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
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.