The Role of Coinhibitory Receptors in B Cell Dysregulation in SARS-CoV-2-Infected Individuals with Severe Disease.
J Immunol
; 212(10): 1540-1552, 2024 May 15.
Article
in En
| MEDLINE
| ID: mdl-38517295
ABSTRACT
Severe SARS-CoV-2 infection is associated with significant immune dysregulation involving different immune cell subsets. In this study, when analyzing critically ill COVID-19 patients versus those with mild disease, we observed a significant reduction in total and memory B cell subsets but an increase in naive B cells. Moreover, B cells from COVID-19 patients displayed impaired effector functions, evidenced by diminished proliferative capacity, reduced cytokine, and Ab production. This functional impairment was accompanied by an increased apoptotic potential upon stimulation in B cells from severely ill COVID-19 patients. Our further studies revealed the expansion of B cells expressing coinhibitory molecules (PD-1, PD-L1, TIM-1, VISTA, CTLA-4, and Gal-9) in intensive care unit (ICU)-admitted patients but not in those with mild disease. The coinhibitory receptor expression was linked to altered IgA and IgG expression and increased the apoptotic capacity of B cells. Also, we found a reduced frequency of CD24hiCD38hi regulatory B cells with impaired IL-10 production. Our mechanistic studies revealed that the upregulation of PD-L1 was linked to elevated plasma IL-6 levels in COVID-19 patients. This implies a connection between the cytokine storm and altered B cell phenotype and function. Finally, our metabolomic analysis showed a significant reduction in tryptophan but elevation of kynurenine in ICU-admitted COVID-19 patients. We found that kynurenine promotes PD-L1 expression in B cells, correlating with increased IL-6R expression and STAT1/STAT3 activation. Our observations provide novel insights into the complex interplay of B cell dysregulation, implicating coinhibitory receptors, IL-6, and kynurenine in impaired B cell effector functions, potentially contributing to the pathogenesis of COVID-19.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
SARS-CoV-2
/
COVID-19
Limits:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
J Immunol
/
J. immunol
/
Journal of immunology
Year:
2024
Type:
Article
Affiliation country:
Canada