Persistent Autoimmune Activation and Proinflammatory State in Post-COVID Syndrome, 2022, Acosta-Ampudia et al

Abstract

Background
The immunopathological pathways enabling post-COVID syndrome (PCS) development are not entirely known. We underwent a longitudinal analysis of patients with COVID-19 who developed PCS aiming to evaluate the autoimmune and immunological status associated with this condition.

Methods
Thirty-three patients were included for longitudinal clinical and autoantibody analyses of whom 12 patients were assessed for cytokines and lymphocyte populations. Patients were followed during 7-11 months after acute COVID-19. Autoimmune profile and immunological status were evaluated mainly by enzyme-linked-immunosorbent assays and flow cytometry.

Results
Latent autoimmunity and overt autoimmunity persisted over time. A proinflammatory state was observed in patients with PCS characterized by upregulated IFN-α, TNF-α, G-CSF, IL-17A, IL-6, IL-1β, and IL-13, whereas IP-10 was decreased. In addition, PCS was characterized by increased levels of Th9, CD8+ effector T cells, naive B cells, and CD4+ effector memory T cells. Total levels of IgG S1-SARS-CoV-2 antibodies remained elevated over time.

Discussion
The clinical manifestations of PCS are associated with the persistence of a proinflammatory, and effector phenotype induced by SARS-CoV-2 infection. This long-term persistent immune activation may contribute to the development of latent and overt autoimmunity. Results suggest the need to evaluate the role of immunomodulation in the treatment of PCS.

Open access, https://academic.oup.com/jid/advance-article-abstract/doi/10.1093/infdis/jiac017/6515371

 

For me, this is where a medical degree would be helpful. Isn't autoimmunity still a theory? The theory is some of our own antibodies or other parts of our immune system attack our own organs or cells etc. For reasons unknown. There are subplots to this theory as well, including molecular mimicry, the bystander effect, and several others, including persistent infection - although I'm not quite sure how the latter qualifies as autoimmune.

My point is, or rather my question, if we assume that our diagnostics are not infallible, and that this can be the case (depending on the pathogen) for large swaths of people, then why would we ever start, in any investigation of persistent symptoms, with the assumption of an autoimmune response - which may in fact only ever be a theory? Shouldn't we automatically default to pathogen persistence and flawed or limited diagnostics?

 

Autoimmunity is a fact rather than a theory. People with certain diseases have antibodies to their own proteins (or DNA or even sugar epitopes). Autoantibodies were first documented by Landsteiner in 1908 or thereabouts. Detecting them is highly reproducible. You can crystallise them and determine their detailed structure.

A causal role for autoantibodies is a theory but there are reliable animal models that show that autoantibodies can cause disease and the use of rituximab provided a pretty good test in human disease in that in many cases disease disappears completely with a close temporal match to autoantibody fall. If you like, the work I and others did on this in the late 1990s show that autoantibodies are pathogenic pretty much for certain.

But this applies to diseases where a high proportion of patients show levels of antibody way outside the normal range. Moreover, there are lots of caveats because non-pathogenic autoantibodies do occur in a minority of the population and in lupus, where there are a range of autoantibodies, at least some are probably irrelevant.

The situation for ME, with anti-G protein couple receptors being very marginally statistically higher than normals but still in the normal range makes theorising about autoimmunity pretty thin.

I have not read the whole paper above but the abstract looks even thinner. If there were any autoantibody results of significance they would have been put in the abstract.

Molecular mimicry is a specific idea that doesn't make much sense and in general the evidence is repeatedly against it. Persistent infection is not relevant to autoimmunity as far as I am aware. In general autoimmunity has nothing to do with infection but for historical reasons this meme has remained in the popular consciousness.

 

Very cool. Thank you, @Jonathan Edwards.

If I can follow up very briefly because I don't want to bore readers with my ignorance: Cases of proven autoantibody disease aside, and with a nod to differential diagnosis, shouldn't we default with unresolved disease etiology to the assumption - at least in cases where we know the disease initiated with a pathogen - that the pathogen persists in some priviledged site or state that eludes antibody response or PCR detection?

Edit to add: Ah, I read through this. So autoantibodies as cause for disease is still theory? Isn't this theory primarily what Rheumatology is built upon? I ask this as I have several conditions that are purported to fall under the auspices of rheumatology - but maybe there is an argument that they might belong under infectious disease e.g. psoriaisis, arthitis etc?

This is not pointless speculation. Many times the way one treats a supposed autoimmune disorder is with immunosuppressants. But if it's ultimately proven to be infectious in nature, isn't that counterintuitive, with the exception of cases we can't resolve the pathogen so the only recourse is to blunt one's immune response to make QoL more tolerable?

 

Not particularly. Autoimmunity is only one of several mechanisms that might produce long term sequelae after infection and, as I said, is probably the least plausible. Other mechanisms look likely for Reiter's disease, rheumatic fever, post-streptococcal nephritis and so on. Situations where there is residual pathogen eluding the immune system are well recognised but fairly easily identified because at some stage a patient will develop immunodeficiency for some other reason and the organism will show itself again. Shingles is the classic case historically. Reactivated TB after TNF inhibitors is a new one. If we have seen tens of thousands of cases of disease X and in nobody with disease X has an organism resurfaced in the face of bone marrow transplantation or high dose steroids it is probably reasonable to assume that the organism is no longer there.

Rheumatology as a scientific or academic discipline arose in the 1950s and autoimmunity was what excited interest. However, by 1980 it was decided that autoantibodies were probably epiphenoma and so unimportant. It was still fashionable to see rheumatic diseases as autoimmune but the assumption was that the real culprits were auto reactive T cells - except that nobody ever found any. More than that, controlled studies showed they were definitely absent when they should have been found. To some extent the T cell myth remains the conventional wisdom. However, our studies in 1998 and onwards made it pretty clear that the reason you could not find the autoreactive T cells was that they were not there and that the autoantibodies that had given rise to the concept of autoimmunity were what mattered after all.

Once that became clear and genetic risk factors for the various diseases were sorted it also became clear that there were some inflammatory T cell diseases - psoriasis, ankylosing spondylitis etc. but without any evidence for the problematic T cells recognising self. Nobody really knows what the problem is but it seems likely that T cells that provide non-antigen-specific pro-inflammatory signals have got expanded and so this is called 'auto-inflammation' rather than autoimmunity.

It certainly would be but the fact that infection does not reactivate suggests that infection is not the problem. We also have the information that several hundred people with autoimmune rheumatic disease have had their entire immune system wiped out by treatment for e.g. myeloma or leukaemia. No infection appears and almost always the rheumatic disease goes in to remission. The same applies for psoriasis in most cases.

 

Thank you for that clear explanation.