Chédiak-Higashi Syndrome, also known as CHS, is a rare autosomal recessive disorder that was named after Alexander Moises Chediak and Ototaka Higashi. Although it was first discovered by the Cuban pediatrician Beguez-Cesar in 1943, it was Chediak and Higashi that significantly influenced our current understanding of CHS by identifying the hematopoietic nature of the syndrome (4). CHS is characterized by a number of sever immunological defects, such as oculocutaneous albinism, peripheral neuropathy, recurrent infections and enlarged intracellular lysosomes. Affected species range from humans over mice to mink and other mammals 1, 2mcwalt&shiflet.
The classic indication of CHS is the presence of large cytoplasmic granules within the circulating cells of the body. Among other things, these mutated granules include melanosomes, lysosomes, cytolytic granules and platelet dense granules, which result in defects in vesicle trafficking, vesicle fusion and vesicle formation. Similar characteristics and symptoms to human patients were found in animal homologues to CHS, such as the Aleutian mink and the beige mouse. In the beige mouse, changes in configuration of cell organelles, leading to the formation of large granules, and recurrent infection-CHS symptoms-were linked back to the beige gene, Lyst. Lyst was first mapped and sequence in 1996, which allowed the identification of the human LYST gene on chromosome 1. An 88% sequence homology was determined between the Lyst and LYST gene with 82% of proteins being identical 2, 4shiflet&Introne.
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In order to identify the function of the protein encoded by LYST, Stinchcombe, Page and Griffith intensively studied the effect of the LYST gene on the lytic ability of cytotoxic T lymphocytes (CTL), monitoring the development of wild-type CTL and CHS CTL. It was concluded that the recurrent pyogenic infections found in all CHS patients are due to the inability of the immune system to successfully remove the disease-causing pathogen from the body. In healthy individuals, cytotoxic CD 8 T cells are strongly involved in the immune response against intracellular infections, killing pathogen-infected cells. They contain lytic granules, storing cytotoxins and degradative hydrolases, such as perforins, granzymes and granulysin. Once activated through binding to the T cell receptor (TCR) with the respective MHC complex on the pathogen, CTL secret their lysosmal content, degrading the pathogen and reinitiating biogenesis and cytotoxin synthesis. In patients with the Chediak-Higashi Syndrome, there are a number of differences observed compared to wild-type CTL.
While the initial response of CHS cytotoxic T lymphocytes is identical to the lymphocytes in healthy organisms, the secretory lysosomes of the CHS CTL fuse together during the maturation step after T cell activation, resulting in a reduced number of internal lysosmes and a great increase in size of each individual lysosome3. This results in a decrease in chemotaxis of cytotoxic T cells and other phagocytes, inhibiting the fusion of pathogen containing endosomes and lysosomes in the cells. Bacteria and viruses within the phagosomes utilize this delay by replicate and escape degradation through cytotoxins and thereby cause recurrent infections 2shiflet. It can be concluded that even though the exact mechanism of the LYST gene remains unknown, its function is to prevent the abnormal formation of fused lysosomes.
Patients that exhibit characteristic symptoms for the symptom are tested by taking a blood smear and a skin biopsy. In case the test results are positive for CHS, both the blood smear and the skin biopsy portray giant granules in lymphocytes and other cells of the body. If the results of the first two tests are not indicative of whether or not a patient has the Chediak-Higashi syndrome, a cell count and additional genetic testing can be performed. Previous cell counts of white blood cells and platelets in individuals suffering under CHS have shown abnormally low numbers compared to healthy individuals. The purpose of genetic testing is the possible identification of a mutation of the CHS1 gene; even if the results of the above test would not allow an impervious diagnosis, a mutation of the LYST gene provides enough evidence to finalize the analysis.
Patients that are diagnosed with Chediak-Higashi syndrome face the problem that there is no specialized treatment for the disease. The recurrent infections that occur as a result of the above mentioned lack of pathogen degradation by cytotoxic T cells and natural killer cells (NK) are treated with antibiotics. Once patients enter the accelerated phase of the disease, in which defective lymphocytes undergo uncontrolled cell proliferation and invade major organs of the body and the bone marrow, antiviral and chemotherapeutic drugs are prescribed shiflet, medline. These drugs mostly target the viral infection (commonly Ebstein Barr Virus) that initially triggered the accelerated phase of CHS. However, these drugs are only a postponement to the inevitable and there is only one
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After entering the accelerated phase, there is only one therapeutic intervention left for doctors to treat CHS patients; bone marrow transplantations (BMT). Bone marrow transplantation (BMT) has been a successful way to treat and improve the condition of patients with the Chediak-Higashi syndrome. Replacing the infected hematopoetic system of a patient with a donor's reverts both the recurrent viral infection and the leukocyte disorder of the accelerated phase. The efficacy of allogeneic BMT has been confirmed in studies with beige mice and humans, indicating that it is a good last option for patients with accelerated phase of CHS as it prevents the reoccurrence of the accelerated phase several years after the procedure haddad. Despite its success, BMT still remains a risky procedure due to the many possibly lethal side effects which keep it from gaining wider acceptance 5tyndall.
Future Directions in the field:
A key achievement for the treatment of Chediak-Higashi syndrome would be the successful determination of the LYST protein function. As soon as the mechanism and the exact role of the LYST protein are known, scientists can work on manipulating of the mutated form of LYST to reverse the effect of the mutation. In theory, a reversal of mutation would result in an inhibition of the progression of CHS and even make bone marrow transplantation redundant. Since a small number of effective lymphocytes is sufficient to contain abnormally activated macrophages and natural killer cells and both recurrent infection and the accelerated phase can be prevented haddad.