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/
















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