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Figure 2 Adaptive and innate immune mechanisms of antigen clearance.

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different components of both gram-negative and gram-positive bacteria to macrophages and monocytes has been shown to be CD14 dependent. Indeed, a nonmonocytic cell line acquired the capacity to bind intact gram-negative bacteria following trans-fection with the CD14 gene. Furthermore, CD14-dependent phagocytosis of whole gram-negative bacteria was recently demonstrated in vitro.

CD14/bacterial interaction induces activation of macrophages. The cytokines produced act to recruit lymphoid cells and possibly direct the resulting adaptive immune response. A recent report has suggested that interleukin 12 (IL-12) production following macrophage contact with LTA from gram-posi-tive bacteria can be CD 14 dependent. IL-12 is a potent stimulator of TH1 CD4 T cells. Therefore CD14-dependent signals might exert an early influence on the nature of any resultant adaptive immune response. Furthermore, the release of the potent inflammatory cytokines tumor necrosis factor a (TNFa), IL-lfJ and IL-6 following bacterial activation of macrophages appears in part to be CD 14 dependent. These mediators recruit phagocytic cells, principally neutrophils, to the site of infection which may enhance the clearance of antigen and influence disease progression. However, if uncontrolled, these same cytokines can contribute to the development of sepsis syndrome in humans. CD14 plays a major role in this disease as CD14-deficient mice are highly resistant to toxic shock. Numerous anti-LPS antibody reagents have been used clinically in an attempt to modify the development of septic shock in infected patients, with to date disappointing results, presumably because the cytokine-mediated physiological response responsible for the syndrome is already established in most cases by the time the therapeutic agent is administered.

Mannose receptors

The mannose receptor is a well-characterized macrophage membrane lectin expressed on tissue macrophages throughout the body but not on circulating monocytes. Evidence strongly suggests that mannose receptors play a role in the clearance of pathogens. The mannose receptor is known to bind to mannose-and fucose-containing microorganisms by carbohydrate recognition domains. Numerous reports have detailed mannose receptor recognition of yeast, bacteria and certain protozoa. Furthermore, non-phagocytic COS cells gained the capacity to bind and ingest microorganisms following transfection with mannose receptor genes, a clear indication that the mannose receptor is a professional receptor for phagocytosis. The engagement and phagocytosis of microorganisms by the macrophage mannose recep tor actively stimulates the release of secretory products including IL-1, TNFa and reactive oxygen intermediates, further enhancing the clearance of antigen.

It is of interest that dendritic cells express the mannose receptor and a membrane lectin (DEC-205) with structural similarities and binding specificities to that of the macrophage mannose receptor. These receptors have a potential role in the enhancement of the capture, processing and presentation of antigen to the adaptive immune system by dendritic cells.

Mannose-binding protein/lectin (MBP/L)

MBP/L is a soluble serum protein and belongs to the collectin family of proteins, which is becoming increasingly recognized as an important component of the nonclonal immune system. MBP/L is a C-type lectin (Figure 1) which mediates calcium-dependent binding of certain carbohydrates. The protein recognizes mannose and N-acetylglucosamine residues on gram-positive and negative bacteria as well as yeast and certain parasites, protozoa, mycobacteria and viruses. Acting in concert with an MBP-associated serine protease (MASP), MBP/L can activate the classical complement pathway by cleaving the C4 and C2 molecules generating C4b2a complexes with C3 convertase activity. Indeed, MBP interaction with rough E. coli induces complement activation and bactericidal lysis. MBP can also act as an opsonin, either by inducing C3b deposition and subsequent clearance by phagocytic cells or independently by binding to Clq receptors.

The different mechanisms of antigen clearance we have described, involving both the innate and adaptive immune systems are summarized in Figure 2.

See also: Bacteria, immunity to; Bacterial cell walls; Carbohydrate antigens; Chemotaxis; Complement receptors; Endotoxin (lipopolysaccharide (LPS)); Fc receptors; Immune adherence; Immune complexes; Innate immunity; Mononuclear phagocyte system; Opsonization.

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