Huitinga Inge, Erkut Zeynel A, van Beurden Denis, Swaab Dick F
Netherlands Institute for Brain Research, Amsterdam, The Netherlands.
Ann N Y Acad Sci. 2003 May;992:118-28. doi: 10.1111/j.1749-6632.2003.tb03143.x.
During multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), activation of the hypothalamo-pituitary-adrenal (HPA) axis is considered to modulate the immune system in such a way that the probability of recovery from a relapse is increased. In a series of postmortem studies we observed a significant activation of corticotropin releasing hormone (CRH) neurons and increased cortisol in the cerebrospinal fluid (CSF) of MS patients, indicating activation of the HPA axis in this disease. On the other hand, sepsis, while elevating cortisol in control subjects, did not associate with a further increase of cortisol in MS patients. Thus, the activated HPA-system in MS does not respond to an acute inflammatory stimulus. In order to investigate the role of chronic inflammation in the CNS in the activation of the HPA axis in MS, MS lesions in the hypothalamus were quantified and interleukin (IL)-6 levels in the CSF were determined. There was no difference in IL-6 levels between MS and control patients. A positive correlation was found between cortisol and IL-6 in control subjects with sepsis, but not in MS patients with sepsis or MS and control groups without sepsis. Thus, IL-6 in the CSF of MS patients is not the cause of the activation of the HPA system in MS. We found a remarkably high incidence (95% of the patients) of MS lesions in the hypothalamus, of which the majority (60%) were active. The more active lesions were present in the hypothalamus, the shorter the disease duration to the moment of death, indicative of a worse disease course. Preliminary data show suppression of the activation of CRH neurons by active hypothalamic MS lesions. We propose that this suppression of CRH neurons by active hypothalamic MS lesions causes the concomitant unfavorable disease course via an inadequate cortisol response during relapses of MS.
在多发性硬化症（MS）——一种中枢神经系统（CNS）的炎性脱髓鞘疾病中，下丘脑-垂体-肾上腺（HPA）轴的激活被认为以某种方式调节免疫系统，从而增加从复发中恢复的可能性。在一系列尸检研究中，我们观察到MS患者脑脊液（CSF）中促肾上腺皮质激素释放激素（CRH）神经元显著激活且皮质醇增加，表明该疾病中HPA轴被激活。另一方面，脓毒症虽然会使对照受试者的皮质醇升高，但与MS患者皮质醇的进一步增加无关。因此，MS中激活的HPA系统对急性炎症刺激无反应。为了研究中枢神经系统慢性炎症在MS中HPA轴激活中的作用，我们对下丘脑的MS病变进行了量化，并测定了脑脊液中的白细胞介素（IL）-6水平。MS患者和对照患者的IL-6水平没有差异。在患有脓毒症的对照受试者中发现皮质醇与IL-6呈正相关，但在患有脓毒症的MS患者或无脓毒症的MS和对照组中未发现这种相关性。因此，MS患者脑脊液中的IL-6不是MS中HPA系统激活的原因。我们发现下丘脑MS病变的发生率非常高（95%的患者），其中大多数（60%）是活跃的。下丘脑存在的活跃病变越多，到死亡时的病程越短，表明疾病进程越差。初步数据显示活跃的下丘脑MS病变可抑制CRH神经元的激活。我们提出，活跃的下丘脑MS病变对CRH神经元的这种抑制通过MS复发期间皮质醇反应不足导致了伴随而来的不良疾病进程。
