Genetic variations in the CεmX domain of human membrane-bound IgE

Abstract

The epsilon chain of membrane-bound IgE (mIgE) is expressed predominantly as a "long" isoform, containing an extra segment of 52 amino acid (a.a.) residues, referred to as C epsilon mX, between the CH4 domain and the C-terminal membrane-anchoring transmembrane peptide. C epsilon mX results from an alternative splicing of the epsilon RNA transcript at 156-bp upstream of the splicing acceptor site used by the "short" isoform. Here, based on an analysis of the C epsilon mX genomic DNA sequences of 320 subjects residing in Taiwan, we report that single-nucleotide polymorphisms have been found at two positions, namely, G/T at #46 and A/G at #93 (along the 156 bp of C epsilon mX), with the former creating an amino acid change from Val to Leu at #16 (along the 52 a.a. of C epsilon mX) and the latter resulting in no change (Gly). Among the 640 C epsilon mX sequences identified, the previously known 46G93A allelic form appeared 293 times, the newly discovered 46T93A allelic form (GeneBank accession no. GU208817) 26 times, and the 46G93G allelic form (GU208818) 321 times. No 46T93G allelic form was found. Serum IgE measurements showed that the polymorphisms did not correlate with the levels of serum IgE. The anti-C epsilon mX monoclonal antibody, 4B12, could bind equally well to mIgE.Fc(L)(16V) and mIgE.Fc(L)(16L). While genetic variation of C epsilon mX of broader populations should also be investigated, these newly discovered genetic variants of C epsilon mX in the Taiwanese population do not seem to affect the feasibility of using an anti-C epsilon mX mAb, such as 4B12, to target mIgE-expressing B cells.

cFLIP expression is altered in severe corticosteroid-resistant asthma

“…These include ß-thalassemia, spinal muscular atrophy and type 1 neurofibromatosis, among others (reviewed in [4] , [40] , [43] ). Transcripts encoded by several asthma-associated genes also undergo alternative splicing [20] , [31] , [34] , [36] , [37] , [39] , [44] , although only in the case of cysteinyl leukotriene type I receptor does there seem to be a connection to asthma immunopathogenesis [34] . These data, coupled with the enormous biological and pathological importance of alternative splicing, suggest that it is highly likely that alternative splicing contributes to asthma pathogenesis.…”

Two potential therapeutic antibodies bind to a peptide segment of membrane-bound IgE in different conformations

“…CemX is present in me but not in membrane-bound immunoglobulin of other isotypes. To date, only two allelic forms differing by a leucine or valine at position 16 along the CemX sequence (which generally does not affect antigenicity) have been found 14 . Although the threedimensional (3D) structure of CemX remains unsolved, previous work showed that two cysteines in CemX form an intrachain disulfide bond (Cys-18 with Cys-39 or Cys-41), while the other two cysteines form an interchain bridge 15 .…”