimura Y, et al: Myositis-specific anti-155/140 autoantibodies target transcriptional intermediary factor 1 family proteins. Arthritis Rheum 64: 513-522, 2012
38) Satoh M, Chan JY, Ross SJ, Li Y, Yamasaki Y, et al: Autoantibodies to transcription intermediary factor (TIF) 1beta associated with dermatomyositis. Arthritis Res Ther 14: R79, 2012
39) Muro Y, Ishikawa A, Sugiura K, Akiyama M: Clinical features of anti-TIF1-alpha antibody-positive dermatomyositis patients are closely associated with coexistent dermatomyositis-specific autoantibodies and anti-TIF1-gamma or anti-Mi-2 autoantibodies. Rheumatology (Oxford) 51: 1508-1513, 2012
40) Hill CL, Zhang Y, Sigurgeirsson B, Pukkala E, Mellemkjaer L, et al: Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet 357: 96-100, 2001
41) Buchbinder R, Forbes A, Hall S, Dennett X, Giles G: Incidence of malignant disease in biopsy-proven inflammatory myopathy: a population-based cohort study. Ann Intern Med 134: 1087-1095, 2001
42) Stockton D, Doherty VR, Brewster DH: Risk of cancer in patients with dermatomyositis or polymyositis, and follow-up implications: a Scottish population-based cohort study. Br J Cancer 85: 41-45, 2001
43) Chen YJ, Wu CY, Huang YL, Wang CB, Shen JL, et al: Cancer risks of dermatomyositis and polymyositis: a nationwide cohort study in Taiwan. Arthritis Res Ther 12: R70, 2010
44) So MW, Koo BS, Kim YG, Lee CK, Yoo B: Idiopathic inflammatory myopathy associated with malignancy: a retrospective cohort of 151 Korean patients with dermatomyositis and polymyositis. J Rheumatol 38: 2432-2435, 2011
45) Azuma K, Yamada H, Ohkubo M, Yamasaki Y, Yamasaki M, et al: Incidence and predictive factors for malignancies in 136 Japanese patients with dermatomyositis, polymyositis and clinically amyopathic dermatomyositis. Mod Rheumatol 21: 178-183, 2011
46) Trallero-Araguás E, Rodrigo-Pendás JÁ, Selva-O'Callaghan A, Martinez-Gómez X, Bosch X, et al: Usefulness of anti-p155 autoantibody for diagnosing cancer-associated dermatomyositis: a systematic review and meta-analysis. Arthritis Rheum 64: 523-532, 2012
47) Chinoy H, Fertig N, Oddis CV, Ollier WE, Cooper RG: The diagnostic utility of myositis autoantibody testing for predicting the risk of cancer-associated myositis. Ann Rheum Dis 66: 1345-1349, 2007
48) Gunawardena H, Wedderburn LR, North J, Betteridge Z, Dunphy J, et al: Clinical associations of autoantibodies to a p155/140 kDa doublet protein in juvenile dermatomyositis. Rheumatology (Oxford) 47: 324-328, 2008
49) Gunawardena H, Wedderburn LR, Chinoy H, Betteridge ZE, North J, et al: Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis. Arthritis Rheum 60: 1807-1814, 2009
50) 岩永 聡, 小川文秀: 小水疱を伴った皮膚筋炎――悪性腫瘍と間質性肺炎の合併例. Visual Dermatology 11: 830-831A, 2012
51) Allton K, Jain AK, Herz HM, Tsai WW, Jung SY, et al: Trim24 targets endogenous p53 for degradation. Proc Natl Acad Sci U S A 106: 11612-11616, 2009
52) Khetchoumian K, Teletin M, Tisserand J, Herquel B, Ouararhni K, et al: Trim24 (Tif1 alpha): an essential 'brake' for retinoic acid-induced transcription to prevent liver cancer. Cell Cycle 7: 3647-3652, 2008
53) Vincent DF, Yan KP, Treilleux I, Gay F, Arfi V, et al: Inactivation of TIF1gamma cooperates with Kras to induce cystic tumors of the pancreas. PLoS Genet 5: e1000575, 2009
54) Targoff IN, Trieu EP, Levy-Neto M, Fertig N, Oddis CV: Sera with autoantibodies to the MJ antigen react with NXP2 ［abstract］. Arthritis Rheum 56: S787, 2007
55) Oddis CV, Fertig N, Goel A, Espada G, Confalone Gregorian M, et al: Clinical and serological characterization of the anti-MJ antibody in childhood myositis ［abstract］. Arthritis Rheum 40: S139, 1997
56) Espada G, Maldonado Cocco JA, Fertig N, Oddis CV: Clinical and serologic characterization of an Argentine pediatric myositis cohort: identification of a novel autoantibody (anti-MJ) to a 142-kDa protein. J Rheumatol 36: 2547-2551, 2009
57) Ichimura Y, Matsushita T, Hamaguchi Y, Kaji K, Hasegawa M, et al: Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy. Ann Rheum Dis 71: 710-713, 2012
58) Ishikawa A, Muro Y, Sugiura K, Akiyama M: Development of an ELISA for detection of autoantibodies to nuclear matrix protein 2．Rheumatology (Oxford) 51: 1181-1187, 2012
59) Ceribelli A, Fredi M, Taraborelli M, Cavazzana I, Franceschini F, et al: Anti-MJ/NXP-2 autoantibody specificity in a cohort of adult Italian patients with polymyositis/dermatomyositis. Arthritis Res Ther 14: R97, 2012
60) Tansley S, Betteridge Z, Gunawardena H, Wedderburn LR, Chinoy H, et al: Clinical differences between adult and juvenile dermatomyositis associated with anti-NXP2 autoantibodies. Arthritis Rheum 64: S98, 2012
61) Fiorentino D, Christopher-Stine L, Chung L, Lingala B, Mammen AL, et al: Antibodies to NXP-2 and transcriptional intermediary factor-gamma identify patients with cancer-associated dermatomyositis. Arthritis Rheum 64: S842, 2012
62) Betteridge Z, Gunawardena H, North J, Slinn J, McHugh N: Identification of a novel autoantibody directed against small ubiquitin-like modifier activating enzyme in dermatomyositis. Arthritis Rheum 56: 3132-3137, 2007
63) Betteridge ZE, Gunawardena H, Chinoy H, North J, Ollier WE, et al: Clinical and human leucocyte antigen class II haplotype associations of autoantibodies to small ubiquitin-like modifier enzyme, a dermatomyositis-specific autoantigen target, in UK Caucasian adult-onset myositis. Ann Rheum Dis 68: 1621-1625, 2009
64) Tarricone E, Ghirardello A, Rampudda M, Bassi N, Punzi L, et al: Anti-SAE antibodies in autoimmune myositis: identification by unlabelled protein immunoprecipitation in an Italian patient cohort. J Immunol Methods 384: 128-134, 2012
65) Fujimoto M, Matsushita T, Hamaguchi Y, Kaji K, Asano Y, et al: Autoantibodies to small ubiquitin-like modifier activating enzymes in Japanese patients with dermatomyositis: comparison with a UK Caucasian cohort. Ann Rheum Dis 72: 151-153, 2013
66) Reeves WH, Nigam SK, Blobel G: Human autoantibodies reactive with the signal-recognition particle. Proc Natl Acad Sci U S A 83: 9507-9511, 1986
67) Targoff IN, Johnson AE, Miller FW: Antibody to signal recognition particle in polymyositis. Arthritis Rheum 33: 1361-1370, 1990
68) Miller T, Al-Lozi MT, Lopate G, Pestronk A: Myopathy with antibodies to the signal recognition particle: clinical and pathological features. J Neurol Neurosurg Psychiatry 73: 420-428, 2002
69) Hengstman GJ, ter Laak HJ, Vree Egberts WT, Lundberg IE, Moutsopoulos HM, et al: anti-signal recognition particle autoantibodies: marker of a necrotising myopathy. Ann Rheum Dis 65: 1635-1638, 2006
70) Rouster-Stevens KA, Pachman LM: Autoantibody to signal recognition particle in African American girls with juvenile polymyositis. J Rheumatol 35: 927-929, 2008
71) Suzuki S, Ohta M, Shimizu Y, Hayashi YK, Nishino I: Anti-signal recognition particle myopathy in the first decade of life. Pediatr Neurol 45: 114-116, 2011
72) Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, et al: A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 62: 2757-2766, 2010
73) Mammen AL, Chung T, Christopher-Stine L, Rosen P, Rosen A, Doering KR, et al: Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 63: 713-721, 2011
11:01 in anti-hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Care Res (Hoboken) 64: 1233-1237, 2012
75) Salajegheh M, Lam T, Greenberg SA: Autoantibodies against a 43 kDa muscle protein in inclusion body myositis. PLoS One 6: e20266, 2011
掲載誌情報
