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Macrophages are phagocytes derived from blood monocytes (Figure 2.13). The monocyte itself is a small, spherical cell with few projections, abundant cytoplasm, little endoplasmic reticulum, and many granules. Following migration of monocytes from the blood to various tissues, they undergo further differentiation into a variety of histological forms which, historically, have been classified in accordance with their anatomical location as follows.

 Kupffer cells, in the liver; large cells with many cytoplasmic projections.

 Alveolar macrophages, in the lung.

 Splenic macrophages, in the red pulp.

 Peritoneal macrophages, free‐floating in peritoneal fluid.

 Microglial cells, in the brain and spinal cord.

 Osteoclasts, in the bone.

More recently, recognition of the functional heterogeneity of macrophage subsets has given rise to a new paradigm for classification of these innate immune cells. Macrophages are functionally polarized into M1 or M2 macrophages. Such polarization is regulated by the cytokines and other molecules and conditions present in the local environment. M1 macrophages are typically activated by IFN‐γ or lipopolysaccharide, and produce proinflammatory cytokines. M1 cells phagocytize microbes and initiate an immune response. They produce nitric oxide (NO) or reactive oxygen intermediates to protect against bacteria and viruses (discussed further in Chapter 3).

M2 macrophages are alternatively activated by exposure to cytokines such as IL‐4, IL‐10, or IL‐13. M2 macrophages produce either polyamines to induce proliferation or proline to induce collagen production. These macrophages are associated with wound healing and tissue repair.

Although associated with diverse names and locations, many of these cells share common features, such as the ability to bind and engulf particulate materials and antigens. Because of their location along capillaries, these cells are most likely to make first contact with invading pathogens and antigens and, as we shall see later, play a large part in the success of innate as well as adaptive immunity (also called acquired immunity). As noted above and discussed in detail in later chapters, another major function of the macrophages is to take up antigens, process them by denaturation or partial digestion, and present them, on their surfaces, to antigen‐specific T cells (i.e., the process of antigen presentation).

Figure 2.12. Cytokine‐promoted differentiation of naïve CD4⁺ T cells into T_H subsets showing some of their characteristic transcription factors.