Dysregulated naive B cells and de novo autoreactivity in severe COVID-19

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 and critical COVID-19 (refs. 14–18). Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-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 after the onset of symptoms. Detailed analysis of the low-selection compartment shows 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 on 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 postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae.

Inflammation and autoreactivity define a discrete subset of patients with post-acute sequelae of COVID-19, or long-COVID

“…To understand the nature of the cellular responses underlying the altered humoral targeting in the inflPASC group, targeted flow cytometry was performed on 39 PASC patients (n = 15 inflPASC, 109 DPSO average; n = 23 plaqPASC, 137 DPSO average). In the acute phase of severe COVID-19, extrafollicular B cell responses correlated with the rapid expansion of antibody secreting cells (ASCs) 21 , resulting in both antiviral and anti-self reactivity 22 . Similar B cell profiling of PASC patients revealed a more mixed response.…”

“…In acute COVID-19, high levels of inflammation in critical illness drove higher levels of SARS-CoV-2-targeted antibody responses with significant cross-reactivity against self-antigens 22 . Serological testing of plaqPASC and inflPASC patients identified no clear serological difference between the groups in targeting the SARS-CoV-2 receptor binding domain binding, although IgM and IgA titers were slightly higher in the inflPASC group (Fig 5a).…”

“…Cellular immune signatures were correlated with the autoantibody signatures identified in the inflPASC cohort suggesting an increased emphasis of the EF B cell response pathway. Recently, this pathway has been directly implicated in the emergence of autoreactivity in severe COVID-19, with permissive B cell selective pressures leading to the emergence of cross-reactive clones capable of targeting both viral- and self-antigens 22 . However, in contrast with those studies, the prominence of the described effectors of that pathway, DN2 B cells and ASCs, was notably more muted in inflPASC patients.…”

“…Nonetheless, patients with severe illness produced high numbers of antibody secreting cells via an alternative extrafollicular (EF) pathway involving the activation of B cell effectors, DN2 B cells, previously described in human autoimmune diseases such as lupus 20,21 . While these responses are highly targeted to the virus, they are also cross reactive against self-antigens resulting in naive B cell-derived, de novo autoreactivity 22 . In patients recovering from severe illness with symptoms consistent with PASC, these autoreactive responses were identifiable for months after infection raising the possibility of persistent inflammatory responses continuing to drive symptoms in a subset of patients well into the recovery phase of disease 22 .…”

“…While these responses are highly targeted to the virus, they are also cross reactive against self-antigens resulting in naive B cell-derived, de novo autoreactivity 22 . In patients recovering from severe illness with symptoms consistent with PASC, these autoreactive responses were identifiable for months after infection raising the possibility of persistent inflammatory responses continuing to drive symptoms in a subset of patients well into the recovery phase of disease 22 .…”