The macrophage scavenger receptors SR-AI and SRAII, discussed by Platt and Gordon in this series (2), likewise make a mockery of any attempt to define ligand specificity in a single phrase. Although all SR-AI/II known ligands are negatively charged, the SR-As are not indiscriminate polyanion receptors, since many polyanions fail to bind. The known SR-A ligands are also notably heterogeneous in their presumed biological functions, since they range from covalently modified forms of several proteins and lipoproteins to the surface components of a diverse array of bacteria. In their review, Platt and Gordon (2) grapple with the issue of whether SR-A is indeed multifunctional, as had been suggested by this range of ligands. As they indicate, this question may be harder to answer now, with several conflicting reports of the phenotypes of SR-A–deficient mice in the literature, than it seemed before these animals were described. The macrophagespecific expression and broad ligand repertoire of the SR-As raised the possibility that they serve as pattern recognition endocytic receptors for host defense. Indeed, their ability to bind and internalize a variety of pathogenic surface components from microorganisms (eg, LPS) and lipoteichoic acid, and the consequences of inactivating mutations on the susceptibility of mutant mice to a wide variety of pathogens strongly suggest that SR-AI/II plays an important role in the innate immune system. As such, it probably forms part of the first line of defense against invading organisms and promotes engagement of adaptive immunity, potentially through the processing of internalized macromolecules for presentation by MHC molecules on the macrophage surface. The physiologic significance of SR-AI/II binding to asbestos fibers, amyloid fibrils, and apoptotic cells, on the other hand, remains to be established.

Expression cloning to identify a novel modified lipoprotein receptor resulted in the cloning of another scavenger receptor, called SR-BI, the topic of the review by Krieger (3) in this series. This receptor engages modified lipoproteins and, like several of the receptors shown in Table 1, it serves as a receptor for the anionic phospholipid phosphatidylserine. As discussed at length by Fadok et al.(4), phosphatidylserine is normally most abundantly expressed on the inner leaflet of the plasma membrane but is exposed on the outer leaflet of apoptotic cells, where it promotes recognition