9 March 2022 Episode 247 COVID and auto-immunity Part 1

Wed, 03/09/2022 - 12:15

Episode 247:  COVID and auto-immunity

Dear colleagues,

This is a complicated story.  It is evident that severe COVID is associated with a hyper-inflammatory state and that some clinical characteristics are reminiscent of various auto-immune manifestations.  In addition, there are multiple reports of increased concentrations of various auto-antibodies.  Moreover, severe COVID shows a favorable response to corticosteroids and to more specific inhibitors of inflammatory mediators (e.g. anti-Interleukin 6). 

However, this collection of elements provides only “circumstantial evidence” and does not necessarily prove that auto-immunity “strictu sensu” is really a crucial pathogenic mechanism.  In fact, many acute and chronic infections are associated with a “hyper-activation” of the innate and adaptive immune system, including polyclonal B and T cell activation with increased auto-antibody production, which are not necessarily pathogenic.

In order to proof that auto-immunity plays an important role, one should show:

  • sufficient “molecular mimicry” between parts of the pathogen and auto-antigens and/or pathogen-induced modification of auto-antigens, which could elicit a strong response of auto-reactive T and B cells;  
  • AND provide sufficient evidence (in humans or animal models) that the auto-reactive T or B cells (and antibodies) actually cause the pathological inflammation and damage that is characteristic for the disease in the affected tissues.    

In the next few episodes, I will critically investigate some of the evidence for auto-immunity during and after COVID disease and also in relation to COVID vaccination. 

For the present episode, I take the recent review in JCI as the framework. Ep 247-0: Jason Intersection between COVID-19 and auto-immunity JCI Dec 2021.


  1. Role of type 1 IFN and pre-existing auto-immunity in severe COVID

Genetic defects in IFN pathway = well known (but is NOT auto-immunity)

Ep 247-1: Zhang in Science 2020 describe a series of find rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity in 3.5 % of  life-threatening COVID cases.


Auto-neutralizing antibodies against type I IFN


These antibodies are mainly directed against IFN-α and IFN-ω, less to IFN-β.  Present in at least 10 % of life-threatening COVID, or 15 % (at lower conc) and up to 20 % in diseased elderly with COVID.

These IFN neutralizing antibodies were known to be present in nearly all patients with APS-1 (auto-immune poly-endocrinopathy type 1) and a proportion of people with systemic lupus erythematosus, thymoma and myasthenia gravis.


For more info about APS see Ep 247-2.  

However, these anti-IFN Ab also occur outside of these clinically defined entities: Analysis of more than 34,000 uninfected individuals demonstrated that these autoantibodies were present in 0.18% of individuals between 18 and 69 years of age, rising to 4% in individuals older than 70 years  a pattern that likely contributes to the age-associated risk of life-threatening COVID-19.


Remarkably, such neutralizing IFN Ab have recently also been shown in yellow fever vaccine–associated viscerotropic disease, a very rare life threatening condition, occurring in less than 1 in 100,000 vaccinations with life-attenuated YFV (Ep 247-3).  


  1. Role of de novo auto-immunity
  1. Some clinical features of severe COVID are reminiscent of

a.1. Anti-phospholipid syndrome: Antibodies against phospholipids, which activate endothelial cells and platelets while also stimulating neutrophils to release neutrophil extracellular traps (NETs).  Symptoms of this syndrome are arterial and venous thrombosis, thrombocytopenia; retinal vasculitis, visual loss, seizures.  

Ep 247-4 is a nice review on the anti-phospholipid syndrome in tempore non suspect (2010) in Lancet.  As can be see, there are several similarities with the extra-pulmonary hyper-coagulatory COVID state.


a.2. Inflammatory arthritis, Systemic Lupus Erythematosus (SLE), including nephropathy

While some symptoms overlap (e.g. pneumonitis, nephropathy, fever, endocarditis, arthritis…), SLE is a much broader “systemic” auto-immune disease than COVID


a.3. Anti-MDA5 syndrome :  Ep 247-5:  auto-antibodies targeting MDA5, an intracellular sensor of viral RNA (including coronavirus) that triggers the innate immune response. 


  1. There are numerous case reports of patients developing autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, and type 1 diabetes, concomitantly with or immediately afterSARS-CoV-2 infection.  


  1. Profiling of antibodies in COVID:
  • Ep 247-6  Sarah Esther Cheng Nature Comm May 2021:  50 % of hospitalized patients (versus 15 % of controls) present with auto-antibodies against cytokines (e.g. IL-17, IL-22, various IFN, MDA5) and various tissue antigens: ACE-2, Scleroderma-70 (Scl-70), Troponin (TPO), bactericidal-increasing permeability protein (BPI), antisynthetase antibodies (anti-Jo-1, anti-PL-7, anti-PL-12, ZO, OJ, anti-KE or KS) etc.  

These various antibodies are associated with several rare auto-immune diseases, some of which have some resemblance with COVID (e.g. interstitial pneumonitis as a symptom).  However, these findings provide very indirect evidence only.


  • Ep 247-7: Wang Nature July 2021 provides more functional evidence for the activity of these auto-Ab
    • patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins).
    • these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition


GM-CSF signalling assay performed with IgG from a patient with COVID-19 who was positive for anti-GM-CSF autoantibody (pink circles) and not for two uninfected healthcare workers (grey squares). Results are averages of duplicates from one experiment

Longitudinal comparisons of SARS-CoV-2 viral load between patients with (positive) and without (negative) autoantibodies against type I IFNs. Linear regressions (solid lines) and 95% confidence bands (shaded areas) for each group are displayed.

    • mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infect


Immune-targeting autoantibodies increase disease severity in a mouse model of COVID-19.

ag, K18-hACE2 mice were intranasally infected with a sublethal dose (b, c) or median lethal dose (dg) of SARS-CoV-2

(USA-WA1/2020 isolate), and treated with indicated antibodies (administered intraperitoneally at the indicated dose per mouse at the time points indicated in a).

b, c, Normalized body weight (b) and survival defined as 10% weight loss or mortality (c) of K18-hACE2 mice treated with PBS or anti-IFNAR from day 1 to 14 after infection.

dg, Survival defined as 20% weight loss or mortality of K18-hACE2 mice treated with anti-IL-18 (d), anti-IL-1β (e), anti-IL-21R (f),

anti-GM-CSF (g) or PBS-treated from day 1 to 14 after infection.

Significance in cg was determined using log-rank (Mantel–Cox) test. All error bars are s.e.m. All n values indicate biologically independent mice, examined over two independent experiments.



  1. Proposed mechanisms; leading to auto-immunity during COVID


    1. Induction of auto-antibodies: Autoantigens can form affinity complexes with the glycosaminoglycan dermatan sulfate (DS) and then engage B cell receptor signaling in autoreactive extrafollicular B1 cells and thereby induce autoantibody production.  Extrafollicular B cell maturation lacks certain checkpoints to prevent autoreactivity and, as such, is more prone to generating auto-antibodies.  These extrafollicular B cells, known as double-negative (DN2) B cells, lack IgD, CD27, CXCR5, and CD21. They are poised to become antibody secreting cells, tend to produce pathogenic autoantibodies, and are enriched in patients with active SLE and COVID.



    1. Potential downstream mechanisms of autoantibodies identified in patients with severe COVID-19.

(A) A subset of patients with severe COVID-19 have anti-phospholipid antibodies (aPLs) and/or anti–neutrophil extracellular trap (anti-NET) autoantibodies. aPLs may activate endothelial cells and platelets and stimulate neutrophils to release NETs. Anti-NET antibodies bind to NETs, impairing NET degradation by DNase. Together, these autoantibodies may activate complement and promote thrombosis.

(B) In some patients with severe COVID-19, antibodies can prevent the expression of interferon-stimulated genes (ISGs) by antagonizing signaling through the type I IFN receptor in an FcγRIIb-dependent fashion, impairing antiviral immunity.


  1. Role of superantigen and T cells in Multi-System Inflammatory Syndrome in Children (MISC)


Ep 247-8: Cheng PNAS Dec. 2020:

  • SARS-CoV-2 spike (S) glycoprotein exhibits a high-affinity motif for binding T cell receptors (TCRs) →may form a ternary complex with major histocompatibility complex type 2 (MHCII).
  • The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in other SARS-related coronaviruses), which is highly similar in both sequence and structure to the bacterial superantigen staphylococcal enterotoxin.
  • A neurotoxin-like sequence motif on the receptor-binding domain also exhibits a high tendency to bind TCRs.
  • Analysis of the TCR repertoire in adult COVID-19 patients demonstrates that those with severe hyperinflammatory disease exhibit TCR skewing consistent with superantigen activation.

Binding of TCR to SARS-CoV-2 spike trimer near the “PRRA” (proline-arginine-arginine-alanine) insert.

(A) Overall and (B) close-up views of the complex and interfacial interactions.

In A, the spike monomers are colored white, ice blue/gray, and spectrally from blue (N-terminal domain) to red, all displayed in surface representation. The N and C termini and RBD of the spectrally colored monomer, which also binds the TCR, are labeled; for better visualization, the S trimer is oriented such that its RBDs are at the bottom. TCR α- and β-chains are in red and cyan ribbons.

In B, the segment S680PPRAR685 including the PRRA insert and the highly conserved cleavage site R685 is shown in van der Waals representation (black labels); nearby CDR residues of the TCR Vβ domain are labeled in blue/white.



Ep 247-9Porritt JCI 2021 HLA class I–associated expansion of TRBV11-2 T cells in MIS-C


  • Profound expansion of TCRβ variable gene 11-2 (TRBV11-2), with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels.
  • Patients with TRBV11-2 expansion shared HLA class I alleles A02, B35, and C04
  • The polyacidic residues of  TRBV11-2 (Vβ21.3) strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein


Selective expansion of TRBV11-2 in severe MISC


Correlation of serum cytokine levels with TRBV11-


  1. Other examples of viruses triggering auto-immunity

Viruses such as cytomegalovirus, parvovirus B19, and Epstein-Barr virus (EBV) have been postulated to be environmental triggers of autoimmunity in genetically predisposed individuals (65).

As one example, serological evidence of EBV reactivation tracks not only with the transition to SLE, but also with increased disease activity in individuals with established SLE: antibodies against EBV nuclear antigen-1 cross-react with the SLE associated antigens Sm and Ro (68–70), and levels of anti-EBV antibodies correlate with SLE-associated autoantibodies.


Mechanistically, viruses may contribute to autoimmunity-prone immune responses in various ways. Examples include molecular and functional mimicry, superantigen activity, and stimulation of inflammatory signaling, including production of type I IFNs (74–76).


Some provisional conclusions


  1. The strongest evidence for implication of auto-immunity is the clear predisposition to severe COVID of people with auto-antibodies to type I interferon.  The mechanism is very clear, as there are many indications that type 1 IFN has a crucial role in early viral control.
  2. The evidence that SARS-CoV-2 has “superantigenic” activity in genetically predisposed individuals (with a certain HLA haplotype) is also rather convincing, as the expansion of particular T cell clones, with a clearly inflammatory cytokine profile.  
  3. A plethora of auto-antibodies has been associated with COVID and it is quite possible that some have a pathogenic role (e.g. the anti-phospholipid Ab in the hyper-coagulation state; anti-cytokine Ab undermining immune defense against the virus), but this evidence is less strong.
  4. Notwithstanding, it is certainly likely that SARS-CoV-2, like many other viruses, triggers auto-immune phenomena via the described mechanisms and that those will lead to auto-immune disease in predisposed individuals.


Tomorrow, I will discuss other data on auto-immunity in Episode 248.


Best wishes,