Anti-Hu antibodies activate enteric and sensory neurons

Abstract

IgG of type 1 anti-neuronal nuclear antibody (ANNA-1, anti-Hu) specificity is a serological marker of paraneoplastic neurological autoimmunity (including enteric/autonomic) usually related to small-cell lung carcinoma. We show here that IgG isolated from such sera and also affinity-purified anti-HuD label enteric neurons and cause an immediate spike discharge in enteric and visceral sensory neurons. Both labelling and activation of enteric neurons was prevented by preincubation with the HuD antigen. Activation of enteric neurons was inhibited by the nicotinic receptor antagonists hexamethonium and dihydro-β-erythroidine and reduced by the P2X antagonist pyridoxal phosphate-6-azo (benzene-2,4-disulfonic acid (PPADS) but not by the 5-HT3 antagonist tropisetron or the N-type Ca-channel blocker ω-Conotoxin GVIA. Ca++ imaging experiments confirmed activation of enteric neurons but not enteric glia. These findings demonstrate a direct excitatory action of ANNA-1, in particular anti-HuD, on visceral sensory and enteric neurons, which involves nicotinic and P2X receptors. The results provide evidence for a novel link between nerve activation and symptom generation in patients with antibody-mediated gut dysfunction.

Autoimmune encephalitis and gastrointestinal dysmotility: achalasia, gastroparesis, and slow transit constipation

“…The RNA binding proteins HuB, HuC, and HuD are specifically expressed in neurons and located in the nucleus or cytoplasm. The results provided evidence for a novel link between nerve activation and symptom generation in patients with antibody-mediated gut dysfunction [10]. It is, therefore, very likely, that at least part of the gastrointestinal dysmotility in our patient was caused by direct alteration of neuronal activity within the enteric nervous system through ANNA-1 and SOX-1 AA.…”

“…The antibody-triggered autoimmune inflammation may disturb all levels of the gut-brain axis including brain, spinal cord, peripheral, and, particularly, the enteric nervous system. This has been shown by immunohistochemical staining of neurons and glia cells within the enteric nervous system of the gut [2,[10][11][12]. Furthermore, a direct excitatory action of ANNA-1, in particular anti-HuD IgGs on human and guinea pig enteric neurons as well as on mouse visceral afferents, which involves nicotinic and P2X receptors, could be demonstrated recently [10].…”

“…This has been shown by immunohistochemical staining of neurons and glia cells within the enteric nervous system of the gut [2,[10][11][12]. Furthermore, a direct excitatory action of ANNA-1, in particular anti-HuD IgGs on human and guinea pig enteric neurons as well as on mouse visceral afferents, which involves nicotinic and P2X receptors, could be demonstrated recently [10]. The RNA binding proteins HuB, HuC, and HuD are specifically expressed in neurons and located in the nucleus or cytoplasm.…”

“…2 Esophageal high-resolution manometry showed typical achalasia type II according to the Chicago classification [7] with incomplete/ absent lower esophageal (LES) relaxation and aperistalis with pan-esophageal pressurization of the tubular esophagus. vates enteric neurons directly and, in the long-term, evokes neurodegeneration [10]. The antibody-triggered autoimmune inflammation may disturb all levels of the gut-brain axis including brain, spinal cord, peripheral, and, particularly, the enteric nervous system.…”

The enteric nervous system: “A little brain in the gut”

“…Chronic exposure of enteric neurons to anti-Hu containing patient serum causes neuronal damage. Even more fascinating is the finding that acute application of the patient serum for only a few hundreds of milliseconds evokes immediate spike discharge involving interaction between anti-HuD and nicotinic receptors on enteric neurons (Li et al, 2016a).…”