Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19

Woodruff, Matthew C.; Ramonell, Richard P.; Nguyen, Doan C.; Cashman, Kevin S.; Saini, Ankur; Haddad, Natalie S.; Ley, Ariel M.; Kyu, Shuya; Howell, J. Christina; Öztürk, Tuğba; Lee, Saeyun; Suryadevara, Naveen Chandra; Case, James Brett; Bugrovsky, Regina; Chen, Weirong; Estrada, Jacob; Morrison-Porter, Andrea; Derrico, Andrew; Anam, Fabliha; Sharma, Monika; Wu, Henry M.; Shi, Le; Jenks, Scott A.; Tipton, Christopher; Staitieh, Bashar S.; Daiss, John L.; Ghosn, Eliver; Diamond, Michael S.; Carnahan, Robert H.; Crowe, James E.; Hu, William T.; Lee, Frances Eun-Hyung; Sanz, Igñacio

doi:10.1038/s41590-020-00814-z

Cited by 578 publications

(704 citation statements)

References 68 publications

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“…This is supported by our finding that the most severely affected patients had the highest levels of inflammatory markers and cytokines, which can drive antibody production. In support of this possibility, a recent study suggests a pathogenic role of immune activation and exuberant antibody production from extrafollicular B cells in critically ill patients (Woodruff et al , 2020) . Indeed, of all the COVID-19…”

Section: Discussionmentioning

confidence: 93%

COVID-19 neutralizing antibodies predict disease severity and survival

García-Beltrán

Lam

Astudillo

et al. 2020

Preprint

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COVID-19 exhibits variable symptom severity ranging from asymptomatic to life-threatening, yet the relationship between severity and the humoral immune response is poorly understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, and high anti-RBD antibody levels. While anti-RBD IgG levels generally correlated with neutralization titer, quantitation of neutralization potency revealed that high potency was a predictor of survival. In addition to neutralization of wild-type SARS-CoV-2, patient sera were also able to neutralize the recently emerged SARS-CoV-2 mutant D614G, suggesting protection from reinfection by this strain. However, SARS-CoV-2 sera was unable to cross-neutralize a highly-homologous pre-emergent bat coronavirus, WIV1-CoV, that has not yet crossed the species barrier. These results highlight the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective interventions to prevent future coronavirus pandemics.

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Section: Discussionmentioning

confidence: 93%

COVID-19 neutralizing antibodies predict disease severity and survival

García-Beltrán

Lam

Astudillo

et al. 2020

Preprint

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“…However, how this activated status of B cells had an impact on disease severity was not studied. By looking at the alleged relationship of activated B cells with disease severity, Woodruff et al (2020) showed robust activation status of extrafollicular B cells which resembled their behavior in autoimmune condition. The activation status of these cells was found more pronounced in critically ill patients (n = 10) than non-critical (n = 7) and healthy control (n = 17), which correlated with SARS-CoV-2specific antibody production and disease progression.…”

Section: Impaired B Cell Response During Covid-19mentioning

confidence: 99%

COVID-19: The Emerging Immunopathological Determinants for Recovery or Death

et al. 2020

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Hyperactivation of the host immune system during infection by SARS-CoV-2 is the leading cause of death in COVID-19 patients. It is also evident that patients who develop mild/moderate symptoms and successfully recover display functional and well-regulated immune response. Whereas a delayed initial interferon response is associated with severe disease outcome and can be the tipping point towards immunopathological deterioration, often preceding death in COVID-19 patients. Further, adaptive immune response during COVID-19 is heterogeneous and poorly understood. At the same time, some studies suggest activated T and B cell response in severe and critically ill patients and the presence of SARS-CoV2-specific antibodies. Thus, understanding this problem and the underlying molecular pathways implicated in host immune function/dysfunction is imperative to devise effective therapeutic interventions. In this comprehensive review, we discuss the emerging immunopathological determinants and the mechanism of virus evasion by the host cell immune system. Using the knowledge gained from previous respiratory viruses and the emerging clinical and molecular findings on SARS-CoV-2, we have tried to provide a holistic understanding of the host innate and adaptive immune response that may determine disease outcome. Considering the critical role of the adaptive immune system during the viral clearance, we have presented the molecular insights of the plausible mechanisms involved in impaired T cell function/dysfunction during various stages of COVID-19.

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“…Notably, the expansion of ASCs is correlated with activation of the extrafollicular activation pathway with increased numbers of naive and DN2 effector B cells. This profile separates severe COVID-19 disease from milder disease 7 , and preliminary analysis suggests its presence in childhood MIS-C as well (M. Woodruff, K. Cashman and I. Sanz, personal communication). Of interest, similar B cell responses are found in severe systemic lupus erythematosus, especially in African Americans 9 , who also suffer from a higher incidence of MIS-C, suggestive of a pathogenic role for these responses in severe COVID-19.…”

Section: B Cell Immunitymentioning

confidence: 96%

“…Understanding the durability and quality of anti-SARS-CoV-2 B cell responses in patients with different clinical presentations and disease severity remains an important task. Ignacio Sanz (Emory University) reported robust expansion of oligoclonal ASCs spanning immunoglobulin M (IgM), IgG and IgA isotypes in adult patients with COVID-19 who required admission to an intensive care unit despite the presence of high titers of neutralizing antibodies 7 . The impact of ASC expansion, which has also been described by others 8 , on protective immunity or disease pathogenesis remains to be determined.…”

Section: B Cell Immunitymentioning

confidence: 99%

The immune roadmap for understanding multi-system inflammatory syndrome in children: opportunities and challenges

Martinez

Bridges

Goldmuntz

et al. 2020

Nat Med

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The immune roadmap for understanding multi-system inflammatory syndrome in children: opportunities and challenges In the spring of 2020, a series of reports from Europe and the USA described clusters of children and adolescents presenting with a life-threatening, hyperinflammatory syndrome-called 'multi-system inflammatory syndrome in children' (MIS-C)-that was seemingly linked to prior exposure to the coronavirus SARS-CoV-2. In June 2020, the US National Institutes of Health convened a workshop of immunologists and clinicians to discuss emerging knowledge and identify key questions surrounding MIS-C, with a focus on innate and adaptive immunity, genetics and epigenetics. This Meeting Report describes the main findings from the workshop. T he emergence of a late-onset COVID-19-associated acute inflammatory syndrome in children, who present with severe abdominal pain, volume-resistant shock and cardiovascular injury, was first described in reports from Europe and the UK in the spring of 2020 (https://www. ecdc.europa.eu/en/publications-data/ paediatric-inflammatory-multisystemsyndrome-and-sars-cov2-rapid-riskassessment) and was subsequently recognized in New York City 1-3. The name 'multi-system inflammatory syndrome in children (MIS-C) temporally associated with COVID-19' was coined, and diagnostic criteria were established (https://health. ny.gov/press/releases/2020/docs/2020-05-13_health_advisory.pdf; https:// emergency.cdc.gov/han/2020/han00432. asp). Two publications described almost 300 US children with MIS-C 4,5. In those cohorts, the evidence for association with antecedent COVID-19 disease or exposure to SARS-CoV-2 was demonstrated by PCR positivity (40-50%), antibody positivity (31-45%) or clear history of exposure. Affected children had a median age of about 8 years, and children of Black race and/or Hispanic ethnicity were over-represented. At presentation, 80-90% had severe abdominal pain, and almost a third presented in shock, with volume-resistant hypotension and evidence of cardiac injury (elevated troponin and echocardiographic evidence of left ventricular dysfunction) and/ or other end-organ damage. Ultimately, 80% required support in an intensive care unit. Coronary-artery ectasia or aneurysms developed in 8-9%. Almost all had laboratory evidence of immune activation, including elevations in C-reactive protein, erythrocyte sedimentation rate,

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Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19

Cited by 578 publications

References 68 publications

COVID-19 neutralizing antibodies predict disease severity and survival

COVID-19 neutralizing antibodies predict disease severity and survival

COVID-19: The Emerging Immunopathological Determinants for Recovery or Death

The immune roadmap for understanding multi-system inflammatory syndrome in children: opportunities and challenges

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