Nature: Diverse Functional Autoantibodies in Patients with COVID-19, Wang et al, 2021

[Andy]

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1–8. While pathological innate immune activation is well documented in severe disease1, the impact of autoantibodies on disease progression is less defined. Here, we used a high-throughput autoantibody discovery technique called Rapid Extracellular Antigen Profiling (REAP) to screen a cohort of 194 SARS-CoV-2 infected COVID-19 patients and healthcare workers for autoantibodies against 2,770 extracellular and secreted proteins (the “exoproteome”). We found that COVID-19 patients exhibit dramatic increases in autoantibody reactivities compared to uninfected controls, with a high prevalence of autoantibodies against immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins. We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signaling and by altering peripheral immune cell composition, and found that murine surrogates of these autoantibodies exacerbate disease severity in a mouse model of SARS-CoV-2 infection. Analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics and disease severity. In summary, these findings implicate a pathological role for exoproteome-directed autoantibodies in COVID-19 with diverse impacts on immune functionality and associations with clinical outcomes.

https://www.medrxiv.org/content/10.1101/2020.12.10.20247205v5

 

[Ravn]

This has now been published in Nature:
https://www.nature.com/articles/s41586-021-03631-y

 

[Hutan]

So, they are looking at autoantibodies reacting against proteins outside cells, in people with Covid-19:

these results indicate that autoantibodies that target the exoproteome are increased in COVID-19.

People with Covid-19 had a higher level of overall reactivity to their own proteins than uninfected people and people with SLE, (but a lower level of overall reactivity than people with a genetic mutation that causes them to not make a protein that helps distinguish own proteins from pathogen proteins). There was no difference between the overall reactivity of men and women with Covid-19. People with more severe Covid-19 had a higher level of reactivity.

Irrespective of the REAP score cut off we used, patients with COVID-19 had a greater number of reactivities compared to uninfected individuals, and the highest scoring reactivities were preferentially enriched in patients with severe disease

As sex differences in the immune response to SARS-CoV-2 have previously been reported17, we compared the number of autoantibody reactivities between men and women with COVID-19 and found no significant differences in reactivity numbers at any score cut off

Finally, in a comparison with the REAP profiles of patients with systemic lupus erythematosus (SLE) or autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), patients with COVID-19 had greater numbers of reactivities than did individuals with SLE but fewer numbers of reactivities than did individuals with APECED

They were able to track reactivity levels for each protein over time. They found some reactivities that could be assumed to pre-date the infection, while others developed after. And many of the proteins being reacted to by people with severe Covid-19 were immune-related. They found that autoantibodies could affect immune function.

To more directly assess potential immunomodulatory effects of cytokine- and chemokine-targeting autoantibodies in patients with COVID-19, we assessed the in vitro activity of selected autoantibodies. We found that IgG from patients with anti-GM-CSF, anti-CXCL1 or anti-CXCL7 autoantibodies could antagonize the signalling of GM-CSF, CXCL1 and CXCL7, respectively (Fig. 2a, b). In addition, we found that plasma or IgG from patients with anti-CD38 or anti-CD3ε autoantibodies led to increased antibody-dependent cellular phagocytosis by macrophages of Raji B cells or Jurkat T cells, respectively (Fig. 2c, Extended Data Fig. 4h, i). These results demonstrate that immune-targeting autoantibodies in patients with COVID-19 can directly inhibit the activity of cytokines and chemokines, and engage FcR effector functions that could lead to immune-cell depletions in affected patients.

So, perhaps the virus is disrupting things? Causing people's immune systems to be distracted with a civil war, rather than fighting the invader? That seems like a good strategy for a virus.

But, by itself, the finding doesn't explain why some people, including some people with mild infections, develop Long Covid, while many people with severe infections don't.

 

[Mithriel]

It does not explain serious illness caused by organ damage but a lot of what we see as illness is the immune system's response to the infection. Interferons cause fever, runny nose and coughs, malaise and so on.

A mild disease could be because the immune system fights of the invader quickly before it replicates very much but it could also be because of immune failure while the virus multiplies unchecked.

It could be that the virus can get deeper into the body with mild disease.