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

Abstract

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.

A Neutrophil Activation Biomarker Panel in Prognosis and Monitoring of Patients With Rheumatoid Arthritis

“…The elevated levels of circulating NETs observed in RA could be due to either increased formation of NETs and/or decreased clearance of NETs. Consistent with the first hypothesis, prior findings have demonstrated increased capacity of RA neutrophils to undergo NETosis (9,16), with RA-associated autoantibodies and inflammatory cytokines driving NET formation (9,43). Similarly, we found that RA patients had circulating factors (e.g., immune complexes) promoting neutrophil activation ex vivo.…”

Antibody Responses to Citrullinated and Noncitrullinated Antigens in the Sputum of Subjects With Rheumatoid Arthritis and Subjects at Risk for Development of Rheumatoid Arthritis

“…These results suggest that there is not a general association between autoantibodies and NETs in the sputum. Of interest, these findings are consistent with those in prior studies that demonstrated a strong association of IgA-RF with NET formation, whereas IgG-RF was weakly associated, and IgM-RF was not associated, with NET formation (32).…”

“…DEMORUELLE ET AL 2A/a-2 1-20 cyclic , and fibrinogen A [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] . Moreover, there was no significant difference in age, sex, race, frequency of SE positivity, or smoking history between the 24 atrisk subjects who underwent NET testing and the 17 who did not (data not shown).…”

Increased IgA anti‐citrullinated protein antibodies in the periodontal inflammatory exudate of healthy individuals compared to rheumatoid arthritis patients

“…Hence, relatively higher levels of IgA‐ACPA are seen in pre‐ and recent‐onset RA patients than IgG ACPA, and may be predictive of RA development and severity. Of note, Aleyd, Al, Tuk, van der Laken, and van Egmond (2016) demonstrated that IgA complexes in the plasma and synovial fluid of patients with RA induce neutrophil extracellular traps via FcaRI, indicating that IgA autoantibodies may play a role in hypercitrullination, induced by NETs.…”