The p.Arg435His Variation of IgG3 With High Affinity to FcRn Is Associated With Susceptibility for Pemphigus Vulgaris-Analysis of Four Different Ethnic Cohorts

Front Immunol. 2018 Aug 2:9:1788. doi: 10.3389/fimmu.2018.01788. eCollection 2018.


IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and the highest degree of allelic variability among all constant immunoglobulin genes. Due to its genetic position, IgG3 is often the first isotype an antibody switches to before IgG1 or IgG4. Compared with the other IgG subclasses, it has a reduced half-life which is probably connected to a decreased affinity to the neonatal Fc receptor (FcRn). However, a few allelic variants harbor an amino acid replacement of His435 to Arg that reverts the half-life of the resulting IgG3 to the same level as the other IgG subclasses. Because of its functional impact, we hypothesized that the p.Arg435His variation could be associated with susceptibility to autoantibody-mediated diseases like pemphigus vulgaris (PV) and bullous pemphigoid (BP). Using a set of samples from German, Turkish, Egyptian, and Iranian patients and controls, we were able to demonstrate a genetic association of the p.Arg435His variation with PV risk, but not with BP risk. Our results suggest a hitherto unknown role for the function of IgG3 in the pathogenesis of PV.

Keywords: allotype; autoantibodies; dermatology; functional genetics; half-life; immunology; pemphigoid; pemphigus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Analysis of Variance
  • Cohort Studies
  • Egypt
  • Enzyme-Linked Immunosorbent Assay / methods
  • Ethnicity / genetics
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Genome, Human
  • Genotype
  • Genotyping Techniques
  • Germany
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Immunoglobulin G / genetics*
  • Iran
  • Pemphigoid, Bullous / genetics*
  • Pemphigus / blood
  • Pemphigus / genetics*
  • Receptors, Fc / immunology*
  • Turkey


  • Histocompatibility Antigens Class I
  • Immunoglobulin G
  • Receptors, Fc
  • Fc receptor, neonatal