Skip to main content

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

Abstract

The ε 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 CεmX, between the CH4 domain and the C-terminal membrane-anchoring transmembrane peptide. CεmX results from an alternative splicing of the ε RNA transcript at 156-bp upstream of the splicing acceptor site used by the “short” isoform. Here, based on an analysis of the CεmX 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 CεmX), with the former creating an amino acid change from Val to Leu at #16 (along the 52 a.a. of CεmX) and the latter resulting in no change (Gly). Among the 640 CεmX 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-CεmX monoclonal antibody, 4B12, could bind equally well to mIgE.FcL(16V) and mIgE.FcL(16L). While genetic variation of CεmX of broader populations should also be investigated, these newly discovered genetic variants of CεmX in the Taiwanese population do not seem to affect the feasibility of using an anti-CεmX mAb, such as 4B12, to target mIgE-expressing B cells.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

Abbreviations

BCR:

B cell receptor

mAb:

Monoclonal antibody

mIgE:

Membrane-bound IgE

migis:

mIg isotype-specific peptide

migis-ε:

Migis peptide of mε chain

SNP:

Single-nucleotide polymorphism

References

  • Achatz G, Nitschke L, Lamers MC (1997) Effect of transmembrane and cytoplasmic domains of IgE on the IgE response. Science 276:409–411

    Article  CAS  PubMed  Google Scholar 

  • Achatz G, Luger E, Geisberger R, Achatz-Straussberger G, Breitenbach M, Lamers M (2001) The IgE antigen receptor: a key regulator for the production of IgE antibodies. Int Arch Allergy Immunol 124:31–34

    Article  CAS  PubMed  Google Scholar 

  • Batista FD, Efremov DG, Burrone OR (1995) Characterization and expression of alternatively spliced IgE heavy chain transcripts produced by peripheral blood lymphocytes. J Immunol 154:209–218

    CAS  PubMed  Google Scholar 

  • Batista FD, Anand S, Presani G, Efremov DG, Burrone OR (1996) The two membrane isoforms of human IgE assemble into functionally distinct B cell antigen receptors. J Exp Med 184:2197–2205

    Article  CAS  PubMed  Google Scholar 

  • Battey J, Max EE, McBride WO, Swan D, Leder P (1982) A processed human immunoglobulin epsilon gene has moved to chromosome 9. Proc Natl Acad Sci USA 79:5956–5960

    Article  CAS  PubMed  Google Scholar 

  • Catto AJ, Kohler HP, Bannan S, Stickland M, Carter A, Grant PJ (1998) Factor XIII Val 34 Leu: a novel association with primary intracerebral hemorrhage. Stroke 29:813–816

    CAS  PubMed  Google Scholar 

  • Chang TW, Wu PC, Hsu CL, Hung AF (2007) Anti-IgE antibodies for the treatment of IgE-mediated allergic diseases. Adv Immunol 93:63–119

    Article  CAS  PubMed  Google Scholar 

  • Chen HY, Liu FT, Hou CM, Huang JS, Sharma BB, Chang TW (2002) Monoclonal antibodies against the C(epsilon)mX domain of human membrane-bound IgE and their potential use for targeting IgE-expressing B cells. Int Arch Allergy Immunol 128:315–324

    Article  CAS  PubMed  Google Scholar 

  • Chen JB, Wu PC, Hung AF, Chu CY, Tsai TF, Yu HM, Chang HY, Chang TW (2010) Unique epitopes on CepsilonmX in IgE-B cell receptors are potentially applicable for targeting IgE-committed B cells. J Immunol 184:1748–1756

    Article  CAS  PubMed  Google Scholar 

  • Corral J, Iniesta JA, Gonzalez-Conejero R, Villalon M, Rivera J, Vicente V (2000) Factor XIII Val34Leu polymorphism in primary intracerebral haemorrhage. Hematol J 1:269–273

    Article  CAS  PubMed  Google Scholar 

  • Davis FM, Gossett LA, Chang TW (1991) An epitope on membrane-bound but not secreted IgE: implications in isotype-specific regulation. Biotechnology (N Y) 9:53–56

    Article  CAS  Google Scholar 

  • Gould HJ, Sutton BJ (2008) IgE in allergy and asthma today. Nat Rev Immunol 8:205–217

    Article  CAS  PubMed  Google Scholar 

  • Hisajima H, Nishida Y, Nakai S, Takahashi N, Ueda S, Honjo T (1983) Structure of the human immunoglobulin C epsilon 2 gene, a truncated pseudogene: implications for its evolutionary origin. Proc Natl Acad Sci USA 80:2995–2999

    Article  CAS  PubMed  Google Scholar 

  • Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C (2005) The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol 115:459–465

    Article  CAS  PubMed  Google Scholar 

  • Hung AF, Chen JB, Chang TW (2008) Alleles and isoforms of human membrane-bound IgA1. Mol Immunol 45:3624–3630

    Article  CAS  PubMed  Google Scholar 

  • Jones RT, Saiontz HI, Head C, Shih DT, Fairbanks VF (1990) Hb Johnstown [beta 109 (G11) Val–Leu]: a new electrophoretically silent variant that causes erythrocytosis. Hemoglobin 14:147–156

    Article  CAS  PubMed  Google Scholar 

  • Kawakami T, Galli SJ (2002) Regulation of mast-cell and basophil function and survival by IgE. Nat Rev Immunol 2:773–786

    Article  CAS  PubMed  Google Scholar 

  • Kirschner M, Monrose V, Paluch M, Techodamrongsin N, Rethwilm A, Moore JP (2006) The production of cleaved, trimeric human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein vaccine antigens and infectious pseudoviruses using linear polyethylenimine as a transfection reagent. Protein Expr Purif 48:61–68

    Article  CAS  PubMed  Google Scholar 

  • Kraft S, Kinet JP (2007) New developments in FcepsilonRI regulation, function and inhibition. Nat Rev Immunol 7:365–378

    Article  CAS  PubMed  Google Scholar 

  • Leduc I, Drouet M, Bodinier MC, Helal A, Cogne M (1997) Membrane isoforms of human immunoglobulins of the A1 and A2 isotypes: structural and functional study. Immunology 90:330–336

    Article  CAS  PubMed  Google Scholar 

  • Max EE, Battey J, Ney R, Kirsch IR, Leder P (1982) Duplication and deletion in the human immunoglobulin epsilon genes. Cell 29:691–699

    Article  CAS  PubMed  Google Scholar 

  • Nanjo K, Sanke T, Miyano M, Okai K, Sowa R, Kondo M, Nishimura S, Iwo K, Miyamura K, Given BD et al (1986) Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama). Clinical and functional characteristics of [LeuA3] insulin. J Clin Invest 77:514–519

    Article  CAS  PubMed  Google Scholar 

  • Nishida Y, Miki T, Hisajima H, Honjo T (1982) Cloning of human immunoglobulin epsilon chain genes: evidence for multiple C epsilon genes. Proc Natl Acad Sci USA 79:3833–3837

    Article  CAS  PubMed  Google Scholar 

  • Oettgen HC, Geha RS (2001) IgE regulation and roles in asthma pathogenesis. J Allergy Clin Immunol 107:429–440

    Article  CAS  PubMed  Google Scholar 

  • Peng C, Davis FM, Sun LK, Liou RS, Kim YW, Chang TW (1992) A new isoform of human membrane-bound IgE. J Immunol 148:129–136

    CAS  PubMed  Google Scholar 

  • Ropero P, Villegas A, Gonzalez AF, Anguita E, Sanchez J, Carreno DL, Arrizabalaga B, Atuxta L (2000) Hb Johnstown [beta 109 (G11) Val– > Leu]: second case described and associated for the first time with beta(0)-thalassemia in two Spanish families. Am J Hematol 65:298–301

    Article  CAS  PubMed  Google Scholar 

  • Sakura H, Iwamoto Y, Sakamoto Y, Kuzuya T, Hirata H (1986) Structurally abnormal insulin in a diabetic patient. Characterization of the mutant insulin A3 (Val––Leu) isolated from the pancreas. J Clin Invest 78:1666–1672

    Article  CAS  PubMed  Google Scholar 

  • Ueda S, Nakai S, Nishida Y, Hisajima H, Honjo T (1982) Long terminal repeat-like elements flank a human immunoglobulin epsilon pseudogene that lacks introns. EMBO J 1:1539–1544

    CAS  PubMed  Google Scholar 

  • Wan ZL, Huang K, Xu B, Hu SQ, Wang S, Chu YC, Katsoyannis PG, Weiss MA (2005) Diabetes-associated mutations in human insulin: crystal structure and photo-cross-linking studies of a-chain variant insulin Wakayama. Biochemistry 44:5000–5016

    Article  CAS  PubMed  Google Scholar 

  • Yu LM, Peng C, Starnes SM, Liou RS, Chang TW (1990) Two isoforms of human membrane-bound alpha Ig resulting from alternative mRNA splicing in the membrane segment. J Immunol 145:3932–3936

    CAS  PubMed  Google Scholar 

  • Zhang K, Saxon A, Max EE (1992) Two unusual forms of human immunoglobulin E encoded by alternative RNA splicing of epsilon heavy chain membrane exons. J Exp Med 176:233–243

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This research was supported by a grant, #96-2320-B001-014-MY3, from the National Science Council, Taiwan. We thank Dr. Harry Wilson for editing the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tse Wen Chang.

Additional information

Lei Wan and Jiun-Bo Chen contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wan, L., Chen, JB., Chen, H.H. et al. Genetic variations in the CεmX domain of human membrane-bound IgE. Immunogenetics 62, 273–280 (2010). https://doi.org/10.1007/s00251-010-0437-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-010-0437-0

Keywords

  • IgE
  • CεmX
  • Single-nucleotide polymorphisms
  • Alleles
  • Allergy