Molecular dissection of an immunodominant epitope in Kv1.2-exclusive autoimmunity.

Introduction: Subgroups of autoantibodies directed against voltage-gated potassium channel (Kv) complex components have been associated with immunotherapy-responsive clinical syndromes. The high prevalence and the role of autoantibodies directly binding Kv remain, however, controversial. Our objective was to determine Kv autoantibody binding requirements and to clarify their contribution to the observed immune response. Methods: Binding epitopes were studied in sera (n = 36) and cerebrospinal fluid (CSF) (n = 12) from a patient cohort positive for Kv1.2 but negative for 32 common neurological autoantigens and controls (sera n = 18 and CSF n = 5) by phospho and deep mutational scans. Autoantibody specificity and contribution to the observed immune response were resolved on recombinant cells, cerebellum slices, and nerve fibers. Results: 83% of the patients (30/36) within the studied cohort shared one out of the two major binding epitopes with Kv1.2-3 reactivity. Eleven percent (4/36) of the serum samples showed no binding. Fingerprinting resolved close to identical sequence requirements for both shared epitopes. Kv autoantibody response is directed against juxtaparanodal regions in peripheral nerves and the axon initial segment in central nervous system neurons and exclusively mediated by the shared epitopes. Discussion: Systematic mapping revealed two shared autoimmune responses, with one dominant Kv1.2-3 autoantibody epitope being unexpectedly prevalent. The conservation of the molecular binding requirements among these patients indicates a uniform autoantibody repertoire with monospecific reactivity. The enhanced sensitivity of the epitope-based (10/12) compared with that of the cell-based detection (7/12) highlights its use for detection. The determined immunodominant epitope is also the primary immune response visible in tissue, suggesting a diagnostic significance and a specific value for routine screening.

Catechol-O-methyltransferase Gene Polymorphism (Val158Met) and Development of Pre-eclampsia.

OBJECTIVES: Catechol-O-methyltransferase (COMT) is a key enzyme in degradation pathways of estrogens and catecholamines. The present meta-analysis was done to elucidate the association of COMT Val158Met polymorphism with pre-eclampsia among pregnant women. METHODS: A literature search was conducted in electronic databases including PubMed, Scopus, Elsevier, Springer and Google Scholar to find eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals were calculated under dominant, recessive, co-dominant, and allelic models. RESULTS: This meta-analysis included 6 eligible studies consisting 2596 cases and 4223 controls. The ORs for the COMT G472A polymorphism and pre-eclampsia were indicative of positive association under several genetic models. The results indicated that COMT Val158Met polymorphism was significantly associated with the increased risk of pre-eclampsia in recessive model (AA vs. AG + GG: OR = 1.522 [95% CI: 1.089-2.127]; p = 0.014), co-dominant model (AA vs. GG: OR = 1.605 [95% CI: 1.102-2.336]; p = 0.014), and allelic model (A vs. T: OR = 1.200 [95% CI: 1.021-1.402]; p = 0.021). CONCLUSIONS: In summary, COMT Val158Met polymorphism is positively associated with the increased risk of pre-eclampsia among pregnant women, especially the homozygous carriers. It could be of value to investigate its association with pre-eclampsia in combination with additional risk factors. However, very large studies with different ethnic population are required to accurately demonstrate the role of this candidate gene in development of pre-eclampsia.