IgA Complexes in Plasma and Synovial Fluid of Patients with Rheumatoid Arthritis Induce Neutrophil Extracellular Traps via FcαRI

J Immunol. 2016 Dec 15;197(12):4552-4559. doi: 10.4049/jimmunol.1502353. Epub 2016 Nov 9.


Autoantibodies, including rheumatoid factor (RF), are an important characteristic of rheumatoid arthritis (RA). Interestingly, several studies reported a correlation between the presence of IgA autoantibodies and worse disease course. We demonstrated previously that triggering the IgA Fc receptor (FcαRI) on neutrophils results in neutrophil recruitment and the release of neutrophil extracellular traps (NETs). Because this can lead to tissue damage, we investigated whether IgA immune complexes in plasma and synovial fluid of RA patients activate neutrophils. RF isotypes were measured with ELISA, and immune complexes were precipitated using polyethylene glycol 6000. Isolated neutrophils were incubated with immune complexes, and activation and release of NETs were determined in the presence or absence of FcαRI-blocking Abs. Plasma and SF of RA patients contained IgM, IgG, and IgA RFs. Patient plasma IgA RF and IgM RF showed a strong correlation. No uptake of IgM and minimal endocytosis of IgG immune complexes by neutrophils was observed, in contrast to avid uptake of IgA complexes. Incubation of neutrophils with immune complexes resulted in the production of reactive oxygen species, as well as the release of NETs, lactoferrin, and chemotactic stimuli. Importantly, activation of neutrophils was reduced when FcαRI was blocked. Neutrophils were activated by IgA immune complexes, which suggests that neutrophils play a role in inducing joint damage in RA patients who have IgA autoantibody complexes, thereby increasing the severity of disease. Blocking FcαRI inhibited neutrophil activation and, as such, may represent an additional attractive novel therapeutic strategy for the treatment of RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Blocking / pharmacology
  • Antigen-Antibody Complex / metabolism
  • Antigens, CD / metabolism*
  • Arthritis, Rheumatoid / immunology*
  • Blood Proteins / metabolism
  • Cells, Cultured
  • Extracellular Traps / metabolism*
  • Female
  • Humans
  • Immunoglobulin A / metabolism
  • Male
  • Middle Aged
  • Neutrophil Activation*
  • Neutrophils / immunology*
  • Reactive Oxygen Species / metabolism
  • Receptors, Fc / metabolism*
  • Rheumatoid Factor / blood
  • Synovial Fluid / metabolism


  • Antibodies, Blocking
  • Antigen-Antibody Complex
  • Antigens, CD
  • Blood Proteins
  • Fc(alpha) receptor
  • Immunoglobulin A
  • Reactive Oxygen Species
  • Receptors, Fc
  • Rheumatoid Factor