BRAIN and NERVE－神経研究の進歩65巻4号

2013年04月発行

増大特集 Antibody Update

脊髄小脳変性症と自己抗体

著者： 三苫博¹ 南里和紀²

所属機関： ¹東京医科大学医学教育学講座 ²東京医科大学八王子医療センター神経内科

ページ範囲：P.355 - P.364

文献概要

Ⅰ．腫瘍随伴性免疫性小脳失調症

　悪性腫瘍の0.2％に小脳症状が出現することが知られている¹⁾が，その歴史は1934年のGreenfield²⁾の乳癌と肺癌を伴う「亜急性小脳変性症」の記載にさかのぼることができる。多くは亜急性に小脳性運動失調が出現し，数週から数カ月で進行し，徐々に小脳の萎縮を示す。小脳性運動失調が出現したときには悪性腫瘍を認めず，約1年以内に悪性腫瘍が発見されることが多い。

　その原因については，「遠隔効果」という表現でさまざまな可能性が議論されてきたが，1980年代以降，腫瘍と神経細胞の共通抗原の関係が注目されるようになった。1983年には，GreenleeとBrashearが卵巣腫瘍を伴う小脳失調症患者において，小脳プルキンエ細胞の細胞質と反応し，さらに，神経組織免疫ブロットで58kDaと34kDaに反応バンドが生じる抗体（抗Yo抗体）を報告した³⁾。これ以降，免疫組織化学法と免疫ブロット法を用いて，さまざまな抗体が見出され，それらが認識する抗原蛋白の特徴も明らかになっている。

参考文献

1) Croft PB, Wilkinson M: The incidence of carcinomatous neuromyopathy in patients with various types of carcinoma. Brain 88: 427-434, 1965

2) Greenfield JG: Subacute spino-cerebellar degeneration occurring in elderly patients. Brain 57: 161-176, 1934

3) Greenlee JE, Brashear HR: Antibodies to cerebellar degeneration and ovarian carcinoma. Ann Neurol 14: 609-613, 1983

4) Graus F, Delatte JY, Antoine JC, Dalmau J, Giometto B, et al: Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 75: 1135-1140, 2004

5) Fathallah-Shayka H, Wolf S, Wong E, Posner JB, Furneaux HM: Cloning of a leucine-zipper protein recognized by the sera of patients with antibody-associated paraneoplastic cerebellar degeneration. Proc Natl Acad Sci U S A 88: 3451-3454, 1991

6) Sakai K, Shirakawa T, Li Y, Kitagawa Y, Hirose G: Interaction of a paraneoplatic cerebellar degeneration-associated neuronal protein with a nuclear helix-loop-helix leucine zipper protein MRG X. Mol Cell Neurosci 19: 477-484, 2002

7) Bataller L, Wade DF, Graus F, Stacey HD, Rosenfeld MR, et al: Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer. Neurology 62: 778-782, 2004

8) Sabater L, Bataller L, Suárez-Calvet M, Saiz A, Dalmau J, et al: ZIC antibodies in paraneoplastic cerebellar degeneration and small cell lung cancer. J Neuroimmunol 201-202: 163-165, 2008

9) Bataller L, Sabater L, Saiz A, Serra C, Claramonte B, et al: Carbonic anhydrase-related protein VIII: autoantigen in paraneoplastic cerebellar degeneration. Ann Neurol 56: 575-579, 2004

10) Graus F, Dalmau J, Valldeoriola F, Ferrer I, Reǹe R, et al: Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's disease. J Neuroimmunol 74: 55-61, 1997

11) Buckanovich RJ, Posner JB, Darnell RB: Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein nd is specifically expressed in the developing motor system. Neuron 11: 657-672, 1993

12) Jensen KB, Dredge BK, Sefani G, Zhong R, Buckanovich RJ, et al: Nova-1 reguates neuron specific alterative splicing and is essential for neuronal viability. Neuron 25: 359-371, 2000

13) Graus F, Cordon-Cardo C, Posner JB: Neuronal antinuclear antibody in sensory neuropathy from lung canser. Neurology 35: 538-543, 1985

14) Greenlee JE, Lipton HL: Anticerebellar antibodies in serum and cerebrospinal fluid of a patient with oat cell carcinoma of the lung and paraneoplastic cerebellar degeneration. Ann Neuol 19: 82-85, 1986

15) Szabo A, Dalmau J, Manley G, Rosenfeld M, Wong E, et al: HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-lethal. Cell 67: 325-333, 1991

16) Sakai K, Kitagawa Y, Sakai M, Sakai S, Hirose G: Binding of the ELAV-like protein in murine autoimmune T-cells to the nonameric AU-rich element in the 3' untranlated region of CD154 mRNA. Mol Immunol 39: 879-883, 2003

17) Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, et al: Clinical analysis of anti-Ma2-associated encephalitis. Brain 127: 1831-1844, 2004

18) Yu Z, Kryzer TJ, Griesmann GE, Kim K, Benarroch EE, et al: CRMP-5 neuronal antibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 49: 146-154, 2001

19) Chan KH, Vernino S, Lennon VA: ANNA-3 antineuronal nuclear antibody: marker of lung cancer related autoimmunity. Ann Neurol 50: 301-311, 2001

20) Vernio S, Lennon VA: New Purkinje cell antibody (PCA-2): marker of lung cancer-related neurological autoimmunity. Ann Neurol 47: 297-305, 2000

21) Fukuda T, Motomura M, Nakao Y, Shiraishi H, Yoshimura T, et al: Reduction of P/Q-type calcium channels in the psotmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert-Eaton myasthenic syndrome. Ann Neurol 53: 21-28, 2003

currents andmimicks cerebellar ataxia in vivo. Proc Natl Acad Sci U S A 105: 2705-2710, 2008

23) Sillevis Smitt P, Kinoshita A, De Leeuw B, Moll W, CCoesans M, et al: Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med 342: 21-27, 2000

24) 犬塚　貴: 傍腫瘍性神経筋疾患とは――定義と歴史. Brain Nerve 62: 301-308, 2010

25) Honnorat J, Trouillas P, Thivolet C, Aguera M, Belin MF: Autoaniboies to glutamate decarboxylase in a patient with cerebellar cortical atrophy, peripheral neuropathy, and slow eye movements. Arch Neurol 52: 462-468, 1995

26) Honnorat J, Saiz A, Giometto B, Vincent A, Brieva J, et al: Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies. Arch Neurol 58: 225-230, 2001

27) Saiz A, Blanco Y, Sabater L, Genzález F, Bataller L, et al: Spectrum of neurological syndrome associated with glutamic acid decarboxylase antibodies: diagnostic clue for this association. Brain 131: 2553-2563, 2008

28) Bonnan M, Cabre P, Olindo S, Signate A, Saint-Vil M, et al: Steroid treatment in four cases of anti-GAD cerebellara ataxia. Rev Neurol (Paris) 164: 427-433, 2008

29) Pedroso JL, Braga-Neto P, Dutral LA, Barsottini OG: Cerebellar ataxia associated to anti-glutamic decarboxylase autoimmunity (anti-GAD): partial improvement with intravenous immunoglobulin therapy. Arq Neurosiquiatr 69: 993, 2011

30) Nanri K, Niwa H, Mitoma H, Takeib A, Ikeda J, et al: Low-titer anti-GAD-antibody-positive cerebelar ataxia. Cerebellum 12: 171-175, 2013

31) Brain L, Jellinek E, Ball K: Hashimoto's disease and encephalopathy. Lancet 7462: 512-514, 1966

32) Shaw PJ, Walls TJ, Newman PK, Cleland PG, Cartlidge NE: Hashimoto's encephalopathy: a steroid-responsive disorder associated with high anti-thyroid antibody titers-report of 5 cases. Neurology 41: 228-233, 1991

33) Fujii A, Yoneda M, Ito T, Yamamura O, Satomi S, et al: Autoantibodies against the amino terminal of α-enolase are a useful diagnostic marker of Hashimoto's encephalopathy. J Neuroimmunol 162: 130-136, 2005

34) Matsunaga A, Ikawa M, Fujii A, Nakamoto Y, Kuriyama, et al: Hashimoto's encephalopathy as a treatable adult-onset cerebellar ataxia mimicking spinocerebellar degeneration. Eur Neurol 69: 4-20, 2012

35) Hadjivassiliou M, Grünewald RA, Chattopadhyay AK, Davies-Jones GA, Gibson A, et al: Clinical, radiological, neurophysiological and neuropathological characteirstics of gluten ataxia. Lancet 352: 1582-1585, 1998

36) Hadjivassiliou M, Grünewald RA, Sharrck B, Sanders, Lobo DA, et al: Gluten ataxia in perspective: epidemiology, genetic susceptibility and clinical characteristics. Brain 126: 685-691, 2003

37) Ihara M, Makino F, Sawada H, Mezaki T, Mizutani K, et al: Gluten sensitivity in Japanese patients with adult-onst cerebeller ataxia. Inter Med 45: 135-140, 2006

38) Tanaka K, Tanaka M, Onodera O, Igarashi S, Miyatake T, et al: Passive transfer and active immunization with the recombinant leucine-zipper (Yo) protein as an attempt to establish an animal model of paraneoplastic cerebellar degeneration. J Neuol Sci 127: 153-158, 1994

39) Sakai K, Gofuku M, Kitagawa Y, Ogasawara T, Hirose G: Induction of anti-Purkinje cell antibodies in vivo by immunizing with a recombinant 53-kDa paraneoplastic cerebellar degeneration-associated protein. J Neuroimmunol 60: 135-141, 1995

40) Sillevis Smitt PA, Manley GT, Posner JB: Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice. Neurology 45: 1873-1878, 1995

41) Mitoma H, Song SY, Ishida K, Yamakuni T, Kobayashi T, et al: Presynaptic impairment of cerebellar inhibitory synapses by an autoantibody to glutamate decarboxylase. J Neurol Sci 175: 40-44, 2000

42) Ishida K, Mitoma H, Song SY, Uchihara T, Inaba A, et al: Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase. Ann Neurol 46: 263-267, 1999

43) Takenoshita H, Shizuka-Ikeda M, Mitoma H, Song SY, Harigaya Y, et al: Presynaptic inhibition of cerebellar GABAergic transmission by glutamate decarboxylase autoantibodies in progressive cerebellar ataxia. J Neurol Neurosurg Pshychiatry 70: 386-369, 2001

44) Manto MU, Laute MA, Aguera M, Rogemond V, Pandolfo M, et al: Effects of anti-glutamate acid decarboxylase antibodies associated with neurological diseases. Ann Neurol 61: 544-551, 2007

-receptor-mediated synaptic response by autoantibodies to glutamic acid decarboxylase. J Neurol Sci 208: 51-56, 2003

46) Ishida K, Mitoma H, Wada Y, Oka T, Shibahara J, et al: Selective loss of Purkinje cells in a patient with anti-glutamic acid decarboxylase-associated cerebellar ataxia. J Neurol Neurosurg Psychiatry 78: 190-192, 2007

47) Nanri K, Koizumi K, Mitoma H, Taguchi T, Takeguchi M, et al: Classification of cerebellar atrophy using voxel-based morphometry and SPECT with an easy Z-score imaging system. Inter Med 49: 535-541, 2010