Dimerization as a key feature of autoreactive IgA antibody responses

The presence of immunoglobulin A (IgA) autoantibodies has been described in many autoimmune diseases, and some of its characteristics, such as IgA dimerization, are considered a sign of a mucosal origin. However, limited information is available about the (patho)physiological conditions leading to the development of monomeric vs dimeric (autoreactive) IgA in humans. Therefore, we investigated IgA dimerization in rheumatic autoimmune diseases with a possible mucosal origin, as well as after vaccination.

Plasma of patients with rheumatic disease (rheumatoid arthritis [RA], systemic sclerosis [SSc], anti-neutrophil cytoplasmic antibody associated vasculitis [AAV], systemic lupus erythematosus [SLE]), SARS-CoV-2 vaccinated healthy individuals, and healthy controls was used for size exclusion chromatography (SEC). Enzyme-linked immunosorbent assays were performed on SEC fractions to determine the size of IgA. Results were confirmed using western blot and tandem mass spectrometry.

The proportion of dimeric IgA was increased for autoantibodies compared to total IgA. This was most evident in RA, AAV, and SLE (dimeric autoreactive IgA ≈ 60%-80% vs total IgA ≈ 20%, SLE ≈ 60% total IgA), but not in SSc. Intramuscular vaccination against SARS-CoV-2 also led to an increased proportion of dimeric anti-spike IgA shortly after vaccination, irrespective of previous mucosal exposure.

These findings indicate that dimeric (autoreactive) IgA responses are associated with newly emerging antigen-specific immune activation, where production temporarily shifts to dimeric IgA. Mucosal triggering is not necessarily always involved in these IgA immune responses. These findings provide key insights into the circumstances for IgA dimerization and suggest that dimeric IgA could serve as a marker for immunological disease activity in autoimmunity.