Enhanced eosinophil-mediated inflammation associated with antibody and complement-dependent pneumonic insults in critical COVID-19

Kim, Dong-Min; Kim, Yuri; Seo, Jun-Won; Lee, Joo-Yeon; Park, Uni; Ha, Na-Young; Koh, Jaemoon; Park, Hyoree; Lee, Jae Won; Ro, Hyo‐Jin; Yun, Na Ra; Kim, Da Young; Yoon, Sung Ho; Na, Yong Sub; Moon, Dosik; Lim, Sung‐Chul; Kim, Choon-Mee; Jeon, Kyeongseok; Kang, Joon Soon; Jang, Na Young; Jeong, Hyeongseok; Kim, Jung Ok; Cheon, Shinhye; Sohn, Kyung Mok; Moon, Jae Youg; Kym, Sungmin; Han, Seung Ro; Lee, Myung‐Shin; Kim, Hyun Je; Park, Woong-Yang; Choi, Ji-Yeob; Shin, Hye‐Rim; Kim, Hye-Young; Cho, Chung–Hyun; Jeon, Yoon Kyung; Kim, So Hyun; Cho, Nam Hyuk

doi:10.1016/j.celrep.2021.109798

Cited by 39 publications

(42 citation statements)

References 44 publications

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“…Two studies showed activation of the lectin pathway in the lungs [ 56 , 57 ], however depositions of the lectin pathway were hardly detectable in another study [ 45 ]. In parenchyma of lung tissues of critically ill patients, increased T helper (Th)2-biased adaptive immune response was observed with apparent activation of the complement system (C3b and C5b-9) [ 58 ]. In the kidneys, cleavage products of C3 were heavily present in renal and glomerular arteries.…”

Section: Resultsmentioning

confidence: 99%

Complement activation in COVID-19 and targeted therapeutic options: A scoping review

Lim

Amstel²,

Boer³

et al. 2023

Blood Reviews

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Section: Resultsmentioning

confidence: 99%

Complement activation in COVID-19 and targeted therapeutic options: A scoping review

Lim

Amstel²,

Boer³

et al. 2023

Blood Reviews

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“…Moreover, this B-cell subset presented the highest enriched gene set scores for phagocytic activity, complement activation, and immune complex response when compared to the other B-cell subsets ( Supplementary Figure 10 ). These enhanced scores suggest a potential contribution in pathogenic humoral responses observed in severe COVID-19 during early stages ( Kim et al., 2021 ). While we could not define whether the differentiation pathway of PC2 cells is linked to an EF B-cell response pathway (AN → DN → AM2), it is plausible that both the AM2 and PC2 cells seem to function as pathogenic B cells.…”

Section: Discussionmentioning

confidence: 94%

“…The presence of substantial evidence has supported the notion that aberrant immune responses to human coronaviruses are typified by the dysregulation of the innate response, including type I and III interferons, alongside an aberrant adaptive immune response against the invading pathogen ( Wong and Perlman, 2022 ). Recently, our group reported that enhanced eosinophil-mediated inflammation and subsequent pulmonary pathogenesis via enhanced T H 2-biased immune responses have been associated with increased formation of immune complexes, and membrane attack complexes in airways and vasculature of inflamed lungs, especially in critical COVID-19 ( Kim et al., 2021 ). In addition, previous seminal studies have reported the potential pathogenic role of dysregulated humoral immune responses, including overt EF B-cell activation ( Woodruff et al., 2020 ) and autoantibodies ( Bastard et al., 2020 ; Wang et al., 2021 ), correlated with severe COVID-19.…”

Section: Discussionmentioning

confidence: 99%

“…While we could not define whether the differentiation pathway of PC2 cells is linked to an EF B-cell response pathway (AN → DN → AM2), it is plausible that both the AM2 and PC2 cells seem to function as pathogenic B cells. This potentially occurs through multiple mechanisms, including the generation of inflammatory mediators, production of autoreactive antibodies, and immune complex formation during the acute phase of COVID-19 ( Woodruff et al., 2020 ; Kim et al., 2021 ; Wang et al., 2021 ), wherein the GC formation is suppressed ( Kaneko et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

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Acute Surge of Atypical Memory and Plasma B-Cell Subsets Driven by an Extrafollicular Response in Severe COVID-19

Lee

Kim

et al. 2022

Front. Cell. Infect. Microbiol.

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BackgroundDespite the use of vaccines and therapeutics against the coronavirus disease 2019 (COVID-19) pandemic, this severe disease has been a critical burden on public health, whereas the pathogenic mechanism remains elusive. Recently, accumulating evidence underscores the potential role of the aberrant B-cell response and humoral immunity in disease progression, especially in high-risk groups.MethodsUsing single-cell RNA (scRNA) sequencing analysis, we investigated transcriptional features of B-cell population in peripheral blood from COVID-19 patients and compared them, according to clinical severity and disease course, against a public B-cell dataset.ResultsWe confirmed that acute B cells differentiate into plasma cells, particularly in severe patients, potentially through enhanced extrafollicular (EF) differentiation. In severe groups, the elevated plasma B-cell response displayed increased B-cell receptor (BCR) diversity, as well as higher levels of anti–severe acute respiratory syndrome coronavirus 2 (anti–SARS-CoV-2) spike antibodies in plasma, than those in moderate cases, suggesting more robust and heterogeneous plasma cell response in severe COVID-19 patients. Trajectory analysis identified a differentiation pathway for the EF B-cell response from active naïve to atypical memory B cells (AM2), in addition to the emergence of an aberrant plasma cell subset (PC2), which was associated with COVID-19 progression and severity. The AM2 and PC2 subsets surged in the acute phase of the severe disease and presented multiple inflammatory features, including higher cytokine expression and humoral effector function, respectively. These features differ from other B-cell subsets, suggesting a pathogenic potential for disease progression.ConclusionThe acute surge of AM2 and PC2 subsets with lower somatic hypermutation and higher inflammatory features may be driven by the EF B-cell response during the acute phase of severe COVID-19 and may represent one of the critical drivers in disease severity.

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“…One study showed that FcγRIIA-mediated activation of platelets is linked to thrombocytopenia in critically ill patients [ 45 , 46 ]. Another study reported that enhanced eosinophil-mediated inflammation in the respiratory tract of critically ill and deceased COVID-19 patients is associated with FcγR signaling in myeloid cells [ 47 ]. Finally, neutrophil activation by immune complexes via FcγRIIA was suggested to negatively impact COVID-19 progression [ 48 ].…”

Section: Ic-mediated Immune Cell Activation and Systemic Inflammation...mentioning

confidence: 99%

Immune complexes as culprits of immunopathology in severe COVID-19

Kolb

Giese

Voll

et al. 2022

Med Microbiol Immunol

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Infection with the pandemic human coronavirus SARS-CoV-2 elicits a respiratory tract disease, termed Coronavirus disease 2019 (COVID-19). While a variable degree of disease-associated symptoms may emerge, severe COVID-19 is commonly associated with respiratory complications such as acute respiratory distress syndrome (ARDS), the necessity for mechanical ventilation or even extracorporeal membrane oxygenation (ECMO). Amongst others, disease outcome depends on age and pre-existing conditions like cardiovascular diseases, metabolic disorders but also age and biological sex. Intriguingly, increasing experimental and clinical evidence suggests that an exacerbated inflammatory response and in particular IgG immune complexes (ICs), significantly contribute to severe and prolonged COVID-19 disease progression. Vast amounts of deposited, unresolved ICs in tissue are capable to initiate an exaggerated Fc gamma receptor (FcγR) mediated signalling cascade which eventually results in common IC-associated organ diseases such as vasculitis, glomerulonephritis and arthritis, comorbidities that have been frequently reported for COVID-19. Moreover and independent of deposited ICs, very recent work identified soluble ICs (sIC) to be also present in the circulation of a majority of severely ill patients, where their systemic abundance correlated with disease severity. Thus, detection of circulating sICs in patients represents a potential marker for critical COVID-19 disease progression. Their detection early after clinical deterioration might become an indicator for the requirement of prompt anti-inflammatory treatment. Here, we review the role of ICs in COVID-19 progression, their possible origins and potential intervention strategies. Graphical abstract

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Enhanced eosinophil-mediated inflammation associated with antibody and complement-dependent pneumonic insults in critical COVID-19

Cited by 39 publications

References 44 publications

Complement activation in COVID-19 and targeted therapeutic options: A scoping review

Complement activation in COVID-19 and targeted therapeutic options: A scoping review

Acute Surge of Atypical Memory and Plasma B-Cell Subsets Driven by an Extrafollicular Response in Severe COVID-19

Immune complexes as culprits of immunopathology in severe COVID-19

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