Stegeman and colleagues [1] reported the association of chronic nasal carriage of Staphylococcus aureus with higher relapse rates in Wegener granulomatosis and discussed the possibility of its causal role in autoimmune phenomena. The c-antineutrophil cytoplasmic antibody (c-ANCA) Wegener granulomatosis autoantigen is a serine protease with strong similarity to other trypsin-family serine proteases. It is homologous in its first 100 amino acids (with >50% identity) to granzyme B (a killer-cell-specific serine protease also known as cytotoxic T-lymphocyte proteinase-2, whose expression may be involved in the acute rejection of renal allografts and in apoptosis. This area of near identity includes areas of predicted high antigenicity using the Jameson-Wolf antigenicity index. Granzyme B is induced by S. aureus enterotoxin A. The protein sequence of granzyme B is encoded by a cDNA clone isolated from staphylococcal enterotoxin A-stimulated lymphocytes [2].

Could induction of serine proteases such as granzyme B by staphylococcal enterotoxin A result in antibody formation to serine protease epitopes manifested as c-ANCA?

Some prokaryotic proteases (including S. aureus) have a charge relay system similar to that in trypsin family serine proteases, including c-ANCA [3, 4]. These prokaryotic proteases probably evolved by independent convergent evolution, given that their sequences, except for the residues around the catalytic triad, are completely different from those of the analogous residues in the trypsin serine proteases. Proteases in this family include both S. aureus V8 proteinase, widely used in protein sequencing, and S. aureus epidermolytic toxins A and B, the proteolytic toxins that cause impetigo [3].

It is also possible that the S. aureus genome directly encodes other serine proteases with antigenic cross-reactivity to the c-ANCA autoantigen. The S. aureus million base pair genome should be sequenced.