Case Report: Severe Complement-Mediated Thrombotic Microangiopathy in IgG4-Related Disease Secondary to Anti-Factor H IgG4 Autoantibodies

Front Immunol. 2021 Feb 11:11:604759. doi: 10.3389/fimmu.2020.604759. eCollection 2020.


Objective: To first describe and estimate the potential pathogenic role of Ig4 autoantibodies in complement-mediated thrombotic microangiopathy (TMA) in a patient with IgG4-related disease (IgG4-RD).

Methods: This study is a case report presenting a retrospective review of the patient's medical chart. Plasma complement C3 and C4 levels, immunoglobulin isotypes and subclasses were determined by nephelometry, the complement pathways' activity (CH50, AP50, MBL) using WIESLAB® Complement System assays. Human complement factor H levels, anti-complement factor H auto-antibodies were analyzed by ELISA, using HRP-labeled secondary antibodies specific for human IgG, IgG4, and IgA, respectively. Genetic analyses were performed by exome sequencing of 14 gens implicated in complement disorders, as well as multiplex ligation-dependent probe amplification looking specifically for CFH, CFHR1-2-3, and 5.

Results: Our brief report presents the first case of IgG4-RD with complement-mediated TMA originating from both pathogenic CFHR 1 and CFHR 4 genes deletions, and inhibitory anti-complement factor H autoantibodies of the IgG4 subclass. Remission was achieved with plasmaphereses, corticosteroids, and cyclophosphamide. Following remission, the patient was diagnosed with lymphocytic meningitis and SARS-CoV-2 pneumonia with an uneventful recovery.

Conclusion: IgG4-RD can be associated with pathogenic IgG4 autoantibodies. Genetic predisposition such as CFHR1 and CFHR4 gene deletions enhance the susceptibility to the formation of inhibitory anti-Factor H IgG4 antibodies.

Keywords: IgG4-related disease; SARS CoV2; anti-factor H auto-antibodies; antibodies; atypical hemolytic uremic syndrome; complement factor H; complement factor H-related protein; thrombotic microangiopathy.

Publication types

  • Case Reports

MeSH terms

  • Apolipoproteins / genetics*
  • Atypical Hemolytic Uremic Syndrome / genetics*
  • Atypical Hemolytic Uremic Syndrome / immunology
  • Atypical Hemolytic Uremic Syndrome / pathology
  • Autoantibodies / immunology*
  • Complement C3b Inactivator Proteins / genetics*
  • Complement Factor H / immunology*
  • Female
  • Gene Deletion
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Immunoglobulin G / immunology
  • Immunoglobulin G4-Related Disease / genetics*
  • Immunoglobulin G4-Related Disease / immunology
  • Immunoglobulin G4-Related Disease / pathology
  • Middle Aged
  • Thrombotic Microangiopathies / immunology
  • Thrombotic Microangiopathies / pathology


  • Apolipoproteins
  • Autoantibodies
  • CFHR1 protein, human
  • CFHR4 protein, human
  • Complement C3b Inactivator Proteins
  • Immunoglobulin G
  • Complement Factor H