The serpin alpha 1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo

We have identified the key protein substrate of gelatinase B/MMP-9 (GB) tha t is cleaved in vivo during dermal-epidermal separation triggered by antibo dies to the hemidesmosomal protein BP180 (collagen XVII, BPAG2). Mice defic ient in either GB or neutrophil elastase (NE) are resistant to blister form ation in response to these antibodies in a mouse model of the autoimmune di sease bullous pemphigoid. Disease develops upon complementation of GB(-/-) mice with NE-/- neutrophils or NE-/- mice with GB(-/-) neutrophils. Only NE degrades BP180 and produces dermal-epidermal separation in vivo and in cul ture. Instead, GB acts upstream to regulates NE activity by inactivating al pha 1-proteinase inhibitor (alpha 1-PI). Excess NE produces lesions in GB(- /-) mice without cleaving alpha 1-PI. Excess alpha 1-PI phenocopies GB and NE deficiency in wild-type mice.