Mitochondrial regulation of acute extrafollicular B‐cell responses to COVID‐19 severity

Abstract

Background Patients with COVID‐19 display a broad spectrum of manifestations from asymptomatic to life‐threatening disease with dysregulated immune responses. Mechanisms underlying the detrimental immune responses and disease severity remain elusive. Methods We investigated a total of 137 APs infected with SARS‐CoV‐2. Patients were divided into mild and severe patient groups based on their requirement of oxygen supplementation. All blood samples from APs were collected within three weeks after symptom onset. Freshly isolated PBMCs were investigated for B cell subsets, their homing potential, activation state, mitochondrial functionality and proliferative response. Plasma samples were tested for cytokine concentration, and titer of Nabs, RBD‐, S1‐, SSA/Ro‐ and dsDNA‐specific IgG. Results While critically ill patients displayed predominantly extrafollicular B cell activation with elevated inflammation, mild patients counteracted the disease through the timely induction of mitochondrial dysfunction in B cells within the first week post symptom onset. Rapidly increased mitochondrial dysfunction, which was caused by infection‐induced excessive intracellular calcium accumulation, suppressed excessive extrafollicular responses, leading to increased neutralizing potency index and decreased inflammatory cytokine production. Patients who received prior COVID‐19 vaccines before infection displayed significantly decreased extrafollicular B cell responses and mild disease. Conclusion Our results reveal an immune mechanism that controls SARS‐CoV‐2‐induced detrimental B cell responses and COVID‐19 severity, which may have implications for viral pathogenesis, therapeutic interventions and vaccine development.

Innate and adaptive immune response in SARS-CoV-2 infection-Current perspectives

“…In addition, immature, activated naïve B cells and the DN3 fraction showed a strong correlation with ventilatory parameters, such as respiratory rate, SpO2, and PaO2/FiO2 ( 105 ). Another study also revealed similar phenomenon about DN2 B cells in acute patients with COVID-19 ( 106 ). This study also revealed that severe patients displayed enhanced extrafollicular B cell activation with accelerated inflammation, while mild patients counteracted the disease through the timely induction of mitochondrial dysfunction in B cells, which suppressed the extrafollicular responses, resulting in increased neutralizing potency index and reduced inflammation ( 106 ).…”

Navigating the Post-COVID-19 Immunological Era: Understanding Long COVID-19 and Immune Response

“…In certain COVID-19 survivors, rheumatoid arthritis and systemic lupus erythematosus have also been recorded, suggesting connections between the viral infection and subsequent autoimmune reactions. It is significant to remember that, although these results indicate a connection between COVID-19 and autoimmunity, further research is still needed to determine the general prevalence of post-COVID-19 autoimmunity and its long-term effects [80]. Following COVID-19 infection, autoimmunity is uncommon, with most patients recovering without experiencing persistent autoimmune problems.…”

“…An immune system-mediated liver inflammation is a hallmark of the chronic liver disease known as autoimmune hepatitis. A case study documented people who developed autoimmune hepatitis after contracting COVID-19 [80]. In certain COVID-19 survivors, rheumatoid arthritis and systemic lupus erythematosus have also been recorded, suggesting connections between the viral infection and subsequent autoimmune reactions.…”