Synergistic action of estradiol and myelin basic protein on mast cell secretion and brain myelin changes resembling early stages of demyelination.
Mast cells are known for their participation in immediate and, more recently, delayed hypersensitivity reactions. They have been found in the meninges and certain brain areas where they are strictly perivascular, in close apposition to neurons, and they are activated by direct nerve stimulation or by neuropeptides. Intracranial mast cells contain many vasoactive substances which can increase the permeability of the blood-brain barrier, proteolytic enzymes which can degrade myelin in vitro, as well as chemotactic molecules which can attract inflammatory molecules in vivo. Connective tissue mast cells, with which intracranial mast cells share many characteristics, contain cytokines which can cause inflammation directly. Multiple sclerosis is a human demyelinating disease of unknown etiology, with a high prevalence in women which results in penetration of blood-borne immune cells within the brain parenchyma and subsequent destruction of myelin. Here, we report that 17 beta-estradiol and myelin basic protein, a major suspected immunogen in multiple sclerosis, had a synergistic action on inducing mast cell secretion. This effect was more pronounced in Lewis rats, which are susceptible to the development of experimental allergic encephalomyelitis, an animal model for multiple sclerosis, than in Sprague-Dawley rats, which are fairly resistant. Moreover, 18 h incubation of purified peritoneal mast cells with homogeneic slices of brain white matter in the presence of 17 beta-estradiol and myelin basic protein resulted in myelin changes resembling early stages of brain demyelination, which were also more evident in Lewis rats than in Sprague-Dawley rats. These results support the notion that mast cells could participate in the pathophysiology of demyelinating diseases.
Theoharides
T C
TC
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111.
Dimitriadou
V
V
Letourneau
R
R
Rozniecki
J J
JJ
Vliagoftis
H
H
Boucher
W
W
D000818:Animals; D001921:Brain / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000378:metabolism*; D004357:Drug Synergism; D004958:Estradiol / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D066298:In Vitro Techniques; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D008854:Microscopy, Electron; D004676:Myelin Basic Protein / Q000494:pharmacology*; D009186:Myelin Sheath / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley
D004676:Myelin Basic Protein; D004958:Estradiol