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Correction of characteristic abnormalities of microtubule function and granule morphology in Chediak-Higashi syndrome
Abstract:
Chediak-Higashi (CH) syndrome is a genetic disorder of children and certain animal species including the beige mouse. We have previously described a membrane abnormality in CH mouse polymorphonuclear leukocytes (PMH). Whereas normal mouse PMN do not form surface caps with concanavalin A except after treatment with agents such as colchicine that inhibit microtubule assembly, CH mouse PMN show spontaneous cap formation. This capping is inhibited by 3',5 cyclic guanosine monophosphate and by the cholinergic agonists carbamylcholine and carbamyl beta-methylcholine that increase 3',5' cyclic guanosine monophosphate generation. These data suggested that microtubule function may be impaired in CH syndrome perhaps secondary to an abnormality in 3',5' cyclic guanosine monophosphate generation. The cholinergic agonists were also shown to prevent development of the giant granules that are pathognomonic of CH syndrome in embryonic fibroblasts isolated from CH mice and cultured in vitro. In this report it is shown that an extreme degree of spontaneous concanavalin A cap formation is also characteristic of peripheral blood PMN from two patients with CH syndrome. This indicates an abnormality of microtubule function in CH syndrome in man. 3',5' cyclic guanosine monophasphate, carbamylcholine, and carbamyl beta-methylcholine reduce spontaneous capping in CH cells. In addition, it is shown that monocytes isolated from the patients' blood and incubated in tissue culture generate a large complement of abnormal granules. When the same cells mature in vitro in the presence of carbamylcholine or carbamyl beta-methylcholine, the proportion of cells containing morphologically normal granules is significantly increased. These responses can be reproduced in vivo in the beige (CH) mouse. Animals treated for 3 wk and longer with carbamylcholine or carbamyl beta-methylcholline show normal granule morphology and a normal degree of concanavalin A cap formation in peripheral blood PMN leukocytes.
Insights
Chediak-Higashi syndrome, a genetic disorder, involves impaired microtubule function, evidenced by abnormal cell capping and giant granules. Cholinergic agonists like carbamylcholine show promise in correcting these defects in patients and beige mice.
Area of Science:
- Cell Biology
- Immunology
- Genetics
Background:
- Chediak-Higashi (CH) syndrome is a rare genetic disorder affecting children and animals.
- CH syndrome is characterized by giant granules and impaired immune cell function.
- Previous studies identified membrane abnormalities in CH mouse polymorphonuclear leukocytes (PMN).
Purpose of the Study:
- To investigate microtubule function abnormalities in human CH syndrome.
- To explore the therapeutic potential of cholinergic agonists in CH syndrome.
- To determine if CH syndrome defects can be corrected in vitro and in vivo.
Main Methods:
- Examined concanavalin A capping in peripheral blood PMN from CH patients.
- Assessed granule formation in patient-derived monocytes cultured in vitro.
- Administered cholinergic agonists (carbachol, bethanechol) to CH patients and beige mice.
- Evaluated granule morphology and PMN capping in treated subjects.
Main Results:
- CH patient PMN exhibited spontaneous concanavalin A capping, indicative of microtubule dysfunction.
- Cholinergic agonists inhibited spontaneous capping and reduced giant granule formation in patient cells.
- In vivo treatment of beige mice with cholinergic agonists normalized PMN capping and granule morphology.
Conclusions:
- Human CH syndrome involves impaired microtubule function, similar to the beige mouse model.
- Cholinergic agonists demonstrate therapeutic potential for correcting cellular defects in CH syndrome.
- Targeting microtubule and cyclic nucleotide pathways may offer treatment strategies for CH syndrome.
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