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Don’t Let a Virus Turn Off Your Interferon With Antibodies.

covid Oct 06, 2020

The plot thickens.  As investigators sift through piles of data left behind by the OCIVD 19 pandemic, they search for patterns to explain why and how this little virus caused so much havoc.  While we can debate the national responses to the virus’ spread, we should all agree that the rapid-fire scientific breakthroughs have been astounding.  From the benefits of vitamin D to the intricacies of immune defenses, science is providing plenty of news headlines to the general public.  This headline caught my attention as it links autoimmunity, genetics, and COVID 19 immunity.

            Three of the biggest questions have been how to fight the virus, how to prevent the virus, and why do some get a more severe case than others.  These three questions intersect in this report describing how self-produced antibodies, auto-antibodies, can disable our immune system and open the door for more severe infection with COVID 19. The researchers enrolled a few thousand COVID 19 patients in their project and screened them for antibodies which were found to turn off one of several different interferons involved in viral immunity.

            Interferons come in different forms like alpha, beta, gamma, and others subtypes.  They are immune system messengers produced both by immune cells and non-immune cells which send a message.  Typically, that message is “infection present, start fighting”.  The immune response fights off the invaders and the interferon alarm signal is turned off.

            These investigators knew from other research into viral immunity that antibodies against these immune messengers could lead to more severe infectious diseases (1-9).  Besides looking for the presence of these antibodies in severe COVID 19 infected patients, they evaluated a large set of healthy controls and a large set of mildly affected COVID 19 patients.  Whereas there were minimal to no instances of the interferon neutralizing antibodies in the healthy controls or mild cases, there were 101 out of 987 severe cases which showed neutralizing auto-antibodies. 

            When they took the antibodies and tested them in cell cultures, they found that the antibodies would turn off the cell’s ability to respond to different interferons.  By then removing the antibodies, they could turn the ability to respond back on again.  With a few other experimental steps, they could reasonably assert that the antibodies were blocking interferon and preventing an immune response.

            They then asked themselves if the antibodies were a cause or an effect.  Did the affected patients have the antibodies before the infection occurred or did the infection trigger the antibodies in some patients?  Looking retrospectively at the patients in question could not fully answer this question, although they did have two patients in their study for whom they had antibody measures before the infection occurred which were elevated. 

However, they could infer more from other research.  Other studies had reported these neutralizing auto-antibodies in patients with a disease called autoimmune polyendocrinopathy syndrome type 1.  The auto-antibodies had also been found in women with a genetic disease called incontinentia pigmenti.  It seems reasonable to conclude that the antibodies were present before the viral infection and then led to a more severe case of the infection.  Some genetic tendency seemed to lie behind this production of auto-antibodies and some other lines of evidence suggested that it was an X-linked condition due to the fact that men with only 1 “X” choromosome had more frequent instances of the condition.

            What difference does this make?  From a functional medicine standpoint, it shows the intricate interdependent nature of our immune system in which one arm, antibodies, could turn off another arm, the cytokines.  This autoimmune self-disarming opens the door for more severe COVID 19 and probably other viral diseases.  From this research, hopefully others will look at this possibility for other viral infections in the chronically ill, such as chronic EBV patients like we care for in our clinic.  From the standpoint of fighting COVID 19, we should screen out patients with such antibodies if we are looking to use their convalescent plasma to fight the infection.  This therapy uses antibodies harvested from COVID 19 survivors to infuse into those with active disease, aiming to kill the virus with other’s antibodies.  It is effective, but we should not give sick patients antibodies that disable their interferon system.  (I wrote a past post on this therapy. Read there for an explanation.)

            Knowing the factors which contribute to viral susceptibility can open the door to discerning who is at higher risk.  Then we can apply this knowledge and wisdom into both preparing and responding to infections in 2020 and beyond.  That is the goal of Immune Prepper 101.

Original Article:

Paul Bastard et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science, Sept. 24, 2010; DOI: 10.1126/science.abd4585

Thanks to Science Daily:

Howard Hughes Medical Institute. “Some severe COVID-19 cases linked to genetic mutations or antibodies that attack the body.” ScienceDaily. ScienceDaily, 24 September 2020. <www.sciencedaily.com/releases/2020/09/200924141529.htm>.

Other references:

  1. J.-L. Casanova, L. Abel, The human genetic determinism of life-threatening infectious diseases: Genetic heterogeneity and physiological homogeneity? Hum. Genet. 139, 681–694 (2020). doi:10.1007/s00439-020-02184-wpmid:32462426
  • R. Döffinger, M. R. Helbert, G. Barcenas-Morales, K. Yang, S. Dupuis, L. Ceron-Gutierrez, C. Espitia-Pinzon, N. Barnes, G. Bothamley, J.-L. Casanova, H. J. Longhurst, D. S. Kumararatne, Autoantibodies to interferon-gamma in a patient with selective susceptibility to mycobacterial infection and organ-specific autoimmunity. Clin. Infect. Dis. 38, e10–e14 (2004). doi:10.1086/380453pmid:14679469
  • C. Höflich, R. Sabat, S. Rosseau, B. Temmesfeld, H. Slevogt, W.-D. Döcke, G. Grütz, C. Meisel, E. Halle, U. B. Göbel, H.-D. Volk, N. Suttorp, Naturally occurring anti-IFN-gamma autoantibody and severe infections with Mycobacterium cheloneae and Burkholderia cocovenenans. Blood 103, 673–675 (2004). doi:10.1182/blood-2003-04-1065pmid:12947000
  • B. Kampmann, C. Hemingway, A. Stephens, R. Davidson, A. Goodsall, S. Anderson, M. Nicol, E. Schölvinck, D. Relman, S. Waddell, P. Langford, B. Sheehan, L. Semple, K. A. Wilkinson, R. J. Wilkinson, S. Ress, M. Hibberd, M. Levin, Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-gamma. J. Clin. Invest. 115, 2480–2488 (2005). doi:10.1172/JCI19316pmid:16127458
  • A. Puel, C. Picard, M. Lorrot, C. Pons, M. Chrabieh, L. Lorenzo, M. Mamani-Matsuda, E. Jouanguy, D. Gendrel, J.-L. Casanova, Recurrent staphylococcal cellulitis and subcutaneous abscesses in a child with autoantibodies against IL-6. J. Immunol. 180, 647–654 (2008). doi:10.4049/jimmunol.180.1.647pmid:18097067
  • A. Puel, R. Döffinger, A. Natividad, M. Chrabieh, G. Barcenas-Morales, C. Picard, A. Cobat, M. Ouachée-Chardin, A. Toulon, J. Bustamante, S. Al-Muhsen, M. Al-Owain, P. D. Arkwright, C. Costigan, V. McConnell, A. J. Cant, M. Abinun, M. Polak, P.-F. Bougnères, D. Kumararatne, L. Marodi, A. Nahum, C. Roifman, S. Blanche, A. Fischer, C. Bodemer, L. Abel, D. Lilic, J.-L. Casanova, Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 207, 291–297 (2010). doi:10.1084/jem.20091983pmid:20123958
  • K. Kisand, A. S. Bøe Wolff, K. T. Podkrajsek, L. Tserel, M. Link, K. V. Kisand, E. Ersvaer, J. Perheentupa, M. M. Erichsen, N. Bratanic, A. Meloni, F. Cetani, R. Perniola, B. Ergun-Longmire, N. Maclaren, K. J. E. Krohn, M. Pura, B. Schalke, P. Ströbel, M. I. Leite, T. Battelino, E. S. Husebye, P. Peterson, N. Willcox, A. Meager, Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207, 299–308 (2010). doi:10.1084/jem.20091669pmid:20123959
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