The fate of the U1 snRNP autoantigen during apoptosis: implications for systemic autoimmunity.
Recent studies have implicated the dying cell as a potential reservoir of modified autoantigens that may initiate and drive systemic autoimmunity in susceptible hosts. The uridine-rich small nuclear ribonucleoprotein complex is a common target for autoantibodies present in the serum of patients with systemic lupus erythematosus and SLE-overlap syndromes. Four modifications occurring in this complex during apoptosis have been described to date: the caspase-mediated cleavage of the U1-70K protein, the U1 RNA and the Sm-F protein, and the association with hyperphosphorylated SR proteins. In addition, the U1 snRNP complex has been shown to translocate from its normal subcellular localization to apoptotic bodies near the surface of cells undergoing apoptosis. This redistribution might facilitate exposure of the modified components of the U1 snRNP complex to the immune system when the clearance of apoptotic cell remnants is somehow disturbed. The modifications in the U1 snRNP components during apoptosis might represent the initial epitopes to which an immune response is generated and may be the trigger for the production of autoantibodies to this complex in patients with SLE or SLE-overlap syndromes. Therefore, it can be hypothesized that the exposure of elevated levels of apoptotically modified U1 snRNP to the immune system of a genetically susceptible individual might lead to the breaking of immunologic tolerance towards the U1 snRNP complex.
Malmegrim
Kelen C R
KC
Department of Biochemistry, Nijmegen Center of Molecular Life Sciences, University of Nijmegen, Nijmegen, The Netherlands.
Pruijn
Ger J M
GJ
van Venrooij
Walther J
WJ
D017209:Apoptosis / Q000235:genetics* / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics* / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000235:genetics* / Q000276:immunology*
D001324:Autoantigens; D017412:Ribonucleoprotein, U1 Small Nuclear