IgG4 antibody repertoire diversity is stable over several years in health and autoimmune disease

Despite its relative anti-inflammatory nature, IgG4 is involved in a variety of pathological conditions such as autoimmune disease and cancer. To investigate whether the IgG4 repertoire presents any abnormalities in diseases where IgG4 autoantibodies predominate, we charted longitudinal IgG4 repertoires in health, in an IgG4-mediated autoimmune disease (AID; muscle-specific kinase myasthenia gravis (MuSK MG)), and in IgG1/IgG3 mediated AIDs (acetylcholine receptor (AChR) MG and Lambert-Eaton myasthenic syndrome (LEMS). In total, we assessed 218 samples of 69 donors using mass spectrometry-based antibody repertoire analysis, covering a timespan of up to eight years. Despite being superficially inconspicuous in clonal diversity and abundances, we detected a slightly elevated number of IgG4 clones in MuSK MG patients compared to healthy donors. Notably, this observation did not coincide with drastic repertoire changes during treatment, suggesting that a large portion of the IgG4 repertoire is not significantly affected by common MuSK MG treatment regimens. Comparing the IgG4 antibody repertoires of all donors, we found that they were exceptionally unique for each individual. Against what would be expected in the case of a constantly adapting antibody repertoire, a large portion of the IgG4 clones remained stable without any further maturation. This observation even extended to patients receiving B cell depleting or IgG modulating treatments. Our findings suggest that a dominating fraction of the IgG4 pool may be produced by long-lived plasma cells, which are unaffected by disease or medical interventions.