Scientists are working to uncover the missing or defective genes and associated proteins that underlie CGD. This information can be used to develop more targeted approaches to therapy. Researchers may be able to develop drugs that either replace critical missing proteins or stimulate their production in cells. In the future, doctors may also be able to replace the defective genes in CGD patients' phagocytes with the correct ones.
How phagocytes kill bacteria or fungi
Normally, phagocytes envelope invading bacteria or fungi and kill them with hydropgen peroxide----- key to the cell's defense mechanism. Contact with an invading organism triggers many chemical reactions that lead to the production of hydrogen peroxide.
One of the initial reactions, conversion of glucose to water, causes release of excess electrons. Phagocytes have a special, four-protein enzyme system that picks up these excess electrons and combines them with oxygen, which was released from other chemical reactions in the cell. In the respiratory burst, the oxygen is converted to a highly energized form, called superoxide. It quickly reacts with wled superoxide. It quickly reacts with water to form hydrogen peroxide. The hydrogen peroxide is changed by an enzyme into bleach and the hydrogen peroxide kill the invading organisms.
Proteins Involved in Genetic Types of CGD
| % of CGD | Mode of | Group | |
| Protein | Cases | Inheritance | Affected |
| 1. cytochrome b, large subunit | 60% | X-Linked Inheritance | males only |
| 2. cytochrome b, small subunit | 5% | autosomal-recessive | males and females |
| 3. cytosol protein, 47K | 30% | autosomal-recessive | males and females |
| 4. cytosol protein, 65K | 5% | autosomal-recessive | males and females |
In CGD, one of the enzyme system's four proteins is either missing or defective. Therefore, the excess electrons do not combine with oxygen, no superoxide is made, and no hydrogen peroxide is produced. The phagocytes are unable to kill bacteria or fungi normally.
There are four genetically distinct types of CGD, each corresponding to an inherited abnormalistinct types of CGD, each corresponding to an inherited abnormallity of one of the four proteins (see table above). The autosomal recessive forms affect both males and females.
Recent studies by NIAID scientists and others have identified a number of proteins that are missing in CGD
patients. Although each protein plays a slightly different role, all are necessary for the respiratory burst,
the process that is essential for phagocytes to perform their disease-fighting function. The X-linked form
of CGD appears to be related to a special membrane protein, called cytochrome b558. The autosomal recessive
form of the disease appears to involve defects in the cytosol, the fluid present inside the phagocyte itself.
Two cytosol proteins have thus far been identified that play crucial roles in the respiratory burst.
Another experimental approach that has been tried in a few centers is bone marrow transplantation. By transfusing healthy bone marrow into a CGD patient, the specific defect of the immune system may be corrected. The major difficulties with this procedure today are the problem with rejection of the marrow by the recipient and the risk that the transplanted cells themselves may attack the donor recipient. An additional problem is the difficulty of finding suitable donors whose bone marrow is least likely to be rejected. In view of the potential complications of bone marrow transplnatation, most physicians do not recommend this approach.end this approach.
Recent achievements have moved scientists one step closer to their ultimate goal: to coreect CGD by replacing the missing proteins or by replacing the defective genes with normal ones. NIAID scientists cloned the gene for one important protein involved in 85 percent of all autosomal recessive CGD and about one-third of all cases of CGD. In laboratory experiments, the protein made by the clones gene restored normal function to patients' defective cells. Other investigators have identified and clone the gene involved in X-linked CGD. It might one day be possible to replace defective CGD genes with ones that would allow phagocytes to manufacture the proteins needed to produce toxic oxygen compounds. Many questions remain about gene therapy, but both gene therapy and protein replacement therapy remain exciting prospects for the future of CGD treatment.
The rapid pace of immunologic research today brings hope that CGD and many other immune deficiency diseases will one day be conquered.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
National Institw.nih.gov/">National Institute of Health
National Institute of Allergy and Infectious Diseases
Division of Intramural Research
Prepared by the NIAID
Office of Communications
