Abstract
Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2-5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6-10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe/critical COVID-1914-18. Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naïve-derived, low-mutation IgG1 population of antibody secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10-15 days post symptom onset. Detailed analysis of the low selection compartment reveals a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway upon recovery, re-establishment of tolerance standards, and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with post-acute sequelae, raising important questions as to the contribution of emerging autoreactivity to ongoing symptomology upon recovery. In total, this study reveals the origins, breadth, and resolution of autoreactivity in severe COVID-19, with implications for early intervention and treatment of patients with post-COVID sequelae.
【초록키워드】 COVID-19, Treatment, SARS-CoV-2, Tolerance, severe COVID-19, antibody, Intervention, Proteins, Antigen, B cell, specificity, immune activation, response, Patient, pathway, Mild, membrane, serological, single-cell, IgG1, breadth, Frequency, Analysis, Inflammatory, severe disease, Autoantigens, symptom onset, Activation, selective, nuclear, dominant, implication, feature, identify, pathologic, remained, clinically, question, reveal, subset, antibody secreting cell, ASC, autoreactive antibody, glomerular, pathogenic autoantibody, persist, raising, 【제목키워드】 severe COVID-19, de novo, naïve B cell,