Is Kawasaki disease an autoimmune disease caused by the cross-targeting of two infections?

Autoimmune cross-targeting hypothesis: Two infections on one target tissue. One infection involves infecting inside of cells the other outside of the cells of the target tissue.

Kawasaki as an autoimmune disease
https://pubmed.ncbi.nlm.nih.gov/25882057/?from_term=kawasaki+disease+autoimmune&from_pos=9

https://pubmed.ncbi.nlm.nih.gov/31013925/?from_term=kawasaki+disease+autoimmune&from_pos=2

The inner viral infections:

Viruses associated with Kawasaki disease : enterovirus adenovirus rhinovirus and coronavirus
https://www.sciencedirect.com/science/article/pii/S0929664614000035

coronavirus
https://pubmed.ncbi.nlm.nih.gov/15655771/?from_term=kawasaki+coronavirus&from_pos=1

The outer bacterial infections:

Strep and Kawasaki
https://www.npjournal.org/article/S1555-4155(12)00621-6/pdf

Location is more important than the type of virus when triggering autoimmune disease. If an infections exists inside of a cell as well as outside then an autoimmune response is triggered.

Coronavirus infection increases the binding of bacterial infections
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168281/

Naphthalene/shampoo from carpet cleaning could trigger Kawasaki how? which infection does it replace ?
https://pubmed.ncbi.nlm.nih.gov/6125730/
https://pubmed.ncbi.nlm.nih.gov/2020511/

naphthalene and ER stress
https://www.dovepress.com/67-dihydroxy-2-4prime-hydroxyphenylnaphthalene-induces-hct116-cell-apo-peer-reviewed-article-DDDT
napthalene and ER damage
https://www.sciencedirect.com/science/article/abs/pii/0022201185901090

Covid-19 and multisystem inflammatory syndrome
https://www.nejm.org/doi/full/10.1056/NEJMoa2021680
https://www.statnews.com/2020/06/29/nejm-inflammation-children-covid19-misc/

Immune system cells involved with antigens outside of cells evolve from the yolk

Resident tissue macrophage
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675852/
https://www.ncbi.nlm.nih.gov/pubmed/26992565

langerhans
https://link.springer.com/chapter/10.1007/978-1-4757-9966-8_76
https://www.ncbi.nlm.nih.gov/pubmed/22565823

M cells and GH
https://joe.bioscientifica.com/view/journals/joe/147/3/joe_147_3_002.xml

B1 and B2 cells
https://www.sciencedaily.com/releases/2019/02/190215082333.htm

Autoimmunity of the Brain: two tertiary lymph regions

Autoimmune disease in the area of the brain: Autoimmune hypothesis is that two infections on one target trigger autoimmunity but one infection must be an outside infection and the other an inside infection.

Neuromyelitis Optica which has antibodies to aquaporin disrupts the blood brain barrier.

Neuromyelitis has been linked to both mycobacterias and viruses like dengue.

Eosinophils and aquaporin-4
https://www.sciencedirect.com/science/article/pii/S096758681731069X

Mycobacteria (TB) and Neuromyelitis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938476/

mycobacteria and swelling of the choroid plexus
https://journals.sagepub.com/doi/abs/10.1177/0284185116633913?journalCode=acrc

lymph structure in choroid plexus
https://insight.jci.org/articles/view/124203

dengue virus can trigger Neuromyelitis
https://www.ncbi.nlm.nih.gov/pubmed/29475624

dengue and the BBB
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606788/

B cells and the blood brain barrier
https://www.jci.org/articles/view/63842

in MS two groups of B cells: BBB and choroid plexus
https://onlinelibrary.ectrims-congress.eu/ectrims/2016/32nd/146268/brigitte.wildemann.cns-transmigration.of.distinct.b-cell.subsets.through.the.html

meningitis (bacteria) and choroid plexus
https://journals.sagepub.com/doi/abs/10.1177/197140091002300507?journalCode=neub

viral infections of the brain and the blood brain barrier
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367119/

 Consider the two zones of the lymph split in the brain into literally two different regions.

Where the choroid plexus deals with the outer antigens and the blood brain barrier is the inner antigens.

For mycobacteria the main outside pathway involves Eosinophils.  So the IgG4 is created to stop the eosinophils.

IgG4 antibodies and shutting down outer pathways...considered again.

IgG4 are the autoimmune antibodies which shut down the outer pathway so the immune system can focus on the inside pathway.

Autoimmune hypothesis: Two infections on one target triggers autoimmune disease. One infection inside and one infection outside of the cell.

Does the B cell that gets pulled from outside antigen pathways to inside antigen pathways become the IgG4 producing B cell with the goal of shutting down the outside pathways?

This would mean that the IgG4 would be similar based on the large infection and the pathway stopped if the autoimmune diseases share the same large infection.    For example, all mycobacteria triggered autoimmune diseases would have the same IgG4 against aquaporins.

IgG4 antibodies represent a down-regulatory response
https://www.ncbi.nlm.nih.gov/pubmed?term=24111912

IgG4 made by Bcells that produce il-10
https://www.jacionline.org/article/S0091-6749(13)00150-4/pdf

Br1 up regulate the plasma cells to become IgG4 producing
https://www.jacionline.org/article/S0091-6749(16)30722-9/pdf

Anti-gangliosides

Involves vacuole bacteria

Guillian-barre and anti-gangliosides
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422685/

http://www.neurologyindia.com/article.asp?issn=0028-3886;year=2018;volume=66;issue=5;spage=1324;epage=1331;aulast=Baskar

https://www.researchgate.net/publication/325884578_Anti-ganglioside_Antibodies_in_Peripheral_Nerve_Pathology


il-15 and gangliosides
https://www.ncbi.nlm.nih.gov/pubmed/16116192

gangliosides in autism
https://www.ncbi.nlm.nih.gov/pubmed/9766735

sutterella and autism spectrum disorder
https://molecularautism.biomedcentral.com/articles/10.1186/2040-2392-4-42


Anti-ANCA / anti-ANA

involves golgi infections and neutrophils 

salmonella and anti-ANCA
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1905360/

reactive arthritis and salmonella
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195798/

anti-ANCA bind the neutrophil traps
https://www.frontiersin.org/articles/10.3389/fimmu.2017.00439/full

Anti-ANCA and Rheumatoid
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552688/

anti-nuclear in strep with tourettes
https://www.ncbi.nlm.nih.gov/pubmed/12699862

TLR8 and strep
http://www.jimmunol.org/content/195/3/1092

TLR8 is the Tcell mailbox for the Endoplasmic reticulum

polyarthritis and strep
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803937/

Anti-CCP

involves ER infections (by mycoplasmas) and the neutrophils

autophagy and ER stress
https://www.ncbi.nlm.nih.gov/pubmed/26391548

autophagy generates citrullinated proteins
https://www.ncbi.nlm.nih.gov/pubmed/27074807

neutrophils and citrullinated proteins in RA
https://www.nature.com/articles/s41598-018-33385-z

some how this antibody stops the neutrophils from coming for mycoplasmas?


Anti-leiomodin

Nodding disease is triggered by the parasitic worm and what virus? The IgG4 was found against leiomodin-1.  Nodding disease is autoimmune disease of the skin where the autoantigen attacks the brain?

Autoimmune cross-targeting hypothesis: two infections on one tissue. The reaction is at the skin but then the antibody attacks the brain?

 For these worms how does this work? The Leiomodin-1 antibody bound the worms...but they were IgG4?

When exposed to cold temperatures or food the children nod their heads uncontrollably. The hippocampus of the brain is responsible for body temperature sensations and hunger urges.

The worm is not in the hippocampus but the autoantibody shows up there.
https://www.ncbi.nlm.nih.gov/pubmed/28202777

Which virus at the skin has co-infected and caused the IgG4?

Does this mean that leiomodin-1 is involved with eosinophils degranulation attack? Since eosinophils at the main cell type attacking the worms how would this work?

eosinophils and smooth muscles
https://www.ncbi.nlm.nih.gov/pubmed/23180361

NEW

Natural killer cells anti-TRR

JIA IgG4 antibody to TRR
https://www.sciencedaily.com/releases/2016/02/160225101100.htm

TTR is a serum cerebrospinal fluid carrier of thyroid hormone thyroxine T4
https://www.acrobiosystems.com/L-514.html?utm_source=google&utm_medium=keywords&utm_campaign=US-proteinno-core-PC&utm_content=hhhis&utm_term=Transthyretin&gclid=Cj0KCQjw2K3rBRDiARIsAOFSW_7MhivjRGdtDNRxMtjDu6ncdwisF-Hr002WWJBfblMQl-yYluCc8ZsaAqbEEALw_wcB

Natural killer cells and Thyroid hormones
https://www.ncbi.nlm.nih.gov/pubmed/21745103

Do mycoplasmas which infect the endoplasma reticulum trigger NK cells but then in the autoimmune cross-targeting event the NK need to be "turned off"?

thyorid and nk cells associated in women with reproductive failure
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806729/

TTR and arthritis
https://www.researchgate.net/figure/TTR-expressions-were-examined-in-other-joint-disease-and-autoimmune-disease-such-as-OA_fig4_261515697

nk and rheumatoid arthritis
https://www.ncbi.nlm.nih.gov/pubmed/30718650

Eosinophils and degranulation

anti-fab IgG4
https://link.springer.com/article/10.1007/BF00269196

FAB is the part of the antibody bound to the FC receptor by cells like Eosinophils

RA and FAB
https://www.ncbi.nlm.nih.gov/pubmed/3928684

Anti-myelin for mycobacteria in cytosol and eosinophils 

anti-myelin for lyme
https://www.ncbi.nlm.nih.gov/pubmed/11987581

Aquaporin and Eosinophils (phagocytosis)

Anti-Aquaporin (from old post)

Mycobacteria and other bacterial cytosol / nuclear infections which involve eosinophils and macrophages in a phagocytosis method appear to develop anti-AQP ( aquaporin antibodies)

aquaporins move eosoinophils
https://www.ncbi.nlm.nih.gov/pubmed/18510218

anti-aquaporin4 and multiple sclerosis
https://www.ncbi.nlm.nih.gov/pubmed/20705110

mycobacteria and multiple sclerosis
https://www.sciencedaily.com/releases/2010/02/100226084007.htm

idiopathic demyelination and anti-AQP4
https://www.hindawi.com/journals/msi/2017/1359761/

anti-aquaporin4 in neuromyelitis
https://www.ncbi.nlm.nih.gov/pubmed/18808744

salivary glands and parkinson's disease
https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=838

salivary gland and psoriasis
https://www.ncbi.nlm.nih.gov/pubmed/7165375

salivary glands and aquaporins
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783900/

parkinson's and mycobacteria
https://www.ncbi.nlm.nih.gov/pubmed/25459140

psoriasis and mycobacteria
https://www.ncbi.nlm.nih.gov/pubmed/9657322

aquaporin and psoriasis
https://www.ncbi.nlm.nih.gov/pubmed/21400035

(Candida also has portions move to the cytosol)

SJ and salivary
https://www.ncbi.nlm.nih.gov/pubmed/1055974

Candida and SJ
https://www.ncbi.nlm.nih.gov/pubmed/12973284

SJ and MS because of salivary
https://www.jwatch.org/jn200112200000006/2001/12/20/possible-association-between-sjogrens-syndrome

Anti-TPO

How would anti-TPO stop TH17 cells which combat fungal infections

TPO increases the numbers of TH17
https://www.ncbi.nlm.nih.gov/pubmed/26836805

TH17 and fungal infections
https://www.ncbi.nlm.nih.gov/pubmed/19283705

quorum of fungus: farnesol
https://www.ingentaconnect.com/contentone/govi/pharmaz/2017/00000072/00000006/art00001?crawler=true&mimetype=application/pdf

Does farnesol stimulate the thyroid to produce TPO?  Is TPO used by TH17 cells?

Would blocking TPO stop TH17 cells?

original post
I have looked at these pathways before https://angelabiggs.blogspot.com/2019/05/igg4-antibodies.html

HLA-dr contemplations

HLA-dr

HLA-dr appears to hold virus RNA
https://www.ncbi.nlm.nih.gov/pubmed/10564819


HLA-dq

HLA-dq appears to hold small antigens like insulin and gliadin

presentation of gluten in HLA-dq2
https://www.jimmunol.org/content/175/1/254

"It is interesting to note that even if the risk for developing CD associated with DQ2.2 is minuscule compared with that of DQ2.5, a recent study revealed that among the small group of DQ2.5- and DQ8-negative CD patients, "


e.coli binds gliadin
https://pdfs.semanticscholar.org/b70f/23916b8f5553baf3a01055725ab9c68add7c.pdf?_ga=2.119014538.2026673398.1566778373-1275520869.1527777598

HLA-dp and type one diabetes
https://link.springer.com/article/10.1007/s10654-004-5176-9

HLA-dq8 holds insulin
https://www.ncbi.nlm.nih.gov/pubmed/11376336


HLA-dp

HLA-dp appears to hold a significant amount of self antigens as well as foreign and is similar to HLA-dq but is not used as often

HLA-dp review
https://www.jimmunol.org/content/184/5/2492
states that it has a lower expression than HLA-dr or HLA-dq and that HLA-dp has few epitopes. HLA-dp is shared by 90% of the population

HLA-dq has been associated with ALL the childhood leukemia (genetic form) ????
http://www.bloodjournal.org/content/120/15/3039.short?sso-checked=true?sso-checked=true

What is the difference between HLA-dq and dp?


might not be relevant:

beryllium binds to HLA-dp
https://www.ncbi.nlm.nih.gov/pubmed/11423174

cobalt binds to HLA-dp
https://www.ncbi.nlm.nih.gov/pubmed/10427976

How does gluten fit into the autoimmune cross-targeting hypothesis?

New hypothesis: Two separate zones for inner and outer antigens in lymph organs.

ILF the inducible lymph follicle deals with the inner antigens while the peyer patch deals with the outer antigens of the mucosal membranes.

ILF  https://www.ncbi.nlm.nih.gov/pubmed/12759424

E.coli infections would involve the outer pathways. At the mucosal's peyer patch they would see high growth hormone GH thus produce IgA.

According to the Cross-targeting hypothesis when a second inner infection appears and calls the B cell to the ILF zone and away from the peyer patch....the B cell becomes a regulatory autoimmune B cell which secretes IgG4 antibodies that stop the outer pathways.

GH-IGF axis and gluten in celiac
https://www.karger.com/article/pdf/185499

Gluten was seen as the infection not the parasite because the parasite moved inside of cells?

UPEC :the e.coli that moves inside cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244466/

If patients remove gluten and outside pathway is stopped? Is that because the infection is on the inside of cells but gluten was seen as the infection?

Note that the anti-gluten antibody is not IgG4 but IgG1.

gluten and e.coli in mice
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630176/

e.coli and celiac
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287676/

? protein from e.coli binds gliadin?
https://www.ncbi.nlm.nih.gov/pubmed/16944918

Do these infection hold gluten on the outside like a cloak?

Anti-gluten response after t.gondii infection in mice?
https://www.ncbi.nlm.nih.gov/pubmed/23209841

anti-gluten and t.gondii
https://www.ncbi.nlm.nih.gov/pubmed/22446142

The Secondary Lymph organs have separate zones for inner and outer antigens

The secondary lymph organs are strategically situated to intercept infections.  The lymph glands capture the infections that breach the skin's barrier.  The ILF and peyer patches guard the mucosal membranes.  The blood brain barrier and the choroid plexus protects the brain.  The spleen filters the blood removing not just dead blood cells but infections that have reached there.  The omentum monitors and protects the peritoneal cavity which  contains the stomach, the liver, the large and small intestines, the kidneys, the gall bladder,  the pancreas, and the adrenal glands.

All secondary lymph organs  have separate zones for fighting inner and outer antigens.

The inner antigens are processed by embryonic HSC derived macrophages. These macrophages communicate with and pass antigens to marginal reticular stromal cells or Astrocyte stromal cells.  These cells with antigen evolve into follicular dendritic cells and secrete CXCL13 calling the B and the T cells to them.  The dendritic cells are derived from adult HSC monocytes. These monocyte derived dendritic cells are the antigen presenting cells to the T cells.  For inner antigens the T cell makes the determination at this point if the antigen is foreign.

The outer antigens are collected by langerhans, marginal zone B cells, B1, or Resident Tissue macrophages (of the CP)  all of which differentiated from the yolk sac not the HSC of the bone marrow.  These yolk sac derived cells communicate and pass antigens on to fibroblastic reticular stromal cells. These antigen holding FRC become follicular dendritic cells with B7-2 involvement and secrete CXCL13.  These FDC cells hand the antigen off to B cells who do the antigen presenting to the T cell.  For outer antigens the B cell determines if the antigen is foreign.