Clinical Terms Related to the Lymphatic System and Immunity

asplenia (ah-sple'ne-ah) Absence of a spleen. immunocompetence (im"u-no-kom'pe-tens) Ability to produce an immune response to the presence of antigens. immunodeficiency (im"u-no-de-fish'en-se) Inability to produce an immune response. lymphadenectomy (lim-fad"e-nek'to-me) Surgical removal of lymph nodes.

lymphadenopathy (lim-fad"e-nop'ah-the) Enlargement of the lymph nodes.

lymphadenotomy (lim-fad"e-not'o-me) Incision of a lymph node.

lymphocytopenia (lim"fo-si"to-pe'ne-ah) Too few lymphocytes in the blood. lymphocytosis (lim"fo-si"to'sis) Too many lymphocytes in the blood.

lymphoma (lim-fo'mah) Tumor composed of lymphatic tissue.

lymphosarcoma (lim"fo-sar-ko'mah) Cancer within the lymphatic tissue. splenectomy (sple-nek'to-me) Surgical removal of the spleen. splenitis (sple-ni'tis) Inflammation of the spleen. splenomegaly (sple"no-meg'ah-le) Abnormal enlargement of the spleen.

splenotomy (sple-not'o-me) Incision of the spleen. thymectomy (thi-mek'to-me) Surgical removal of the thymus. thymitis (thi-mi'tis) Inflammation of the thymus.

Immunity Breakdown: AIDS

Natural History of a Modern plague

In late 1981 and early 1982, physicians from large cities in the United States began reporting to the Centers for Disease Control and Prevention cases of formerly rare infections in otherwise healthy young men. Some of the infections were prevalent in the general population, such as herpes simplex and cytomegalovirus, but in these young men were unusually severe. Oddly, some of the infections were caused by organisms known to infect only nonhuman animals. Other infections, particularly pneumonia caused by the microorganism Pneumocystis carinii and a cancer, Kaposi's sarcoma, were known only in individuals whose immune systems were suppressed (fig. 16B).

The bodies of the sick young men had become nesting places for all types of infectious agents, including viruses, bacteria, protozoans, and fungi. The infections were opportunistic, which means that they take advantage of a weakened immune system.

As the infections spread, a portrait of a lethal disease emerged. Acquired immunodeficiency syndrome, or AIDS, starts with recurrent fever, weakness, and weight loss. Then usually after a relatively healthy period, infections begin. Many patients die within two or three years of symptom onset, but the human immunodeficiency virus (HIV) that causes AIDS can be present for a decade or longer before a person feels ill. Five percent of infected people have remained healthy for more than fifteen years.

HIV has RNA as its genetic material. It is a type of RNA virus called a retrovirus, because it converts RNA information into DNA, the reverse of the usual direction of genetic information flow.

HIV infection gradually shuts down the immune system. First, HIV enters macrophages, impairing this first line of defense. In these cells and later in helper T cells, the virus adheres with its surface protein, called gp120, to two-coreceptors on the host cell surface, called CD4 and CCR5. Once the virus enters the cell, a viral enzyme reverse transcriptase, catalyzes the construction of a DNA strand complementary to the viral RNA sequence. The initial viral DNA strand replicates to form a DNA double helix, which enters the cell's nucleus and inserts into a chromosome. The viral DNA sequences are then transcribed and translated. The cell fills with viral pieces, which are assembled into complete new viral particles that eventually burst from the cell.

Once helper T cells begin to die at a high rate, bacterial infections begin, because B cells aren't activated to produce antibodies. Much later in infection, HIV variants arise that can bind to a receptor called CXCR4 that is found on cytotoxic T cells. This explains the longstanding mystery of how the virus kills these cells, which lack CD4 receptors. When HIV binds to the cyto-toxic cells, it triggers apoptosis. Loss of these cells renders the body very vulnerable to viral infections and cancer.

HIV has an advantage over the human immune system because it replicates quickly, changes quickly, and can hide. The virus is especially prone to mutation, because it cannot repair replication errors, and because those errors occur frequently — at a rate of 1 per every 5,000 or so bases — because of the "sloppiness" of reverse transcriptase. The immune system simply cannot keep up; antibodies against one viral variant are useless against another. For several years, the bone marrow produces 2 billion new T and B cells a day to counter the million to a billion new HIV particles that burst daily from shattered cells.

So genetically diverse is the population of HIV in a human host that within days of the initial infection, variants arise that resist the drugs used to treat AIDS. HIV's changeable nature has important clinical implications. Combining drugs that act in different ways provides the greatest chance of slowing the disease process. For example, two types of drugs, protease inhibitors and nucleoside analogs, intervene at different stages of HIV replication. When teamed early in infection, they may greatly slow the virus's progress. However, researchers are still not sure when to begin drug treatment. The policy of giving AIDS drug "cocktails" as soon as possible is being reconsidered, because such action may hasten the appearance and accumulation of drug-resistant strains of the virus.

A new type of drug has been in development since 1998, when X-ray crystallography showed a hidden side of HIV. The virus can evade detection by the immune system because it is cloaked in a halo of sugars that mimic those on human cells, as well as a layer of amino acids that frequently changes. The vulnerable portion of the viral surface that these layers protect assumes a pocket shape at the precise instant when the virus contacts the coreceptors on a helper T cell's surface. New drugs and vaccines will target this area.

A very promising approach to conquering AIDS is to discover how certain people resist infection, and then attempt to mimic their conditions with drugs. So far, researchers have identified four receptors or the molecules that bind to them that are altered by mutation to keep HIV out. To find these receptors, epidemiologists searched the DNA of people at high risk of HIV infection but who nevertheless have not become infected — people who had

unprotected sex with many partners, and people with hemophilia who had received HIV-tainted blood in the 1980s. Molecular biologists discovered the CCR5 receptor, and the epidemiologists soon found that people who had a piece missing from both copies of their CCR5 gene were among those who had, seemingly miraculously, avoided AIDS. Their CCR5 co-receptors were too stunted to reach the cell's surface. Like a ferry arriving at shore to find no dock, HIV has nowhere to bind in these lucky individuals. ■

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