Autoimmune dysfunction of certain vasoactive
neuropeptides (VNs) has been postulated as a contributing cause of
sudden infant death syndrome (
SIDS),
chronic fatigue syndrome (CFS),
Gulf War syndrome (GWS) and other
fatigue-related disorders. This family of VNs includes
pituitary adenylate cyclase activating polypeptide (
PACAP),
vasoactive intestinal peptide (VIP) and
calcitonin gene related peptide (CGRP). The postulated mechanism is compromise of
adenylate cyclase activation, a vital and unique step in
cyclic AMP production from
ATP, through autoimmune dysfunction of VNs, their receptors or their genes possibly involving
cytosine-
phosphate-
guanine (CpG) fragments. CpG fragments are immunomodulatory dinucleotides serving as 'friend or foe' recognition systems to differentiate bacterial and viral (hypomethylated CpG) from mammalian (methylated CpG)
DNA. However hypomethylation disorders affecting these fragments in mammals may convert them to dysfunctional states by promoting autoimmune inflammatory reactions. Epigenetic mechanisms acting on gene promoter regions may contribute to the development of VN autoimmune
fatigue-related disorders through CpG fragments located in vital segments of VN/receptor genes by causing signalling defects with profound implications for VN function.
Neurotransmitter dysfunction particularly glutamatergic transmission could also result with disruption of neuronal cellular biochemical functions such as
ammonia regulation. Endosomal acidity and mitochondrial membrane potential modifiers such as
chloroquine, together with immunoregulatory
therapies, may have therapeutic implications in protecting against these apparent autoimmune disorders. This paper examines specific epigenetic and biochemical mechanisms possibly mediated by VN or receptor genes resulting in postulated VN autoimmune
fatigue-related disorders. These mechanisms may have implications for treatment and prevention options for VN autoimmune disorders. VN autoimmune processes have implications for military medicine where radiological, chemical and
biological agents may play an important role in pathogenesis.