| Summary: | Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies. Loss of B cell tolerance is a hallmark feature of this disease and increased numbers of autoreactive mature naive B cells have been described in SLE patients. Autoantibodies have been shown to arise from both autoreactive and non-autoreactive precursors, signifying that secondary tolerance is also impaired. How defects in the regulation of B cell tolerance and selection influence germinal center (GC) reactions that are directed towards foreign antigens has yet to be investigated. Here, we examined the characteristics of post-GC, foreign antigen-specific B cells from SLE patients and healthy controls after influenza vaccination. We analyzed monoclonal antibodies generated from single-cell isolated plasmablasts specifically induced by influenza vaccination. We report that many of the SLE patients produced anti-influenza antibodies of higher binding avidity and neutralization capacity than those from controls. Although overall frequencies of autoreactivity in the influenza-specific plasmablasts were similar for SLE patients and controls, we noted differences in HEp-2 reactivity. High avidity antibodies generally characterized the plasmablast responses of SLE patients with low levels of autoreactivity, though exceptions were noted. We also found that cytokines abnormally expressed in lupus differentiate high-avidity antibody responders from low-avidity responders. In addition, the variable gene repertoire of influenza-specific plasmablasts from SLE patients had increased usage of JH6 and long heavy chain CDR3 segments. Improved antibody responses against influenza were also demonstrated in lupus-prone MRL/lpr mice. These findings provide insights into the effects of autoimmunity on the quality of B cell responses against influenza and further our understanding of the underlying abnormalities of autoimmune diseases.
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