Nonclonal receptors in antigen clearance

Growing evidence suggests that initial interaction of pathogens with the innate immune system can initiate and direct the development of the adaptive immune response. As discussed, pathogens opsonized by serum proteins are phagocytosed and cleared from the body by cells of the immune system. In addition, germline-encoded receptors with the capacity directly to recognize nonopsonized microorganisms have been identified on cells of the innate immune system. Janeway proposed that such nonclonal receptors, termed 'pattern-recognition molecules', bind common constituents of pathogenic microorganisms, providing a first line of defense in the preimmune host. The wide spectrum of molecules recognized would not be expressed on the surface of normal cells, thus allowing discrimination of non-self from self. Scavenger receptors, CD36, CD 14, and mannose receptors have been proposed as candidate pattern-recognition receptors.

Scavenger receptors

Initially identified for the ability to bind low-density lipoproteins (LDLs), macrophage scavenger receptors (SRs) were found to exhibit broad polyanionic ligand binding specificity, a characteristic of pattern-recognition molecules. Three independent subclasses of receptor, SR-A, B and C have been described, with expression limited to monocytes, macrophages and hemocytes. Type I and II class A SRs bind to and remove endotoxin (lipid A of LPS) from plasma. Whole gram-positive bacteria and lipoteichoic acid (LTA), a ubiquitous gram-positive cell wall constituent, were shown to be additional iigands for type I SR-As. A third recently described SR-A, 'MARCO', expressed on splenic and lymph node macrophages was also reported to interact with E. coli and Staphylococcus aureus. A primary function of SR-As on macrophages, monocytes and hemocytes appears to be the clearance of toxic shock-inducing microbial cell surface constituents and pathogenic microorganisms from the body.

The rapid phagocytosis of damaged and apoptotic cells prevents the release of noxious intracellular molecules into the body and prevents exposure of the adaptive immune system to unseen components of self. Ailing cells express surface molecular structures not characteristically found on normal cells. Growing evidence supports the proposal that SRs function in the clearance of apoptotic and damaged cells. COS cells acquired the capacity to phagocytose apoptotic cells when transfected with the class B SR CD36. CD36 has also been implicated in mediating the

Figure 1 The structure of mannose-binding lectin.

clearance of Plasmodium falciparum-mfccttd red blood cells, apoptotic neutrophils and leukocytes, and as a rhinovirus receptor. Recent reports indicated that class A SRs facilitated the uptake of oxidatively damaged erythrocytes. The uptake of approximately 50% of apoptotic thymocytes in vitro was recently reported to be SR-A dependent, a finding yet to be demonstrated in vivo. Therefore, SRs appear to be candidate receptors for molecules expressed on damaged or apoptotic cells.

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