Human leukocyte antigens, HLAs, are cell surface proteins that serve as mailboxes to T cells. T cells having been educated in the thymus to know all internal cell self antigens thus would react to foreign antigens presented in these HLA mailboxes. Currently HLAs have been recognized as reflecting genetic susceptibility to various autoimmune diseases. Viruses have been suspected of triggering autoimmune disease. When the HLAs and the viruses for an autoimmune disease are matched up patterns emerge revealing that different HLAs represent different areas of the cell.
Hypothesis:
HLAs identify not just the foreign antigen from inside the cell but where in the cell, which organelle, the antigen was found. When the patterns of the HLAs in autoimmune diseases are looked at with the suspected viral triggers a pattern emerges suggesting that the type of HLA reflects the location within the cell because viruses only infect certain areas within the cell.
HLA-DP the plasma membrane (outside of cell)
After NK attack the infected cell's cytosol is visible to APCs
Analysis of Hypothesis:
Specific HLAs have been associated with genetic susceptibility to particular autoimmune diseases. These same autoimmune diseases have also been associated with viral triggers. The purpose of an HLA is to bind foreign viral pieces and display them mailbox like to Tcells which means we can link the HLAs to the viruses.
When you look at an autoimmune disease, like alopecia for example, with the known HLAs and the suspected viral triggers you notice a pattern. Considering where inside the cell these viruses end up a pattern emerged. Herpes alpha viruses infect the mitochondria. Polyomaviruses infect the endoplasmic reticulum. Herpes gamma and beta viruses infect the nucleus. Flu viruses and flavivurses infect the cytosol.
HLA-DQ : Reovirus : Areata Alopecia
HLA-C : Polyomavirus: Universalis Alopecia
HLA-DR4 : Flu : Totalis Alopecia
The same thing can be done with parkinson's
Late onset sporadic parkinson's : flaviviruses or flu : HLA-DR
Parkinsonism with dementia/alzheimer's : herpes viruses HLA- A, B
Multiple sclerosis
HLA-B: Herpes-alpha (zoster): Relapsing remitting
HLA-DR15 : Flavivirus (hepatitis C/dengue ) :Secondary progressive
HLA-A: Herpes-gamma (epstein barr): progressive relapsing
HLA-C: Polyomavirus (hepatitis B/ JC, BK) : primary progressive
Which could mean that:
HLA-A the nucleus
HLA-B the mitochondria
HLA-C the endoplasmic reticulum
HLA-DR the cytosol (encapsulated virus)
HLA-DQ the cytosol (not an encapsulated virus)
HLA-DP the plasma membrane/ endocytosis (APC)
The locations of the HLAs can be further verified by the genes and protein sequences of the HLAs themselves.
HLA-As are linked to viral infections that infect the nucleus like HPVs or herpes-beta or herpes gamma viruses. These viral infections are also linked to cancers because they infect the nucleus where they interfere with the DNA, the cell's cookbook.
HLA-A genes appear to be linked to the autosomal dominate spinocerebellar ataxia. The syne-1 mutation which is linked to the recessive spinocerebellar ataxia is located on chromosome 6 right next to HLA-A. The Syne-1 gene makes the nesprin-1 protein which connects the cytosolic cytoskeleton to the nuclear membrane. Is the HLA-A also a nuclear protein? Is this relationship significant?
Nuclear leader sequences contain very basic lysine and arginine sequences. HLA-A, HLA-B, and HLA-C all contain a RRKSS sequence that is missing from HLA-D. Since this sequence is conserved it could prove to be the nuclear sequence that HLA-A uses to get to the nucleus.
HLA-Bs don't use their nuclear sequence because they have a more dominant location sequence, a mitochondrial one. Mitochondrial sequences are the hydroxyl amino acids otherwise known as water-loving amino acids. Serine, threonine, and tyrosine all have an OH group. The HLA-B protein at first glance does not have a mitochondrial sequence but there does exist a sequence that could become one. HLA-B genes have been linked to the steroid 21-hydroxylase gene on chromosome 6. These genes are right next to each other. When this 21-hydroxylase enzyme is expressed it converts alanine to serine and valine to threonine. The end sequence of the HLA-B protein "VS-L-TA" would become "TS-L-TS" which is a mitochondrial location sequence.
HLA-Bs are linked to viral infections that infect the mitochondrial such as the herpes-alpha viruses. Herpes zoster specifically is known to travel down the nerve in the mitochondria like a little car during shingles infections. As the nerves branch out the viral infection does too infecting the next nerves in the line. HLA-Bs can also be linked to viral, fungal, or bacterial proteins that find their way to the host's mitochondria and cause disfunction.
HLA-Cs are linked to polyomaviruses which infect the endoplasmic reticulum. Hepatitis B, JC, and BK viruses are found in the endoplasmic reticulum during infection and may be using the serotonin or similar receptors to get there.
Newly translated HLA-Cs never use their nuclear sequence because they don't leave the endoplasmic reticulum. HLA-Cs have been found to bind tight to the ER proteins called TAP which is short for "transporter associated with antigen processing". HLA-A and HLA-B only bound weakly to TAP and were able to leave the endoplasmic reticulum. Further the gene for TAP has also been found on chromosome 6 near the HLA-C gene.
Which brings us to the HLA genes at the bottom of Chromosome 6 that do not have endoplasmic reticulum sequences or nuclear sequences. Are the HLA-D mailboxes are linked to viruses in the cytosol?
Reoviruses of celiac disease match up with HLA-DQ whereas the HLA-DR type of mailboxes appear to pick up viruses like the flu. The distinction between these two types of viruses is encapsulation. When the HLA-DRs are further divided up by numbers it is obvious that certain mailboxes grab certain viruses. Just knowing the HLA mailbox associated with a disease could help predict which viruses could are involved.
HLAs can pick up anything foreign material not just viruses. Viral proteins, bacterial proteins, fungal proteins, and even medications will be picked up. What is interesting here is that the non viral associated HLAs seemed to be connecting in other ways. For example when examining a few of the HLA-Bs, the exact foreign protein was not the same between infections but the effect on the the mitochondria appeared to be matching. Apoptosis and oxidative stress seemed linked to HLA-B49 but when the mitochondria was in a state of fission from the foreign protein HLA-B8 was used. The exact HLA mailbox could be telling us even more information than the where in the cell but what is happening.
Further note that HLAs that interact with T cells are glycosylated. Is this how they end up outside of the cell? When these HLA mailboxes bind their antigens is there a conformation change that allows glycosylation? Sugars are the instructions on membrane proteins indicating which sections are not in the cytosol. Are HLAs on the inside until they have glycosylation, large sugars attached, and then they are pushed to the outside of the cell?
HLA-DPs are on the antigen presenting cells binding things that are outside of cells (until broken down by macrophages etc). HLA-DPs hold the antigens of large infections or the viral coats. HLA-DPs also bind to MHCIIs (HLA-DQ or HLA-DR) stabilizing them until it binds it's antigen.
http://www.uniprot.org/uniprot/P20036
Conclusion:
The location of the HLAs can be confirmed two ways. HLAs can be matched up with the viruses they bind which reveal where the HLA is because the virus infects that area of the cell. HLA genes and protein sequences themselves have telling relationships that reveal where the HLA belongs.
Title:
Toll-like receptor location hypothesis
Abstract:
The internal TLRs match up with the internal HLAs. The internal TLRs identify foreign material inside the cytosol, mitochondria, nucleus, and the endoplasmic reticulum. These TLRs have corresponding IFNs which when released trigger the corresponding HLAs for specific locations inside the cell and the appropriate TAMs to be worn by the macrophages.
Introduction:
TLRs are the innate immune system nets that catch large groups of foreign material. Unlike the HLAs which grab and display specific antigens; TLRs catch broader groups. TLRs were initially found to grab generic bacterial components. TLR5s bind flagallins, TLR1s bind peptidoglycans of yeast and bacteria, TLR4 binds the sugars on gram negative bacteria and mycobacterias, and TLR6 binds the proteins of gram positive bacteria. The internal TLRs seem to be binding DNA and RNA components. What are the internal TLRS? TLR3, TLR9, TLR7, and TLR8.
Hypothesis:
The internal TLRs are location specific and trigger specific IFNs which trigger the corresponding HLAs for that same location, the NK cells, and tell the macrophages which TAM arms to wear.
Analysis of hypothesis:
Looking at each of the internal TLRs, which viruses they catch like generic nets, and which IFN is then expressed as a result reveals where each TLR is. To begin with TLR3, TLR7, TLR8, and TLR9 are all found intracellularly.
TLR3 : cytosolic viruses: IFN beta: HLA-D : TAM- TYRO3
TLR7: nuclear viruses: IFN alpha: HLA-A : TAM-MER
TLR9: mitochondrial viruses: IFN alpha: HLA-B : TAM-MER
TLR8: endoplasmic reticulum: IFN gamma: HLA-C : TAM- AXL
IFN gamma is made primarily by Natural Killer T cells. Natural Killer cells strike when no TLRs or HLAs are visible on the cell's surface. These proteins are processed in the endoplasmic reticulum. When the endoplasmic reticulum (ER) is infected with a virus there would be an issue with TLR8 or HLA-C ever making it to the surface of the cell. If they can't make it to the surface IFN might not be made but the Natural Killer cells have evolved to compensate for these ER viruses.
The other zones of the cell have a simple pattern of the TLR net catching a virus and then the corresponding IFN. Here are some possible scenarios.
The flu virus is caught by TLR3 which then causes IFNbeta to be made. As the infected cell secretes IFNbeta the natural killer cells (NKs) are drawn to the area to kill the infected cells. Neighboring cells see the IFN and react. Antigen presenting cells start producing HLA-Ds to diagnose exactly which cytosol virus pours out of the cell and the macrophages start to express the correct TAM. The flu virus would then be grabbed with a very specific mailbox HLA-DR4. The HLA-DR4 would then present it to a T cytotoxic cell. The macrophages would put on the TYRO3 TAM hand allowing it to eat self cells that are infected.
The Epstein Barr Virus is a nuclear virus which would be caught by TLR7 and IFNalpha is secreted. When the Natural killer T cell breaks open these infected cells secreting IFN the virus will still be hidden inside the nucleus. The Antigen presenting cells are not the ones to told to express HLA-A because they can't see anything while the cells at risk in the area are told to do so. The IFN alpha also tells the macrophages to wear the MER TAM hands.
And the IFN can connect to the TAMs...the macrophage hands.
http://angelabiggs.blogspot.com/2017/02/tam-receptors-and-ifns.html
