Sunday, April 15, 2018

HLAs, TLRs, and IFN diagram

TLR are the butterfly nets catching in a nonspecific way. TLR3 and TLR8 are worn by dendritic cells and macrophages. TLR 7 and TLR9 are worn by B cells. If you match up the TLRs with the locations of the host cell they appear to catch things in this is the pattern you see. 

TLR8 and Natural killer cells

TLR3 and natural killer cells

IFN is the coordination cytokine that triggers the correct HLA expression and Macrophage hands (Tyro3, AXL, Mer) .

Macrophage hands allow macrophages to attack virally infected cells.

HLAs are the mailboxes that hold up specific pieces to T cells or natural killer cells. It is my hypothesis that like the TLRs they are zone specific.

Note that the HLAs of the nucleus and the mitochondria are MHC1 : HLA-A and HLA-B and are worn by all cells.  While MHC2 are worn by Antigen presenting cells like macrophages.

Tc cells look at MHC1
Th1cells look at MHC2: HLA-Dr, DQ, DP
NK cells look at HLA-C, HLA-E, HLA-F and HLA-G

The mailboxes for the NK cells involve the pathway of protein synthesis to the plasma membrane. If proteins can't make it to the plasma membrane then the cell would be "naked" and the NK cell would kill it anyway.

Thursday, April 12, 2018

New HLA thoughts

HLA-DM on dendritic bone marrow cells

HLA-DM matches up with IgA1 which is primarily made at the bone marrow plasma cells

il-5 is the bone marrow cytokine (highest amount there)

il-5 was once called the eosinophil factor because they have the most il-5 receptors (basophils also have il-5 receptors)

il-5 can also be secreted by eosinophils

Does il-5 favor the HLA-DM and the IgA1 ?

Previously linking the HLAs to the viruses' locations resulted in:

HLA-A nuclear
HLA-B mitochondria
HLA-Dq/ Dr cytosol

These HLAs were viewed by T cells....but HLA-C was viewed by NK cells

HLA-C and Natural killer cells

The HLA looked at by NK natural killer cells have specific locations they represent.

HLA-E salmonella (nests in the golgi)

HLA-G Pseudomonas aeruginosa (exosomes)

HLA-F Japanese encepalitis virus (Lysomsomes ?)

Monday, April 9, 2018

25 Medical Hypotheses

1. Allergy hypothesis: Allergies reveal the infections we have.  Severe allergies and infections can be matched up: peanut and Staph, bee and T.gondii, daisy and Clostridium, poison ivy and spirochetes. If an infection can be killed by a compound or inhibited by the compound our immune system sees the interaction and we associate all the compounds present with the infection.  If an infection makes a pigment from a compound we will react to that too.  For example aflatoxin with peanuts could cause staph to counter respond.  Our immune system would identify everything there at the scene of the crime as part of the infection.

2. Quorum hypothesis: Infections talk using quorums and these quorums interfere with our body's pathways. ( for example mycobacteria's cGMP causes such things as type 2  diabetes, high cholesterol, and synuclein bodies)

3. Autoimmune cross-targeting hypothesis:  The Cross-targeting of simultaneous infections on one tissue, one infection inside and one infections outside, triggers autoimmunity.  Antibodies or chemicals/drugs can replace one of the infections.  By antibodies I mean even those triggered by vaccines.  For example a flu virus inside of the pancreas and e.coli latching on to the outside could trigger type one diabetes.

4. Co-carcinogenesis: a virus and a carcinogen together cause cancer. Taking Francis Peyton Rous’ hypothesis further, the carcinogen is a polymerase inhibitor which binds the viral polymerase with higher affinity. Thus the DNA methylation state has been changed but the virus is no longer viable.  DNA damage does not cause most cancers, the interaction of carcinogens inhibiting viruses do.  Further these cancers wear the receptors that the virus  used to enter and the characteristics of the cancer will be from the receptor's pathways.

5. The Gluten hypothesis:  Barrier crossing infections are ones that can cross the intestine or the blood brain barrier causing gluten sensitivity with the hole they leave behind. This explains the gluten sensitivity of Schizophernia from T.gondii, Celiac disease from e.coli, Tourettes from staph, and crohn’s from mycobacteria.

6. Viral families use receptor families. Influenzas use dopamine receptors. HPVs use Cannabinoid receptors. Herpes viruses use estrogen and estrogen-like receptors. Flaviviruses use melanocortin receptors. Polyomaviruses use serotonin receptors.

7. Aflatoxin like compounds cause tau bodies.  ALS and picks disease are caused by different infections but both have tau.  Both infections secrete an aflatoxin like compound.  Vitamin D is protective against it because aflatoxin uses the vit D receptor.

8. Pituitary tumors are caused by an infection releasing butyrolactones which interfere with normal GABA signals and cause the immune system to confuse nerves with the infection. (or someone taking too many GHB sleeping pills)

9.  The receptors used by a virus when triggering autoimmunity cause pathways to be activated which makes the various types of one autoimmune disease.  There are 3 types of schizophrenia which match up with the 3 receptors use by the 3 herpes viruses. (sort of a continuation of 6)

The receptor pathway triggered by a virus involved in an autoimmune disease can cause symptoms of the disease that will be distinct. Example:  The 3 types of schizophrenia has all 3 herpes virus families and each receptor activated can be matched to symptoms.  Estrogen-related receptor and disorganized symptoms for example.  3 receptors used equals 3 types of schizophrenia

10. Alzheimer's disease is caused by damage to the mitochondria: alpha-herpes family, diacetyl, inherited and linked to down syndrome, or radiation damaged mitochondria.

11. Postural orthostatic tachycardia could be caused by reoviruses and the adrenergic receptors they bind.

12.  The HLAs are mailboxes for T cells or NK cells from different areas of the cell. HLA-A is the nuclear mailbox for Tc cells. HLA-B is the mitochondria's mailbox for Tc cells. HLA-DR/DQ is the cytosol's mailbox for RNA viruses for Th cells.  HLA-C is the endoplasmic reticulum's mailbox  for NK cells. HLA-E is the Golgi, HLA-F is the lysosomes, and HLA-G is the exosomes which also trigger NK cells. 

HLA-DQ could be the cytosol's mailbox for non-encapsulated viruses there like reoviruses.   HLA-DP is the outer infection mailbox?

The TLR 7 / 9 butterfly nets for DNA in the mitochondria and nucleus trigger TGF-B1 which causes B cells to express MHC1 which are the HLA-A and HLA-B.

13. Carcinogens use certain receptors to get into cells which matches them up with specific cancers.

14. TLRs, toll like receptors, are the innane immune system of nets catching conserved molecules in a non specific way but identifying the region as well as general type of infection. Like HLAs they exist in the different areas of the cell.  When the internal viral seeking TLRs are activated the IFN matches the region they are in thus the appropriate HLA is produced helping to find the exact culprit.

15. TLRs send IFNs which tells infected cells to express the corresponding HLAs and macrophages to wear the corresponding TAMs (hands to grab infected cells) TAMS: tyro T , axl A , mer M

Golgi           TLR3      IFN lamda   HLA-D               Tyro3
Nucleus/ Mito    TLR7/9   IFNalpha    HLA-A HLA-B   Mer
Endoplasmic R   TLR 8     IFNgamma HLA-C                 Axl

( Cytosol       TLR4    IFNbeta which is not an endosome tlr and carried out by Fibroblasts for bacterial infections that enter host cells )

  Because an infected ER means little gets to the surface of a host cell the Natural killer cells step in here and secrete IFNgamma. (note that low levels of IFN gamma is secreted to favor MHC2)

Cytosolic viruses go through the golgi before exiting which is why they trigger TLR3.

16. More for the Co-carcinogenesis:  Nuclear viruses awaken embryonic Hervs.  They do so by methylating or demethylating DNA.  If the virus family demethylates the cancer will be aggressive while the methylating viruses are slow growing.  (Cancer occurs when a carcinogen inhibits the viral the virus opens the DNA up but can't use it) 

Note that the infant/child form of genetically caused cancer are for the genes that regulate these embryonic division cycles.

17. Bacterial infections will hide inside of host cells like viruses. Hypothesis:  Like the IFN cytokines there should be cytokines that signify where in the host cell they are hiding.  Mycoplasmas nest inside the ER, chlamydia hide in vacuoles, salmonella hide in the golgi, and mycobacteria sit in the cytosol.   The cytokines seem to match up the features of an infection family with where they hide inside.  

For example infections that use modulins tend to move into vacuoles when infecting the host so TLR2 triggers il-23 which then (in hypothesis 20) triggers TGF3 which repairs vacuoles.

18. Could there be 4 different types of asthma caused by different infections which could be diagnosed using cytokine patterns and the allergies present in the host.

19.  The problem concerning autism and vaccines could be solved if autism is viewed as an autoimmune disease.  The autoimmune cross-targeting hypothesis when applied to autism reveals there could be 3 different types of autism:

Group Flu and RA : frontal lobe autism
Group DTP (tetanus) and HHV6 : temporal lobe autism
Group MMR and sutterella/ campylobacteria: cerebellum autism

Two of these have been linked to vaccines the MMR and the DTP.

Combining the notion that viruses use receptors to enter cells with the notion that "parts" of a virus can set off autoimmunity on the tissue one can only conclude that what is contaminating vaccines setting off autoimmunity are the tiny pieces the virus uses to bind the receptors.  Running vaccine solutions through binding columns of the receptors could "clean " the vaccine of the one piece that triggers the autoimmunity.

20. TGF-Beta has been linked to both embryogenesis and cancer as well as the immune system.  The area an infection could be damaging causes a specific TGF-B to repair the area. First the TLR butterfly net is triggered by the infection.

TLR9 or TLR7 trigger TGF-B1 which stimulates the mitochondria to grow and smad to the nucleus for DNA repair.

 TLR2 triggers TGF-b3 because the infections that use vacuoles tend to be the same ones that use modulins, 

TLR-6 which binds lipoproteins found on gram positive bacteria and mycobacterias which divide in the cytosol triggers TGF-b2 which encourages Tcells to check the cytosol of cells,

 finally TL3 of the golgi triggers TGf-B4.  TGF-B4 stimulates growth of the golgi.

21. T h17 cells are involved in second pops.  When does this happen? When large infections move inside of host cells or viral infections are hiding inside of the mitochondria or nucleus. When the viruses are not visible in the cytosol or ER which would be visible when the host cell is popped. Thus a "second popping" must occur.

il-6 and il-23 trigger Th17 to release il-22

note that il-6 is a "reset all in immune respose where phagocytes and TH1 are triggered"and il-23 are released by phagocytes when they can't find the infection they are looking for

il-21 and TGF-b1 trigger the release of il-26 and il19

note that TLR7/9 release TGF-b1 and Tcells release il-21 when activated

22. The type of Lambda IFN matches up with the type of virus going through the golgi. (looks like all viruses go through the golgi before exiting even when they start in different areas)

IFN lambda1 Nuclear virus
IFN lambda2 Mitochondrial virus
IFN lambda 3 cytosolic virus

23. Hypothesis: the TNF family is involved with infections of the immune system itself.  Bcells wear TNF-beta(lymphotoxin-alpha) and secrete it at the peyer patches interacting with FDC. This can be seen with viral infections that invade Bcells.  Macrophages wear TNF-c (lymphotoxin-beta)when they are infected with bacterias.  Macrophages (and other APC) secrete TNF-alpha when infected with either a virus or a bacteria. They key here is that TNF-c receptors on Mast cells switch the focus of the mast cell.  They normally secrete cytokines geared at viruses but after lymphotoxin-beta receptor activation they secrete il-6, il-4, and TNF-alpha.

24. The il-20 family hypothesis of cytokines are H+ pores leaking the H+ our of their assigned membranes

il-20 plasma membrane
il-22 vacuoles
il-24 golgi
il-26 nuclear membrane
il-19 mitochondria

These are used by Th17 to pop membranes.  The il-20 cytokines could also used for differentiation for example il-19 converting Th1 to Th2.

25. 25-hydroxycholesterol (25HC ) is secreted by M1 macrophages to help cells infected with cytosolic viral infections.  The IgG2a antibodies made by the interaction of Th1 with the Bcells need to be able to see the viral RNA to bind the viral RNA.  The hypothesis is that 25HC doesn't just inhibit viral infections by changing the fluidity of the plasma membrane but by holding viral RNA out for the the antibodies.     When the antibody sees the RNA the IgG2a then triggers complement.

No evidence yet that 25HC binds RNA. However the Hydroxyl group of the 25HC could attach to the sugar phosphate backbone of RNA....possible?

Friday, April 6, 2018

IgG2 hypotheses requests the role of 25HC to be examined.

How does IgG2 work?

IgG2 is strongly complement. Which means the antibody triggers the complement production of a pore on the cell's surface.  In this case it could be the host cell's surface if it is infected with a cytosolic virus.

The question is how does the IgG2 find the infected host cell? Is the viral RNA somehow loosely held on the surface?

Cytosolic viruses trigger IFNbeta which could do 2 things : increase macrophage consumption of virally infected cells using tyro3  and secondly increase complement...somehow.

(note that viral infections that move into the mitochondria or nucleus would trigger HLA-A/B and CTL pathways)

IFNbeta changes the plasma membrane...more rigid

IFNbeta decreases plasma cholesterol levels

flu and complement

 IFNbeta triggers macrophages to produce and secrete 25 hydroxycholesterol (25 HC)

Do cells take up the 25HC which binds RNA in their cytosol and holds it on the surface for IgG2 complement?

25HC makes the plasma membrane more rigid which could prevent viral infections from starting but it seems to also block existing infections

I can find evidence of 25HC slowing viral replication but no evidence of direct binding of RNA or  25HC taking RNA viruses to the plasma membrane outer surface...still looking.

If the viral RNA is bound by 25HC and held at the plasma membrane is it then recognized by IgG2 is that when a pore is made leaking the host cell?

macrophages produce 25HC with IFN from viral infections

How 25HC is thought to function

25HC also protects against zika

Does 25HC bind the RNA and then hold it on the plasma membrane for IgG2?

IFNbeta also tells macrophages to express tyro3 receptors. Macrophages will engulf only these virally infected cells?

Zika and tyro 3

some flu viruses actually try to avoid being eaten by macrophages by down regulating tyro3

25HC blocks HCV's  RNA replication
Does it bind the RNA of the virus???

cholesterol binds and inhibits SCAP directly but 25HC does not

What does 25HC do?

Note that M1 macrophages secrete 25HC which matches up with the TH1 cells.

structure of 25HC

How does the 25HC hydroxyl group capture viral RNA? through the Sugar-phosphate backbone?

Thursday, April 5, 2018

il-17, Neutrophils, and fungal infections

Th17 cells are involved with the second popping of infections hiding inside host cells.

The il-17 cytokines associated with Th17 are also involved with killing extremely large infections where il-17 up regulates neutrophils and CTLs

il-17a il-17f and neutrophils

neutrophils kill fungal infections

C-type lectin receptors on macrophages, dendritic cells, and neutrophils sense fungal infections. Dectin-1 detects B13glucan on candida, aspergillus, and saccharmyces. Dectin-2 binds high mannose structures on cryptococcus and trichophyton. 


neutrophils produce il-17a in a dectin-1 

il-17a induces CTL cells which have been shown to kill not just host cells infected with viruses but fungal infections

fungal infections trigger the release of TGF-b1

My current cytokine hypothesis for TH17 cells