IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 2. Cells Executing the Immune Response

MONONUCLEAR PHAGOCYTES

The mononuclear phagocyte system performs two main Functions executed by two distinct Cell Types of bone marrow origin:

✵ "professional" macrophages, whose primary role is the elimination of particulate Antigens, and

✵ antigen-presenting Cells (APCs), whose role consists in the uptake, Processing, and presentation of antigen to T cells.

(Formerly, tissue macrophages together with endothelial cells were functionally grouped under the term reticuloendothelial system.) Macrophages are present in many Organs (Fig. 2.24) and can be detected, for example in the mouse, by intravenous injection of minute carbon particles, which become localized within phagocytes (Fig. 2.25).

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Fig. 2.24. The mononuclear phagocyte system includes Blood monocytes, resident tissue macrophages, and macrophages attached to the endothelial lining of blood capillaries. Resident macrophages of the Liver are known as Kupffer cells, whereas those located in the Kidneys are termed intraglomerular mesangial cells. Alveolar macrophages and phagocytes of serous cavities (e.g., peritoneal) are classified as "wandering". Microglia of the Brain are cells that invaded the Nervous Tissue at birth and differentiated into fixed phagocytes. (Relative cell sizes in the diagram are not to scale.)

Fig. 2.25. Intravenously injected particles localize in the reticuloendothelial system. Minute carbon particles were injected into the tail vein of a mouse, and 5 min later the animal was sacrificed. Carbon accumulated in organs rich in mononuclear phagocytes: the Lungs (L), liver (L), Spleen (S), and intestinal wall (IW). Left: control mouse (normal coloration of Internal Organs).

Myeloid precursors in the Bone Marrow differentiate into promonocytes and subsequently into mature monocytes, which enter the bloodstream (see Ch. 12). Cells of this circulating pool migrate across vessel walls into various organs, where they transform into macrophages. Compared with lymphocytes, human monocytes are larger cells (10–18 µm in diameter) with a characteristic horseshoe-shaped Nucleus and azurophilic granules in the Cytoplasm (Fig. 2.26). Transmission Electron Microscopy reveals specific ULTRASTRUCTURAL FEATURES OF monocytes, including folding of the outer membrane, a well-developed Golgi apparatus, and numerous cytoplasmic Lysosomes (Fig. 2.27). These lysosomes contain peroxidase and several acidic Hydrolases required for the intracellular destruction of microbial cells.

Fig. 2.26. Monocyte Morphology. Blood monocytes are larger than most circulating lymphocytes and possess a characteristic horseshoe-shaped nucleus. Giemsa staining, x 1200.

Fig. 2.27. Monocyte ultrastructure showing a horseshoe-shaped nucleus (N), pinocytic vesicles (PV), lysosomal granules (G), Mitochondria (M), and isolated cisternae of The Endoplasmic reticulum (ER), x 8000. (Micrograph kindly provided by Dr. W. Nichols; J. Cell. Biol. 1971 50: 498).

Monocytes and macrophages are capable of firmly adhering to Glass and plastic surfaces, as well as actively phagocytosing microorganisms and even tumor cells in vitro. The binding of specialized monocytic receptors to microbial cells triggers their adhesion and uptake by monocytes. These receptors interact with specific CARBOHYDRATES in MICROBIAL CELL WALLS or with IgG and Complement components that have opsonized their surface.

Molecular markers of monocytes and macrophages

Human and murine monocytes and macrophages possess mannose-fucosyl receptors that bind to these sugars On the surface of microbes or defective host cells, such as senescent erythrocytes. Carbohydrate-specific receptors also include N-acetylglucosamine receptors and receptors recognizing cellular debris. Apoptotic cells removed by monocytes and macrophages are recognized, in particular, by phosphatidylserine receptors. In addition, monocytes/macrophages express CD14, a receptor for lipopolysaccharide-binding protein, which is normally present in serum and binds to Gram-negative Bacteria. The surface of monocytes/macrophages also bears Three types of Fc receptors for IgG:

✵ FcγRI (CD64); present on human cells and exhibits high affinity; homologous to murine FcγRIIa;

✵ FcγRII (CD32); exhibits intermediate affinity and is equivalent to murine FcγRIIb/1;

✵ FcγRIII (CD16); present on a subpopulation of monocytes, exhibits low affinity, equivalent to murine FcγR10. Presumably, these types of Fc receptors perform distinct functions, including the induction of extracellular cytotoxicity and phagocytosis of opsonized microbes. The complement receptor CR3 (C3bi receptors, CD11b/CD18, Mac-1, present predominantly on activated macrophages), as well as leukocyte function-associated antigen LFA-1 (CD11a/CD18), p150,95 (CD11c/CD18), and αDβ₂, also play a role in the uptake of the latter, with CR1 (C3b receptor, CD35; see Ch. 4) being similarly important. LFA-1 and p150,95 markers, found in macrophage cytoplasmic vesicles, are expressed immediately upon activation. MHC class II Proteins, required for antigen presentation to T cells, are present on the surface of a subset of monocytes and macrophages. Activated macrophages also express the low-affinity Fc receptor for IgE (FcεRII, CD23). Furthermore, human macrophages express CD13, CD15, CD68, and VLA-4 (CD29/CD49d) markers. It should be noted that none of the aforementioned markers is exclusively specific to human monocytes and macrophages, yet FcγRI remains the most reliable hallmark of these cells. Meanwhile, in the mouse, macrophage-specific markers include F4/80 (160 kDa), the sheep erythrocyte receptor (SER; not to be confused with CD2!), and the erythroblast receptor (EbR). The principal markers of human and murine monocytes and macrophages are listed in Fig. 2.28.

Fig. 2.28. Several CD molecules equivalent to human markers have not yet been identified on murine cells. (MR - mannose receptor.)

In addition to all the molecular markers mentioned above, monocytes and macrophages also bear receptors for cytokines such as IL-2, IL-4, and IFNγ. Therefore, the functional activity of these cells can be enhanced by T-cell cytokines via these receptors. Monocytes and macrophages activated in this manner produce cytokines themselves—including IFN, IL-1, and TNFα (see Ch. 10)—along with complement components, Prostaglandins, reactive oxygen metabolites, and nitric oxide (NO). Like neutrophils, monocytes and, to a lesser extent, mature macrophages contain peroxidase, which degrades hydrogen peroxide.