Increased Immune Complexes of Hypocretin Autoantibodies in Narcolepsy

Abstract

BackgroundHypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. However, the mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. Here we studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes.MethodologySerum levels of free and dissociated (total) autoantibodies reacting with hypocretin-1 peptide were measured by enzyme-linked immunosorbent assay and analyzed with regard to clinical parameters in 82 subjects with narcolepsy-cataplexy, narcolepsy without cataplexy or idiopathic hypersomnia and were compared to 25 healthy controls.Principal FindingsSerum levels of total but not free IgG autoantibodies against hypocretin-1 were increased in narcolepsy-cataplexy. Increased levels of complexed IgG autoantibodies against hypocretin-1 were found in all patients groups with a further increase in narcolepsy-cataplexy. Levels of total IgM hypocretin-1 autoantibodies were also elevated in all groups of patients. Increased levels of anti-idiotypic IgM autoantibodies reacting with hypocretin-1 IgG autoantibodies affinity purified from sera of subjects with narcolepsy-cataplexy were found in all three groups of patients. Disease duration correlated negatively with serum levels of hypocretin-1 IgG and IgM autoantibodies and with anti-idiotypic IgM autoantibodies.ConclusionCentral hypersomnias and particularly narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation.

Sex-related effects of nutritional supplementation of Escherichia coli: Relevance to eating disorders

“…Increased levels of total (dissociated) a-MSH IgG in E. coli K12-treated rats also supported existence of higher affinity autoAbs for a-MSH in female rats, possibly forming immune complexes with either antigenic microbial proteins [35] or with antiidiotypic antibodies [36]. In contrast, increased response in a-MSH IgM class of autoAbs was observed only in males, indicating that E. coli K12 bacteria were rather new to male but not female rats.…”

Vaccine-associated inflammatory diseases of the central nervous system

“…However, efforts to identify specific antibodies against orexin, hypothalamic neurons, or neuronal antigens such as N-methyl-D-aspartate receptor, and contactin-associated protein 2 in both sporadic and postvaccination narcolepsy were either negative or inconclusive [136,[151][152][153][154][155]. Although some sporadic narcoleptic patients have elevated levels of autoantibodies against tribbles homologue 2 [156][157][158], this was not the case in Pandemrixassociated narcolepsy [159].…”

The autoimmune basis of narcolepsy

“…Many of the findings were either negative or inconclusive, though a humoral contribution cannot be completely ruled out as an important component [33]. Recent studies have shown altered levels of total IgG and hypocretin-specific IgM in narcoleptic patients, though these findings were not specific to patients with low levels of hypocretin [51, 52]. Using a transgenic mouse model to identify proteins co-localized with hypocretin, researchers were able to detect autoantibodies against tribbles homologue 2 (TRIB2) in the serum of 14% of narcoleptic individuals compared to 5% in controls [53]*.…”