Gelatinase B/
matrix metalloproteinase-9 (MMP-9) is a key
enzyme involved in inflammatory, hematological, vascular and neoplastic diseases. In previous studies, we explored the intracellular substrate set or 'degradome' of MMP-9 and found many systemic
autoantigens as novel intracellular
gelatinase B substrates. Little is known, however, about the functional role of MMP-9 in the development of systemic autoimmunity in vivo. B6(lpr/lpr) mice with defective Fas-mediated apoptosis were used to investigate the functions of MMP-9 in lymphocyte proliferation and in the development of systemic autoimmunity. Combined Fas and
gelatinase B deficiency resulted in extreme lymphoproliferative disease with enhanced
lymphadenopathy and
splenomegaly, and significantly reduced survival compared with single Fas deficiency. At the cellular level, this was corroborated by increased lymph node accumulation of 'double negative' T cells, B cells and myeloid cells. In addition, higher
autoantibody titers and more pronounced autoimmune tissue injury were found in the absence of MMP-9, culminating in chronically enhanced
systemic lupus erythematosus (SLE)-like autoimmunity. After cleavage by MMP-9 the SLE
autoantigens U1snRNP A and
ribosomal protein P0 were hardly recognized by plasma samples of both B6(lpr/lpr).
MMP-9⁻/⁻ and B6(lpr/lpr).
MMP-9+/+ mice, pointing to a destruction of
B cell epitopes by MMP-9-mediated proteolysis. In addition, the same loss of
immunodominant epitopes was observed with plasma samples from SLE patients, suggesting that MMP-9 suppresses systemic antibody-mediated autoimmunity by clearance of autoepitopes in immunogenic substrates. Thus, new protective functions for MMP-9 were revealed in the suppression of lymphoproliferation and dampening of systemic autoimmunity, cautioning against the long-term use of
MMP inhibitors in
autoimmune lymphoproliferative syndrome (ALPS) and SLE.