Glycopeptidolipids (GPLs) comprise a major Surface glycolipid of Mycobacterium avium complex (MAC), and their unique oligosaccharide extensions arc known to define MAC serotypes. Beside the mature form of "serotype-specific" GPLs (ssGPLs), those that share the backbone structure but lack the oligosaccharide extensions exist as abundantly in all MAC serotypes, but the presumption was that antibody responses might not be directed to these "serotype-nonspecific" GPLs (nsGPLs) due to the lack of the sugar chain epitope. Here, we show that IgG responses to nsGPLs indeed occur in MAC-infected guinea pigs. The pool of anti-nsGPL antibodies was distinct from that of anti-ssGPL antibodies in terms of requirements for the oligosaccharide and acetylation for their target recognition. Because nsGPLs are shared in virtually ill MAC strains, but totally absent in Mycobacterium tuberculosis. this study suggests that detecting serum anti-nsGPL antibodies call potentially be useful for differential diagnosis of MAC infection and tuberculosis. (C) 2008 Elsevier Inc. All rights reserved.