HLA-dr contemplations

HLA-dr

HLA-dr appears to hold virus RNA
https://www.ncbi.nlm.nih.gov/pubmed/10564819


HLA-dq

HLA-dq appears to hold small antigens like insulin and gliadin

presentation of gluten in HLA-dq2
https://www.jimmunol.org/content/175/1/254

"It is interesting to note that even if the risk for developing CD associated with DQ2.2 is minuscule compared with that of DQ2.5, a recent study revealed that among the small group of DQ2.5- and DQ8-negative CD patients, "


e.coli binds gliadin
https://pdfs.semanticscholar.org/b70f/23916b8f5553baf3a01055725ab9c68add7c.pdf?_ga=2.119014538.2026673398.1566778373-1275520869.1527777598

HLA-dp and type one diabetes
https://link.springer.com/article/10.1007/s10654-004-5176-9

HLA-dq8 holds insulin
https://www.ncbi.nlm.nih.gov/pubmed/11376336


HLA-dp

HLA-dp appears to hold a significant amount of self antigens as well as foreign and is similar to HLA-dq but is not used as often

HLA-dp review
https://www.jimmunol.org/content/184/5/2492
states that it has a lower expression than HLA-dr or HLA-dq and that HLA-dp has few epitopes. HLA-dp is shared by 90% of the population

HLA-dq has been associated with ALL the childhood leukemia (genetic form) ????
http://www.bloodjournal.org/content/120/15/3039.short?sso-checked=true?sso-checked=true

What is the difference between HLA-dq and dp?


might not be relevant:

beryllium binds to HLA-dp
https://www.ncbi.nlm.nih.gov/pubmed/11423174

cobalt binds to HLA-dp
https://www.ncbi.nlm.nih.gov/pubmed/10427976

How does gluten fit into the autoimmune cross-targeting hypothesis?

New hypothesis: Two separate zones for inner and outer antigens in lymph organs.

ILF the inducible lymph follicle deals with the inner antigens while the peyer patch deals with the outer antigens of the mucosal membranes.

ILF  https://www.ncbi.nlm.nih.gov/pubmed/12759424

E.coli infections would involve the outer pathways. At the mucosal's peyer patch they would see high growth hormone GH thus produce IgA.

According to the Cross-targeting hypothesis when a second inner infection appears and calls the B cell to the ILF zone and away from the peyer patch....the B cell becomes a regulatory autoimmune B cell which secretes IgG4 antibodies that stop the outer pathways.

GH-IGF axis and gluten in celiac
https://www.karger.com/article/pdf/185499

Gluten was seen as the infection not the parasite because the parasite moved inside of cells?

UPEC :the e.coli that moves inside cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244466/

If patients remove gluten and outside pathway is stopped? Is that because the infection is on the inside of cells but gluten was seen as the infection?

Note that the anti-gluten antibody is not IgG4 but IgG1.

gluten and e.coli in mice
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630176/

e.coli and celiac
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287676/

? protein from e.coli binds gliadin?
https://www.ncbi.nlm.nih.gov/pubmed/16944918

Do these infection hold gluten on the outside like a cloak?

Anti-gluten response after t.gondii infection in mice?
https://www.ncbi.nlm.nih.gov/pubmed/23209841

anti-gluten and t.gondii
https://www.ncbi.nlm.nih.gov/pubmed/22446142

The Secondary Lymph organs have separate zones for inner and outer antigens

The secondary lymph organs are strategically situated to intercept infections.  The lymph glands capture the infections that breach the skin's barrier.  The ILF and peyer patches guard the mucosal membranes.  The blood brain barrier and the choroid plexus protects the brain.  The spleen filters the blood removing not just dead blood cells but infections that have reached there.  The omentum monitors and protects the peritoneal cavity which  contains the stomach, the liver, the large and small intestines, the kidneys, the gall bladder,  the pancreas, and the adrenal glands.

All secondary lymph organs  have separate zones for fighting inner and outer antigens.

The inner antigens are processed by embryonic HSC derived macrophages. These macrophages communicate with and pass antigens to marginal reticular stromal cells or Astrocyte stromal cells.  These cells with antigen evolve into follicular dendritic cells and secrete CXCL13 calling the B and the T cells to them.  The dendritic cells are derived from adult HSC monocytes. These monocyte derived dendritic cells are the antigen presenting cells to the T cells.  For inner antigens the T cell makes the determination at this point if the antigen is foreign.

The outer antigens are collected by langerhans, marginal zone B cells, B1, or Resident Tissue macrophages (of the CP)  all of which differentiated from the yolk sac not the HSC of the bone marrow.  These yolk sac derived cells communicate and pass antigens on to fibroblastic reticular stromal cells. These antigen holding FRC become follicular dendritic cells with B7-2 involvement and secrete CXCL13.  These FDC cells hand the antigen off to B cells who do the antigen presenting to the T cell.  For outer antigens the B cell determines if the antigen is foreign.

The 2 antigen zones of the peritoneal cavity

The omentum protects the peritoneal cavity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812451/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754314/

the peritoneal cavity contains the stomach, liver, large and small intestines, the kidneys, the gall bladder, pancreas, and the adrenal glands.

omentum stromal cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3481843/

there are two types of omentum cells involved in tissue repair as stromal cells
myeloid derived suppressor cells and MSC cells
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038368

pericytes and myeloid derived suppressor cells
https://www.ncbi.nlm.nih.gov/pubmed/26296362

subgroup of myeloid derived suppressor cells : fibrocytes
https://www.ncbi.nlm.nih.gov/pubmed/26405600/
https://www.ncbi.nlm.nih.gov/pubmed/23757729

fibrocytes are potent stimulators of T cytotoxic cells
https://www.ncbi.nlm.nih.gov/pubmed/15767291

Based on our patten of inside and outside antigens is seems that the outer antigens would be collected by the B1 cells and processed by the MSC cells while the inner antigens would be taken up by the pericytes and shown to the myeloid derived stromal cells.

Chorioid Plexus compared to the BBB blood brain barrier

Chorioid Plexus compared to the BBB blood brain barrier and the hypothesis that they deal with different antigens.


Each of the brain's ventricles has their own CP region

Capillary blood is filtered here at the CP to become cerebrospinal fluid.

Resident macrophages and dendritic cells are in the CP
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496674/

Note that resident macrophages come from the yolk and focus on outer antigens while travel monocytes come from bone marrow and develop into dendritic cells or macrophages that deal with inner antigens based on the hormone that they see. High insulin favors macrophages while IGF-1 or GH exposed monocytes develop into dendritic cells.

IGF-1 made by CP epithelial
https://www.ncbi.nlm.nih.gov/pubmed/7513042

this would favor dendritic over macrophages (traveling)

myeloid dendritic cells of the cp
https://www.ncbi.nlm.nih.gov/pubmed/16817190

CP : fibroblasts, macrophages, dendritic cells
https://www.frontiersin.org/articles/10.3389/fncel.2015.00136/full

astrocytes (stromal cells) attract dendritic cells
https://www.ncbi.nlm.nih.gov/pubmed/16106219

astrocytes activate B cells
https://www.ncbi.nlm.nih.gov/pubmed/29673365
https://www.ncbi.nlm.nih.gov/pubmed/26223505

pericytes and and astrocytes communication
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042982/

FRC-like cells in CNS
https://www.cell.com/immunity/pdfExtended/S1074-7613(16)30001-2

At the intestine: inner antigens are processed at ILFs while outer antigens are processed in Peyer patches (hypothesis)

At the intestine: inner antigens are processed at ILFs while outer antigens are processed in Peyer patches.

ILF: inducible lymph follicle
https://www.ncbi.nlm.nih.gov/pubmed/12759424

"In contrast to the spleen, LNs and PPs, ILFs are inducible structures developed after birth due to the presence of external stimuli43"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015111/

The MRC marginal reticular cells develop here at the inducible ILF of the intestine.

pericytes in the gut
https://www.ncbi.nlm.nih.gov/pubmed/30937864

Peyer patches have the FRC fibroblast reticular cells.

Brain macrophages : pericytes
https://www.ncbi.nlm.nih.gov/pubmed/10611494

MHC2 expression by pericytes
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844098/

pericytes and the BBB
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292164/

peyer patch lacking mice had no IgA only IgG from ILFs
https://www.jimmunol.org/content/jimmunol/173/2/762.full.pdf

Remember the lymph structure and the separate zones for inner and outer antigens:

Then the spleen's separate zones:

Now looking for the MRC and the FRC we find very separate zones in the intestine: