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THE IMMUNE SYSTEM

Fig. 3. (a) White cells of the immune system. The cells surrounded by deep red halos are the primary targets of HIV infection; those surrounded by pale red halos are less frequent targets. Among the primary targets are monocytes and macrophages (upper left), part of a functional system of scavenging cells (phagocytes) and antigen-presenting cells called the reticuloendothelial system (b). Whereas monocytes circulate in the blood, macrophages are strategically located in various organs of the body and in the lymph nodes. (Note that the monocytes and macrophages have kidneyshaped nuclei.) Another line of immune defense is provided by the lymphocytes (upper \right), an adaptive system that acts against specific foreign antigens (proteins). T lymphocytes mature, differentiate and acquire their antigen-specificity in the thymus. In the presence of specific foreign antigens, the T4 helper lymphocytes direct the activities of other immune cells by sending out chemical messages and the T8 killer lymphocytes send out cytotoxins, which kill the foreign cells. B lymphocytes, in the presence of specific foreign antigens, mature into plasma cells and manufacture Y-shaped antigen-specific protein molecules called antibodies, which bind to the foreign antigens. Most white cells of the immune sytem flow through the bloodstream, and at specific sites in capillary walls, they exit to the lymphatic system (c), a network of tiny vessels permeating the body whose walls are only onecell thick. These tiny vessels act as conduits for white cells and collect all the extracellular lymphatic fluids in the body. These cells and fluids are then recirculated back to the bloodstream through vessels that merge into even larger lymphatic ducts, like the streams in a watershed, and eventually converge into the large thoracic duct, which empties into a large vein at the base of the neck called the left subclavian vein. The flow of white cells through the lymphatics and bloodstream provides continual immune surveillance of the entire body.

can be invaded by disease-producing organisms. An additional problem for the body's ecosystem is the spontaneous generation of mutant cells, that is, tumor cells that could threaten its own survival. Thus, depending on the size of the multicellular organism, a unique set of cells had to evolve to assure that no members of the organism's ecosystem be parasitized by intracellular pathogens or altered in a way that would damage their critical day-to-day functions. In a large number of animals, including man, that set is composed of two special types of white cells (Fig. 2): the monocytes and macrophages, and the T lymphocytes (the T stands for thymus-derived). Although evolutionarily they are among the oldest cells of the immune system and are well-adapted to perform their functions, these cells have provided the perfect niche for certain nonliving parasites-namely, the lentiviruses! To understand the impact of lentiviral infections, we will first outline the genesis and normal functioning of monocytes, macrophages, and T lymphocytes.

The immune system is a complicated network of white cells and their chemical products (Fig. 3), which interact synergistically to eliminate foreign invaders, abnormal cells, and toxic cell products. White cells generally originate from stem cells found in foetal liver and bone marrow. As they mature, they differentiate into many cell types with separate or overlapping functions (Fig. 3a). Most white cells in the blood are shortlived scavenger cells (neutrophils) that engulf and digest foreign microbes and die. The pus seen in bacterial infections are primarily these dead scavenger cells.

The monocytes and macrophages are also scavenger cells, but they may live months or years. They are particularly good at detecting, engulfing, and digesting tumor or virally infected cells. Some monocytes circulate in the bloodstream and later in their life receive

immune signals from the lymphocytes that cause the monocytes to migrate into tissues and transform into tissuespecific macrophages. There they either wander freely through the connective tissue in organs or attach to the basement membranes of the tiny capillaries in those organs. Other monocytes differentiate directly into tissue-specific macrophages. Macrophages are concentrated and strategically located in the liver, lungs, and lymph nodes— organs that receive blood from parts of the body exposed to the outside world, such as the gastrointestinal or respiratory tract. Should the invading pathogen escape this early level of immune defense, other macrophages located in the spleen, kidney, joints, and brain provide a second level of defense. Together, monocytes and macrophages form what is known as the reticuloendothelial system (Fig. 3b), one major line of defense in the immune system.

Another major line of defense in the immune system is the lymphoid system, a set of glands, organs, and cells (Fig. 3c). The lymph nodes, which are distributed throughout the body, serve as way stations, storage facilities, and manufacturing and shipping sites for specific cells of the immune system, including the T and B lymphocytes (literally meaning cells of the lymph). In the process of maturing, the lymphocytes differentiate into hundreds of thousands of lymphocyte subgroups, each very small and each designed to recognize and mount a defense against a specific foreign protein, or antigen. But how does each antigen-specific subgroup prepare its attack when its target antigen enters the body?

Macrophages entering the lymph nodes or interacting with lymphocytes in tissues have the job of "presenting" foreign antigen to the appropriate lymphocyte subgoup and thereby activating it. More specifically, when macrophages engulf and digest foreign microbes or

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infected cells, they incorporate into their surface membranes the proteins of the foreign invaders (Fig. 4). The foreign antigens are inserted on the macrophage surface next to other normal receptors, called MHC antigens (for antigens of the major histocompatibility complex). The MHC antigens are part of the associative recognition network of surface receptors that enable the macrophages and lymphocytes to recognize each other as parts of the self and to receive appropriate instructions from each other. When a foreign antigen is present in the macrophage surface, only those lymphocytes that recognize or bind to both an MHC receptor and the specific foreign antigen are activated. Figure 4 illustrates this dual recognition by lymphocytes. In this case, we have chosen to show how a special type of lymphocyte called a T4 helper cell recognizes both an MHC II receptor and the antigen gp120, one of the envelope proteins of HIV. Although this example is particularly relevant for our story, it also illustrates the normal phenomenon of recognition between antigen-presenting macrophages and lymphocytes.

Figure 5 goes on to illustrate the many immune responses induced by the dual recognition between a T4 helper cell and an antigen-presenting macrophage. Contact between the T4-cell receptors and the MHC and foreign antigens of the macrophage stimulates the T4 lymphocyte to send out chemical instructions to other immune cells. The chemical instructions induce a variety of effects: they activate monocytes and macrophages and thereby enhance their ability to engulf and destroy the invading pathogen; they stimulate cytotoxic lymphocytes, called T8 killer cells, to proliferate and kill cells that display the foreign antigens on their surfaces; and they stimulate B lymphocytes (the B stands for bursal or bone marrow-derived) to proliferate and produce antigen-specific antibodies capable

ANTIGEN PRESENTATION TO T4 CELLS

Fig. 4. (a) A macrophage engulfs a foreign monocyte infected with HIV. Some virus particles have budded into a vacuole in the infected monocyte. (b) The engulfed cell is enclosed within a vacuole of the macrophage where it is partially digested by lysosomes and other enzymes. For purposes of illustration, some intact foreign antigens are shown inside the vacuole but, in reality, antigen is broken down into much smaller pieces. Foreign antigens as small as eight amino acids in length, when presented on the macrophage surface, may initiate an immune response. The large vacuole breaks up into smaller and smaller vacuoles that bring the foreign products to the cell surface where they are either released or are presented on the surface in conjunction with MHC II antigens produced by the macrophage. (c) Finally, the macrophage is shown presenting the foreign antigens, in this case gp120, to a T4 helper cell. The blowup shows the dual recognition by the T4 cell's receptor CD4 of both MHC II and gp120. Note that CD4 appears in conjunction with TCR (T cell receptor) and both are involved in the recognition of MHC II antigens on macrophages and other cells. The dual recognition by the T4 cell of both the self antigen MHC II and the foreign antigen stimulates the T4 cell to orchestrate a defense against the foreign invader.

of binding to the foreign antigen. The antibodies produced by B lymphocytes help the macrophages and other cells to carry out their function either as scavenger cells or as killer cells.

In addition to all this complex activity against a foreign invader, the body must keep the immune response from getting out of hand. Control is accomplished by conveniently activating other T lymphocytes, called T8 suppressor cells, which produce chemical messages capable of slowing or stopping the immune reactions. Thus, when the macrophages and lymphocytes interact, they mount

Infected Foreign Monocyte

Macrophage

(b) Macrophage Digests

Infected Foreign Cell and Presents Foreign Antigens on the Surface

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