Cleavage by granzyme B is strongly predictive of autoantigen status: Implications for initiation of autoimmunity

Citation
L. Casciola-rosen et al., Cleavage by granzyme B is strongly predictive of autoantigen status: Implications for initiation of autoimmunity, J EXP MED, 190(6), 1999, pp. 815-825
Citations number
50
Categorie Soggetti
Medical Research General Topics
Journal title
JOURNAL OF EXPERIMENTAL MEDICINE
ISSN journal
00221007 → ACNP
Volume
190
Issue
6
Year of publication
1999
Pages
815 - 825
Database
ISI
SICI code
0022-1007(19990920)190:6<815:CBGBIS>2.0.ZU;2-O
Abstract
Systemic autoimmune diseases are a genetically complex, heterogeneous group of disorders in which the immune system targets a diverse but highly speci fic group of intracellular autoantigens. The molecules targeted are not uni fied by common structure, function, or distribution in control cells but be come clustered and concentrated in surface blebs when cells undergo apoptos is. We show here that the majority of autoantigens targeted across the spec trum of human systemic autoimmune diseases are efficiently cleaved by granz yme B in vitro and during cytotoxic lymphocyte granule-induced death, gener ating unique fragments not observed during any other form of apoptosis. The se molecules are not cleaved by caspase-8, although this protease has a ver y similar specificity to granzyme B. The granzyme B cleavage sites in autoa ntigens contain amino acids in the P-2 and P-3 positions that are preferred by granzyme B but are not tolerated by caspase-8. In contrast to autoantig ens, nonautoantigens are either not cleaved by granzyme B or are cleaved to generate fragments identical to those formed in other forms of apoptosis. The striking ability of granzyme B to generate unique fragments is therefor e an exclusive property of autoantigens and unifies the majority of molecul es targeted in this spectrum of diseases. These results focus attention on the role of the cytotoxic lymphocyte granule-induced death pathway in the i nitiation and propagation of systemic autoimmunity.