The MAZ protein is an autoantigen of Hodgkin's disease and paraneoplastic cerebellar dysfunction
Luis Bataller MD
Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR.
Search for more papers by this authorDeborly F. Wade BS
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR.
Search for more papers by this authorFrancesc Graus MD
Department of Neurology, Hospital Clinic, Barcelona, Spain
Search for more papers by this authorMyrna R. Rosenfeld MD, PhD
Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR.
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR.
Central Arkansas Veterans Health Care System, Little Rock, AR.
Search for more papers by this authorCorresponding Author
Josep Dalmau MD, PhD
Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR.
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR.
Department of Neurology, University of Pennsylvania, 3400 Spruce Street, 3 W. Gates, Philadelphia, PA 19104Search for more papers by this authorLuis Bataller MD
Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR.
Search for more papers by this authorDeborly F. Wade BS
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR.
Search for more papers by this authorFrancesc Graus MD
Department of Neurology, Hospital Clinic, Barcelona, Spain
Search for more papers by this authorMyrna R. Rosenfeld MD, PhD
Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR.
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR.
Central Arkansas Veterans Health Care System, Little Rock, AR.
Search for more papers by this authorCorresponding Author
Josep Dalmau MD, PhD
Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR.
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR.
Department of Neurology, University of Pennsylvania, 3400 Spruce Street, 3 W. Gates, Philadelphia, PA 19104Search for more papers by this authorAbstract
Probing a cerebellar expression library with TrAb sera from patients with Hodgkin's disease and paraneoplastic cerebellar degeneration resulted in the isolation of MAZ (myc-associated zinc-finger protein). Eleven of 19 TrAb sera and 16 of 131 controls reacted with MAZ, indicating a significant, although not specific, association between Tr and MAZ immunities (p < 0.001). Interestingly, 9 of 16 positive control patients also had cerebellar dysfunction. Purified MAZ antibodies reacted with Purkinje cells. In neuronal cells, MAZ interacts with DCC (Deleted in Colorectal Cancer product), the receptor for netrin-1, a neuronal survival factor. These findings suggest epitope spreading between the Tr antigen and the MAZ–DCC complex and offer a possible model of immune-mediated cerebellar disease. Ann Neurol 2003;53:000–000
References
- 1 Hammack J, Kotanides H, Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration. II. Clinical and immunologic findings in 21 patients with Hodgkin's disease. Neurology 1992; 42: 1938–1943.
- 2 Graus F, Dalmau J, Valldeoriola F, et al. Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's disease. J Neuroimmunol 1997; 74: 55–61.
- 3 Graus F, Gultekin SH, Ferrer I, et al. Localization of the neuronal antigen recognized by anti-Tr antibodies from patients with paraneoplastic cerebellar degeneration and Hodgkin's disease in the rat nervous system. Acta Neuropathol 1998; 96: 1–7.
- 4 Verschuuren JJ, Dalmau J, Tunkel R, et al. Antibodies against the calcium channel beta-subunit in Lambert-Eaton myasthenic syndrome. Neurology 1998; 50: 475–479.
- 5 Sodeyama N, Ishida K, Jaeckle KA, et al. Pattern of epitopic reactivity of the anti-Hu antibody on HuD with and without paraneoplastic syndrome. J Neurol Neurosurg Psychiatry 1999; 66: 97–99.
- 6 Nishikawa H, Tanida K, Ikeda H, et al. Role of SEREX-defined immunogenic wild-type cellular molecules in the development of tumor-specific immunity. Proc Natl Acad Sci USA 2001; 98: 14571–14576.
- 7 Jager E, Chen YT, Drijfhout JW, et al. Simultaneous humoral and cellular immune response against cancer-testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes. J Exp Med 1998; 187: 265–270.
- 8 Dalmau J, Gultekin SH, Voltz R, et al. Ma1, a novel neuronal and testis specific protein, is recognized by the serum of patients with paraneoplastic neurologic disorders. Brain 1999; 122: 27–39.
- 9 Furneaux HM, Rosenblum MK, Dalmau J, et al. Selective expression of Purkinje-cell antigens in tumor tissue from patients with paraneoplastic cerebellar degeneration. N Engl J Med 1990; 322: 1844–1851.
- 10 Ugai H, Li HO, Komatsu M, et al. Interaction of Myc-associated zinc finger protein with DCC, the product of a tumor-suppressor gene, during the neural differentiation of P19 EC cells. Biochem Biophys Res Commun 2001; 286: 1087–1097.
- 11 Bossone SA, Asselin C, Patel AJ, Marcu KB. MAZ, a zinc finger protein, binds to c-MYC and C2 gene sequences regulating transcriptional initiation and termination. Proc Natl Acad Sci USA 1992; 89: 7452–7456.
- 12 Komatsu M, Li HO, Tsutsui H, et al. MAZ, a Myc-associated zinc finger protein, is essential for the ME1a1-mediated expression of the c-myc gene during neuroectodermal differentiation of P19 cells. Oncogene 1997; 15: 1123–1131.
- 13 Williams LJ, Abou-Samra AB. The transcription factors SP1 and MAZ regulate expression of the parathyroid hormone/parathyroid hormone-related peptide receptor gene. J Mol Endocrinol 2000; 25: 309–319.
- 14 Llambi F, Causeret F, Bloch-Gallego E, Mehlen P. Netrin-1 acts as a survival factor via its receptors UNC5H and DCC. EMBO J 2001; 20: 2715–2722.
- 15 Sillevis SP, Kinoshita A, De Leeuw B, et al. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med 2000; 342: 21–27.
- 16 Bernal F, Shamsili S, Rojas I, et al. Clinical and immunological features of patients with anti-Tr antibodies. Neurology (in press).
- 17 Manley GT, Smitt PS, Dalmau J, Posner JB. Hu antigens: reactivity with Hu antibodies, tumor expression, and major immunogenic sites. Ann Neurol 1995; 38: 102–110.
- 18 Rosenfeld MR, Wong E, Dalmau J, et al. Cloning and characterization of a Lambert-Eaton myasthenic syndrome antigen. Ann Neurol 1993; 33: 113–120.
- 19 Leveque C, Hoshino T, David P, et al. The synaptic vesicle protein synaptotagmin associates with calcium channels and is a putative Lambert-Eaton myasthenic syndrome antigen. Proc Natl Acad Sci USA 1992; 89: 3625–3629.
- 20 Takamori M, Iwasa K, Komai K. Antibodies to synthetic peptides of the α1A subunit of the voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome. Neurology 1997; 48: 1261–1265.
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