TY - JOUR
T1 - Autoantigens as substrates for apoptotic proteases
T2 - Implications for the pathogenesis of systemic autoimmune disease
AU - Rosen, Antony
AU - Casciola-Rosen, Livia
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) grants AR44684 (LCR) and DE12354 (AR), and an Arthritis Foundation (Maryland Chapter) Institutional Grant. A. Rosen is a Pew Scholar in the Biomedical Sciences.
PY - 1999/1
Y1 - 1999/1
N2 - Systemic autoimmune diseases are a genetically complex, heterogeneous group of diseases in which the immune system targets a diverse, but highly specific group of intracellular autoantigens. The clustering and marked concentration of these molecules in the surface blebs of apoptotic cells, and their modification by apoptosis-specific proteolytic cleavage and/or phosphorylation at these sites, has focused attention on a unique apoptotic setting as the potential initiating stimulus for systemic autoimmunity. This apoptotic event is likely to (i) occur in a microenvironment containing high concentrations of the targeted antigens, (ii) be pro-immune in nature (e.g. viral infection), and (iii) allow suprathreshold concentrations of antigen with non-tolerized structure (either novel fragments, post-translational modifications, or complexes) to enter the class II processing pathway and initiate a primary immune response. Defective clearance or reduced anti-inflammatory consequences of apoptotic material may be important susceptibility factors in this group of diseases. Once the primary immune response to apoptotic antigens has been initiated, other apoptotic events (occurring in the course of homeostasis or damage) may stimulate the secondary immune response with less stringency, resulting in flares.
AB - Systemic autoimmune diseases are a genetically complex, heterogeneous group of diseases in which the immune system targets a diverse, but highly specific group of intracellular autoantigens. The clustering and marked concentration of these molecules in the surface blebs of apoptotic cells, and their modification by apoptosis-specific proteolytic cleavage and/or phosphorylation at these sites, has focused attention on a unique apoptotic setting as the potential initiating stimulus for systemic autoimmunity. This apoptotic event is likely to (i) occur in a microenvironment containing high concentrations of the targeted antigens, (ii) be pro-immune in nature (e.g. viral infection), and (iii) allow suprathreshold concentrations of antigen with non-tolerized structure (either novel fragments, post-translational modifications, or complexes) to enter the class II processing pathway and initiate a primary immune response. Defective clearance or reduced anti-inflammatory consequences of apoptotic material may be important susceptibility factors in this group of diseases. Once the primary immune response to apoptotic antigens has been initiated, other apoptotic events (occurring in the course of homeostasis or damage) may stimulate the secondary immune response with less stringency, resulting in flares.
KW - Apoptosis
KW - Autoantigen
KW - Autoimmunity
KW - Caspase
KW - Granzyme B
KW - Protease
UR - http://www.scopus.com/inward/record.url?scp=0032917731&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032917731&partnerID=8YFLogxK
U2 - 10.1038/sj.cdd.4400460
DO - 10.1038/sj.cdd.4400460
M3 - Review article
C2 - 10200542
AN - SCOPUS:0032917731
SN - 1350-9047
VL - 6
SP - 6
EP - 12
JO - Cell death and differentiation
JF - Cell death and differentiation
IS - 1
ER -