Apoptosis in the rheumatic diseases

Vaishnaw, Akshay; McNally, Jeremy; Elkon, Keith B.

doi:10.1002/art.1780401102

Cited by 90 publications

(58 citation statements)

References 77 publications

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“…6 The mechanisms by which these components of the U1 snRNP complex and other autoantigens escape immunological tolerance are largely unknown, although a number of recent observations suggest that modified self-proteins that are generated during apoptosis (i.e. programmed cell death) 7 or necrosis, 8 may play an important role in the development of autoimmunity. It has been shown that autoantigens targeted in SLE become concentrated in two discrete populations of surface structures on apoptotic cells, namely apoptotic bodies and apoptotic surface blebs.…”

Section: Introductionmentioning

confidence: 99%

The fate of U1 snRNP during anti-Fas induced apoptosis: specific cleavage of the U1 snRNA molecule

et al. 2000

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During apoptosis, the U1-70K protein, a component of the spliceosomal U1 snRNP complex, is specifically cleaved by the enzyme caspase-3, converting it into a C-terminally truncated 40-kDa fragment. In this study, we show that the 40-kDa U1-70K fragment is still associated with the complete U1 snRNP complex, and that no obvious modifications occur with the U1 snRNP associated proteins U1A, U1C and Sm-B/B'. Furthermore, it is described for the first time that the U1 snRNA molecule, which is the backbone of the U1 snRNP complex, is modified during apoptosis by the specific removal of the first 5 ± 6 nucleotides including the 2,2,7-trimethylguanosine (TMG) cap. The observations that U1 snRNA cleavage is very specific (no such modifications were detected for the other U snRNAs tested) and that U1 snRNA cleavage is markedly inhibited in the presence of caspase inhibitors, indicate that an apoptotically activated ribonuclease is responsible for the specific modification of U1 snRNA during apoptosis. Cell Death and Differentiation (2000) 7, 70 ± 79.

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Section: Introductionmentioning

confidence: 99%

The fate of U1 snRNP during anti-Fas induced apoptosis: specific cleavage of the U1 snRNA molecule

et al. 2000

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“…A typical example of a process in which many selfproteins are cleaved or modified is apoptosis, 3,4 a genetically determined program that eliminates unneeded, senescent, or damaged cells. It has been shown that autoantigens targeted in SLE become concentrated in two discrete populations of surface structures on apoptotic cells, namely apoptotic bodies and apoptotic surface blebs.…”

Section: Immunological Tolerance Broken By Autoantigen Modi®cations?mentioning

confidence: 99%

Caspase-dependent cleavage of nucleic acids

et al. 2000

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Autoimmune diseases are frequently characterized by the presence of autoantibodies directed against nucleic acidprotein complexes present in the nucleus of the cell. The mechanisms by which these autoantigenic molecules escape immunological tolerance are largely unknown, although a number of recent observations suggest that modified selfproteins generated during apoptosis may play an important role in the development of autoimmunity. It has been hypothesized that the recognition of these modified selfproteins by the immune system may promote autoantibody production. While apoptosis is specifically characterized by posttranslational modification of proteins, recent findings also show that nucleic acids are modified. This review summarizes the specific cleavages of some of these key nucleic acids, i.e. chromosomal DNA, ribosomal RNA and small structural RNAs (U1 snRNA, Y RNA), in apoptotic cells.

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“…Novel attractive strategies propose the blockade of synovial cell activation (by inhibiting specific signal transduction pathways) and inhibition of matrix-degrading enzymes. Moreover, recent experimental evidence have illuminated the idea that induction of apoptosis of rheumatoid synovium can be used to gain therapeutic advantage (Vaishnaw et al 1997, Jorgensen & Gay 1998, Chernajovsky et al 1999. Therapeutic genes may be introduced locally into diseased joints (local gene delivery) or at extra-articular locations where the gene products become systemically available (systemic gene delivery).…”

Section: Rheumatoid Arthritis: a Candidate Dis-ease For Gene Therapymentioning

confidence: 99%

“…Nuclear factor kappa B (NF-kB) is a heterodimeric transcription factor that is a critical element in the regulation of many genes involved in the regulation of the immune response (Vaishnaw et al 1997). It has been shown that TNF-α signals predominantly through the NF-kB pathway, promoting the expression of adhesion molecules (ICAM-1, VCAM-1) and recruiting additional cytokines (IL-1, IL-6, GM-CSF) in the inflamed joint.…”

Section: Gene Therapy In Ra By Blocking Activa-tion Of Specific Transmentioning

confidence: 99%

“…Antigen-provoked death of lymphocytes is mediated by Fas (CD95/ APO-1), tumor necrosis factor (TNF) and related molecules. Other death ligands such as TRAIL and its corresponding death receptors DR4 and DR5 are expressed in immune cells, but their physiological functions are now well understood (Vaishnaw et al 1997).…”

Section: Gene Transfer In Ra By Promoting Apop-tosis Of Synoviocytes mentioning

confidence: 99%

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