TH17 Called for a "second popping of membranes" then the cytokines that signify where

TH17 are called with the infections is too huge for macrophages to consume or if the infections are hiding inside cells where a second popping of membranes is required.

TH17 and mycobacteria
https://www.hindawi.com/journals/mi/2015/854507/

TH17 and mycoplasmas
https://www.ncbi.nlm.nih.gov/pubmed/27240139

TH17 and chlamydia

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162445

TH17 and candida / salmonella
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652671/

TH17 and herpes zoster (mitochondria)
http://www.globethesis.com/?t=2284330488484866

TH17 and HIV (nucleus)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886291/

TH17 and EBV (nucleus)
http://www.bloodadvances.org/content/1/17/1324

Now lets look at the cytokines to help identify where in the cell the infections are

il-18 mycoplasmas nesting in the ER and is NOT an in the il-20 Family

Endoplasmic Reticulum:

ER and il-18
http://www.jimmunol.org/content/196/1_Supplement/207.1

mycoplasmas and the ER (electron microscope images)
https://www.ncbi.nlm.nih.gov/pubmed/25651334
http://www.tandfonline.com/doi/pdf/10.1080/00087114.1970.10796399
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325531/

polyomavirus and il-18
https://www.ncbi.nlm.nih.gov/pubmed/26863474

polyomaviruses infect the ER

il-18 acts on TH1 cells to make IFN gamma

Note that when the ER is infected self proteins do not make it to the surface which means there will be no self proteins to be recognized.  An ER infected cell will look like a foreign cell which explains why IFNgamma is the default.  Kill anything that doesn't have self proteins on the outside.


The il-20 Family is secreted by Th17

il-20 Family includes: il-26, il-19, il-22, and il-24

il-26 nucleus

il-19 disruption of mitochondria

il-22 chlamydia/ gonorrhoeae/ h.pylori in vacuoles

il-24 salmonella in the golgi

Nucleus: il-26

il-26 PORE (used for a second popping of membranes like the mitochondria and nucleus or internalized infections)
https://www.nature.com/articles/ni.3211

( TLR-9 I had linked to being the net of the mitochondria )
http://angelabiggs.blogspot.com/2017/01/tlrs-toll-like-receptors-summary.html

il-26 and herpes viruses
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070281


Golgi: il-24

salmonella nests inside of cells in vacole near golgi
https://www.ncbi.nlm.nih.gov/pubmed/18778407

Golgi and il-24 with melanoma (supporting connection)
https://www.ncbi.nlm.nih.gov/pubmed/15126330

golgi and ER relationship....IFNgamma
https://www.ncbi.nlm.nih.gov/pubmed/10712678

ifn gamma and tnf with salmonella
https://www.karger.com/Article/Pdf/163643


Vacuoles: il-22

Chlamydia moves inside of cells to replicate
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886739/

il-23 triggers Th17 to release il-22 and il-17
https://www.ncbi.nlm.nih.gov/pubmed/24238108


H.pylori and il-23
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342083/

H.pylori and il-22
https://www.ncbi.nlm.nih.gov/pubmed/26867135

H.pylori replicates in vacuoles
http://iai.asm.org/content/78/10/4157.full




Immunology Review paper
https://manugowdagn.files.wordpress.com/2016/01/kuby-immunology-7th-edition-2013.pdf

Think of the surface of infections:

Staph has a fairly flat surface and the antibodies of complement work well.

Strep has sugars sticking up making it harder for antibodies to touch but the lectin-mannose pathway works.

E.coli has a furry mess of a surface making it next to impossible for things to collect on the surface so the alternative pathway is followed.

Then you have the TH17 infections.  These are the infections that are too large or moving inside of the host cells.  Which means a second wave of membrane breaking must occur.

I believe that some cytokines help coordinate where the infections are.

The trick is when infections like Staph decide to move inside of the host to escape the immune system.

Th17 cells and then Th22 cells would then become involved.

p53

What about p53?

P53 is a transcription factor.  P53 would end a cancer cell if functional. (but it doesn't start the cancer) This is one of the most critical defense genes against cancer.

P53 regulates cell cycle and pushes cells from stem to differentiated
http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1001268
https://www.ncbi.nlm.nih.gov/pubmed/1614522

P53 review:  haulting growth, repair, apoptosis (so low levels are common)
http://www.bioinformatics.org/p53/introduction.html

50% of cancers have lost the P53 gene (mutation or inactivation)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756401/
http://www.nature.com/onc/journal/v26/n15/full/1210280a.html

The cancers with p53 may be the "chemo-resistant" cancers
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756401/

In breast cancer the p53 mutation appears with the most aggressive forms
https://breast-cancer-research.biomedcentral.com/articles/10.1186/bcr426

Triple negative Breast cancer and p53 mutations
https://www.futuremedicine.com/doi/abs/10.2217/bmt.13.59?journalCode=bmt

Methylation of p53 in ovarian cancer
https://www.ncbi.nlm.nih.gov/pubmed/22855178

methylation of p53 decreases its ability to arrest the cell cycle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762123/

The methylated version is with the slower cancers

In order for viruses to replicate in the nucleus they must control the P53....seems confusing

EBV (herpes virus) and P53
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754062/

SV40 (polyomavirus) inhibits P53 completely or mutates it
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1560412/
https://www.ncbi.nlm.nih.gov/pubmed/9129663

HPV (human papilloma virus)  inhibits P53
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC236349/

But in co-carcinogenesis the virus polymerase has been bound by the carcinogen and the viral proteins are not made. 

But there is a difference between viruses. Some infect using receptors that methylate DNA while others use receptors that would demethylate.

Herpes viruses which are connected to estrogen receptors methylate.
HPVs which are connected to cannabinoid receptors demethylate.

EBV has been associated with Ovarian and estrogen positive breast cancer.
HPV has been associated with TNBC and cervical.

P53, HPV, and cervical cancer
https://www.ncbi.nlm.nih.gov/pubmed/21672450

Lynch syndrome, Hypermethylation, DNA repair proteins, and the herpes viruses

MSH2, MSH3, MLH2, and PMS2

Methylation of  these genes, or mutations, favors cancer during co-carcinogenesis. The cell division would be triggered by a viral infection. Co-carcinogenesis is what awakens the state of embryonic cell division not these mutations.

As "repair" genes they do not cause cell division but they would accelerate chaos once it had started if they were turned off.  Risking the lost off genes that are critical to control of cell cycle.

Colon rectal cancer and Herpes viruses
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075144/

herpes viruses use estrogen receptors

estrogen receptors which when magnified would methylate (shown in breast cancer)
https://www.ncbi.nlm.nih.gov/pubmed/24434785

hypermethylation of MSH2 in lynch syndrome
https://www.ncbi.nlm.nih.gov/pubmed/20388775

MSH2 combines with MSH3 to repair DNA

hypermethylation of MLH2 in lynch syndrome
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376264/

MLH1 combines with PMS2 to repair DNA

Co-carcinogeness
http://angelabiggs.blogspot.com/2017/04/co-carcinogenesis-emphasis-of-5-nuclear.html

Lynch syndrome involves the inheritance of mutations in these repair genes. Which means that HPV with it's demethylation would have these types of mutations...not methylation.

Lynch and DNA repair genes and TNBC
https://www.ncbi.nlm.nih.gov/pubmed/22992699
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548324/

Lynch is therefore the inheritance of a few mutations but not mutations in all of them.

BRCA and cancer

One of the genes linked to breast cancer and ovarian cancer is the BRCA gene. Inheriting this gene mutated increases the chances of breast cancer but spontaneous breast cancer does not have it mutated. So it is not required for cancer.

BRCA makes a protein that repairs DNA. So this gene when mutated or inhibited by methylation the dividing cancer cells have increasingly more mutations.

BRCA hypermethylation and silencing prevented by resveratrol
https://www.ncbi.nlm.nih.gov/pubmed/22197621

BRCA hypermethylation found in cancers
https://www.ncbi.nlm.nih.gov/pubmed/24889916

So what is happening?  When a cell has been set on a course to divide rapidly  errors occur.  Normally the BRCA would repair them during this process but if it is mutated or hypermethylated it doesn't work.

Looking at the viruses that may be involved in breast cancer risk:

HPV uses the cannabinoid receptor ( CB1 use by HPV is hypothesized on my blog on another post)

The cannabinoid receptor prevents the inhibitory effect of BRCA.  Therefore if this receptor pathway was magnified then it could look as though BRCA was lost.

CMV/EBV use the estrogen alpha and estrogen like receptors which would methylate the gene and turn it off.

Triple negative breast cancers and BRCA
https://www.bcrf.org/blog/most-patients-triple-negative-breast-cancer-would-benefit-genetic-testing

BRCA mutation and triple negative breast cancer
https://www.ncbi.nlm.nih.gov/pubmed/28164176

Triple negative breast cancer and HPV
http://arizona.openrepository.com/arizona/handle/10150/623542

Ovarian cancer and hypermethylation of BRCA
https://www.ncbi.nlm.nih.gov/pubmed/24889916

Herpes virus mRNA and ovarian cancer
http://www.ncbi.nlm.nih.gov/pubmed/25485872

are ovarian cysts caused by the herpes virus?

Ovarian cysts are a risk for ovarian cancer
http://www.aafp.org/afp/2009/0915/p609.html

Knudson's heredity 2-hit cancer compared to Co-carcinogenesis: a contemplation of how this fits together

Knudson's heredity "2 hit cancers" involves the mutation driven cancers found in some childhood cancers.

In 1927 Muller proved that radiation makes mutations in fruit fly DNA thus connecting the cancer caused by radiation directly to the mutations occurring in the DNA.
https://en.wikipedia.org/wiki/Hermann_Joseph_Muller

In 1934 Muller suggested that one mutation was not enough since cancer did not immediately occur at the time of the mutation.  The question was then how many mutations does it take?

In 1971 Knudson found the answer studying cancers in children In Retinalblastoma cancer could be caused by mutating both RB alleles.  The smallest number of mutations possible to cause cancer was 2. Hence his "2 hit model"

In order for cancer to occur the genes mutated must be monumentally significant in the process of cancer and embryogenesis.  Mutational childhood cancer is not how much DNA damage rather did the critical genes get damaged.

The retinalblastoma gene encodes a protein that suppresses cell cycles. (called a tumor suppressor but think in terms of embryogenesis where this protein stops the divisions)
https://en.wikipedia.org/wiki/Retinoblastoma_protein

RB is the lynch pin stopping cells from dividing.

Cancer is the division of cells without control.
Not the accumulations of mutations in DNA over a lifetime until some DNA damage level is reached.

Heredity and childhood cancer will reveal the small group of key genes involved in cancer through mutation and these damaged genes are all participants of cell division.

Most cancers are more complex.  Most cancers will not be mutation triggered.  Most cancers will begin through Co-carcinogenesis. Then the heredity of cell cycle mutations favor the continued life of these cancer cells.

Co-carcinogenesis is when a carcinogen interacts with a virus to cause cancer.    The host's cell cycle divisions are turned on as if in embryogenesis.  Further it is during these massive divisions that  mutations can occur progressing the cancer. The virus and carcinogen are triggering the division of cells.

RB is the focus of nuclear viral oncoproteins.
http://www.nature.com/onc/journal/v25/n38/full/1209621a.html

Co-carcinogenesis
http://angelabiggs.blogspot.com/2017/04/co-carcinogenesis-emphasis-of-5-nuclear.html

Nuclear viruses turn on the high rate transcription involved with cell division. Which if they become inhibited by a carcinogen and their own polymerase can't use the freed system...cancer occurs.

Myc-c gene codes for a cell cycle transcription factor.  Myc is expressed during the epiblast stage of embryogenesis.
https://www.nature.com/nature/journal/v500/n7460/full/nature12389.html

Myc-c favors a cell continuing to divide while low levels in the epiblast state dies.  If the cell is cancerous with high myc it is favored to live.

Methylation occurs right before the Epiblast state. Methylation looks like it turns Myc on.

Myc-c is expressed in Burkitt lymphoma.

Epstein Barr virus has been linked to Burkitt lymphoma.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2095571/

Herpes viruses and retinoblastoma proteins
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2636798/

The EBV uses the estrogen receptors which trigger methylation.  (the pathway is then magnified by the virus)
http://angelabiggs.blogspot.com/2017/05/virus-families-use-receptor-families.html

Which means the virus "awoke" more myc-c than is normally expressed through the receptor it used to infect

T.gondii, the ER, and IFNgamma...puzzling out where this infection hides

T gondii moves into the host cell's cytosol

T.gondii triggers tlr-3 (the tlr of the cytosol)
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088398

T.gondii triggers both IFN beta (of the cytosol) and IFN gamma of the ER
https://www.researchgate.net/publication/20648178_Relationship_between_the_production_of_interferon-alphabeta_and_interferon-gamma_during_acute_toxoplasmosis

Image of t.gondii attaching to surface
http://www.microbiologyresearch.org/docserver/fulltext/micro/75/1/mic-75-1-111.pdf?expires=1508334641&id=id&accname=guest&checksum=F3CF119D2ED7B806150A504A35E08BAD

TNF alpha and t.gondii (when it infects macrophages or other immune cells)
http://iai.asm.org/content/63/2/591.full.pdf

T.gondii  then attaches itself to the host's ER and mitochondria
https://www.ncbi.nlm.nih.gov/pubmed/9378762
https://www.ncbi.nlm.nih.gov/pubmed/17300514

Disruption of the ER causes the IFNgamma

t. gondii and IFN gamma
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC356035/
http://iai.asm.org/content/75/10/4799.full

ifn gamma appears with T.cruzi
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118600

T.gondii infection somehow inhibits Th17?
http://iai.asm.org/content/80/4/1437.full

IFNgamma/il-18 impairs the Th17 response?

Here T gondii causes TGF beta to be increased
https://www.ncbi.nlm.nih.gov/pubmed/8406801

which then increases Th17?

Does the high level of C4a help remind the immune system that it is dealing with a large infection not a viral infection?

mast cells are critcal against t.gondii
https://www.ncbi.nlm.nih.gov/pubmed/25091816
https://www.ncbi.nlm.nih.gov/pubmed/28428784

C4a could be the cytokine for these mast cells?

C3a and C5a call mast cells
http://www.jimmunol.org/content/157/4/1693.short

C4a levels are high during t.gondii infections

there are 2 types of mast cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC323754/
http://www.nature.com/ni/journal/v12/n11/fig_tab/ni.2109_F2.html

the Chymase containing type is involved with t.gondii
http://www.jbc.org/content/285/49/38005.full

T.gondii infects the muscles (even the heart)
http://www.bio.unipd.it/bam/PDF/5-3/Lindsay2.pdf

chymase involves the inflammation of the vascular as well as the heart

Is it possible that C4a calls a specific mast cell?

C4a and il-1 beta
https://www.ncbi.nlm.nih.gov/pubmed/20433584

il-1 beta, mast cells, and th17
https://www.ncbi.nlm.nih.gov/pubmed/27799306

il-18 aka IFN gamma inducer: do mycoplasmas infect the ER?

il-18 aka IFNgamma inducing factor
https://www.ncbi.nlm.nih.gov/pubmed/9551984

il-18 is the mannose cytokine

il-18 increases tlr4 and the mannose receptor
https://www.hindawi.com/journals/mi/2015/236839/

When a bacterial infection like strep occurs which has mannose as part of it's coat IFNgamma is  also produced..in low quantities.  High levels are made with ER viral infections.

Mannose is on the surface of mycoplasmas
https://www.ncbi.nlm.nih.gov/pubmed/16041047

Consider also that Mannose is added to proteins in the ER and golgi complexes.

Mannose-lectin pathway of innane immune system
https://www.ncbi.nlm.nih.gov/pubmed/16041047

Mycoplasmas...might actually be hiding in the ER of cells?
https://www.ncbi.nlm.nih.gov/pubmed/4844719

Antibodies locating mycoplasmas to the ER
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2249.2004.02535.x/full

"Immunofluorescence colocalization of mycoplasma-induced autoantibodies with antibodies to calnexin (Fig. 6) and Bip (binding protein of the endoplasmic reticulum, data not shown"

Mycoplasmas increase the release of calcium from ER stores
http://iai.asm.org/content/70/5/2502.full

If mycoplasmas are in the ER this would explain how mycoplasmas trigger IFNgamma like polyomaviruses.


When the body has a viral infection of the ER, like polyomaviruses,  IFNgamma is increased.

TLR8 (ER ) increase il-18
https://www.ncbi.nlm.nih.gov/pubmed/26928328

mycoplasmas in the ER have been connect to rheumatoid arthritis which is also connected to il-18

RA and il-18
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC409841/
https://www.ncbi.nlm.nih.gov/pubmed/15168150

endoplasmic reticulum stress in RA
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890471/

Yellow fever and TCR signaling

Only yellow fever altered TCR signaling
https://www.ncbi.nlm.nih.gov/pubmed/28968905

Is this because Yellow fever uses the MCR4 receptor?

I have been dividing up the flaviviruses with the melanocortin receptor they could use:

mcr1   Tick borne encephalitis virus/ hepatitis C   (Thrombocytopenia due to red blood cells with mcr1)

mcr2 (ACTH receptor)   Zika (placenta, developing brain)

mcr3  West nile (kidneys)

mcr3 and mcr1  Japanese encephalitis

mcr4  Yellow fever (liver)/ hepatitis C
                        
mcr5  Dengue (immune system T cells)

alpha MSH and T cells
https://www.ncbi.nlm.nih.gov/pubmed/10985666

MCR4: binds alpha MSH
https://en.wikipedia.org/wiki/Melanocortin_4_receptor

Liver and MCR4
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312751/

Infections, receptors, and autoimmune brain disorders ?

Finding antibodies to receptors can lead to identifying the infections involved with the autoimmune disease..they do not cause the disease but rather help link the infections.

CASPR2: contacti- associated like-2 receptor

Morvan's syndrome and anti-CASPR2
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4793739/

what large infection could this be?

Dopamine Receptor

Tourettes and anti-dopamine2 receptor
https://www.tourette.org/grant/cross-sectional-study-of-dopamine-2-receptor-antibodies-in-patients-with-tourette-syndrome-and-obsessive-compulsive-disorder/

Tourettes, strep and anti-nuclear antibodies
https://www.ncbi.nlm.nih.gov/pubmed/12699862

Strep and anti-dopamine receptor
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779221/

NMDAR: N-methyl-D-asparatate receptor

antibodies to NMDAR in schizophrenia
https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=24882425

NMDAR, T.gondii, and schizophrenia
http://journal.frontiersin.org/article/10.3389/fpsyt.2017.00037/full

NMDAR antibodies in first episode schizophrenia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358648/

NMDAR dysfunction and schizophrenia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608949/

GABA receptor :

GABA receptor with speech/motor ataxia and autism
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477717/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251489/

Campylobacteria

Gaba receptors and campylobactera
http://www.pnas.org/content/108/38/16050.long