Targets & Mechanisms
Tissue-targeting autoantibodies as a driver of long COVID
One implication of the recent Yale study linking autoantibody production to the development of long COVID is that treatment with therapies directed at B cells or antibody clearance might prove useful in preventing the condition.
But caution would need to be taken to avoid impairing antibody-mediated antiviral responses during acute infection study co-leader Aaron Ring, an assistant professor of immunobiology at Yale University, told BioCentury. “We imagine that timing will be absolutely critical.”
Long COVID is a still poorly defined constellation of long-term, multi-organ complications that affect a subset of COVID-19 patients. A recent survey found the majority of BioCentury’s scientific advisory board members expect the CDC to issue an international classification of disease (ICD) code in 2021.
Ring and Yale University’s Akiko Iwasaki demonstrated a link between infection-induced autoantibodies and chronic COVID-19 symptoms in a Dec. 12 medRxiv paper.
Using a screening approach they dubbed Rapid Extracellular Antigen Profiling (REAP), the team detected autoantibodies against a broad variety of targets in samples from 194 infected individuals with varying disease severity, including a longitudinal cohort.
The study also linked immune-targeting autoantibodies to higher disease severity and bolstered support for the role of type I interferons in controlling SARS-CoV-2.
The self antigens observed in the study included interferons and other cytokines and chemokines; innate and adaptive immune cell surface markers; proteins expressed on vascular, CNS and connective tissues; and extracellular matrix targets.
In a subset of cases, autoreactivity predated SARS-CoV-2 infection, but in others, “We clearly observed the formation of autoantibodies while patients were hospitalized for COVID-19, indicating that they were triggered by infection,” Ring told BioCentury.
Ring said autoantibodies induced by infection most likely resulted from the release of tissue antigens following virus-induced tissue damage and inflammation, which primed new antigenic responses.
“These same processes could activate latent autoreactive B cells to produce their autoantibodies,” he added.
Increased autoreactivity against several tissue groups — such as CNS, cardiac, hepatic and epithelial tissue — was more strongly associated with high levels of inflammatory markers in patients with severe vs. moderate COVID-19.
The team also observed an greater expansion of a B cell subset associated with lupus in moderate and severe COVID-19 patients than in uninfected individuals. These “double-negative B cells” do not express IgD or the memory B cell marker CD27.
It is too early to know the duration of autoantibody production in COVID-19 patients. But Ring told BioCentury, “We currently hypothesize that some patients with COVID-19 may unfortunately develop autoantibodies that persist well after the virus has been cleared and that those antibodies may underlie certain features of post-COVID syndromes.”
“The most important next step will be to apply our antibody profiling approach to patients with long COVID,” he said. The team has been following “numerous patients” since the pandemic started to enable a deep-dive on how autoantibodies change over time in COVID-19 patients who fully recover compared with those who have persistant symptoms.
Ring postulated that B cell-targeting drugs such as rituximab, or approaches such as FcRn inhibition to promote antibody clearance, could address chronic autoantibody-mediated COVID-19 pathology, though care would be needed to avoid preventing antiviral responses.
The team also plans to use REAP to explore the connections between other infections and autoimmunity.
Strengthening ties between autoantibodies, disease severity
The new study built on previous work that correlated antibodies against type I interferons with poor COVID-19 outcomes.
The Yale team linked elevated levels of immune-targeting autoantibodies with impaired viral control, reduced innate and adaptive immune cell numbers, and target-associated signaling defects.
They then showed in a transgenic mouse model of COVID-19 that antibodies against IL-18 or the type I interferon receptor worsened outcomes.
In the mice, pre-infection administration of antibodies against either target exacerbated weight loss; reduced numbers of activated lymphoid cells including CD4+ T cells, CD8+ T cells and NK cells; and worsened survival rates. Additionally, the antibodies against the interferon receptor “severely impaired” monocyte recruitment, maturation and differentiation into proinflammatory macrophages in the lungs; and the anti-IL-18 antibodies led to higher lung viral levels.
IFNAR1 (IFNAR) – Interferon alpha and beta receptor 1
IL-18 – Interleukin-18