Antibodies against cell adhesion molecules and neural structures in paraneoplastic neuropathies

Abstract

ObjectiveParaneoplastic neurological syndromes (PNS) are rare neurological disorders in which ectopic expression of neural antigens by a tumor results in an autoimmune attack against the nervous system. Onconeural antibodies not only guide PNS diagnosis but may also help detecting underlying malignancies. Our project aims to uncover new potential antibodies in paraneoplastic neuropathies (PN).MethodsThirty‐four patients fulfilling diagnostic criteria of possible (n = 9; 26.5%) and definite (n = 25; 73.5%) PN without onconeural antibodies and 28 healthy controls were included in our study. Sera were tested for known antibodies against neural cell adhesion molecules and screened for novel IgG and IgM reactivities against nerve components: dorsal root ganglia (DRG) neurons, motor neurons, and Schwann cells. Patients showing autoantibodies against any of these cell types were used for immunoprecipitation (IP) studies.ResultsOverall, 9 (26.5%) patients showed significant reactivity against DRG neurons, motor neurons, or Schwann cells, whereas 5 (17.9%) healthy controls only showed moderate reactivity. Compared with control sera, serum samples from patients with paraneoplastic sensory‐motor neuropathies had a higher frequency of IgM antibodies against Schwann cells (0% vs. 40%; P = 0.0028). No novel antigens were identified from our IP experiments. Antibodies against the neural adhesion molecules CNTN1, NF155, NF140, NF186, NCAM1, L1CAM, and the CNTN1/CASPR1 complex were not detected in patients with PN. One (2.9%) patient with CIDP and thymoma had CASPR2 antibodies.InterpretationAlmost 30% of patients with PN harbor antibodies targeting neural structures, suggesting that novel neoplasm‐associated antigens remain to be discovered.

Identification of enhancer regulatory elements that direct epicardial gene expression during zebrafish heart regeneration

“…To prioritize a list of candidates for functional validation of enhancer activity, we first examined the top 20 distal regions with the highest fold increases in accessibility during heart regeneration (Figure 3A). These peaks were assigned to nearest genes, which included fibronectin 1a ( fn1a ) - an epicardially expressed gene that is required for zebrafish heart regeneration (Wang et al, 2013), neural cell adhesion molecule 1a ( ncam1a ) - a gene involved in axon development (Siles et al, 2018) (listed by the enrichment annotation results in Figure 2E and Table S3), repulsive guidance molecule BMP co-receptor b ( rgmb ) – encoding a TGF-β superfamily signaling component that participates in neuronal development (Liu et al, 2016; Samad et al, 2005) (Table S3), and guanine nucleotide binding protein, alpha inhibiting activity polypeptide 3 ( gnai3 ) – encoding a G protein. We next combined the bulk RNA-seq and ATAC-seq datasets and identified 3,026 ATAC-peaks with their related 1,008 genes and RNA levels, with both features increased at 3 dpa (Figure 3B, red dots; Figure 3C; Tables S4, S5).…”

“…The human homolog NCAM1 encodes a cell adhesion protein of the immunoglobulin superfamily that regulates cell-cell and cell-matrix interactions during development and differentiation processes (Duncan et al, 2021; Siles et al, 2018). The Zebrafish Regeneration Database recorded that ncam1a RNA levels increase during heart, fin, or spinal cord regeneration (Figure S4).…”

Acute anti-Ma2 paraneoplastic encephalitis associated to pembrolizumab: a case report and review of literature

“…Paraneoplastic neurological syndromes (PNS) are rare disorders in which the ectopic expression of neural antigens by tumor cells triggers the production of onconeural Abs. Although onconeural Abs have not been demonstrated to be pathogenic, their expression is often associated to a neurological impairment due to an autoimmune or inflammatory response (8). Several Abs have been identified, being anti-Hu and anti-Yo the most frequent.…”

Distinct clinical characteristics of paraneoplastic optic neuropathy

“…When neuro-ophthalmological symptoms are the first presentation of a PNS, the recognition of the disorder as paraneoplastic can be difficult. Recent progress in the serological screening of paraneoplastic antibodies and diagnostic imaging techniques to detect malignancies has enabled a broadening of the concept of paraneoplastic neurological syndromes, including paraneoplastic neuropathy, with integrated non-traditional clinical features 14. The Paraneoplastic Neurological Syndrome Euronetwork defined six antibodies (anti-Hu, Yo, CV2/CRMP-5,Ri, Ma2 and amphiphysin) as being ‘well characterised’ for PNS, which can help guide the diagnosis of PNS in spite of whether the presence of an underlying malignancy or not 15–17.…”