Chdiakhigashi Syndrome

Charles M Pérou and Jerry Kaplan, Division of Cell Biology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, USA

Chédiak-Higashi syndrome (CHS) is an autosomal recessive disorder of humans that results in the formation of 'giant' intracellular vesicles. The formation of these large vesicles results in impaired function, which often compromises cellular activities. Many of the granule types affected in this disorder are required for proper immune cell function, and hence cause a severe immunodeficiency in afflicted individuals.

This rare human disorder has numerous pheno-

typically similar disorders in other species including beige mice, Aleutian minks, cats, cattle, and even killer whales. The beige mouse has been used as a model organism for the study of CHS for many decades, and much of what is known about CHS has been obtained through the study of these mice. Somatic cell fusion studies have suggested that beige mice, Aleutian minks and CHS patients have defects within homologous genes, therefore providing genetic evidence which supports the hypothesis that beige and CHS are genetically similar disorders.

CHS/beige primarily affects four classes of intracellular vesicles: lysosomes, melanosomes, platelet-dense granules and cytolytic granules (Figure 1). It is thought that the formation of these 'giant' vesicles is due to a malregulation of either vesicle fusion or fission. The net result of this single gene defect is a reduction in the number of vesicles and an increase in their average size. The mouse beige gene has recently been identified and will be discussed below.

The clinical phenotypes in CHS/beige are the formation of giant vesicles, pigment dilution, a bleeding tendency and a severe immunodeficiency. Giant lysosomes are found in almost every cell of the body. This defect causes impaired lysosome function, which is tolerated by many cell types but which may ultimately kill others (e.g. neurons). The formation of giant melanosomes causes a pigment dilution that results in a near albino appearance of most CHS patients. In these individuals, the hair, eyes, skin, or any combination of the three, are the sites of pigment alterations. In mice and other mammals this defect results in an alteration in coat color. Platelet-dense granules also form anomalous large structures that result in a platelet storage pool deficiency. Due to this deficiency, CHS patients and beige mice have decreased platelet aggregation and a bleeding tendency.

It is within the immune system that the CHS/beige defect exerts its most profound and deadly effects. The cell types known to show the CHS defect of enlarged granules include CD8+ T cells, eosinophils, basophils, neutrophils, mast cells, macrophages, megakaryocytes, B cells and natural killer (NK) cells. Each of these cell types contains large lysosomes as well as enlarged specialized granules; for example, neutrophils often contain large granules derived from the fusion of azurophilic and specific granules. Neutrophils from affected individuals also show defective chemotaxis; they have normal bacterial phagocytosis but impaired intracellular killing of bacteria. It has been demonstrated for neutrophils and macrophages that the newly formed phagosomes often fail to fuse with lysosomes, thereby allowing the internalized bacteria to survive longer and to multiply.

A second cell type profoundly affected by the CHS/beige defect is the NK cell. The numbers of NK cells and their target specificity and binding appear normal, but these cells are unable to kill their targets. The beige mouse is often used as a NK cell-deficient animal in order to study the role of NK cells in various immune responses. It is believed that defective NK cell activity is due to impaired exocytosis of cytolytic granules. A very similar defect is also observed

Figure 1 Bone marrow macrophages from (A) a C57BL/6J mouse and (B) a C57BLV6J-bg/bg mouse (100 x magnification). Note the 'giant' lysosomes clustered near the nucleus in (B). (Reproduced with permission of Company of Biologists Ltd from Perou CM and Kaplan J (1993) Chediak-Higashi-syndrome is not due to a defect in microtubulo based lysosome mobility. Journal of Cell Science 106: 99-107.)

Figure 1 Bone marrow macrophages from (A) a C57BL/6J mouse and (B) a C57BLV6J-bg/bg mouse (100 x magnification). Note the 'giant' lysosomes clustered near the nucleus in (B). (Reproduced with permission of Company of Biologists Ltd from Perou CM and Kaplan J (1993) Chediak-Higashi-syndrome is not due to a defect in microtubulo based lysosome mobility. Journal of Cell Science 106: 99-107.)

in CD8+ T cells. The decreased activity of these cell types can be overcome in vitro by chronic stimulation with exogenously added cytokines and longer incubation times. Unfortunately, these results cannot be replicated in vivo. Other cell types of the immune system show the CHS defect (e.g. B cells, eosinophils, basophils and mast cells), but their function does not appear to be significantly compromised. For example, CHS patients and beige mice are capable of making antibodies against invading organisms.

Until the advent of antibiotics, infections killed most CHS patients. Today, the most deadly effect of the CHS mutation is the 'accelerated phase'. The accelerated phase is a mononuclear lymphoma-like cellular infiltrate that invades the major organs of the body. This infiltrate, along with the bleeding tendency, causes major organ failure, hemorrhage and the death of the afflicted individual. It is thought that the accelerated phase is triggered by a viral infection but the precise virus or even the cellular origin of this lymphoma, is not known.

The only cure for CHS is to prevent the accelerated phase. This can be done by whole body irradiation to kill the endogenous bone marrow that gives rise to the lymphoma, followed by allogeneic bone marrow transplantation. This treatment has worked in many cases, and has prevented the accelerated phase from recurring for up to 13 years in one patient. As these CHS patients age, however, other problems may arise, such as neurologic defects due to the loss of neurons. CHS is a candidate for gene replacement in hematopoetic stem cells, which would cure the immunodeficiency and prevent the accelerated phase, while also circumventing the problem of graft-versus-host disease.

The mouse beige gene has recently been identified using a Yeast Artificial Chromosome complementation approach. The human homolog of the beige gene was then isolated and shown to contain mutations within CHS patients. These data demonstrate that beige and CHS are due to mutations within orthologous genes. The Beige/CHS protein is approximately 3800 amino acids in length and contains a protein-protein interaction motif (WD40 repeats) and a highly conserved domain of unknown function. This conserved domain identifies homologs in Saccharontyces cerevisiae and Caenorhabditis ele-gans, demonstrating that this protein is conserved throughout evolution. The overall sequence of the

Beige/CHS protein is novel and gives few clues as to its biochemical function.

See also: Exocytosis; Hematopoietic stem cell transplantation; Immunodeficiency, animal models; Natural killer (NK) cells; Phagocytosis.

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