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.

The 2 antigen zones of the peritoneal cavity

The omentum protects the peritoneal cavity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812451/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754314/

the peritoneal cavity contains the stomach, liver, large and small intestines, the kidneys, the gall bladder, pancreas, and the adrenal glands.

omentum stromal cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3481843/

there are two types of omentum cells involved in tissue repair as stromal cells
myeloid derived suppressor cells and MSC cells
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038368

pericytes and myeloid derived suppressor cells
https://www.ncbi.nlm.nih.gov/pubmed/26296362

subgroup of myeloid derived suppressor cells : fibrocytes
https://www.ncbi.nlm.nih.gov/pubmed/26405600/
https://www.ncbi.nlm.nih.gov/pubmed/23757729

fibrocytes are potent stimulators of T cytotoxic cells
https://www.ncbi.nlm.nih.gov/pubmed/15767291

Based on our patten of inside and outside antigens is seems that the outer antigens would be collected by the B1 cells and processed by the MSC cells while the inner antigens would be taken up by the pericytes and shown to the myeloid derived stromal cells.

Chorioid Plexus compared to the BBB blood brain barrier

Chorioid Plexus compared to the BBB blood brain barrier and the hypothesis that they deal with different antigens.


Each of the brain's ventricles has their own CP region

Capillary blood is filtered here at the CP to become cerebrospinal fluid.

Resident macrophages and dendritic cells are in the CP
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496674/

Note that resident macrophages come from the yolk and focus on outer antigens while travel monocytes come from bone marrow and develop into dendritic cells or macrophages that deal with inner antigens based on the hormone that they see. High insulin favors macrophages while IGF-1 or GH exposed monocytes develop into dendritic cells.

IGF-1 made by CP epithelial
https://www.ncbi.nlm.nih.gov/pubmed/7513042

this would favor dendritic over macrophages (traveling)

myeloid dendritic cells of the cp
https://www.ncbi.nlm.nih.gov/pubmed/16817190

CP : fibroblasts, macrophages, dendritic cells
https://www.frontiersin.org/articles/10.3389/fncel.2015.00136/full

astrocytes (stromal cells) attract dendritic cells
https://www.ncbi.nlm.nih.gov/pubmed/16106219

astrocytes activate B cells
https://www.ncbi.nlm.nih.gov/pubmed/29673365
https://www.ncbi.nlm.nih.gov/pubmed/26223505

pericytes and and astrocytes communication
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042982/

FRC-like cells in CNS
https://www.cell.com/immunity/pdfExtended/S1074-7613(16)30001-2

At the intestine: inner antigens are processed at ILFs while outer antigens are processed in Peyer patches (hypothesis)

At the intestine: inner antigens are processed at ILFs while outer antigens are processed in Peyer patches.

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

"In contrast to the spleen, LNs and PPs, ILFs are inducible structures developed after birth due to the presence of external stimuli43"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015111/

The MRC marginal reticular cells develop here at the inducible ILF of the intestine.

pericytes in the gut
https://www.ncbi.nlm.nih.gov/pubmed/30937864

Peyer patches have the FRC fibroblast reticular cells.

Brain macrophages : pericytes
https://www.ncbi.nlm.nih.gov/pubmed/10611494

MHC2 expression by pericytes
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844098/

pericytes and the BBB
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292164/

peyer patch lacking mice had no IgA only IgG from ILFs
https://www.jimmunol.org/content/jimmunol/173/2/762.full.pdf

Remember the lymph structure and the separate zones for inner and outer antigens:

Then the spleen's separate zones:

Now looking for the MRC and the FRC we find very separate zones in the intestine:

Bee allergy, t.gondii, and the cells cytosol : I am not sure what I am looking at.

cd16 is on Basophils of patients with insect venom allergy
https://www.ncbi.nlm.nih.gov/pubmed/30288810

IgG2 and insect venom allergy
https://link.springer.com/article/10.1007%2FBF00441707

malaria and IgG2
https://iai.asm.org/content/68/3/1252

t.cruzi and IgG2
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1577053/

malaria also infects the cytosol
https://science.sciencemag.org/content/328/5980/862/F2

old post about Bee allergy and T.gondii
https://angelabiggs.blogspot.com/2015/04/tgondii-and-bee-venom.html

T.gondii infects the cytosol. Previous hypothesis was that IgG2 is the antibody made against cytosol infections.  I was sorting the Fc receptors with the IgGsubsets...when this occurred to me.

These are not proven just appears to be a pattern
cd16 (fcgammaRIII) binds IgG3 which is high on platelets? mito/nucl viruses
cd16 (fcgammaRIV) binds IgG2b which is high on eosinophils? cytosol infection?
cd64 (fcgammaRI) binds IgG2a cytosol virus?
cd32 (fcgammaRII) binds IgG1 and is high on Langerhans?  outer antigens

Is this why the patients with insect allergy would have cd16?

T.gondii and Bee venom

Do people with bee sting allergies have t.gondii infections?

I have connected T.gondii with a variety of things: Seizures, Epilepsy, schizophrenia....but they are all  autoimmune which means cross-targeting autoimmunity must be occurring. A virus has to trigger the attack at the target tissue from the inside.  Are these autoimmune diseases all bee sensitive because of their connection to T.gondii?


Schizophrenia: t.gondii and the cytomegavirus
http://www.sciencedaily.com/releases/2013/03/130308111315.htm

Bee sting reactions have been found in schizophrenia patients
http://www.ncbi.nlm.nih.gov/pubmed/5239954

I have connected in the past seizures/epilepsy with t.gondii and enteroviruses 
http://angelabiggs.blogspot.com/2015/01/nodding-disease-epilepsy-seizuresare.html

Seizures and bee stings 
http://epilepsyfoundation.ning.com/group/support-for-cps/forum/topics/bee-stings-and-seizures?commentId=2217546%3AComment%3A908079&xg_source=activity&groupId=2217546%3AGroup%3A819391
http://www.ncbi.nlm.nih.gov/pubmed/22100477
http://www.japi.org/february_2012/11_cr_stroke_after_multiple.pdf

epilepsy and wasp stings
http://www.ncbi.nlm.nih.gov/pubmed/8844507
http://jnnp.bmj.com/content/74/1/134.2.full

Does Apis mellifera venom (honey bee venom) effect T.gondii?

I can't see this paper to find out: 

• Effect of Bee Venom on Toxoplasma gondii Tachyzoites in vitro - Ahmad G. Hegazi, Hassan A. El-Fadaly and Ashraf M. BARAKAT (Egypt)

T.gondii is carried by mice and cats
T.cruzi is carried by kissing bugs and the dogs that eat them

T.cruzi which causes changas is killed by honey bee venom
http://www.ncbi.nlm.nih.gov/pubmed/23562368

The Kissing bug carries the T.cruzi the way mice carry T.gondii
http://blog.mysanantonio.com/animals/2013/09/san-antonio-humane-society-says-chagas-disease-possible-in-local-dogs/
note that kissing bugs are nocturnal so keep your pet in at night

Hymenoptera are the venom group of  Apoidea (bees), Vespoidea (wasps, hornets, and yellow jackets), and Formicidae (ants). 

What is it in the bee sting that Toxoplasmas dislike? perhaps the compound apamin which can cross the blood brain barrier. (our nerves don't like it either)
http://pubs.acs.org/doi/abs/10.1021/bi00682a035

Interestingly HoneyBee venom has been a remedy for malaria too.

Panafrican News Agency (PANA). 17 September 1997. Yahya el Hassan. "Curing Malaria with Bee Stings in Sudan." [Internet]. [Accessed 24 Dec. 1998].

https://books.google.com/books?id=JlSJDj5Lt98C&pg=PA153&lpg=PA153&dq=bee+stings+and+malaria&source=bl&ots=kXRWjUnlba&sig=Q7s5Av9JLOys_nMEi8I5pfzmRUg&hl=en&sa=X&ei=oeQlVZaHA8K1oQTxpoHACQ&ved=0CCkQ6AEwAg#v=onepage&q=bee%20stings%20and%20malaria&f=false

il-27, 25HC, and IgG2a against cytosol viral infections ?

il-27 induces IgG2a from Bcells
https://www.ncbi.nlm.nih.gov/pubmed/15294962

il-27 induces 25hc
https://www.researchgate.net/figure/IL-27-specifically-induces-cholesterol-25-hydroxylase-Ch25h-expression-and-25-OHC_fig1_320017159

https://www.researchgate.net/publication/320017159_IL-27-Induced_Type_1_Regulatory_T-Cells_Produce_Oxysterols_that_Constrain_IL-10_Production

25HC blocks viral entry
https://www.ncbi.nlm.nih.gov/pubmed/25501851

https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=27086126

Does 25hc help create exosomes which then binds with dendritic cells and SCS lymph cells?

cd169 binds 25HC to capture exosomes
https://www.ncbi.nlm.nih.gov/pubmed/24255917
https://www.ncbi.nlm.nih.gov/pubmed/29425504

Complement and  IgG2a
https://www.jimmunol.org/content/178/1_Supplement/S159.5
https://www.ncbi.nlm.nih.gov/pubmed/6610105

IgG2a and influenza
https://cvi.asm.org/content/13/9/981

IgG2a with viruses and parasites?
https://academic.oup.com/intimm/article/12/2/223/652665

Does 25hc hold viruses on the surface? how would complement work?

Hypothesis: il-27 cytokine is secreted by B cells when there is a viral infection or cancer damage involving the cytosol of cells.

Hypothesis: il-27 cytokine is secreted by B cells when there is a viral infection or cancer damage involving the cytosol of cells.

p53 and il-27
http://clincancerres.aacrjournals.org/content/clincanres/early/2016/05/27/1078-0432.CCR-15-2052.full.pdf

Is il-27 involved with DNA damage?

melanoma and il-27
https://www.ncbi.nlm.nih.gov/pubmed/18453571

melanoma is a cancer caused by DNA damage (from sun exposure)

DNA damage and the cytosolic sensors
http://jem.rupress.org/content/215/5/1287

B cells major source of il-27
https://www.jimmunol.org/content/200/1_Supplement/107.5

B cells produce IgG2a (class switch) after il-27
https://www.jimmunol.org/content/173/4/2479.long?utm_source=TrendMD&utm_medium=cpc&utm_campaign=J_Immunol_TrendMD_0

IgG2a against reoviruses and parasites
https://academic.oup.com/intimm/article/12/2/223/652665

il-27 attracts myeloid dendritic cells to the lymph
https://www.jimmunol.org/content/192/6/2634

previous hypothesis:
myeloid dendritic cells are involved with infections of the cytosol
plasmacytoid dendritic cells are involved with infection of the mitochondria/ nucleus

il-27 not il-35 suppresses gm-csf
https://www.nature.com/articles/s41598-017-16702-w


GM-csf is involved with vacuole bacteria and TH17 triggering

GM-csf exposed Basophil's produce il-6 and trigger th17
https://www.nature.com/articles/srep41744

GM-csf exposed mDendritic make il-23
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297527/

As a cytosol infection TH1 is involved
https://www.nature.com/articles/7310017?error=server_error

il-27 is saying it is in the cytosol..what ever it is...not a bacteria hiding in the cytosol or in a virus in the nucleus or mitochondria.

Furthermore

il-27 suppressed il-5 and il-13 from TH2 cells which is used against parasites in the cytosol. Which means il-27 could be strictly a cytokine for viruses or for DNA from cancer in the cytosol?

https://www.jimmunol.org/content/179/7/4415

When does the B cell decide to make il-27? Does the T follicular cell recognize it as DNA and signal back to the B cell?

IgG2, cytosol infections, and the lectin pathway.

Complement activation and Antibodies
https://www.ncbi.nlm.nih.gov/pubmed/20151159

Classical pathway: IgG1 and IgG3

Alternative and lectin: IgG2 and IgG4

LPS triggers the TLR4 or the lectin-mannose complement activation.  These tend to be the type of infections that can move inside of cells.  Some infections move into the vacuoles and organelles others the cytosol.

Strep has even been shown to move inside of cells allowing the bacteria to survive antibiotics. https://www.ncbi.nlm.nih.gov/books/NBK333420/

basophils as APC to TH2 inducing il-13
https://onlinelibrary.wiley.com/doi/pdf/10.1002/eji.201040588

IgG2, GSDMD, and cytosol infections

Hypothesis: GSDM pores are windows for eosinophils

Does the GSDM pore hold the infection inside of cells at the surface and allow eosinphils to phagocytosis infected cells through antibody binding at the pore?

il-13 and IgG2 production by B cells
https://www.ncbi.nlm.nih.gov/pubmed/10415009

High IgG2 and Cryptococcus neoformans 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828574/

Cryptococcus neoformans inside macrophages
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127716/

il-13 and C. neoformans
https://www.ncbi.nlm.nih.gov/pubmed/17911623

Does the GSDM pore hold the infection inside of cells at the surface and allow eosinphils to phagocytosis infected cells through antibody binding at the pore?

IgE at the skin's IGF-1  with the GSDMA pore
IgA , GH with GSDMB
IgG1,  insulin with GSDMC

IgG2 with GSDMD...all areas involving cytosol infections

High IgG2 and Plasmodium
https://iai.asm.org/content/iai/68/3/1252.full.pdf

Plasmodium are inside erythrocytes
https://academic.oup.com/femsre/article/40/5/701/2198099

eosinophils and plasmodium (malaria parasite)

mycobacteria and cytosol
https://academic.oup.com/femsre/article/43/4/341/5420823

mycobacteria and IgG2
https://gh.bmj.com/content/4/Suppl_3/A31.2

mycobacteria and GSDMD
https://www.biorxiv.org/content/biorxiv/early/2019/02/17/514125.full.pdf

Stromal cells produce cxcl13 attracting B cells and they have 3 areas of importance

Stromal cells produce cxcl13 attracting B cells and they have 3 areas of importance: two stromal cells in the lymph node ; one area is for internal antigens and  the other area is for outer antigens. The third stromal cell area is for catching infections that have escaped the gut's organs in the omentum zone.

adipose stromal cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3481843/

omentum milky fat spots have adipose stromal cells (ASC) which produce the CXCL13
the B1 cells involved there are the primary source of IgM
https://www.researchgate.net/publication/265860846_Human_adipose_tissue-derived_mesenchymal_stromal_cells_promote_B-cell_motility_and_chemoattraction

Marginal Reticular cells MRC are mesenchymal stromal cells of the scs area

Fibroblastic Reticular cells  FRC are bundled into the conduit leading to the follicular dendritic cells

All 3 of these stromal subsets make cxcl13 which attract B cells and follicular T cells thus creating the germinal centers
https://www.ncbi.nlm.nih.gov/pubmed/28454789

The MRC-SCS zone creates antibodies against the inner antigens (IgG2 or IgG3)  while the FRC-FDC zone creates the antigens against the outer antigens.  (IgG1 at the spleen, IgE at the lymph, and IgA dimers in peyer patches.)  The milky spots with the ASC attract the B1 cells thus producing IgM.

MRC was thought to transport antigens from SCS to FDC which could be the differentiation of MRC into FDC of inner antigens.
http://jem.rupress.org/content/211/6/1109
https://www.ncbi.nlm.nih.gov/pubmed/?term=jem.20132409

Does SCS not present to B cells directly rather hands the antigen to MRC who presents?

Here is a paper that has the SCS handing off to a nonphagocytic cell they call ATC (antigen transporting cell ) that appears to mature into a FDC type of cell
https://www.jimmunol.org/content/131/4/1714.long

MRC as phagocyte of apoptotic B cells
https://www.ncbi.nlm.nih.gov/pubmed/29686051

Is this incase the B cells are infected?

the conduit transports soluble antigens
https://www.ncbi.nlm.nih.gov/pubmed/15664156

Langerhans bring antigen through conduit
https://www.ncbi.nlm.nih.gov/pubmed/16818784

exosomes derived from dendritic cells migrate to spleen
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320445/

cd169 mediates the capture of exosomes
https://www.ncbi.nlm.nih.gov/pubmed/24255917

25hc and viral infections
https://www.nature.com/articles/nri3755/figures/4

immature exosomes teach tolerance while mature dendritic cell exosomes induce immune reaction
https://link.springer.com/article/10.1007/s10753-012-9539-1

scs and viral infection of the central nervous system
https://www.nature.com/articles/nature09118

Behcet's disease is autoimmune cross-targeting of strep and HSV1 update

Behcet's disease is autoimmune cross-targeting of strep and HSV1

Behcets has anti-cardiolipin and is associated with strep
http://angelabiggs.blogspot.com/2013/04/behcets-disease.html

Behcets and mitochondria polymorphisms
https://acrabstracts.org/abstract/genetic-association-of-mitochondrial-dna-polymorphisms-with-behcets-disease-in-a-korean-population/

HLA-B5, Behcets and autoimmune disease
https://acrabstracts.org/abstract/hla-b51-and-possible-associated-autoimmune-disorders-other-than-behcets-disease-a-retrospective-cohort-study/

HLA-B is the t cell mailbox for mitochondrial infections which HSV-1 is

Behcet's and herpes simplex 1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857840/

erythema nodosum and behcets
https://www.ncbi.nlm.nih.gov/pubmed/22504656

TLR9 and behcet's
https://www.ncbi.nlm.nih.gov/pubmed/23237868

TLR9 is the butterfly net for mitochondria infections. When triggered it causes the expression of HLA-b and IFNalpha

Behcets has anti-cardiolipin and is associated with strep
http://angelabiggs.blogspot.com/2013/04/behcets-disease.html

Behcet's Disease is it a cross-targeting autoimmune disease?

The autoimmune hypothesis pattern: an infection first inducing antibodies followed by a viral infection which causes cross-targeting thus triggering the immune system to attack causing autoimmune disease. 

For Behcet's disease the infection culprits are Streptococcus sanguinis and herpes simplex (mouth ulcers)

http://www.ncbi.nlm.nih.gov/pubmed/23137016
http://www.ncbi.nlm.nih.gov/pubmed/18693149 
http://www.ncbi.nlm.nih.gov/pubmed/21052488
http://www.ncbi.nlm.nih.gov/pubmed/22204815
http://www.ncbi.nlm.nih.gov/pubmed/22766172


I found a strange overlap with MS and Behcet's.
http://www.ncbi.nlm.nih.gov/pubmed/12645628 

For MS I have as psoriasis or eczema with herpes zoster triggering the autoimmune disease.    

Could this be an entirely different type of MS? Where the strep has opened the blood brain barrier and the herpes virus is there?  Is this actually a form of Alzheimer's?   Where the herpes simplex virus is destroying the mitochondria?  Or do I need to become much more specific with the herpes viruses? That could be the case.  

Balo was/is a different type of MS where the virus is a hepatitis C virus and causing the ring shaped lesions. Balo is really a distinct autoimmune disease from MS. 

NK and B cells in the lymph with il-15 or il-18

Previously hypothesis of how the lymph is organized in this sketich, so how does nk fit in?

il-18 and neutrophil activation
https://www.ncbi.nlm.nih.gov/pubmed/11509635

il-18 and nk activation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154249/

il-18 listeria
https://www.gastrojournal.org/article/S0016-5085(09)63232-7/abstract

listeria and golgi/ER
http://www.jimmunol.org/content/jimmunol/168/7/3428.full.pdf

il-15 and nk
https://www.pnas.org/content/101/47/16606

il-15 receptor and mantle B cells
http://www.jimmunol.org/content/171/2/569

RSV and il-15
https://www.ncbi.nlm.nih.gov/pubmed/17158609

il-15 tells the nk there is a viral infection of the ER and the golgi

il-18 tells the nk there is a bacterial infection of the ER and the golgi

il-15 receptors are on the mantle B cells

il-18 receptors are on the GC B cells

il-18 secreted by dendritic cells and macrophages
https://www.frontiersin.org/articles/10.3389/fimmu.2013.00289/full

il-15 secreted by monocytes and macrophages

mycoplasmas and RA
https://academic.oup.com/rheumatology/article/44/7/912/1788375

mycoplasmas and ER
https://www.ncbi.nlm.nih.gov/pubmed/4844719

ANA antibodies
https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Antinuclear-Antibodies-ANA

listeria associated arthritis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153789/

Is autoantibody IgG4 created when the B cell saw il-18 in the GC area first but then moved to the mantle when exposed to a virus?

Note that the receptor on the B cell matches up with bacterial vs. viral.

il-15 activated NK can help against HIV
https://jvi.asm.org/content/92/12/e00235-18

IgG4 antibodies

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-Aquaporin

Mycobacteria and other bacterial cytosol infection 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-insulin

Type one diabetes : coxsackie/flu  and e.coli

Neutrophils kill e.coli. How are these connected to insulin?

neutrophils suppress insulin signalling ( enzyme secreted disrupts the receptor)
https://stke.sciencemag.org/content/5/243/ec250

Insulin seems to be required for the functioning of neutrophils.
https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.0104050

Does anti-growth hormone match up with celiac disease and anti-IGF-1 match up with alopecia? Is the IgG4 trying to stop the outer antigen pathway?

celiac and Growth hormone deficiency
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1570481/

alopecia and IGF-1 deficiency
https://www.sciencedirect.com/science/article/pii/S1087002415305372

Does it always switch to il-10 and no IFN when B switches places or is it like this?

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

natural killer cells

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/ER bacterias

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-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