Friday, June 8, 2018

The Immune system: review the way I see it but borders on fiction with new hypotheses weaved in


The immune system is very complex but if examined considering the preferred locations of infections the pathways of the immune system are easier to see.  This text will constantly give examples of the type of infection involved with each pathway.

In humans there is an interplay between the Innate immune system we are born with which can recognize the basic characteristics of our enemy and the adaptive immune system that improves upon recognizing our enemy with any “adjustments” they may have made.  This adaptive immune system exists only in vertebrates.  Invertebrates rely only on the basic innate immune system.

The immune system attack is both coordinated and supportive.  Secreted cytokines coordinate the immune system cells to know what kind of infection they are dealing with.  Immune system cells have become specialized to deal with certain infections and to aid the reactions with cytokines which are not their assigned infection.

The innate immune system has several specialized cells.  The Neutrophils who trap and kill bacteria or yeast.  Natural killer cells who destroy stressed and infected cells.  The phagocyte family of Monocytes, Dendritic cells, and macrophages who patrol and consume foreign objects and infected cells. Basophils who contain serotonin and heparin with which to help kill mycobacteria but are also the starting shot for all visible infections.  Eosinophils are the cleaners of the immune system whose priority is parasites but can kill bacteria or fungal infections with acid. Then there are the Mast cells who help innane immune system cells enter infected areas using histamine and when viral infections are involved they awaken the proper T cells of the adaptive immune system.

The Innate Immune system starts with the barrier regions of the skin, the intestine, and the lungs. These regions consist of epithelial cells and connective fibroblast cells. Surface damaged epithelial cells release the cytokine il-6 and infected epithelial cells release TNFalpha.  Immediately the immune system responses.

When the skin surface is damaged the immune system assumes an infection has entered.  The il-6 travels to the lymph gland where it triggers B cells to make IgM.  IgM travels in the blood until it reaches the wound.  If the infection is something like Staph with a smooth surface the IgM antibody easily binds. This IgM antibody method is called complement. Using the Fc back of the antibody small c proteins splice, bind, and slowly build a pore like hole into the bacteria called MAC.

This MAC pore can be formed 3 ways: the complement method just discussed, the Lectin-mannose-binding method, or by the alternative method.

Strep has developed long mannose strings to block antibodies from reaching the surface.  Since antibodies can’t get in a Mannose-binding lectin binds the string and starts the cascade.

E.coli has gone even further to protect itself developing so many surface structures that the pore must form in the cytosol then force itself onto the surface.  The alternative method. 

Infections don’t always enter the body because of damage. Epithelial cells and fibroblasts at the skin surface also have TLRs.  TLRs are the butterfly nets of the innate which have evolved to snare infections as they attempt to invade the body. The TLR senses an infection then triggers a change in gene expression and secretes cytokines warning the immune system what it thinks it saw so the proper defense can be waged.   The patrolling immune system of macrophages, dendritic cells, mast cells, and basophils also use these TLRs. 

TLR2 catches the sugars, the lipopolysaccharides LPS, of infections that like to move into the cell.  Cytosolic viruses and gram negative bacterium are typically the suspects snagged by TLR2.

TLR4 catches the proteins of gram positive bacterium. These are typically large and are often broken down by the innane immune system cells.

TLR3, TLR7, TLR8, and TLR9 tag antigens know to be inside the cell.  TLR3 is the golgi net, TLR7 is the nuclear net, TLR8 is the ER net, and TLR9 is the mitochondria net.

When one of these inside nets are triggered specific cytokines are produced coordinating the attack.  When herpes zoster infects the mitochondria the TLR7 net is triggered.  IFNalphaA is produced which tell macrophages and dendritic cells to wear MET hands so that they can bind and kill cells infected with the herpes virus. TGF-b1 is also produced which helps to activate TH9 cells and TH17 cells.  TH9 causes the development of TH17 from other Thelper cells. The TH17 cells secretes the organelle popping cytokines of the il-20 family. The cytokine that pops the mitochondrial membrane is il-19.  Then il-17F activates the CTL cells.  Any freed viral antigens are bound by IgG3. 

How did IgG3 get produced by B cells? It begins with il-2.   TH9 requires il-2 not just TGF-B1.   High il-2 also causes the development of CTL.  Where did the il-2 come from? Il-2 is secreted by activated Tc (cd8) cells.

How do T cells become "activated" ? When both the TCR and cd28 are stimulated.  This triggers the ability to secrete cytokines and the expression of ICOS.

When the macrophages or dendritic cells digest the viral infected cells they then hold up the viral pieces in HLA mailboxes to T cells and the TCR binds examines it.  When the T cells are activated by these mailboxes with foreign content, these cd8 T cells secrete il-2 and seek out B cells.  Upon finding a B cell with ICOS ligand the T cells COS stimulation secretes il-4 and il-21 resulting in the B cell producing the IgG3 antibodies. 

What happens with cytosol infections like the flu? TLR3 or there are cytosolic receptors that bind cytosolic viral infections’ antigens. The flu would bind the cytosol receptor Rig-1.  The cytokine IFN-beta then coordinates the response. IFNbeta tells dendritic cells and macrophages to wear the tyro3 hands in order to eat virally infected cells.  They also choose to express the HLA-Dr MHC2 mailbox.  The phagocytes also express il-12 and 25HC.  Il-12 is the cytokine stimulates the development of TH1.  TH1 interacts with the mailboxes of the dendritic cells, verifies it is foreign then finds a B cell. Using il-4 and il-21 the cd4 T cell stimulates the B cell to make IgG2 antibodies. 

How do the IgG2 antibodies see the antigens in the cytosol? The 25HC is a specialized cholesterol that binds RNA.  The macrophages secrete these around infected cells.  If the cells contain an excess of RNA in the cytosol the 25HC would bind it and hold it outside of the infected cell.  The IgG2 antibody can then see the antigens.  Complement now be carried out on infected cells where MAC pores can be created on infected host cells. 

How did the IgG3 see inside of the mitochondria or nucleus? TH17 cells appear whenever there is an infection inside an organelle.  When bacterias enter cells through vacuoles or when IgG3 is involved because a virus is in the mitochondria or nucleus.  These interior membranes are popped by the il-20 family cytokines secreted by TH17.    The  il-22 pops vacuoles, il-24  pops the golgi, il-19 pops the mitochondria, and il-26 pops the nucleus based on where the infections are and which cytokine is secreted.  So while the IgG3 antibodies are being produced TH17 cells would be popping the mitochondria where the virus, like herpes zoster, is hiding. Then calling CTL with il-17f.  NK also have receptors for IgG3.  Note that il-26 which locates to the nucleus in host cells has already been found to produce pores on bacterias in addition to binding receptors on immune system cells. 

So TH1 cells secreting il-15 and Tc cells secreting il-2 when activated tell the B cells exiting the bone marrow that the infection is inside of cells, don't bother making IgM.  The B cells respond by making IgD instead when they reach the secondary lymph.  IgD activates Basophils and Mast cells.





Wednesday, June 6, 2018

Looking at the infections involved with TLR2 and TLR4 and how the immune system reacts

TLRs are the butterfly nets of the immune system attempting to catch sight of a piece of infections in order to mount the correct defense

Foreign Sugars: TLR4

Bacterias that like to sneak inside of cells  or RNA viral capsules have lipopolysaccarides LPS
Examples are salmonella which hides in the golgi or the Flu virus which replicates in the cytosol.

il-6 and LPS stimulate spleen B cells to make IgM
https://www.nature.com/articles/srep30004/figures/2

LPS directly stimulates Bcells to make IgM
http://journals.sagepub.com/doi/full/10.1177/1753425916644675

LPS triggers TLR4 (foreign sugar antigen butterfly net)  in fibroblasts or epithelial cells which releases either il-12 or il-18

il-12 starts the TH1 pathway. These infections will need MHC2 to trigger B cells to secrete IgG2.

MHC2 are worn by the APC : macrophages, Bcells and Dendritic cells which present to TH1 cells.  TH1 is involved with cytosolic infections

TLR4 can also triggers 25HC expression by macrophages
http://www.pnas.org/content/pnas/106/39/16764.full.pdf

These 25HC hold the viral pieces up for the IgG2 which then triggers complement pore on the host's own cell.

The bacterias that move into cells hide in vacuoles, the golgi, or the ER.  The TH17 cells must pop these inner membranes.

TLR4 can trigger il-23 in macrophages
https://www.sciencedirect.com/science/article/abs/pii/S1043466617302478

il-23 with il-6 turn on the TH17 cells where they release il-22 popping vacuoles or il-24 popping golgi membranes and then il-17a call Neutrophils to trap and kill the bacterias that come out.

il-22 also stimulates Th22 which calls the Eosinophils in addition to secreting more il-22.

Gm-csf increases LPS through TLR4
https://www.ncbi.nlm.nih.gov/pubmed/23234315

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

Foreign Proteins: TLR2

TLR2 triggers il-6
https://www.ncbi.nlm.nih.gov/pubmed/20945380

il-6 and LPS stimulate spleen B cells to make IgM
https://www.nature.com/articles/srep30004/figures/2

B cells are further activated by IgM bound antigen or it's BCR crosslinking antigen on FDC in lymph river:
http://www.pnas.org/content/pnas/92/8/3348.full.pdf

the Antigen is pulled off the FDC then loaded onto Bcell's HLA-DM
where it interacts with the TFH
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948085/

FDC hold the antigens for the BCR cross linking
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886728/

These visible bacterias trigger the germinal center B cells producing IgG1, IgA, or IgE.

Strep/staph/ e.coli are examples of gram positive and these are typically large and visible. Note that these are also the infections that are typically broken down by the MAC membrane attack pore.

The bacterias are broken down into pieces and then sent to the lymph.

TLR2 recognizes foreign protein antigens  on  many gram positive bacteria
https://onlinelibrary.wiley.com/doi/full/10.1111/imr.12627

TLR2 also triggers Basophils to burst il-4
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403736/

il-4 promotes the development of TH2 who produces the cytokines that awaken the effector cells: eosinophils, basophils, and mast cells.  Eosinophils break bacterias down using acids.

TH2 will turn into TFH with il-7 which can induce Bcells in the germinal center to make IgG1, IgA, or IgE.

Special subset of TH2 cells make il-5
http://www.jimmunol.org/content/jimmunol/187/6/3111.full.pdf

il-5 and IgA of the mucosal area are closely connected.  This could be occurring when these infections have moved into mucosal areas like the throat or the lungs.

staph, eczema, and some forms of asthma are connected

asthma and il-5
https://www.ncbi.nlm.nih.gov/pubmed/28933516

Staph and il-5
https://www.ncbi.nlm.nih.gov/pubmed/12653801

Eczema and staph
https://www.newscientist.com/article/2139827-bad-eczema-flare-ups-may-be-caused-by-strains-of-bacteria/

il-5 and eczema
https://www.tandfonline.com/doi/full/10.1080/1744666X.2016.1208564

TH2 produces il-4 and il-13

il-13 stimulates eosinophils who drop acids to destroy the infection

eczema and eosinophila
https://www.tandfonline.com/doi/full/10.1080/09540105.2016.1148669

strep cytokines
https://www.ncbi.nlm.nih.gov/pubmed/9082815



TLR2 and TLR4 together

Strep can trigger both because it is covered in sugars. Heparin release is seen with strep.
https://www.ncbi.nlm.nih.gov/pubmed/20107486


Mycobacterias also stimulate both TLR2 and TLR4. Basophils have both TLR2 and TLR4 which when triggered together release heparin.  Heparin is the immune system's attempt to prevent mycobacteria attachment to cells' myelin protein.  Mycobacteria typically move into cells living in the cytosol without vacuoles.

https://www.ncbi.nlm.nih.gov/pubmed/19919859
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504976/
















Tuesday, June 5, 2018

T cells responding to il-2, il-15, and il-7

The gamma chain cytokines are involved with T cell proliferation and B cells.

Hypothesis:  il-7 can turn TH2 into Tfh in the Germinal center and then replace the need for TCR activation of Tfh cells.  Stimulated B cells make IgG1 with insulin, IgA with growth hormone, IgE with IGF-1.

In the T zone

il-15 turns the TH1 cells into a Tfh like state where it can stimulate B cells to make IgG2.

il-2 turns Tc cells into a Tfh like state where it can stimulate B cells to make IgG3.

il-2, il-15, and il-7
https://www.ncbi.nlm.nih.gov/pubmed/16551262

Gamma chain il-2, il-15, il-7
https://www.ncbi.nlm.nih.gov/pubmed/29664568

il-15 makes TH1 into a Tfh like proflile
https://www.nature.com/articles/srep15722

CD8 like Tfh cells
http://www.jimmunol.org/content/196/1_Supplement/186.1

il-7 involves the TCR rearrangement
https://www.ncbi.nlm.nih.gov/pubmed/9307061
http://www.pnas.org/content/107/43/18505

Note that this hypotheses suggests 3 adaptive zones: outside of cells, in the cytosol of cells and in the mitochondria or nucleus.

Previous post matched up dendritic cells to these zones

http://angelabiggs.blogspot.com/2018/05/hypothesis-dendritic-cells-match-up.html

Thursday, May 31, 2018

Two types of Mast cells

The two types of mast cells are derived from different sources. Both involve high levels of Histamine to dilate the capillaries and bring more immune cells to the inflammation site.

The bone marrow mast cell is involved with fungal and bacterial infections.  The TLRs for this bone mast cell are: TLR2 lipoproteins, TLR4 LPS, and the TLR5 flagellin tails which are all basic traits of bacterias and fungal infections.  Bone mast cells secrete GM-csf when encountering vacuole bacteria, il-5, TNFalpha, and il-33.

The skin mast cell is involved with viral infections.  The TLRs it has are the internal ones that snag viruses. TLR7 of the nucleus, TLR9 of the mitochondria, and TLR3 of the golgi.  Skin mast cells secrete TGF-b1, il-21, TNFalpha, and il-1. 

bone vs skin mast cell reference

What is fascinating here is that skin mast cells wear IgE when allergies exist.  Toxins like snake venom, bee venom, or staph toxin damage the mitochondria.  Mice that are deficient in TLR9 do not have the normal anaphlylatic reactions to these toxins. 

venom and tlr9

looking for ref of venom and tlr9 def mice

peanut allergy and tlr9

Wednesday, May 30, 2018

GM-CSF, il-5, and il-3 are linked to different infections that require eosinophils

GM-CSF Granulocyte macrophage colony stimulating factor, il-5, and il-3 appear linked to different infections that eosinophils are recruited for. (not just myeloid progenitor development)

GM-CSF, il-3 and il-5 are the Beta chain family cytokines
https://www.ncbi.nlm.nih.gov/pubmed/23046136
https://www.ncbi.nlm.nih.gov/pubmed/8466757

All 3 are involved with eosinophil development
http://www.jimmunol.org/content/180/2/1199

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-5 is involved with fungal infections?  nuclear viral infections?

il-5 and fungal
http://iai.asm.org/content/82/2/683.full

il-5 and eosinophils
https://academic.oup.com/intimm/article/21/12/1303/686327

TGF-b and il-5
https://www.ncbi.nlm.nih.gov/pubmed/1739984

il-5 is also involved with mast cells
https://www.sciencedirect.com/science/article/pii/S0024320501011651

mast cells: mito/nuclear viral infections or fungal infections

il-5, cd8 cells, and viral infections
http://jem.rupress.org/content/jem/181/3/1229.full.pdf

RSV virus and eosinophila
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1941978/

EBV and eosinophila
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606072/

fungal infections seem to be killed by neutrophils....so this section is not as clear
maybe the yeast for is neutrophils and large hyphal bodies are eosinophils?


il-3 is involved with visible parasites like helminth (worms) and parasites

il-3 exposed basophils produce il-4  when exposed to helminth
http://www.pnas.org/content/109/37/14954
https://www.nature.com/articles/32190
https://academic.oup.com/intimm/article/20/9/1201/667221

il-3 or MHC2-follicule-type binding trigger Basophils to burst il-4 developing TH2?



Eosinophils and mucus
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822241/