Reviewing TLRs (the immune system's butterfly nets catching general groups of items in a region)

B cells' TLRs
Infections outside of the cell: TLR1, TLR2, TLR4, TLR6
Infections inside the mitochondria and nucleus: TLR7, TLR9  (exposed by TH17)


Macrophages and Dendritic TLRs
Infections outside of the cell: TLR1, TLR2, TLR4, TLR6
Infections inside the cytosol and ER:  TLR3, TLR8

Notes:

B cells can't handle bringing RNA viruses in?

TLR4 are low on B cells because they bind to the complex sugars of large complex  infections like gram negative E.coli which has an elaborately covered surface that the antibodies can't bind well and mycobacterias which so large they need to be broken down by the alternative method with the help of macrophages or dentritic cells.

Tyrosine Kinases

First the TAMs (receptor tyrosine kinases)

cytosol  TLR3  IFNbeta  HLA-DQ  Tyro3

ER         TLR8 IFNgamma  HLA-C AXL

Mito       TLR9 IFN alpha   HLA-B  MER

Nucleus   TLR7 IFN alpha  HLA-A   MER


Next SRCs and JAKs (non receptor tyrosine kinases)

TLR -Lyn/Fyn - IFN- JAK- HLAi- Lck/Fyn- TAM

Notes:

Jak is the Janus kinase named for the roman 2 faced god because it has 2 phosphate transferring domains.  Jak appears to be the tyrosine kinase of choice for massive production. (calls for the production of HLAs which can more specifically identify the infection than the TLR )

BCR is B cell receptor containing  the Ig alpha and Ig beta on the surface of the B cell where it binds antigens

BCR with antigen - Lyn/Fyn/Blk- Antibody

HLA-DR- Blk/ Fyn- increases BCR?

Note that B cell's CD22 inhibits BCR  by binding to the CD45RO of T cells in it's place favoring the Tcell's viral pathway

B cells are educated to identify infections outside of cells while T cells are educated to recognize infections inside of cells.

So BCR is used for favoring antibodies for large infections or cytosol infections and it is blocked during most other viral infections?

HLA-DR on B cells causes SKY and the production of more IgM
http://www.jbc.org/content/275/45/34998.full

SRCs 

Membrane binding
c-src
fyn
yes
lck
lyn
hcr
fgr
blk
yrk

Cytoplasmic
syk
btk

There are 5 or 6 isoforms of CD45 on Tcells which makes me wonder
why

CD45 isoforms
https://www.bio-rad-antibodies.com/cd45-characterization-isoforms-structure-function-antibodies-minireview.html

Is it based on the type of infection?

EBV and CD45RO (EBV is a nuclear virus)
https://www.ncbi.nlm.nih.gov/pubmed/1370260

previously the high and low MW CD45 link T cells to Bcells
https://www.nature.com/icb/journal/v75/n5/pdf/icb199768a.pdf

Naive virgin T cells have the high mw form CD45RA
CD45RA associate with the B cell antigen receptor. BCR...large infections

Memory T cells have the low WM form CD45RO
CD45RO associate with the B cell CD22....viral infections

CD45RB  secretes a high amount of TNF alpha...calls NK cells

TLR3 and TLR4 involve CD45

https://www.ncbi.nlm.nih.gov/pubmed/18523265

Fluoxetine, Hepatitis C, MCR4, and eating disorders

Looking at the areas of overlap to reinforce the connection of Hep C with MS

Fluoxetine is a serotonin reuptake inhibitor
https://en.wikipedia.org/wiki/Fluoxetine

Fluoxetine and Hep C
http://forums.phoenixrising.me/index.php?threads/fluoxetine-antiviral-application.39225/

Fluoxetine and secondary progressive MS
https://www.msconnection.org/Blog/September-2016/Research-News-on-Secondary-Progressive-MS-from-ECT

Serotonin and MCR4 and appetite
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466475/

serotonin activates serotonin receptors which causes the secretion of alpha-MSH which triggers the MC4R

MC4R controls appetite and I had hypothesized that Hep C uses MCR4 receptors

Previous post on Hep C
http://angelabiggs.blogspot.com/2017/05/flaviviruses-melanocortin-receptors-and.html

Hep C and appetite disorders
https://www.ncbi.nlm.nih.gov/pubmed/22932161

Eating disorders in a sub population of MS
https://www.omicsonline.org/open-access/eating-disorders-in-a-multiple-sclerosis-clinical-population-and-its-associationwith-social-anxiety-2376-0389-1000183.php?aid=82623


antibodies to alpha-MSH and eating disorders (anorexia or bulimia)

http://psychnews.psychiatryonline.org/doi/10.1176/pn.38.1.0021

Note that Hep C would use the same receptor as alpha-MSH....the MCR4 receptor

Does the eating disorder appear and indicate MS that leads to Secondary progressive MS ?

Schizophrenia with Multiple sclerosis caused by autoimmunity triggered by a shared Herpes infection

Autoimmune cross-targeting hypothesis: autoimmunity is triggered by a large infection marking the outside of a cell and a virus marking the inside of the cell.

The overlapping of autoimmune diseases could be due to a shared infection; in this case a herpes virus.

coexistance of ms and schizophrenia
https://www.ncbi.nlm.nih.gov/pubmed/28805697
https://www.ncbi.nlm.nih.gov/pubmed/3059470
https://www.ncbi.nlm.nih.gov/pubmed/3968052

Herpes zoster and CMV with schizophrenia
https://www.ncbi.nlm.nih.gov/pubmed/27336045

In MS the nerves are the target. Mycobacteria as the large infection and there are several possible viral triggers.

These are my guesses:

HLA-B: Herpes-alpha (zoster): Relapsing remitting
HLA-C: Polyomavirus (hepatitis B) ?or hep C- MCR4 flavivirus? : primary progressive
HLA-DR15 : Flavivirus (Hep C ) :Secondary progressive
HLA-A: Herpes-gamma (epstein barr): progressive relapsing (or CMV?)

http://angelabiggs.blogspot.com/2016/10/multiple-sclerosis-viral-triggers-and.html

In schizophrenia the large infection would be t.gondii or fungal and then the virus would be a herpes. The herpes infection would overlap MS.

Schizophrenia : HLA-A/B

The 3 types of schizophrenia HLA match up with the 3 types of herpes viruses
http://angelabiggs.blogspot.com/2016/09/schizophrenia-and-autoimmune-cross.html

my guesses:

DISORGANIZED : HLA-A2 and HLA-A11 : beta-herpes (CMV)
CATATONIC : HLA-B16 : Alpha-herpes (zoster, simplex)
PARANOID: HLA-A9 and HLA-A3 : Gamma Herpes (EBV)


Prediction: 

relapsing remitting MS that overlaps with the catatonic schizophrenia 
progressive relapsing MS that overlaps with the  paranoid schizophrenia (EPV) or disorganized (CMV)

TLR4 / TLR8, cd16, and NK cells

Just supporting the notion that TLR8 is the TLR of the ER for viral infections there

Nk cells with FcR(cd16)  will make IFNgamma and TNF
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2188858/

TLR8 and cd16
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148764

Hepatitis C : flavivirus and Hepatitis B : polyomavirus

Hepatitis B(a polyomavirus which infects the ER then nucleus) and Nk
https://www.ncbi.nlm.nih.gov/pubmed/20643584

Hepatitis C (a flavivirus that like yellow fever looks like it infects the ER)
https://www.ncbi.nlm.nih.gov/pubmed/16571411

Hep C infects the ER
https://www.ncbi.nlm.nih.gov/pubmed/15817385

Yellow fever and the ER
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC525104/

Yellow fever and Hep C I had previously suggested used the melanocortin 4 receptor which looks like it takes them to the ER

TLR 7 is the nucleus and TLR 8 is the ER

Hepatitis B with TLR7/8
https://www.ncbi.nlm.nih.gov/pubmed/26315138

Hepatits C with tlr7/8.
https://www.ncbi.nlm.nih.gov/pubmed/28122964

The KIR (cd158) is the HLA receptor on NK cells
http://journal.frontiersin.org/article/10.3389/fimmu.2014.00105/full

KIR has the strongest affinity for HLA-C because when the polyomavirus infects the ER very little HLA-C makes it to the surface and these are the infected cells NK needs to destroy

TLR8 might be the weakest because many polyomaviruses inhibit the production of TLRs and HLAs from inside the endoplasmic reticulum. This absence of TLR or HLA-C could be how killer T cells evolved  to automatically kill "naked cells" and why killer T cells secrete IFN gamma.

polyomavirus tumors and NK
http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1000924

So how does TLR4 trigger the NK ?

TLR4 binds lipopolysaccharides on gram neg bacteria (like e.coli)

TLR4 and cd16
http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1000464

E.coli  binds CD16 and tries to block
https://www.ncbi.nlm.nih.gov/pubmed/17934470
http://onlinelibrary.wiley.com/store/10.1002/eji.201546118/asset/eji3678.pdf?v=1&t=j7s0btvu&s=e6ad34a57c13f6f3e475ffe1fe5862f5ac4e9883

NK are also triggered by aggregated antibodies

CD16 binds the aggregated IgG or complexed IgG
https://ximbio.com/reagent/151919/anti-cd16-3g8

AXL/gas6 and the il-15 pathway for NK
http://www.bloodjournal.org/content/bloodjournal/113/11/2470.full.pdf?sso-checked=true

il-15 is a cytokine made by macrophages and dendritic cells following viral infection

TNF alpha stimulates the secretion of il-15
https://www.ncbi.nlm.nih.gov/pubmed/23950892

TNF alpha is released by the macrophage/dendritic cell that is infected or when Nk are activated by cd16

TNF alpha and NK
https://www.ncbi.nlm.nih.gov/pubmed/8207246

If zika uses the ACTH receptor do glioblastomas have ACTH receptors?

Zika virus kills neural stem cells in cancer
https://www.usatoday.com/story/news/nation-now/2017/09/06/injecting-zika-virus-into-adult-brains-researchers-say-could-shrink-cancer/636704001/

zika has activity against glioblastomas specifically
https://www.ncbi.nlm.nih.gov/pubmed/28916645
https://www.ncbi.nlm.nih.gov/pubmed/28874392

ACTH promotes brain growth in embryos but is not in adult brains

https://books.google.com/books?id=tw5jAosiTh8C&pg=PA31&lpg=PA31&dq=glioma%27s+melanocortin+receptors&source=bl&ots=IkuNEowWdi&sig=Ln0iNC1bYg6NUpdiDP4uyM7pRUw&hl=en&sa=X&ved=0ahUKEwjFyaPk1a_WAhXGrlQKHardBCsQ6AEIZTAJ#v=onepage&q=glioma's%20melanocortin%20receptors&f=false

If zika uses the ACTH receptor do glioblastomas have ACTH receptors?

previous blog posts of Zika and ACTH
http://angelabiggs.blogspot.com/2017/01/zika-acth-receptors-and-clatherin.html

temozolomide to treat pituitary tumors
https://www.ncbi.nlm.nih.gov/pubmed/26586560

temozolomide to treat glioblastoma
http://www.nejm.org/doi/full/10.1056/NEJMc1704726#t=article

Are Nuclear or mitochondrial viral infections trapped and need to be released by Th17 's il-26 to be seen by the immune system?

il-1 beta stimulates Th17 cells.  Th17 cells produce il-26 which is a membrane pore forming.  il-26 kills bacterias but what is it doing when a viral infection is involved?

TLR9 and TLR7 have been found to increase levels of il-1 beta. il-1beta stimulates Th17.

TLR3, TLR9, TLR7, and TLR8 are located intracellularly of cells catching viral infections/foreign bacterial nucleotides via net and  when the are triggered they tell the cells to wear the correct HLA and express a specific IFN

Hypothesis of location was based on viruses snagged

TLR3 cytosol RNA virus (like the flu )
TLR9 mitochondrial DNA virus (herpes zoster)
TLR7 nuclear DNA virus (hpv, HIV)
TLR8 endoplasmic reticulum RNA virus (polyomavirus)

Review of Tlrs 3, 9, 7 and 8
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC406426/

the internal location of tlr 3, 9, 7 and 8
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4037363/

When the immune system breaks open virally infected cells if the viruses are inside the nucleus or inside the mitochondria they are still not visible. Hence the mitochondria or nucleus need to be popped.  il-26 could be the tool here.

(just like il-26 is used to create pores in mycobacterias in Crohn's disease)
https://www.researchgate.net/publication/5368756_The_role_of_the_novel_Th17_cytokine_IL-26_in_intestinal_inflammation
(mycobacteria and crohn's)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894645/


il-26 and extracellular DNA transporter
http://www.jimmunol.org/content/early/2017/03/29/jimmunol.1600594

il-26 as a pore
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776746/

Nuclear viruses

HIV and tlr7
https://www.nature.com/ni/journal/v16/n1/full/ni.3036.html
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700304/
http://www.bloodjournal.org/content/bloodjournal/113/2/377.full.pdf?sso-checked=true

HPV16 and tlr7
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952342/

note that Epstein barr and tlr7 are some how connected but it is not clear if tlr7 is a sensor for it
http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1249&context=virologypub

il-1beta and hiv
https://www.ncbi.nlm.nih.gov/pubmed/9218824

il-1beta and HPV
https://www.ncbi.nlm.nih.gov/pubmed/23935506 

il-1beta and epstein barr
http://www.sciencedirect.com/science/article/pii/S0042682298994417



Mitochondrial viruses

Herpes zoster and tlr9
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465860/
Herpes simplex 1 and tlr9
https://www.ncbi.nlm.nih.gov/pubmed/14563635/

il-1beta and herpes zoster
http://www.jbc.org/content/286/20/17921.full

il-1beta triggers the Th17

Note that Th17 cells make the il-26

il-26 and tlr9
https://www.researchgate.net/publication/294167676_Interleukin_IL-26_is_over_expressed_in_psoriasis_and_regulates_TLR9_activation_to_self-DNA

tlr7 and Th17 cells
http://www.jimmunol.org/content/jimmunol/184/3/1159.full.pdf

Tlr9 and Th17 cells
https://www.jci.org/articles/view/35647

Previous blog post linking up TAMS, TLRs, IFNs, and HLAs
http://angelabiggs.blogspot.com/2017/02/tam-receptors-and-ifns.html

il-1 beta induces TGF-beta
https://www.ncbi.nlm.nih.gov/pubmed/7980594
https://www.ncbi.nlm.nih.gov/pubmed/21779356

TGF-beta then stimulates Th17

Th17 and mold infections

People with mold infections have elevated TGF-beta elevated (CIRS chronic inflammatory response syndrome)

Th17 produces the il-26 pore protein which would aid in the destruction of mold infections


TGF is key in wound healing, it increases extracellular matrix proteins, decreases Red blood cells, and triggers neutrophils to release traps...the body is trying to contain the mold in a confined area.

Neutrophil traps
https://www.ncbi.nlm.nih.gov/pubmed/27486461

Cells and the sugars on membrane proteins...then considering the sugars on antibodies' Fc domains

Often times the golgi has been described as the post office of the cell delivering proteins to appropriate areas of the cell. The golgi has another very important role of modifying sugars on specific parts of a protein.

When a protein is placed into the membranes these sugars identify the sections of the protein that are not to be in the cytosol.  The parts of a transmembrane protein with sugars are on the outside of the cell or on the inside of an organelle. The complete removal of mannose sugars signals that the protein is to be secreted.

The sugar Galactose on the outside of red blood cells have evolved the important duty of participating in clotting.   Called the "blood type antigen" these galactose proteins on RBC are similar to van willebrand factor protein which is involved with platelets.  The Galactose mediates the adhesion of platelets and Red blood cells to sites of vascular damage.

Type O has the weakest level of clotting
Type B has medium level clotting
Type A has the strongest level of clotting (the easiest to bind)

Bacterias, mycobacterias, and yeasts like candida grab on to the surface of cells through sugars and have evolved a strong affinity for galactose.  Obviously the ideal place to infect is where a cut is.

To combat infections our bodies have developed "lewis antigens"  The sugar Fucose of  "lewis antigens" is very similar to Galactose.  Fucose is the decoy for Galactose.  Lewis antigens are secreted into the fluids and lower the infection rate.

People who lack the genes for lewis antigens have increased rates of intestinal infections and higher rates of ulcers.

The opposite can be said for blood type antigens. Those with type A and B are at increased risk of  infections.

(if you have type A hope that you have Lewis Antigens to be decoys)

This leads to some interesting contemplations: antibodies can have lactose and that changes the binding to Fc receptors.

Read an interesting article where the Fc domain of IgG antibodies have sialic acid residues and these sugars are responsible for the inflammation properties of IgG antibodies
https://www.chemistryworld.com/news/sugar-coated-antibody/3003810.article

Does the presence  of lactose in antibodies match up with the antibodies directed against  viruses?  Does the altered Fc binding of the antibody tell the immune system that it is viral by not having lacose and having galactose instead?

Fucose, galactose, sialic and antibodies....the fucose antibodies activate NK
https://www.ncbi.nlm.nih.gov/pubmed/18566325

why is fucose on the antibody's Fc for NK ?

NK cells are involved when ER infecting polyomaviruses are involved.  No proteins make it to the surface to present antigens if the ER is infected.

does fucose helps jagged-notch binding ?
http://www.pnas.org/content/111/20/7290.full
http://www.jbc.org/content/280/37/32133.full

Does high amounts of galactose represent other non ER viruses?

HIV, Fc and galactose
https://www.ncbi.nlm.nih.gov/pubmed/25160934
https://www.ncbi.nlm.nih.gov/pubmed/21041724

Consider:

Fucose:  lewis antigen decoy/ bacteria binds / in the antibody for polyomaviruses ...triggering nk

Galactose: clotting factor/ bacteria binds / in the antibody for other viruses  HIV etc

Sialic:  anti-inflammation when on antibody for bacteria or large infections / virus binds/  not on antibodies for viruses?

Example: sialic antibodies against T.cruzi
https://www.hindawi.com/journals/scientifica/2013/965856/

However....there are articles where they say the Fc closes and can not bind to the receptors with sialic acid?

So fucose deficient IgG bound FcR111A (the Fc receptor connected to NK activation) tighter!!
http://www.jbc.org/content/277/30/26733.full

What exactly is happening here?