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

L Casciola-Rosen, F Andrade, D Ulanet… - The Journal of …, 1999 - rupress.org
L Casciola-Rosen, F Andrade, D Ulanet, WB Wong, A Rosen
The Journal of experimental medicine, 1999rupress.org
Systemic autoimmune diseases are a genetically complex, heterogeneous group of
disorders in which the immune system targets a diverse but highly specific group of
intracellular autoantigens. The molecules targeted are not unified by common structure,
function, or distribution in control cells but become clustered and concentrated in surface
blebs when cells undergo apoptosis. We show here that the majority of autoantigens
targeted across the spectrum of human systemic autoimmune diseases are efficiently …
Systemic autoimmune diseases are a genetically complex, heterogeneous group of disorders in which the immune system targets a diverse but highly specific group of intracellular autoantigens. The molecules targeted are not unified by common structure, function, or distribution in control cells but become clustered and concentrated in surface blebs when cells undergo apoptosis. We show here that the majority of autoantigens targeted across the spectrum of human systemic autoimmune diseases are efficiently cleaved by granzyme B in vitro and during cytotoxic lymphocyte granule–induced death, generating unique fragments not observed during any other form of apoptosis. These molecules are not cleaved by caspase-8, although this protease has a very similar specificity to granzyme B. The granzyme B cleavage sites in autoantigens contain amino acids in the P2 and P3 positions that are preferred by granzyme B but are not tolerated by caspase-8. In contrast to autoantigens, 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 therefore an exclusive property of autoantigens and unifies the majority of molecules targeted in this spectrum of diseases. These results focus attention on the role of the cytotoxic lymphocyte granule–induced death pathway in the initiation and propagation of systemic autoimmunity.
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