C a s e f I l e

About one in 200,000 children in the United States are diagnosed yearly with chronic granulomatous disease (CGD); of these, around 90% are males. CGD is somewhat complex in its inheritance, but there are essentially two forms. The X-linked type occurs as a defective gene on the X chromosome and is more severe. Over half of all cases are X-linked. The autosomal defect is located on a different chromosome and tends to be milder. In both types, the genetic codes carry errors that prevent phagocytes from producing certain key metabolic enzymes.

The neutrophils and macrophages of CGD patients can carry out the usual phagocytic activities such as amoeboid motion, chemotaxis, engulfment, and digestion of microbes in phagocytic vesicles, but they are unable to actively kill certain types of aerobic pathogens. They lack the enzymes to synthesize the battery of reactive oxygen intermediates (ROIs) – superoxide ion, hydrogen peroxide, and hydroxyl radical – that are essential to kill these microbes. As a result, the ineffective phagocytes harbor live microbes that can break away and continue their infectious path. In time, these phagocytes shut down, die, and build up in the infected tissue in masses (granulomas).

■ Why would children with CGD be more prone to infections from fungi and bacteria and not viruses?

■ Why is interferon an effective treatment for CGD?

This case is a striking example of how important every element of immunity can be. Although the components do overlap in some of their effects, each one carries out some essential function that cannot be totally duplicated. CGD individuals have a mostly intact immune response, but they lack a complete phagocyte defense that comes into play early in the infection process. Phagocytes (neutrophils, monocytes, and macrophages) are most active against bacteria and eukaryotic pathogens, but they also are important participants in many other immune reactions.

The swelling and inflammation of the child’s bones (osteomyelitis) were triggered by the Aspergillus hyphae growing into bone cavities. The presence of these foreign cells initiated a series of local events, beginning with infiltration of phagocytes and other white blood cells into the infected area. The white blood cells released biochemical mediators that give rise to the classic inflammatory signals of rubor, calor, tumor, and dolor. These mediators dilate blood vessels, creating rubor or redness, which also has the effect of increasing the local temperature (calor). The reactions flood the site with tissue fluid and cause swelling (tumor) and pain (dolor).

Even people with healthy phagocytes can produce granulomas, but CGD individuals produce them in pathological amounts. The granulomatous nature of this disease is triggered by chronic inflammation and buildup of dead neutrophils that could not completely finish the job of clearing the pathogen. When the backup team of macrophages enters the scene to “clean up” the dead neutrophils and infection debris, it also is unable to resolve the inflammation and leaves behind large inactive packets of cells that remain in tissues for long periods of time.

The major infectious agents that invade CGD patients are catalase-producing aerobic bacteria and fungi. These types of organisms would usually be kept in check by normal phagocytes that literally douse them in toxic oxygen intermediates such as superoxide ions, hydroxyl radicals, and hypochlorites. Because CGD phagocytes lack these intermediates, they have little or no effect on organisms such as Staphylococcus, Klebsiella, Aspergillus, and Candida. Viruses are not a significant cause of opportunistic infections in these patients because viruses are not controlled by oxygen-based chemicals. They are eliminated by other immune defenses such as interferon.

The immune stimulant gamma interferon has been beneficial in resolving infections in CGD patients. This may be due to several factors. One contribution of interferon is to activate macrophages and enhance the effectiveness of phagocytosis. Another is that it modulates T cells that can destroy infectious agents without the need for phagocyte-killing mechanisms. Interferon is often prescribed in combination with antimicrobial drugs that target the pathogen. Since this disease is genetic, it must be treated continuously with long-term prophylactic medications and other therapies. There is no cure, but several trials of gene therapy to correct the genetic defect are in progress.

TAKE NOTE: NEUTROPHILS GIVE THEIR ALL

Neutrophils are truly one of the “workhorses” of innate immunity. In addition to their phagocytic functions, a recent discovery revealed that they also have a distinct system of capturing pathogens called neutrophil extracellular traps or NETS. Neutrophils are programmed to die after they have gone through their regular engulfment and killing of bacteria and other pathogens. But they undergo one last aggressive act while they are dying, which is to throw out a fibrous matrix that consists of their lysed DNA, enzymes, histones, and other cell contents that works outside the cell even after it is dead. This NET works at several levels to trap bacteria and fungi, degrade their virulence factors, kill them with microbicidal chemicals, and, to top it off, immobilize microbes and prevent them from spreading.

The absence of a sufficient immune response is called an immunodeficiency, which can be either congenital or acquired.

Дата добавления: 2015-06-04