Evidence of Persisting Autoreactivity in Post-Acute Sequelae of SARS-CoV-2 Infection

While significant attention has been paid to the immunologic determinants of disease states associated with COVID-191,2, their contributions to post-acute sequelae of COVID-19 (PASC) remain less clear3-5. Due to the wide array of PASC presentations6, it is critical to understand if specific features of the disease are associated with discrete immune processes, and whether those processes may be therapeutically targeted. To this end, we performed wide immunologic and serological characterization of patients in the early recovery phase of COVID-19 across a breadth of symptomatic presentations. Using high-parameter proteomics screening and applied machine learning (ML), we identify clear signatures of immunologic activity between PASC patients and uncomplicated recovery, dominated by inflammatory cytokine signaling, neutrophil activity, and markers of cell death. Consistent with disease complexity, heterogeneity in plasma profiling reveals distinct PASC subsets with striking divergence in these ongoing inflammatory processes, here termed plasma quiescent (plaq) and inflammatory (infl) PASC. In addition to elevated inflammatory blood proteomics, inflPASC patients display positive clinical tests of acute inflammation including C-reactive protein and fibrinogen, increased B cell activity with extrafollicular involvement coupled with elevated targeting of viral nucleocapsid protein and clinical autoreactivity. Further, the unique plasma signatures of PASC patients allowed for the creation of refined models with high sensitivity and specificity for the positive identification of inflPASC with a streamlined assessment of 12 blood markers. Additionally, refined ML modeling highlights the unexpected significance of several markers of potential diagnostic or therapeutic use for PASC in general, including the peptide hormone, epiregulin. In all, this work identifies clear biological signatures of PASC with potential diagnostic and therapeutic potential and establishes clear disease subtypes that are both easily identifiable and highly relevant to ongoing efforts in both therapeutic targeting and epidemiological investigation of this highly complex disease.

Critically ill SARS-CoV-2 patients display lupus-like hallmarks of extrafollicular B cell activation

Abstract/IntroductionA wide clinical spectrum has become a hallmark of the SARS-CoV-2 (COVID-19) pandemic, although its immunologic underpinnings remain to be defined. We have performed deep characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation as previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody secreting cell expansion and early production of high levels of SARS-CoV-2-specific antibodies. Yet, these patients fared poorly with elevated inflammatory biomarkers, multi-organ failure, and death. Combined, the findings strongly indicate a major pathogenic role for immune activation in subsets of COVID-19 patients. Our study suggests that, as in autoimmunity, targeted immunomodulatory therapy may be beneficial in specific patient subpopulations that can be identified by careful immune profiling.