Hypothesis : GSDM pyroptosis is a parasite window for Eosinophils

Hypothesis:
Parasitic cell death through inflammasome which create GSDM pores are not just  to release il-1Beta but a 10-20 nm window revealing a piece of the parasite which also sticks to GSDM for IgE antibody binding triggering Eosinophils .

3 types of inflammasomes (wiki)
NLRP1 which forms when lethal toxins detected
NLRP3 which forms when PAMPS whole pathogens or microbial toxins are detected
IPAF which forms when flagellins are detected

The inflammasomes are active caspase-1  which cleave and create GSDM.  Groups of which form the pores at the cells plasma membrane.

GSDM also binds cardolipin on parasites/mycobacteria/gram positive bacteria which would cause them to plug up the GSDM pore.

Cell Death
https://www.nature.com/articles/cr2017133/figures/1

inflammasome and GSDMD creates a pore in the plasma membrane
https://www.ncbi.nlm.nih.gov/pubmed/27383986?dopt=Abstract

20nm pore GSDMD
http://emboj.embopress.org/content/35/16/1766.abstract

GSDMD is the mechanism of cell death
http://emboj.embopress.org/content/35/16/1766.abstract

magnesium moves TH1 to TH2
https://www.ncbi.nlm.nih.gov/pubmed/23816766

Antibodies in T.gondii infections
https://www.ncbi.nlm.nih.gov/pubmed/24864110

GSDMD has a strong link to asthma
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135378/

IgE airway inflammation asthma
https://www.ncbi.nlm.nih.gov/pubmed/17760568

cardiolipin antibodies and t.gondii
https://eujournal.org/index.php/esj/article/view/4213

cardiolipin and mycobacteria
https://www.ncbi.nlm.nih.gov/pubmed/23910993

GSDMD pore induced traps (pit)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565696/

diabetes and chronic back pain
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510921/

GSDMC gene and chronic back pain

https://genomecontext.com/chronic-back-pain-associated-with-three-genes-sox5-dcc-dis3l2-and-intergenic-ccdc26-gsdmc/

Hypothesis: using Human protein atlas : GSDM expression changes based on hormone

GSDMA  IGF-1 of skin and umbilical cord 

https://www.proteinatlas.org/ENSG00000167914-GSDMA/tissue

GSDMB growth hormone of the lungs and peyer patches (colon/intestine)

https://www.proteinatlas.org/ENSG00000073605-GSDMB/tissue

GSDMC has been linked to diabetes. The spleen grows into pancreas and it is in this area that insulin is high.

GSDMD expressed in all tissue types
https://www.proteinatlas.org/ENSG00000104518-GSDMD/tissue

Why would your body have 4 types? are they matching up with the antibodies somehow?

IgE at the skin's IGF-1  with the GSDMA pore?
IgA , GH with GSDMB ?
IgG1,  insulin with GSDMC ?

looking at the disulfide bridges
https://www.researchgate.net/figure/A-Immunoglobulin-domain-structures-of-human-IgG1-4-and-IgA1-2-Schematic-representations_fig1_273470442

Septic shock from staph followed by Berger Disease (IgA)
https://www.ncbi.nlm.nih.gov/pubmed/12671604

septic shock patients and high GSDMB expression
https://www.ncbi.nlm.nih.gov/pubmed/30321352

GSDMD with macrophages which are the sentinel all over

phagocytosis with GSDMD
http://jem.rupress.org/content/213/10/2113

Note that this fits with il-5 not just triggering differentiation of eosinophils but switching the dimer IgA to the monomer form with tends to come from bone marrow. (at the mucosal region)

so during a T gondii infection damaged epithelial cells would release il-33 which triggers TH2 to make il-5 and il-13.  il-33 would trigger the trogocytosis of mhc with bacteria from the cytosol to basophils who would then show Th2.

Eosinophis would then use Fc antibody binding to phagocytosis infected cells which it would then internally destroy them.  The IgA antibody would would bind through the GSDM pore on cells that had cytosolic receptors (nods) triggered by t. gondii.

Trogocytosis on mhc from mD to  basophil
https://academic.oup.com/intimm/article/30/9/391/4946541

TSLP thymic stromal lymphopoietin creates the langerhans and converts th2 into Tfh.

What still needs to be elucidated is the relationship of the inflammasome with the GSDM pore. If the main purpose of the pore is to serve as a window to infections then the the virally triggered inflammasomes favor apoptosis not GSDM.

The AIM2 inflammasome appears to be connected to nuclear infections which would suggest that no GSDM pore would be formed since the infection is not in the cytosol.  The NLRP3 inflammasomes on the other had seems to sway between apoptosis and pyroptosis.

AIM2 inflammasome and apoptosis, NLRP3 inflammasome and pyrotosis..and the fuzzy zone
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741496/

Viral infections tend to end with apoptosis while parasitic/bacterial  infections need to end with pyroptosis.

extra cellular bacteria trigger tlrs to create ifn lambda
http://www.jimmunol.org/content/jimmunol/early/2017/09/27/jimmunol.1700250.full.pdf

ifn lambda from not just golgi viruses but from Bacteria in the cytosol
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328987/

Perhaps with different IFN triggered receptors (IFN Beta or IFN lambda) the NLRP3 inflammasome behaves differently?

IFNbeta receptors trigger caspase 8. FasL triggers caspase 8 too.

Cytosol receptors and IFNbeta (still working on this)

There are cytosol receptors that bind infections and then alert the immune system through secreting IFNbeta .  Nod1 and nod2 bind bacterial/parasitic infections of the cytosol while rig-1and mda5 bind viruses of the cytosol.

Cytosol bacteria or parasites:

Nod2 and IFNbeta
https://www.frontiersin.org/articles/10.3389/fimmu.2016.00652/full

Nod1 and IFNalpha ?

Nod1 and th17
https://www.sciencedirect.com/science/article/pii/S1074761307002129

Nod1 and Rip-2
https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(14)00135-8

does nod1 and nod2 both use Rip-2?

Rip-2 and Th17
http://grantome.com/grant/NIH/R01-AI117968-03

nod 2 and t.gondii
https://www.ncbi.nlm.nih.gov/pubmed/19881508

nod2 and mycobacteria
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438743/
https://www.ncbi.nlm.nih.gov/pubmed/25483349
https://www.karger.com/Article/PDF/341472

nod1 and listeria
https://iai.asm.org/content/77/7/2908

nod1 and campylobacteria
https://www.ncbi.nlm.nih.gov/pubmed/17521327

nod1 and inflammasome
http://www.jimmunol.org/content/193/9/4548



Cytosol viruses:

rig-1 and mda5 and IFNbeta
https://www.ncbi.nlm.nih.gov/pubmed/29102119

rig-1 and MDA5 (viral cytosol receptors)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107945/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177755/

inflammasome and rig-1
https://www.cell.com/trends/microbiology/pdf/S0966-842X(14)00198-X.pdf

rig-1 and MDA5 triggered by different types of cytosol viruses
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2224404/

mda5 flu
https://www.ncbi.nlm.nih.gov/pubmed/26074083

An infected cell secretes ifnbeta which sets in motion the pathways for cytosol immune system . The immune system then determines which type of cytosol infection it is dealing with.

Eosinophils and ifn beta
https://www.frontiersin.org/articles/10.3389/fimmu.2018.02330/full

ifn beta induces il-12 from macrophages
https://www.ncbi.nlm.nih.gov/pubmed/9781808

ifn beta induces b7-H1
https://www.ncbi.nlm.nih.gov/pubmed/15342209

ifn-beta il-12 causes TH1 producing ifn gamma
https://www.ncbi.nlm.nih.gov/pubmed/14607924

Contemplating Langerhans and marginal zone B cells: they appear to deliver the antigens to FDC

Do lymphatic Langerhans deliver antigens to the Germinal center Follicular Dendritic Cell like the marginal zone B cells in the spleen?

Marginal zone B cells shuttle antigens to FDC
https://www.ncbi.nlm.nih.gov/pubmed/18037889

Langerhans promotes the GC-B/Tfh formation during a leishmania infection
https://www.ncbi.nlm.nih.gov/pubmed/25070244

cd169 mediates the capture of exosomes in lymph and spleen
https://www.ncbi.nlm.nih.gov/pubmed/24255917

cd169 cells : Marginal zone B,  langerhans, scs, and MM
scs
https://www.ncbi.nlm.nih.gov/pubmed/22675532?dopt=Abstract
https://www.ncbi.nlm.nih.gov/pubmed/22192781?dopt=Abstract

If only langerhans and Marginal zone B cells interact with the FDC giving it antigens then what do they have in common? (langerhans at the lymph and MZB at the spleen)

marginal zone B cell cancer followed by langerhans cancer in 77 year old
https://www.ncbi.nlm.nih.gov/pubmed/26286813

langerhans histocytosis following lymphoma
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839484/

langerhans histocytosis resembling marginal zone lymphoma
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0714.2006.00436.x

epstein barr virus and marginal zone lymphoma
https://www.ncbi.nlm.nih.gov/pubmed/29228090
https://www.ncbi.nlm.nih.gov/pubmed/25692616
https://www.ncbi.nlm.nih.gov/pubmed/21552113

epstein barr is thought to bind cd21 but I believe it uses the estrogen alpha receptor

FDC and estrogen alpha receptor
https://ajp.amjpathol.org/article/S0002-9440(10)63490-6/pdf

estrogen promotes langerhans differentiation
https://www.ncbi.nlm.nih.gov/pubmed/16210618
https://www.researchgate.net/publication/7554414_Estrogen_Selectively_Promotes_the_Differentiation_of_Dendritic_Cells_with_Characteristics_of_Langerhans_Cells

estrogen favors marginal zone B cells
https://www.ncbi.nlm.nih.gov/pubmed/21107497

estrogen secreted by lymph tissue
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133356/
https://www.ncbi.nlm.nih.gov/pubmed/29486537

Benzene as the carcinogen: man who handled benzene developed marginal zone lymphoma
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605838/

alaska and benzene risk (thinking of my grandmother)
http://www.farnorthscience.com/2007/12/10/ak-sci-forum/benzene-exposure-in-anchorage/


Hypothesis Review:
alpha herpes use beta estrogen receptor hsv1 hsv2 zoster
beta herpes use estrogen related receptors cmz hhv6 hhv7
gamma herpes use alpha estrogen receptors EBV hhv8

marker for FDC is cd21
https://www.ncbi.nlm.nih.gov/pubmed/16280657

contemplating follicular T cells and B7-2

The B7 ligands inform the T cell which pathway to take: to become follicular T cells or to become regulator Tcells  then as a T follicular to find a B cell to make antibodies. B7 when binding CTL-4 can also slowly stop the reactions.

Capture of Antigen by BCR of B cell from FDC
https://www.ncbi.nlm.nih.gov/pubmed/19506051

cd169 macrophages APC (these are the SCS of the lymph and the metallophillic macrophage of the spleen)
https://onlinelibrary.wiley.com/doi/full/10.1002/eji.201444983

THfollicular Th1 to Tfh1 or Th2 to Tfh2 ?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193096/

Does B7-2 on APC cause the conversion of Th1 or Th2 to the follicular type of T cell? Tfh1 and Tfh2?

B7-2 and follicular T cell development
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089765/

B7-2 is on Langerhans, medial zone B cells, macrophages, and dendritic cells which bring the antigens to the lymph or spleen

B7-1 is on the follicular B cell that presents to the follicular T cell that with TCR stimulation activates the T cell and Icos is expressed.

(B7-1 is also on activated T cells and activated macrophages)

Pd-L is increased with ifn gamma on cd4 and cd8 cells so they can interact with the myeloid or plasmacytoid dendritic cells.

B7-DC(pd-L1) on myeloid dendritic

B7-H1 (pd-L2) plasmacytoid dendritic

B7-1 (cd80) follicular B cells which present

B7-2 (cd86)  Langerhans, macrophages, dendritic cells, and marginal zone B cells (antigen carriers)

where the Th1 is actually a follicular Th1 and the Tc is a follicular Tc.  Note that I am not showing the interaction of the inner antigens on the scs macrophages antigen presenting to the B cells BCR.

CD8 T cells becoming follicular like
https://www.ncbi.nlm.nih.gov/pubmed/29743314

The notion that B7-2 tells the T cells to become follicular is logistical. The antigen carrier wearing B7-2 informs the T cell that we have the antigen so please find an antigen presenter, a B cell and make antibodies with them.

in the absence of additional dendritic/antigen carrying cells  the T cells having seen APC can't make il-21 ( become follicular?)
https://www.ncbi.nlm.nih.gov/pubmed/21715693/

Is this the B7-2 ?

Tfollicular cells and autoimmune disease
https://www.bioportfolio.com/resources/trial/161554/Study-the-Role-of-T-Lymphocytes-in-Autoimmune-Hemolytic-Anemia.html

How do B cells see the antigen for internal antigens? SCS macrophages are key

When you separate the inner and outer antigen pathways you can see where B cells become antigen presenters themselves but how do they see the antigens and make the proper antibody when the TCR of T cells are critical ?

In these scenarios we have left out the macrophages.  The SCS macrophages display viruses and antigens but macrophages are the "second stimulators".  They keep T cells activated and I believe they might also show the viral antigen to B cells that have been activated.

The macrophages are required for GC formation:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647009/

The SCS macrophages present the viral antigens to the BCR of B cells
https://www.cell.com/fulltext/S0092-8674(07)01401-8
https://www.ncbi.nlm.nih.gov/pubmed/17934446?dopt=Abstract (flypaper)
http://iannaconelab.com/wp-content/uploads/2011/03/Ann-NY-Acad-Sci-2014-Kuka.pdf

scs, viral infections, and Nk
http://www.bloodjournal.org/content/bloodjournal/120/24/4744.full.pdf?sso-checked=true

the 3 lymph node macrophages divided into 3 groups
https://www.karger.com/Article/FullText/337007?id=pmid:8050349

only dendritic cells presented to cd8  T cells (not the macrophages)
https://www.ncbi.nlm.nih.gov/pubmed/11828323/

memory B cells are reactivated by scs macophages
https://www.nature.com/articles/s41467-018-05772-7

SCS is the subcapular sinus macrophage

Marginal zone B cells shuttle antigens to FDC
https://www.ncbi.nlm.nih.gov/pubmed/18037889

Langerhans promotes the GC-B/Tfh formation during a leishmania infection
https://www.ncbi.nlm.nih.gov/pubmed/25070244

Possible that langerhans shuttles antigens like MZ B cells

Contemplations of IgG2 and IgG3 antibodies

When it comes to viruses IgG2 binds cytosolic viruses and IgG3 binds mitochondrial and nuclear viruses but what happens when bacterias and parasites move inside of the host cell? Which IgG antibodies are involved?

Cytosol infections : mycobacteria and fungus

IgG2 and mycobacteria
https://cvi.asm.org/content/10/1/88

IgG2 and cryptococcus
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828574/

cryptococcus neuformans (fungus) in the cytosol of cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127716/

IgG3 and bacteria? complement?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979173/

Vacuole/golgi bacteria or parasites hypothesis involves TH17 il-22 or il-24 to pop them and does this involve IgG3?

il-17 and il-22 with leishmaniasis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719936/

IgG3 and il-10 with leishmaniasis

plasmacytoid dendritic cells and leishmaniasis ?
https://www.ncbi.nlm.nih.gov/pubmed/17705130

IgG3 and listeria
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC201853/

listeria and vacuoles
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006734

pDendritic cells and listeria ?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078036/


IgG3 and Follicular dendritic cells
https://www.nature.com/articles/s41598-017-05704-3

This would loop back to the outside antigens (after the bacteria was released from internal regions and allow Somatic hypermutation against the now visible bacteria/parasite)

IgG3 complexes are bound by Neutrophils 3x faster than IgG1
https://www.ncbi.nlm.nih.gov/pubmed/2784461

note that il-17A calls neutrophils
https://www.nature.com/articles/mi201680

LEC educates on local antigens before allowing cells into lymph gland

LEC educates on local antigens before allowing cells into lymph gland

Tolerance is the "self education" given the B and T cells. B cells have been taught the external antigens in the bone marrow while T cells have learned the internal DNA/RNA antigens in the thymus. These self educations where all genes are expressed are called Central Tolerance.

Peripheral Tolerance is given to B and T cells by the gatekeeper cells of the lymph glands: the Lymphatic Endothelial cells.  Lymphatic endothelial cells express the tissue specific genes of the cells of their area. They also sample and wear the antigens commonly found in their area.

These lymphatic endothelial cells will only allow in T and B cells that do not react with the self antigens specific to the tissues of the of the peripheral area into the lymph gland.  (B cells are hypothesized to be educated too but this is not proven)

Current ideology is that if we can get antigens from a transplanted organ into the LEC tolerance to the transplanted organ will occur. The question is how is this done exactly and how often do LEC update their antigens.

lymphatic endothelial cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226940/

bone marrow cells
http://www.jimmunol.org/content/196/1_Supplement/55.28

VEC and BEC express their areas antigens
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2137938/

LEC have mhc1 and mhc2
https://www.jci.org/articles/view/73316