Spike as a superantigen

Superantigen theory notes

https://sci-hub.se/https://doi.org/10.1016/0882-4010(87)90003-9 - In the TMEV virus, inbred mice can be more susceptible or more resistant to the virus.

HPV Gardasil vaccine

https://www.nature.com/articles/srep36943 - This Japanese group demonstrated an animal model for the HPV vaccine using pertussis toxin to skew the autoimmunity towards neurological phenotypes that include low responsiveness of the tail reflex and locomotive mobility. They compared HPV + pertussis to MOG (myelin oligodendrocyte glycoprotein) antigen + pertussis toxin.

Kawasaki disease (similar to MIS-C)

https://sci-hub.se/10.1097/00001432-199506000-00005 - This 1995 links superantigens from S. Aureus and group A streptococci to staphlococcal and streptococcal toxic shock syndrome, Kawasaki syndrome, and the chronic diseases arthritis, guttate psoriasis, and atopic dermatitis.

SARS-CoV-2 spike protein

https://www.nature.com/articles/s41422-021-00495-9 - SARS COV 2 spike protein activates TLR4 and acts as a superantigen

https://www.mdpi.com/2073-4409/11/16/2526 - Unlike SEB, the SARS-CoV-2 spike does not exhibit an intrinsic superantigen-like activity (!!!).

TLR4

https://pubmed.ncbi.nlm.nih.gov/12799214/ - LPS is used in Experimental autoimmune thyroiditis (EAT) model. LPS and Freund's adjuvant behave differently.

https://www.jimmunol.org/content/175/2/959 - LPS induces relapse of EAE (Experimental Autoimmune Encephalomyelitis) in mice.

https://pubmed.ncbi.nlm.nih.gov/18203139/ - !!! The TLR4 pathway seems to regulate the priming of Th17 cells and reduce the severity of EAE.

https://pubmed.ncbi.nlm.nih.gov/19211042/ - "TLR4 down regulates disease severity in EAE and Th17 cell responses"

https://pubmed.ncbi.nlm.nih.gov/21685327/ - This study had conflicting results. TLR4 knockout mice had the same susceptibility to experimental autoimmune encephalomyelitis (EAE).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1375233/ - TLR4 ligands include LPS, Taxol

https://jitc.biomedcentral.com/articles/10.1186/s40425-019-0625-x - LPS is used to treat cancer as a TLR4 ligand / vaccine adjuvant.

http://www.worldcat.org/title/1051926526 - LPS and Freund's are used in the livestock industry for a commercial purpose (???measuring vaccine response???)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064511/ - Review of TLRs (Toll-like receptors) in Multiple Sclerosis / experimental autoimmune encephalomyelitis (EAE)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2327198/ - Bacterial LPS acts as an adjuvant to induce autoimmune arthritis in mice. LPS enhances MRL/lpr nephritis, experimental autoimmune uveitis, experimental autoimmune myocarditis and experimental autoimmune enterocolitis.

Complete Freund's adjuvant

https://pubmed.ncbi.nlm.nih.gov/2139617/ - a single injection of complete Freund's adjuvant (CFA) given at an early age (5 wk) prevented the appearance of diabetes and greatly increased the life span of NOD mice without additional therapy

https://pubmed.ncbi.nlm.nih.gov/8436836/ - The BCG vaccine (or a single injection of CFA) protected mice against diabetes. However, immunosuppression via the chemo drug cyclophosphamide could induce disease in 'protected' mice.

EAE - Experimental Allergic Encephalomyelitis / Experimental Autoimmune Encephalomyelitis

https://oxfordrecoverycenter.com/wp-content/uploads/2017/02/Ameliorating-Effects-of-Hyperbaric-oxygenation-on-Experimental-Allergic-Encephalomyelitis.pdf - HBOT was successful in pushing EAE (experimental allergic encephalomyelitis) into remission. CFA (complete freund's adjuvant) with guinea pig spinal cord.

Myocarditis

https://onlinelibrary.wiley.com/doi/full/10.1002/iid3.155 - Autoimmune myocarditis model, CFA / TiterMax Gold Adjuvant + myocarditogenic peptides in male mice

https://pubmed.ncbi.nlm.nih.gov/31005592/ - Leonurine alleviates LPS-induced myocarditis through suppressing the NF-кB signaling pathway

Animal models

• Myocarditis
• Arthritis
• Encephalomyelitis / Multiple sclerosis
• Enterocolitis
• Uveitis
• Nephritis
• Non-obese diabetic / Type 1 diabetes
• Depressive-like behavior (forced swim test) in HPV-vaccinated mice https://autoimmunity-network.com/articles/Maria%20Biobody.pdf
• ASIA syndrome - commercial sheep were given repeated vaccinations (thiomersal/thimerosal, aluminium salts, antigen) https://sci-hub.se/https://doi.org/10.1007/s12026-013-8404-0
• Vasculitis? https://sci-hub.se/https://doi.org/10.1177/0961203311429553
• Acute motor axonal neuropathy (AMAN, a GBS variant) https://sci-hub.se/https://doi.org/10.1016/j.neulet.2004.06.059
• Peripheral neuropathy https://doi.org/10.1016/S0304-3940(01)02143-7 - CFA applied to the saphenous nerves (with its spread limited by Oxycel) leads to mechanosensitivity.
• Allergic neuritis (EAN / experimental allergic neuritis) - Sci hub | DOI:10.1111/j.1529-8027.2000.22-44.x - Triple combination of CFA, pertussis toxin in the presence/absence of murine recombinant IL-12, and bovine peripheral nerve myelin (BPNM).

Researchers

• Chronic Lyme researchers: Monica Embers, Ying Zhang, Anna Goc
• Satoko Aratani et al. - Tokyo Medical University - HPV vaccine animal model
• Kaohsiung Medical University / Chiou et al. HBOT study on EAE.
• Bhagirath Singh - Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6A 5C1, Canada - publication on NOD mice given CFA and BCG vaccine. Funded by Canadian government grants.
• Bassi et al. - University of Padova, Italy - talks about ASIA syndrome - https://sci-hub.se/https://doi.org/10.1177/0961203311429553

• Girolamo Giannotta - ASIA syndrome advocate, commented on retracted HPV paper
• Toshie　Ikeda ???

Treatments + Autoimmunity inducers

THC

• https://sci-hub.se/10.1016/0165-5728(89)90075-1 - THC for multiple sclerosis / experimental autoimmune encephalomyelitis (EAE).

HBOT

• https://oxfordrecoverycenter.com/wp-content/uploads/2017/02/Ameliorating-Effects-of-Hyperbaric-oxygenation-on-Experimental-Allergic-Encephalomyelitis.pdf - HBOT was successful in pushing EAE (experimental allergic encephalomyelitis) into remission. CFA (complete freund's adjuvant) with guinea pig spinal cord.
• Warren et al. 1978 - The development of the delayed hypersensitivity reaction to myelin basic protein and to tuberculin is also suppressed by 02 therapy indicating that its effects upon autoimmune encephalomyelitis involves fundamental alterations of the cellular components of the immune response, some or all of which are reversible.
• https://www.mdpi.com/2227-9059/9/8/943 - Study from Taiwanese researchers. "semi-therapeutic HBOT significantly alleviated the progression of EAE, at least, via the suppression of Th17 response, the downregulation of CD4 T helper cells expressing GM-CSF or TNF-α, and the boosting of immunomodulatory IL-4 or IL-10-expressed CD4 T cells in the CNS lesions. Conclusively, HBOT attenuated EAE through the modulation of T cell responses in an earlier stage"

Tetanus vaccine

• https://journals.sagepub.com/doi/10.1177/0961203311429816 - Tetanus vaccine was used to induce antiphospholipid syndrome (APS). APS was induced with 2 different adjuvants (glycerol, aluminium hydroxide) and different adjuvant pretreatments (glycerol, CFA).

Gardasil HPV vaccine, aluminium adjuvant (and phospholipid supplementation)

• https://autoimmunity-network.com/articles/Behavioral%20abnormalities%20in%20female%20mice%20following%20HPV%20vac%20%20%202017.pdf Mice were given aluminium adjuvant only, Gardasil or Gardasil + pertussis toxin. Forced swimming test 3 months after injection was the most sensitive test.
• https://autoimmunity-network.com/articles/Maria%20Biobody.pdf - Mice vaccinated with Gardasil and aluminium adjuvant only fared worse on a forced swim test. Phospholipid supplementation can attenuate vaccine-induced depressive-like behavior.

Hepatitis B vaccine?

• https://sci-hub.se/https://doi.org/10.1016/j.jaut.2014.06.006 - Mice were immunized with Hep-B vaccine, aluminium adjuvant, or the control injection (phosphate-buffered saline). SLE-disease resulted for the vaccine and alum group. Immunization with either HBVv or alum affected blood counts, neurocognitive functions and brain gliosis. Various biomarkers were examined, though measurements had mixed results.

Repeated vaccination

• https://sci-hub.se/https://doi.org/10.1007/s12026-013-8404-0 - An experimental flock of sheep were given 14 inoculations containing thiomersal, aluminium salt, and ovine pathogens. Lower weight in the vaccinated group was observed, becoming statistically significant on day 177.

Metrics / biomarkers of disease severity

https://sci-hub.se/https://doi.org/10.1016/j.jaut.2014.06.006

• Forced swim test / immobility time
• Number of rears (standing on rear limbs)
• Stairs climbed
• Antibodies, e.g. ds-DNA
• Autoantibodies
• Weight, organ weight
• Urine protein concentration (SLE model)
• Blood counts
• Novel object recognition (NOR) test
• Y maze test
• Staircase - number of climbed stairs, rearing events during stair climb

https://journals.sagepub.com/doi/10.1177/0961203311429553 - 3X injection of CFA

• Anti-dsDNA
• Urine / proteinuria

AMAN (GBS variant) model - https://sci-hub.se/https://doi.org/10.1016/j.neulet.2004.06.059

• Abnormal posture
• Neck weakness
• Slip of forelimbs
• Slip of hindlimbs
• Dragging forelimbs
• Dragging hindlimbs
• Unable to walk
• Slow righting reflex
• No righting reflex
• Ptosis
• Tremor of limbs or trunk induced by pulling tail
• Spontaneous tremor of limbs or trunk
• Animal appeared systemically unwell