Staines Donald R
Gold Coast Public Health Unit, 10-12 Young Street, Southport 4215, Qld, Australia.
Med Hypotheses. 2004;62(5):646-52. doi: 10.1016/j.mehy.2004.01.012.
Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory. Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to smaller peptide fragments by antibody hydrolysis. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Vasoactive neuropeptides are widely distributed in the body particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, nitric oxide, endogenous opioids and insulin, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault, promotion of neural development and the maintenance of homeostasis. This paper describes a biologically plausible mechanism for the development of CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection, significant physical exercise or de novo. It is proposed that release of these substances is accompanied by a loss of tolerance either to them or their receptor binding sites in CFS. Such an occurrence would have predictably serious consequences resulting from compromised function of the key roles these substances perform. All documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation. Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition. The novel status of these substances together with their extremely small concentrations in blood and tissues means that clinical research into them is still in its infancy. A biologically plausible theory of CFS causation associated with vasoactive neuropeptide dysfunction would promote a coherent and systematic approach to research into this and other possibly associated disabling conditions.
慢性疲劳综合征是一种以长期疲劳和身体虚弱为特征的疾病，虽然尚未证实存在持续性感染，但大多与感染后后遗症有关。免疫异常很可能存在，在分子模拟和不适当的免疫记忆背景下，这可能与一组不断扩大的血管活性神经肽有关。包括血管活性肠肽（VIP）和垂体腺苷酸活化多肽（PACAP）在内与血管活性神经肽属于促胰液素/胰高血糖素超家族，具有激素、神经递质、免疫调节剂和神经营养因子的作用。它们很容易被抗体水解为较小的肽片段。它们及其结合位点具有免疫原性，已知与一系列自身免疫性疾病有关。血管活性神经肽广泛分布于体内，尤其是在中枢、自主和外周神经系统，在肠道、肾上腺、生殖器官、脉管系统、血细胞和其他组织中也已被发现。它们在维持器官的血管血流、体温调节、记忆和注意力方面起着至关重要的作用。它们是乙酰胆碱、一氧化氮、内源性阿片类物质和胰岛素的共同递质，是具有主要抗炎活性的强效免疫调节剂，在保护神经系统免受毒性攻击、促进神经发育和维持体内平衡方面具有重要作用。本文描述了一种基于感染、大量体育锻炼或新发疾病后对血管活性神经肽免疫耐受性丧失而导致慢性疲劳综合征发生的生物学上合理的机制。有人提出，在慢性疲劳综合征中，这些物质的释放伴随着对它们或其受体结合位点耐受性的丧失。这种情况将因这些物质所发挥的关键作用功能受损而产生可预见的严重后果。慢性疲劳综合征所有已记录的症状都可以用血管活性神经肽受损来解释，即通过受损的乙酰胆碱活性导致疲劳和神经系统功能障碍，通过一氧化氮和内源性阿片类物质功能障碍导致肌痛，通过过氧亚硝酸盐和腺苷功能障碍导致化学敏感性，以及通过免疫调节变化导致免疫紊乱。针对这些物质或其受体建立的异常免疫记忆可能是这种疾病病程迁延的原因。这些物质的新特性以及它们在血液和组织中的极低浓度意味着对它们的临床研究仍处于起步阶段。一种与血管活性神经肽功能障碍相关的慢性疲劳综合征病因的生物学上合理的理论将促进对这一疾病以及其他可能相关的致残性疾病进行连贯和系统的研究。
