Trial to establish an animal model of paraneoplastic cerebellar degeneration with anti-Yo antibody: 1. Mouse strains bearing different MHC molecules produce antibodies on immunization with recombinant Yo protein, but do not cause Purkinje cell loss

doi:10.1016/0303-8467(95)00005-5

Clinical Neurology and Neurosurgery

Volume 97, Issue 1, February 1995, Pages 95-100

https://doi.org/10.1016/0303-8467(95)00005-5 Get rights and content

Abstract

Passive transfer of anti-Yo antibody from patients with paraneoplastic cerebellar degeneration (PCD) associated with gynecological or breast carcinoma has not been successful in inducing an animal model. We used active immunization with recombinant Yo protein of four strains of mice bearing different MHC molecules: BALB/c (H-2d), C3H (H-2k), C57BL/6 (H-2b), SJL/J (H-2s). All the strains produced high anti-Yo antibody titer but none developed cerebellar ataxia or showed Purkinje cell loss. Spleen cells from the immunized mice also reacted with recombinant protein. Because C57BL/6(nu/nu) mice produce no anti-Yo antibody, mature helper T cells are required for its production. Results suggest that antibody production in peripheral blood alone is not sufficient for the development of PCD and that MHC class II molecules function in the activation of T cells to help B cells produce antibodies.

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Neoplastic expression of the onconeuronal cerebellar degeneration-related antigen Cdr2 in ovary and breast tumors is associated with paraneoplastic cerebellar degeneration (PCD). Cdr2 protein expression is normally restricted to neurons, but aberrant Cdr2 expression has mainly been described for breast and ovarian tumors. Previously, we found strong Cdr2 protein expression in the papillary subtype of renal cell carcinoma (pRCC) and showed that Cdr2 interacts with the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1. High Cdr2 protein levels are associated with decreased HIF-dependent gene expression in cells as well as in clinical pRCC samples, providing a possible explanation why pRCCs are the most hypovascular renal tumors. Here, we demonstrate that strong Cdr2 protein expression in clinical samples from pRCC patients correlates with elevated PHD1 protein levels, suggesting that increased PHD1 activity attenuates HIF-dependent gene expression. Interestingly, survival analysis revealed a significant correlation between high levels of Cdr2 expression and worse patient outcome in clear cell (cc) RCC patients. These findings provide evidence that Cdr2 might represent an important tumor antigen in kidney cancer and possibly in other cancer types as well. In contrast to ovary and breast tumor patients who develop PCD, no Cdr2 auto-antibodies were detected in the serum of pRCC patients, which is in line with the fact that pRCC patients have not been reported to display paraneoplastic neurodegenerative syndromes. This suggests that, despite a shared target antigen, tumor immunity and autoimmunity only partially overlap, and also highlights to which extent immuno-surveillance against cancer can be clinically silent.
Changing concepts about paraneoplastic neurological syndromes
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Les syndromes neurologiques paranéoplasiques (SNP) sont des pathologies dysimmunitaires rares qui étaient définis jusqu’à présent par la présence d’un trouble neurologique associé à un cancer en l’absence d’invasion du système nerveux par les cellules tumorales. La découverte et la description depuis une trentaine d’années d’autoanticorps circulants spécifiques des SNP ont révolutionné le diagnostic et la connaissance de ces syndromes. Jusqu’à ces dernières années, nous pensions que ces autoanticorps n’étaient que des marqueurs de la maladie et ne jouaient aucun rôle dans la physiopathologie. La description récente d’autoanticorps dirigés contre des cibles membranaires et pouvant jouer un rôle pathologique direct a transformé le concept de SNP, d’autant plus, qu’il apparaît que plus de 50 % de ces patients peuvent avoir un syndrome neurologique et des autoanticorps contre des cibles membranaires sans jamais développer de cancer. Il en découle une classification s’appuyant sur la nature de la cible antigénique reconnue par les autoanticorps (membranaire ou intracellulaire) et la présence d’un cancer n’est plus un critère essentiel. En cas d’autoanticorps avec cible intracellulaire, un cancer est presque systématiquement associé (plus de 90 % des cas), les troubles sont liés à une mort neuronale, les patients sont peu sensibles aux traitements immunomodulateurs et l’immunité cellulaire semble jouer un rôle majeur. Au contraire, chez les patients ayant un autoanticorps ciblant une protéine ou un récepteur membranaire, les cancers sont plus rares (globalement moins de 50 % des cas), les troubles sont liés à un dysfonctionnement neuronal réversible, les patients sont en majorité sensibles aux traitements immunomodulateurs et c’est l’immunité humorale qui semble jouer un rôle primordial.
Paraneoplastic neurological syndromes (PNS) are rare dysimmune diseases which to date had been defined by the presence of a neurological disorder associated with cancer, but without cancer cells invading the nervous system. The discovery and description of circulating autoantibodies specific for PNS have revolutionized diagnosis and knowledge of these syndromes. Until recently, it was thought that these autoantibodies were only makers of the disease without playing any role in its pathogenesis. The recent description of autoantibodies directed against membrane targets with the capacity to play a direct pathogenic role has transformed the concept of PNS, especially since more than 50% of patients can apparently have the neurological syndrome and its autoantibodies directed against membrane targets without ever developing cancer. Consequently, classifications based on the nature of the antigen and its target recognized by the membrane or intracellular autoantibody and the presence of cancer are no longer essential. For autoantibodies having an intracellular target, cancer is nearly always associated (more than 90% of cases), disorders are related to neuron death, patients exhibit little sensitivity to immunomodulator treatments, and cell immunity appears to play a major role. On the contrary, in patients with an autoantibody targeting a membrane protein or receptor, cancer is rare (less than 50% of cases), disorders are related to reversible neuron dysfunction, patients are generally sensitive to immunomodulators, and humor immunity appears to play the main role.
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Citation Excerpt :
Indeed, in vivo experiments after injection in rats or mice brain of human ONA such as anti-Yo or anti-Hu causes no neurological abnormality (Sillevis Smitt et al., 1995, Tanaka et al., 1995). Similarly, immunization of rodents with purified Yo or Hu antigens leads to the production of antibodies against these proteins, but does not cause neurological symptoms (Tanaka et al., 1995). Following this work, many authors have assumed that cellular immunity was the main actor in the neurological damages of these patients and that the ONA were only markers of immune response.
Paraneoplastic neurological syndromes (PNS) are rare diseases defined so far by the presence of a neurological disorder associated with cancer in the absence of invasion of the nervous system by tumor cells. Discovery of circulating autoantibodies specific for these patients has revolutionized the diagnosis and understanding of these syndromes and demonstrated a role of the immune system in the neurological syndromes. Until recent years, we thought that these autoantibodies were only markers of the disease and had no role in the pathophysiology. The recent description of autoantibodies directed against membrane receptors or channels and playing a direct pathological role has transformed the concept of PNS. Especially, it appears that many patients may have a neurological syndrome and autoantibodies without cancer. This results in a classification based on the nature of the autoantibodies associated with neurological syndrome. In case of autoantibodies targeting intracellular antigens, cancer is almost always associated, the neurological disorders are mainly related to neuronal death, patients are rarely sensitive to immunomodulatory treatments and cellular immunity appears to play a major role. In contrast, patients with autoantibodies targeting membrane antigens (receptors, channels or receptor associated proteins) have rarely cancer, neurological disorders are related to a reversible neuronal dysfunction, patients are mostly sensitive to immunomodulatory treatments and it seems that humoral immunity and autoantibodies play a major role.
Les syndromes neurologiques paranéoplasiques (SNP) sont des pathologies rares qui étaient définies jusqu’à présent par la présence d’un trouble neurologique associé à un cancer en l’absence d’invasion du système nerveux par les cellules tumorales. La découverte d’autoanticorps circulants spécifiques des SNP a révolutionné le diagnostic et la connaissance de ces syndromes en établissant leur origine dysimmunitaire et en facilitant leur reconnaissance. Jusqu’à ces dernières années, nous pensions que ces autoanticorps n’étaient que des marqueurs de la maladie et qu’ils ne jouaient aucun rôle dans la physiopathologie. La description récente d’autoanticorps dirigés contre des cibles membranaires et pouvant jouer un rôle pathologique direct a transformé le concept de SNP, d’autant plus, qu’il apparaît qu’un grand nombre de patients peuvent avoir le même type de syndrome neurologique et les mêmes autoanticorps sans développer de cancer. La nature de la réaction dysimmunitaire semble un élément clé du développement de ces syndromes et pourrait être différente suivant les autoanticorps développés par les patients. Il en découle une classification s’appuyant sur la nature de l’autoanticorps associé au syndrome neurologique. En cas de cible intracellulaire, un cancer est presque systématiquement associé, les troubles sont liés à une mort neuronale, les patients sont peu sensibles aux traitements immunomodulateurs et l’immunité cellulaire semble jouer un rôle majeur. Au contraire, les patients ayant un autoanticorps ciblant une protéine ou un récepteur membranaire ont plus rarement un cancer, les troubles sont liés à un dysfonctionnement neuronal réversible, les patients sont en majorité sensibles aux traitements immunomodulateurs et c’est l’immunité humorale qui semble jouer un rôle primordial. Les travaux en cours devraient rapidement permettre, de mieux comprendre la physiopathologie des SNP et, le développement de nouveaux traitements.
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Trial to establish an animal model of paraneoplastic cerebellar degeneration with anti-Yo antibody: 1. Mouse strains bearing different MHC molecules produce antibodies on immunization with recombinant Yo protein, but do not cause Purkinje cell loss

Abstract

J. Neurol. Sci.

J. Neurol. Sci.

Brain Res.

Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuropathy. A clinical study of 71 patients

Medicine

Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients

Neurology

Long-term course of change in anti-Yo antibody content in paraneoplastic cerebellar degeneration

J. Neurol. Neurosurg. Psychiat.

Calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome

Ann. Neurol.

Effect of intravenous immunoglobulin in Lambert-Eaton myasthenic syndrome with small-cell lung cancer: Correlation with the titer of anti-voltage gated calcium channel antibody

Muscle Nerve

The detection of anti- Purkinje cell antibody (anti-Yo antibody) by ELISA using recombinant Yo fusion protein

Brain Nerve

Isolation of a complementary DNA clone encoding an autoantigen recognized by an anti-neuronal cell antibody from a patient with paraneoplastic cerebellar degeneration

Ann. Neurol.