Abstract
OBJECTIVE: The spontaneous K/BxN mouse model of rheumatoid arthritis has been used extensively to study chronic inflammation, contribution of immune cells, and the primordial role of autoreactive antibodies in disease initiation and severity. Only the ubiquitous enzyme glucose-6-phosphate isomerase (GPI) is the target of IgG autoantibodies secreted by autoreactive plasma cells and plasmablasts in K/BxN mice. Strikingly, the appearance and evolution of these autoreactive IgG-secreting cells (IgG-SC) remain unstudied. METHODS: Here, we quantitatively and qualitatively investigated the plasmablast and plasma cell responses by measuring the affinity of their secreted antibody for GPI from single cells in cohorts of K/BxN mice from 3 weeks to 87 weeks old. RESULTS: Analysis of more than 36,000 individual IgG-SC from spleen, popliteal lymph nodes, and bone marrow revealed high intercellular variability in affinity for GPI, with variations over three logs, with stable secretion rates over the life of the mice. Autoreactive IgG-SC were detectable at 3 to 4 weeks and reached peak proportions of IgG-SC at 35 weeks before stabilizing. High-affinity anti-GPI IgG-SC appeared only transiently in the 6 to 9 weeks postnatal window, whereas low-affinity IgG-SC represented more than 80% of the response at all time points. Serum anti-GPI IgG antibodies evolved in a similar kinetic manner, peaking in proportion to total IgG and in affinity for GPI at 35 weeks. CONCLUSION: Our results report the dynamic nature of the autoimmune B cell response in the K/BxN model, revealing a transient phase of antibody affinity maturation early in disease that allows high-affinity antibody responses.