Nuclear localization of anti-Hu antibody is not associated with in vitro cytotoxicity

doi:10.1016/0165-5728(94)90011-6

Journal of Neuroimmunology

Volume 55, Issue 2, December 1994, Pages 205-212

https://doi.org/10.1016/0165-5728(94)90011-6 Get rights and content

Abstract

IgG fractions of sera containing anti-Hu antibodies or control sera were influenced with Hu-positive and Hu-negative cell lines. Anti-Hu IgG specifically localized in the nucleus of Hu-positive cells. Anti-Hu-positive and control sera were incubated with Hu-positive cells and human complement or peripheral blood mononuclear cells. Hu antibody caused neither complement-mediated lysis nor augmented antibody-dependent cell-mediated cytotoxicity. Anti-Hu IgG did not affect proliferation of Hu-positive cells. Anti-Hu antibodies may not play a direct role in tissue injury in patients with paraneoplastic encephalomyeloneuropathy and anti-Hu antibodies.

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Paraneoplastic neurological disorders (PNDs) are heterogeneous clinicopathologic syndromes that occur throughout the neuraxis resulting from damage to organs or tissues remote from the site of a malignant neoplasm or its metastases. The discordance between severe neurological disability and even an indolent malignancy suggests an underlying neuroimmunologic host immune response that inflicts nervous tissue damage while inhibiting malignant tumor growth. Motor system involvement, like other symptoms and signs, is associated with focal or diffuse involvement of the brain, spinal cord, peripheral nerve, neuromuscular junction or muscle, alone or in combination due to an underlying neuroimmune and neuroinflammatory process targeting neural-specific antigens. Unrecognized and therefore untreated, PNDs are often lethal making early detection and aggressive treatment of paramount importance. While the combination of clinical symptoms and signs, and analysis of detailed body and neuroimaging, clinical neurophysiology and electrodiagnostic studies, and tumor and nervous system tissue biopsies are all vitally important, the certain diagnosis of a PND rests with the discovery of a corresponding neural-specific paraneoplastic autoantibody in the blood and/or spinal cerebrospinal fluid.
Neuropathology of autoimmune encephalitides
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Citation Excerpt :
In vitro studies with onconeural antibodies such as those against the Hu nuclear antigen gave contradictory results. Some studies showed that these antibodies accessed cultured neurons but did not damage them (Hormigo et al., 1994; Tanaka et al., 2004). Another study, however, revealed induction of cell death after uptake of such antibodies (De Giorgio et al., 2003).
In recent years a large number of antibody-associated or antibody-defined encephalitides have been discovered. These conditions are often referred to as autoimmune encephalitides. The clinical features include prominent epileptic seizures, cognitive and psychiatric disturbance. These encephalitides can be divided in those with antibodies against intracellular antigens and those with antibodies against surface antigens. The discovery of new antibodies against targets on the surface of neurons is especially interesting since patients with such antibodies can be successfully treated immunologically. This chapter focuses on the pathology and the pathogenetic mechanisms involved in these encephalitides and discusses some of the questions that are raised in this exciting new field. It is important to realise, however, that because of the use of antibodies to diagnose the patients, and their improvement with treatment, there are relatively few biopsy or postmortem reports, limiting the neuropathological data and conclusions that can be drawn. For this reason we especially focus on the most frequent autoimmune encephalitides, those with antibodies to the NMDA receptor and with antibodies to the known protein components of the VGKC complex. Analysis of these encephalitides show completely different pathogenic mechanisms. In VGKC complex encephalitis, antibodies seem to bind to their target and activate complement, leading to destruction and loss of neurons. On the other hand, in NMDAR encephalitis, complement activation and neuronal degeneration seems to be largely absent. Instead, binding of antibodies leads to a decrease of NMDA receptors resulting in a hypofunction. This hypofunction offers an explanation for some of the clinical features such as psychosis and episodic memory impairment, but not for the frequent seizures. Thus, additional analysis of the few human brain specimens present and the use of specific animal models are needed to further understand the effects of these antibodies in autoimmune encephalitides.
Four different synthetic peptides of proteolipid protein induce a distinct antibody response in MP4-induced experimental autoimmune encephalomyelitis
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Contrasting the traditional notion of primary antibody binding to extracellular epitopes in autoimmune diseases, antibodies directed against the intracellular antigen hnRNP A1 have only recently been found to penetrate into neuronal cells through clathrin-mediated endocytosis, causing depletion of cellular ATP and apoptosis [36]. Other antibodies including anti-AQP4, anti-U1RNP, anti-dsDNA, anti-Ro/SSA, anti-La/SSB and anti-Hu have also been reported to penetrate cells in vitro or in vivo [37–42]. Overall, the mechanisms of recognition of intracellular epitopes have remained unclear.
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Fine specificity of antibodies against AQP4: Epitope mapping reveals intracellular epitopes
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Citation Excerpt :
The mechanisms of recognition of intracellular epitopes are more complex, and to a great extend unknown. Many autoantibodies directed against intracellular antigens, including anti-U1RNP, anti-dsDNA, anti-Ro/SSA, anti-La/SSB, anti-Hu and others, have the potential to penetrate cells [30–33], in vivo [34,35]. Alternatively, the priming of the autoimmune response can follow apoptosis and release of intracellular epitopes or internalization.
The autoantibody to aquaporin-4 (AQP4) is a marker and a pathogenetic factor in Neuromyelitis Optica (NMO) (Devic’s syndrome). Our aim was to identify B-cell antigenic linear epitopes of the AQP4 protein and investigate similarities with other molecules. To this end, we screened sera from 21 patients positive for anti-AQP4 antibodies (study group), from 23 SLE and 23 pSS patients without neurologic involvement (disease controls) and from 28 healthy individuals (normal controls). Eleven peptides, spanning the entire intracellular and extracellular domains of the AQP4 molecule, were synthesized, and all sera were screened for anti-peptide antibodies by ELISA. Specificity was evaluated by homologous inhibition assays. NMO positive sera exhibited reactivity against 3 different peptides spanning the sequences aa1–22 (AQPpep1) (42.9% of patients), aa88–113 (AQPpep4) (33%) and aa252–275 (AQPpep8) (23.8%). All epitopes were localized in the intracellular domains of AQP4. Homologous inhibition rates were ranging from 71.1% to 84.3%. A 73% sequence homology was observed between AQPpep8′ aa257–271, a 15-mer peptide part of the AQPpep8 aa252–275, and the aa219–233 domain of the Tax1-HTLV-1 binding protein (TAX1BP1), a host protein associated with replication of the Human T-Lymphotropic Virus 1 (HTLV-1). Antibodies against the AQP4 and the TAX1BP1 15-mer peptides were detected in 26.3% (N = 5) and 31.6% (N = 6) of NMO positive sera (r_s = 0.81, P < 0.0001). Healthy controls did not react with these peptides, while homologous and cross-inhibition assays confirmed binding specificity. This first epitope mapping for AQP4 reveals that a significant proportion of anti-AQP4 antibodies target linear epitopes localized in the intracellular domains of the channel. One of the epitopes displays high similarity with a portion of TAX1BP1 protein.
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2006, Journal of the Neurological Sciences
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Research paperNuclear localization of anti-Hu antibody is not associated with in vitro cytotoxicity

Abstract

J. Neurol. Sci.

Neurosci. Lett.

Dev. Biol.

Cell

Antibody to nuclear ribonucleoprotein penetrates live human mononuclear cells through Fc receptors

Nature

Autoantibodies in paraneoplastic syndromes associated with small-cell lung cancer

Neurology

Localization of antibody in the central nervous system of a patient with paraneoplastic encephalomyeloneuritis

Neurology

Expression of an antigen in small cell lung carcinoma lines detected by antibodies from patients with paraneopalstic dorsal ganglionopathy

Cancer Res.

Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer — a quantitative Western blot analysis

Ann. Neurol.

Detection of the anti-Hu antibody in specific regions of the nervous system and tumor from patients with paraneoplastic encephalomyelitis/sensory neuronopathy

Neurology

Uptake of plasma IgG by CNS motoneurons: comparison of antineuronal and normal IgG

Neurology

Research paper
Nuclear localization of anti-Hu antibody is not associated with in vitro cytotoxicity