Impaired hypothalamus-pituitary-adrenal axis activity and more severe multiple sclerosis with hypothalamic lesions.
In this postmortem study, we investigated the relationship between multiple sclerosis (MS) lesions in the hypothalamus and the state of activity of corticotropin-releasing hormone (CRH)-producing neurons that control the hypothalamus-pituitary-adrenal (HPA) axis. A high incidence (15/16) of MS lesions was found in the hypothalamus, of which more than 50% was active, that is, contained activated macrophages. MS patients have increased numbers of CRH-immunoreactive neurons coexpressing vasopressin (CRH/VP neurons), a sign of chronic activation of CRH neurons and increased CRH mRNA expression. Active MS lesions correlated with a low number of hyperactive CRH/VP neurons. High human leukocyte antigen (HLA)-DR, -DP, -DQ expression, a measure for macrophage and microglial activation, correlated with low CRH mRNA expression. The nearer the HLA expression was situated to the CRH neurons, the stronger the inhibiting effect, suggesting that activated microglial cells or macrophages suppress these neurons. The more active MS lesions were present in the hypothalamus, the shorter was the disease duration until the moment of death, indicating an unfavorable course of the disease. Thus, MS patients have a chronically activated CRH system, but, in the subgroup of patients with active MS lesions in the hypothalamus, this activation is impaired and the disease course is worse.
Huitinga
Inge
I
Netherlands Institute for Brain Research, Amsterdam, The Netherlands. i.huitinga@nih.knaw.nl
Erkut
Zeynel A
ZA
van Beurden
Denis
D
Swaab
Dick F
DF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D005260:Female; D006680:HLA Antigens / Q000502:physiology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008262:Macrophage Activation / Q000502:physiology; D008297:Male; D017628:Microglia / Q000502:physiology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis; D014667:Vasopressins / Q000378:metabolism
D006680:HLA Antigens; D012333:RNA, Messenger; D014667:Vasopressins; D003346:Corticotropin-Releasing Hormone