Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice

Pa, Sillevis Smitt; Gt, Manley; Jb, Posner

doi:10.1212/wnl.45.10.1873

Cited by 152 publications

(28 citation statements)

References 7 publications

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“…Our finding that anti-Hu antibody induced neuronal cell death is in contrast to observations reported by Sillevis Smitt and colleagues [33]. These investigators were unable to produce neurological injury in mice, rats, and guinea pigs by immunization with species-specific HuD antigen or, in mice, by intravenous infusion of human anti-Hu IgG [33].…”

Section: Discussioncontrasting

confidence: 84%

“…These investigators were unable to produce neurological injury in mice, rats, and guinea pigs by immunization with species-specific HuD antigen or, in mice, by intravenous infusion of human anti-Hu IgG [33]. However, their study differed from ours in three important aspects.…”

Section: Discussionmentioning

confidence: 92%

“…Because both anti-Hu and anti-Ri antibodies recognize intracellular antigens, it has been thought that neither antibody would be able to react with its target antigens in vivo to induce disease [29,30]. We and others have previously reported destruction of neurons by anti-Hu antibody in dispersed cell cultures [31,32]; however, the relevance of these findings to events occurring in vivo has been uncertain, and attempts by others to produce neurological injury in experimental animals by immunization with recombinant Hu antigens have been unsuccessful [33]. …”

Section: Introductionmentioning

confidence: 99%

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Neuronal uptake of anti-Hu antibody, but not anti-Ri antibody, leads to cell death in brain slice cultures

Greenlee

Clawson

Hill

et al. 2014

J Neuroinflammation

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BackgroundAnti-Hu and anti-Ri antibodies are paraneoplastic immunoglobulin (Ig)G autoantibodies which recognize cytoplasmic and nuclear antigens present in all neurons. Although both antibodies produce similar immunohistological labeling, they recognize different neuronal proteins. Both antibodies are associated with syndromes of central nervous system dysfunction. However, the neurological deficits associated with anti-Hu antibody are associated with neuronal death and are usually irreversible, whereas neurological deficits in patients with anti-Ri antibody may diminish following tumor removal or immunosuppression.MethodsTo study the effect of anti-Hu and anti-Ri antibodies on neurons, we incubated rat hippocampal and cerebellar slice cultures with anti-Hu or anti-Ri sera from multiple patients. Cultures were evaluated in real time for neuronal antibody uptake and during prolonged incubation for neuronal death. To test the specificity of anti-Hu antibody cytotoxic effect, anti-Hu serum IgG was incubated with rat brain slice cultures prior to and after adsorption with its target Hu antigen, HuD.ResultsWe demonstrated that: 1) both anti-Hu and anti-Ri antibodies were rapidly taken up by neurons throughout both cerebellum and hippocampus; 2) antibody uptake occurred in living neurons and was not an artifact of antibody diffusion into dead cells; 3) intracellular binding of anti-Hu antibody produced neuronal cell death, whereas uptake of anti-Ri antibody did not affect cell viability during the period of study; and 4) adsorption of anti-Hu antisera against HuD greatly reduced intraneuronal IgG accumulation and abolished cytotoxicity, confirming specificity of antibody-mediated neuronal death.ConclusionsBoth anti-Hu and anti-Ri antibodies were readily taken up by viable neurons in slice cultures, but the two antibodies differed markedly in terms of their effects on neuronal viability. The ability of anti-Hu antibodies to cause neuronal death could account for the irreversible nature of paraneoplastic neurological deficits in patients with this antibody response. Our results raise questions as to whether anti-Ri antibody might initially induce reversible neuronal dysfunction, rather than causing cell death. The ability of IgG antibodies to access and react with intracellular neuronal proteins could have implications for other autoimmune diseases involving the central nervous system.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0160-0) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 84%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Neuronal uptake of anti-Hu antibody, but not anti-Ri antibody, leads to cell death in brain slice cultures

Greenlee

Clawson

Hill

et al. 2014

J Neuroinflammation

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“…In rare cases, severe autoimmune anti-ELAVL responses in SCLC patients result in acute neurological symptoms and death. However, previous studies in which animals were immunized with native ELAVL4 did not yield any neurological symptoms (Sillevis Smitt et al, 1995) and SCLC patients with substantial antibody titers but no autoimmune symptoms have been noted(Monstad et al, 2004). Therapeutic efficacy of ELAVL4 immunization has been suggested when mice were implanted with simulated SCLC cells (cells transfected with ELAVL4, (Ohwada et al, 1999)).…”

Section: Discussionmentioning

confidence: 94%

Isoaspartylation appears to trigger small cell lung cancer-associated autoimmunity against neuronal protein ELAVL4

Pulido¹,

DerHartunian²,

Qin³

et al. 2016

Journal of Neuroimmunology

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Autoantibodies against SCLC-associated neuronal antigen ELAVL4 (HuD) have been linked to smaller tumors and improved survival, but the antigenic epitope and mechanism of autoimmunity have never been solved. We report that recombinant human ELAVL4 protein incubated under physiological conditions acquires isoaspartylation, a type of immunogenic protein damage. Specifically, the N-terminal region of ELAVL4, previously implicated in SCLC-associated autoimmunity, undergoes isoaspartylation in vitro, is recognized by sera from anti-ELAVL4 positive SCLC patients and is highly immunogenic in subcutaneously injected mice and in vitro stimulated human lymphocytes. Our data suggest that isoaspartylated ELAVL4 is the trigger for the SCLC-associated anti-ELAVL4 autoimmune response.

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“…The intravenous administration of IgGs from patients with PEM/PSN and high titers of anti-Hu antibody to mice did not result in any CNS lesion 51 , 52 . In addition, all attempts to generate rodent models of the anti-Hu syndrome upon immunization with recombinant HuD failed to induce any signs of disease, CNS inflammation or neuronal degeneration, despite the development of high circulating titers of anti-HuD antibodies 51 , 53 …”

Section: Autoimmune Responses Against Hu Proteinsmentioning

confidence: 99%

Immunopathogenesis of paraneoplastic neurological syndromes associated with anti-Hu antibodies

2013

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Paraneoplastic neurological disorders (PNDs) are syndromes that develop in cancer patients when an efficient antitumor immune response, directed against antigens expressed by both malignant cells and healthy neurons, damages the nervous system. Herein, we analyze existing data on the mechanisms of loss of self tolerance and nervous tissue damage that underpin one of the most frequent PNDs, the anti-Hu syndrome. In addition, we discuss future directions and propose potential strategies aimed at blocking deleterious encephalitogenic immune responses while preserving the antineoplastic potential of treatment.

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Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice

Cited by 152 publications

References 7 publications

Neuronal uptake of anti-Hu antibody, but not anti-Ri antibody, leads to cell death in brain slice cultures

Neuronal uptake of anti-Hu antibody, but not anti-Ri antibody, leads to cell death in brain slice cultures

Isoaspartylation appears to trigger small cell lung cancer-associated autoimmunity against neuronal protein ELAVL4

Immunopathogenesis of paraneoplastic neurological syndromes associated with anti-Hu antibodies

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