Autoantibodies that recognize functional domains of hnRNPA1 implicate molecular mimicry in the pathogenesis of neurological disease

Lee, Sang Min; Dunnavant, Floyd D.; Jang, Haeman; Zunt, Joseph R.; Levin, Michael C.

doi:10.1016/j.neulet.2006.03.016

Cited by 32 publications

(47 citation statements)

References 21 publications

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“…However, antibodies from patients with autoimmune diseases have been found to cross-react with hnRNP A1 (Lee et al, 2006), suggesting that the cross-reaction is some kind of molecular mimicry.…”

Section: Discussionmentioning

confidence: 99%

Genotoxic stress-induced nuclear localization of oncoprotein YB-1 in the absence of proteolytic processing

Cohen

Valova

et al. 2009

Oncogene

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Y-box-binding protein 1 (YB-1) is an oncogenic transcription factor whose overexpression and nuclear localization is associated with tumor progression and drug resistance. Transcriptional activation of YB-1 in response to genotoxic stress is believed to occur in the cytoplasm through sequence-specific endoproteolytic cleavage by the 20S Proteasome, followed by nuclear translocation of cleaved YB-1. To study the proteolysis model, we developed a two-step affinity purification of endogenous YB-1 protein species and characterized the products using mass spectrometry. Whereas full-length YB-1 was readily identified, the smaller protein band thought to be activated YB-1 was identified as hnRNP A1. An antibody specific for YB-1 was generated, which revealed only one YB-1 species, even after genotoxic stress-induced nuclear YB-1 translocation. These findings warrant re-evaluation of the mechanism of YB-1 nuclear translocation and transcriptional activation. The relationship between nuclear YB-1 and tumor progression may also have to re-evaluated in some cases.

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Section: Discussionmentioning

confidence: 99%

Genotoxic stress-induced nuclear localization of oncoprotein YB-1 in the absence of proteolytic processing

Cohen

Valova

et al. 2009

Oncogene

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“…Trabajos previos han presentado evidencias de que la hnRNP A1 tiene una reactividad cruzada con anticuerpos monoclonales para la proteína tax p40 del HTLV-I, y muestran que el reconocimiento de este autoantígeno involucra dominios definidos de esta proteína nuclear (30,31). Las ribonucleoproteínas heterogéneas nucleares (hnRNPs) son las proteínas más abundantes del núcleo de células eucarióticas (32).…”

Section: Discussionunclassified

Síndrome autoinmune en la paraparesia tropical espástica/ mielopatía asociada a la infección por el virus linfotrópico humano tipo I de la costa pacífica colombiana

Domínguez¹,

Torres²,

Tamayo³

et al. 2008

biomedica

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Introducción. Trabajos previos han aportado evidencias de que en la paraparesia espástica tropical/mielopatía asociada con el virus linfotrópico humano tipo I, existe un componente autoinmune asociado a su patogénesis. Objetivo. Evaluar el estado autoinmune y la existencia de mimetismo molecular en pacientes con paraparesia espástica tropical del pacífico colombiano. Materiales y métodos. A partir de muestras de plasma de 37 pacientes con paraparesia espástica tropical/mielopatía asociada al HTLV-I, 10 con leucemia de células T del adulto, 22 individuos portadores asintomáticos y 20 seronegativos para el HTLV-I, se determinaron niveles plasmáticos de anticuerpos antinucleares y anticardiolipina-2 y de interferón-γ e interleucina-4. Se evaluó, por Western blot, la reactividad cruzada de plasmas contra proteínas obtenidas de varias fuentes celulares normales del sistema nervioso. Además, se estudió la reactividad cruzada de plasmas de seropositivos y del anticuerpo monoclonal LT4 anti-taxp40 en secciones de médula espinal de ratas Wistar no infectadas. Resultados. El 70,2% y el 83,8% de los pacientes con paraparesia espástica tropical fueron reactivos para anticuerpos ANA y ACL-2, respectivamente, en contraste con los de leucemia de células T del adulto y los seropositivos asintomáticos (P<0,001). Además, el 70,3% y el 43,2% de los pacientes con paraparesia espástica tropical tuvieron niveles detectables de IFN-γ e IL-4, respectivamente. El anticuerpo LT4 anti tax-p40 y los plasmas de paraparesia espástica tropical/mielopatía asociada al HTLV-I mostraron una reacción cruzada con una proteína de PM r 33-35 kDa, obtenida del núcleo de neuronas de la médula espinal de ratas Wistar no infectadas. Conclusión. Se obtuvieron evidencias que apoyan la existencia de un síndrome autoinmune mediado por mimetismo molecular como parte de la etiopatogénesis de la degeneración axonal observada en la paraparesia espástica tropical en pacientes colombianos de la costa pacífica.Palabras clave: paraparesia espástica, virus linfotrópico de células T humanas tipo 1, virus 1 T-linfotrópico de los primates, médula espinal, autoanticuerpos, autoinmunidad, imitación molecular.

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“…It has been shown that patients with MS and HAM/ TSP produce autoantibodies to the intracellular RNA binding protein heterogeneous ribonuclear protein A1 (hnRNP A1) 3, 5-7, 9, 11 . Recent data indicate that antibodies to both intra-neuronal and surface antigens are pathogenic 3,[5][6][7][8][9]11 . Thus, a procedure that allows for the study of intracellular antibody:protein interactions would lend great insight into disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…The ability to produce highly specific antibodies to target proteins has allowed for very precise biological questions to be addressed. Importantly, antibodies have been implicated in the pathogenesis of a number of human diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), paraneoplastic syndromes, multiple sclerosis (MS) and human T-lymphotropic virus type 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/ TSP) [1][2][3][4][5][6][7][8][9] . How antibodies cause disease is an area of ongoing investigation, and data suggests that interactions between antibodies and various intracellular molecules results in inflammation, altered cellular messaging, and apoptosis 10 .…”

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confidence: 99%

Antibody Transfection into Neurons as a Tool to Study Disease Pathogenesis

Douglas

Gardner

Lee

et al. 2012

JoVE

Self Cite

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Antibodies provide the ability to gain novel insight into various events taking place in living systems. The ability to produce highly specific antibodies to target proteins has allowed for very precise biological questions to be addressed. Importantly, antibodies have been implicated in the pathogenesis of a number of human diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), paraneoplastic syndromes, multiple sclerosis (MS) and human T-lymphotropic virus type 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/ TSP) [1][2][3][4][5][6][7][8][9] . How antibodies cause disease is an area of ongoing investigation, and data suggests that interactions between antibodies and various intracellular molecules results in inflammation, altered cellular messaging, and apoptosis 10 . It has been shown that patients with MS and HAM/ TSP produce autoantibodies to the intracellular RNA binding protein heterogeneous ribonuclear protein A1 (hnRNP A1) 3, 5-7, 9, 11 . Recent data indicate that antibodies to both intra-neuronal and surface antigens are pathogenic 3,[5][6][7][8][9]11 . Thus, a procedure that allows for the study of intracellular antibody:protein interactions would lend great insight into disease pathogenesis.Genes are commonly transfected into primary cells and cell lines in culture, however transfection of antibodies into cells has been hindered by alteration of antibody structure or poor transfection efficiency 12 . Other methods of transfection include antibody transfection based on cationic liposomes (consisting of DOTAP/DOPE) and polyethylenimines (PEI); both of which resulted in a ten-fold decrease in antibody transfection compared to controls 12 . The method performed in our study is similar to cationic lipid-mediated methods and uses a lipid-based mechanism to form non-covalent complexes with the antibodies through electrostatic and hydrophobic interactions 13 . We utilized Ab-DeliverIN reagent, which is a lipid formulation capable of capturing antibodies through non-covalent electrostatic and hydrophobic interactions and delivering them inside cells. Thus chemical and genetic couplings are not necessary for delivery of functional antibodies into living cells. This method has enabled us to perform various antibody tracing and protein localization experiments, as well as the analyses of the molecular consequences of intracellular antibody:protein interactions 9 .In this protocol, we will show how to transfect antibodies into neurons rapidly, reproducibly and with a high degree of transfection efficiency. As an example, we will use anti-hnRNP A1 and anti-IgG antibodies. For easy quantification of transfection efficiency we used anti-hnRNP A1 antibodies labelled with Atto-550-NHS and FITC-labeled IgG. Atto550 NHS is a new label with high molecular absorbtion and quantum yield. Excitation source and fluorescent filters for Atto550 are similar to Cy3 (Ex. 556 Em. 578). In addition, Atto550 has high photostability. FITClabeled IgG were used as a control to sho...

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Autoantibodies that recognize functional domains of hnRNPA1 implicate molecular mimicry in the pathogenesis of neurological disease

Cited by 32 publications

References 21 publications

Genotoxic stress-induced nuclear localization of oncoprotein YB-1 in the absence of proteolytic processing

Genotoxic stress-induced nuclear localization of oncoprotein YB-1 in the absence of proteolytic processing

Síndrome autoinmune en la paraparesia tropical espástica/ mielopatía asociada a la infección por el virus linfotrópico humano tipo I de la costa pacífica colombiana

Antibody Transfection into Neurons as a Tool to Study Disease Pathogenesis

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