In an earlier post, I discussed autoantibodies against Interferon I and how this interfered with the first line of defense against SARS-CoV-2. Now recent data has revealed that the virus induces other autoantibodies against other targets which explains the variety of symptoms and perhaps chronic disease following initial COVID recovery. Autoantibodies are not unprecedented in viral diseases. The exclusion of cells in the immune system that produce antibody or cellular immune responses directly against self is a central tenet of immunology. Sir Frank McFarlane Burnet was awarded the Nobel Prize for Medicine and Physiology in 1960 for his work on the immunological recognition distinguishing non-self from self. He coined the term for immune cells’ generating antibodies against self the “forbidden clone”, and formulated the hypothesis, of the same name, that in autoimmunity there exist immune cells able to make antibodies against a variety of self-antigens. He proposed autoimmune disease develops because of the escape of self-reactive clones of lymphocytes’, which are normally deleted during development to generate immune tolerance of self. These autoreactive clones can multiply and cause immune-mediated organ damage through peripheral self-antigen immune recognition and direction of effector cells to kill targets cell in a variety of tissues and organs. He thought these clones might arise as a result of somatic mutation early in lymphoid development. The proposal pre-dated knowledge of the roles of T and B lymphocytes. During his time, the role of autoantibodies was recognized in diseases such as Grave’s Disease, associated with thyroid stimulating antibodies, directed against the human thyroid stimulating hormone receptor. Later in the 20th century, T cells came to be central in theories of autoimmunity and B cells fell off the map. The truth lies somewhere in between. https://pmj.bmj.com/content/postgradmedj/88/1038/226.full.pdf.
However, autoimmunity may persist not only because of detrimental mutation, but also because it serves an evolutionary, beneficial purpose. It has been counterbalanced by apoptosis, which suppresses immune signals while still getting rid of unwanted or unneeded cells, without triggering inflammation. When necrotic tissue infected by pathogens or cells undergoing disease processes contain intracellular pathogens hidden from antibodies or immune surveillance, the tiniest departure from normal surface structure or exposure of internal cell structures to the immune response may be essential to elimination of the pathogen. Various forms of programmed cell death may lead to various levels of immune response exposure: autophagic cell death, necroptosis, elimination by shedding, keratinocyte death by cornification,and cell–cell cannibalism by entosis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994033/. These various self- killing mechanisms and autoimmunity may also be important in preventing the development of cancer, or allowing it to proceed, when these countermeasures are out of balance.
The autoimmune response is not new to viral infection https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723519/pdf/viruses-11-00762.pdf. Examples of infections that yield autoantibodies are those with enteric viruses such as Coxsackie B virus and rotavirus and other types such as influenza A viruses, herpesviruses, measles, mumps, and rubella. Autoimmune B cell responses contribute to mixed cryoglobulinemia, glomerulonephritis, and vasculitis, of hepatitis B and C virus infection. Another example in animals is antibody to feline oncornavirus-associated cell membrane antigen (FOCMA) on the surface of feline lymphosarcoma cells in sera of cats relatively resistant to development of FeLV (feline leukemia virus), Lymphosarcoma, and FeSV (feline sarcoma virus) fibrosarcoma. The antibodies do not exclusively attack viral antigens but consistently bind to 70-kDa proteins on the surface of lymphosarcoma cells https://pubmed.ncbi.nlm.nih.gov/6318434/. Therefore, resistance to cancer, caused by these viruses, is associated with this anti-host cell antibody, not necessarily direct antiviral antibody.
Other chronic disease conditions triggered by viruses and caused by autoimmunity include Type 1 juvenile diabetes and Type 1.5 adult onset autoimmune diabetes. Type 1 diabetes is a lifelong chronic disease characterized by the loss of or severely reduced number of insulin-producing β cells in the islet of Langerhans, presence of islet autoantibodies, and, especially in younger individuals, insulitis consisting of infiltration of the islets predominantly by CD8+ T cytotoxic cells and macrophages. In explanted islets cultured from coxsackievirus B-1-infected islets, the expression of the coxsackie–adenovirus receptor gene was increased and was 10-fold higher in endocrine compared with exocrine cells of the pancreas. There is high suspicion of viral causality because of these observed experimental results https://drc.bmj.com/content/4/1/e000219.
Another autoimmune disease where virus is suspected but not immediately linked is multiple sclerosis (MS). The comparison of chronic canine distemper, which leads to spinal cord and CNS nerve process demyelination, has led to this suspicion by analogy, but incrimination of the canine distemper virus being the cause in human MS has not withstood scientific examination. T cells have been considered the main (MS) protagonists in the pathogenesis of multiple sclerosis. Only recently has evidence arose supporting B cells as major contributors. Rather than merely producing autoantibodies, they collaborate with T cells by priming and regulating T cells, and mediate both pro- and anti-inflammatory interactions. However, despite intensive searching, the target antigen(s) of B cells in MS have not been identified https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519967/pdf/ijms-16-16576.pdf. The original viral instigator may have only left a ghost antigen behind long after it was eliminated.
Such examples make the autoimmune pathogenesis of COVID not unexpected. Autoantibodies which recognize cell membrane phospholipids cause an autoimmune disease called antiphospholipid syndrome (APS). In APS patients, autoantibodies activate clot-forming cells, putting those patients at higher risk of blood clot formation. These antibodies may also be present in a variety of bacterial or viral infections. However, cause and effect of blood clotting during infection is difficult to prove. Severely ill COVID-19 patients can have high levels of neutrophils, and some have phospholipid-binding antibodies in their blood. Of the patients studied, of those who developed blood clots, only half had the auto antibodies https://stm.sciencemag.org/content/scitransmed/early/2020/11/02/scitranslmed.abd3876.full.pdf. Additionally, the immunological response in severe COVID-19 infection, including TLR7 activation by SARS-CoV2 single-stranded RNA, is sufficient to drive new autoimmunity without the patient’s response against a variety of self-antigens being genetically pre-determined. https://www.medrxiv.org/content/10.1101/2020.10.21.20216192v2.full.pdf. All this being said, the immune system has several possible pathways to follow in COVID-19, some of which I have discussed in earlier posts. The good and bad news is that the progression has these choices. This means that chemically programmable immunity using antigen-aptamer conjugates has a significant probability of re-directing the response down one such pathway that effectively eliminates the SARS-CoV-2 virus without triggering pathogenic autoimmunity or chronic autoimmune disease, which would persist after the virus is gone. There is even a possibility that redirection can ameliorate such residual autoimmunity or even, under ideal conditions, end it. However, until research is supported toward testing these hypotheses, we will never know.
Global Biosurveillance 