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Figure.

Cyclic AMP (cAMP) signaling inhibits TCR and CD28 signaling in lymphocytes. cAMP accumulates in T cells in the region of lipid rafts in response to TCR activation, and more globally in response to strong Gs-coupled AR activation. cAMP inhibits proximal TCR signaling through a pathway involving activation of protein kinase A-1 (PKA-1) and C-terminal Src kinase (Csk) to inhibit lymphocyte-specific protein kinase (Lck) and to reduce recruitment to CD3 of zeta-chain–associated protein kinase–70 (ZAP-70). PKA-1 also phosphorylates (indicated by red dots ) and inhibits NF-AT. NF-AT inhibition is reversed by the Ca-calmodulin-dependent phosphatase, calcineurin. TCR-induced accumulation of cAMP near lipid rafts is reduced on CD28 stimulation due to the activation of phosphatidylinositol-3-kinase (PI3-K) to produce PIP3. This results in translocation from the cytosol to the lipid raft of a complex consisting of AKT, PDE4 and β-arrestin (β-arr) by binding of the plextrin homology (PH) domain of AKT to PIP3. PDE4 degrades cAMP to relieve inhibition of TCR signaling. AR indicates adenosine A receptor; Ado, adenosine; Ino, inosine; ADA, adenosine deaminase; αβγ, subunits of the heterotrimeric G protein, Gs; AC, adenylyl cyclase; AKT, a serine/threonine-specific protein kinase, also known as protein kinase B; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PDE4, type 4 phosphodiesterase; MHC, major histocompatibility complex; Ag, antigen; RhoH, as Homolog, a small GTP hydrolyzing protein; AKAP, A kinase anchor protein; TCR, T cell receptor; LAT, linker for activation of T cells; PLC, phospholipase C; PKC, protein kinase C; CaM, calmodulin; NF-AT, nuclear factor of activated T cells; CREB, .

Adenosine AR Activation Selectively Inhibits Cytokine Production by T Cell Subsets

Depending on the environment during antigen encounter, CD4+ T cells can differentiate into T helper 1 cells (Th1) that secrete primarily type 1 cytokines including interleukin (IL) 2, interferon γ (IFN-γ), and tumor necrosis factor α; Th2 that secrete primarily IL-4, IL-5, and IL-10; or Th17 cells that secrete IL-17A, IL-17F, and IL-21. Type 1/type 2 cytokine polarization exists for both MHC class 2–restricted CD4 T cells (Th1/Th2 subsets) and for MHC class 1–restricted cytotoxic CD8 T cells (Tc1/Tc2 subsets). Agonist binding to ARs activates the heterotrimeric G protein, Gs, to catalyze cAMP production. The protein kinase A (PKA) pathway negatively regulates the production of type 1 cytokines, with lessor effects on type 2 cytokines. AR activation reduces production of IL-2, tumor necrosis factor α, and IFNγ secretion from Tc1 and Tc2 cells, but does not affect IL-4 or IL-5 secretion. AR activation also strongly inhibits the production of IFNγ by iNKT cells. AR activation has not been reported to directly influence cytokine release from purified Th-17 cells. When given in vivo or in mixed cell T cell development assays with APCs, A agonists inhibit production of IL-6 and enhance production of IL-10. This results in indirect inhibition of Th1, Th2, and Th17 effector cell development. In sum, the strongest direct effects of AR stimulation on lymphocytes is on type 1 cytokine production by Th1, Tc1, and iNKT cells.

How cAMP and PKA Mediate AR Signaling in T Cells

The activation of Gs after agonist binding to ARs stimulates adenylyl cyclase to produce cAMP. Two downstream effectors, PKA and exchange protein directly activated by cAMP, are the principal mediators of cAMP action in T cells. The cAMP mimetic, 8-(4-chlorophenylthio) adenosine-3´,5´-cyclic monophosphate is a useful tool for distinguishing between these 2 pathways because it activates PKA but fails to activate exchange protein directly activated by cAMP. Experiments using 8-(4-chlorophenylthio) adenosine-3´,5´-cyclic monophosphate indicate that most transcriptional effects of cAMP in T cells are mediated by PKA. In addition to adenosine, several other Gs-coupled receptors are found on T cells. These include β2-adrenergic, prostaglandin E2, dopamine D1, and vasoactive intestinal peptide. Adenosine is particularly important for limiting lymphocyte activation because ARs are induced on activation of T cells and iNKT cells. cAMP is degraded in T cells primarily by phosphodiesterase 4, and phosphodiesterase 4 inhibitors facilitate the actions of adenosine and other Gs-coupled receptor agonists.

cAMP regulates T cell cytokine secretion and proliferation by directly phosphorylating the transcription factors cAMP response element-binding protein and nuclear factor of activated T cells (NF-AT). Suppression of proximal T cell signaling pathways indirectly inhibits activation of another transcription factor, nuclear factor κB. The most abundant isoform of PKA found in T cells, PKA-1, activates C-terminal Src kinase, which inhibits the Src family tyrosine kinases lymphocyte-specific protein tyrosine kinase and Fyn and thus functions to check T cell activation ( Figure ). PKA-1 is targeted to the TCR-CD3 complex during T cell activation via an A-kinase-anchoring protein that serves as a scaffold for the cAMP-PKA/C-terminal Src kinase pathway in lipid rafts of the T cell plasma membrane. The small GTP-binding protein, RhoH, also serves as an adaptor molecule for lymphocyte-specific protein tyrosine kinase and zeta-chain–associated protein kinase–70 to regulate TCR signaling. Protein kinase Cθ and PKA inversely affect cytokine expression, whereas other protein kinase C isotypes do not influence TCR signaling. The opposing cAMP/PKA and protein kinase Cθ pathways converge at the level of NF-AT. NF-AT proteins are retained in the cytoplasm after serine phosphorylation by PKA. After T cell activation, NF-AT proteins are dephosphorylated by the Ca-calmodulin activated protein phosphatase calcineurin. This dephosphorylation unmasks a nuclear localization signal, facilitating the rapid translocation of NF-AT proteins to the nucleus where they pair with AP-1 and bind to consensus NF-AT sites on DNA. The immunosuppressive drugs cyclosporin A and FK506 prevent the calcineurin-mediated dephosphorylation of NF-AT, accounting for some of their immunosuppressive effects on T cells. PKA also regulates T cell function at the level of other transcription factors and kinases including members of the mitogen-activated protein kinase pathway, RhoA and proteins involved in the control of cell cycle progression.

Signal 2 and cAMP

Signal 1 activation of TCRs alone produces limited T cell activation because TCR engagement locally enhances cAMP production and activates C-terminal Src kinase in the region of the immunologic synapse. Activation of TCRs is amplified by signal 2, that is, costimulation of CD28 by ligands expressed on the surface of APCs, B7.1, and B7.2 (CD80 and CD86). On TCR/CD28 costimulation phosphatidylinositol-3-kinase activation leads to phosphatidylinositol-(3,4,5)-triphosphate production. This stimulates recruitment of an AKT/β-arrestin/phosphodiesterase 4 complex to the plasma membrane via the AKT (a serine/threonine-specific protein kinase, also known as protein kinase B) plextrin homology domain, resulting in the degradation of cAMP located near lipid rafts It is not entirely clear how stimulation of the TCR results in elevated cAMP levels, but recruitment of Gs to lipid rafts may be involved. It is also possible that cell activation due to TCR signaling stimulates production of adenosine that exits the cell to act on autocrine or paracrine ARs.

Adenosine Signaling Increases T cell Tolerance and Treg Development

Unlike the localized production of cAMP that occurs as a result of signal 1, strong activation of ARs or other Gs-coupled receptors can produce whole cell increases in cAMP that are not limited just to the region of lipid rafts. Thus, extracellular adenosine reduces the activation of T cells by APCs and modifies T cell differentiation, cytokine production, and proliferation by preventing rapid tyrosine phosphorylation of zeta-chain–associated protein kinase–70 and downstream signaling such as activation of AKT and extracellular signal-regulated kinases (ERK1/2). cAMP elevation in naïve T cells also favors development of a regulatory phenotype (Treg) characterized by high expression of CD25, cytotoxic-T-lymphocyte–associated protein 4 (CTLA4), and Forkhead box protein 3 (FoxP3). CTLA4 is involved in suppressive activities by Tregs. Unlike T effector cells, Tregs also express ecto-enzymes CD39 and CD73 ( Table ) that metabolize adenine nucleotides in the extracellular space to adenosine that locally inhibits the activation of effector T cells and APCs.

Inhibition of Apoptosis

Activation-induced cell death describes an apoptotic program initiated by restimulation of previously activated peripheral T cells. AR activation reduces activation-induced cell death in mouse CD4+ hybridomas and human Jurkat cells. AR activation reduces activation-induced cell death by interfering with the production of factors that stimulate T cell activation, IL-2, and the downstream expression of the costimulatory molecules CD2 and CD28.

Enhancement of Apoptosis

In contrast to the antiapoptotic effect of transient cAMP elevation, prolonged elevation of cAMP triggers T cell apoptosis. This property of persistent cAMP elevation to kill T cells has been used to select T cell lines that have mutations in the cAMP signaling pathway. Recent studies have identified the mechanism by which cAMP triggers an apoptotic program in T cells. Treatment of wild-type S49 T cells with the PKA-activating cAMP analog, 8-(4-chlorophenylthio) adenosine-3´,5´-cyclic monophosphate, increases the expression of cytotoxic T lymphocyte antigen-2α (CTLA-2α), a cathepsin L-like cysteine protease inhibitor that triggers apoptosis. Treatment of kinase-S49 cells T cells that lack functional PKA with 8-(4-chlorophenylthio) adenosine-3´,5´-cyclic monophosphate fails to stimulate CTLA-2α expression and apoptosis indicating that the increase in CTLA-2α in wild-type S49 cells is PKA dependent.

Effects of Adenosine Deaminase Deficiencyon T Cell Survival

Several investigators have sought to determine whether PKA-mediated killing of T cells contributes to severe combined immunodeficiency that occurs in individuals lacking adenosine deaminase (ADA). Since ADA deficiency causes adenosine concentrations to increase in the thymus and other tissues, it is reasonable to suspect that the resulting increase in AR signaling via adenosine, Gs, and PKA in thymocytes might evoke T cell killing by PKA-induced apoptosis. Apasov et al concluded that a portion of thymocyte apoptosis that occurs in response to ADA deficiency can be attributed to AR activation. However, the primary cause of toxicity in developing human thymocytes is the accumulation of deoxyATP which triggers mitochondrial-dependent apoptosis.

CD26 Dampens Adenosine Signaling in T Cells

In human cells a soluble form of ADA can bind to cell surface CD26 that is expressed by lymphocytes, epithelial cells, and capillary endothelial cells. CD26 expression is strongly upregulated after T cell activation. ADA binding to CD26 on human T cells results in ADA accumulation on the T cell surface and is associated with T cell activation.

The concentration of adenosine in the extracellular space is regulated by adenosine transport as well as adenosine formation and degradation ( Table ). Nucleoside transporters are divided into 2 families; the Na + -dependent solute carrier family 28 and the equilibrative solute carrier family 29. Solute carrier family 28 family transporters (CNT1–3) display subtype-selective expression patterns; CNT1 is localized primarily to epithelial tissues whereas CNT2 and CNT3 have more widespread distributions. Solute carrier family 29 family transporters (ectonucleoside triphosphate 1–4) are glycosylated proteins localized to the plasma and mitochondrial membranes. They are expressed in the heart, brain, mammary gland, erythrocytes, and placenta, and also in fetal liver and spleen, and mediate nucleoside influx and efflux. Insulin and glucose induce changes in expression levels of nucleoside transporters in T lymphocytes. 40

The Australian brand is at http://www.b12oils.com/

(I don’t have any affiliation with it, tho I have got to know the scientist-owner via his remarkably generous question-answering.)

You have to be careful with the sublinguals. A poster named Freddd at the Phoenix Rising CFS forum has tested the brands extensively, found the majority to be sub-par or duds.

I found that the sublinguals worked if you kept them in your mouth for 45+ minutes, but they rotted my teeth a lot; plus the ride was quite a bit rockier than with transdermal, which is very smooth even due to the gradual (6-8-hour) uptake.

Thanks for the Info John M.. So far the combination I am taking seem to be working for me (symptoms heading in the right direction). So I will probably stick to what I am doing. I will definitely check out the Phoenix Rising CFS forum.

Hi Marpy! First, multivitamins/mineral supplements are unnecessary. The B-12 would be just fine. If you want a B-complex vitamin supplement, I would recommend you look for “Alive water enhancers” at the Vitamin Shoppe (.com) …or from a different website, if they don’t deliver to Canada. Second, you may want to consider consuming a small amount of sodium bicarbonate daily. It is proven to help maintain kidney function… and it sounds like your kidneys could use the help. (Baking soda may also help with IBS and cleans teeth well.) If you have trouble producing saliva (spit), you may want to mix with a little water. ArmHammer is a good brand. Always make sure there is a nutrition or drug facts label before purchasing. Lastly, you may be experiencing “heart palpitations” from having a bit too much magnesium (and/or copper) in your body at the time that you experience these “heart palpitations”. Magnesium and copper in excess have been proven to cause hypertension (high blood pressure). Very light arrhythmias or heart palpitations can also be early signs of hypertension. Coffee and cocoa powder are often the sources of an abnormal amount of magnesium, and coffee can also contain an unusually high amount of copper.

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cyanocobalamin isn’t a natural form of B12. It is synthetic. Possibly you might do better with a ‘natural’ methyl form. http://www.onegreenplanet.org/natural-health/the-top-things-to-look-for-when-choosing-a-vitamin-b12-supplement/

Reply

Hi Joseph,

What’s the dose of B12 you are now taking? What form is it in. There are guidelines for supplementation doctors are now supposed to follow in the US and the UK if a patient even just shows signs of B12 deficiency; however, most of them never even heard of B12, kit seems. The Pernicious Anemia Society probably have links. You could then print them out to show your doctor.

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Cheryl says

Yes. I agree with you Ian.

Reply

Ian,

Everyone needs more B12 than average. Though there are B12 vitamins that are made from non-animal sources, there are hardly many sources of B12. If you are privy to such sources, how about being specific.

Eat meat or don’t, but don’t make vague statements. Being B12 deficient has really taken a toll on me. I did not know I was deficient until everything started going…I could not think, remember anything, walk without sever pain, or see straight. I could not walk without bumping into walls and felt dizzy all the time. Now I have uncontrolled blood pressure, asthma and a hyperactive thyroid, and I wonder if it is because of being low on B12 for years. It’s real, not propaganda.

Reply

Amanda says

I notice from my recent testing that B12 is now being measured in total and ACTIVE form. If my TOTAL B12 is very low but ACTIVe B12c is low-normal, what is that telling me? I’m totally confused but I definitely am suffering from several symptoms of deficiency.

Reply

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says

Red Star nutritional yeast T-6635 is a Vegan source of B12, 1 Tablespoon supplies the adult RDA. I have been Vegan for 11 years, and DO NOT have a deficiency. This makes me wonder about the data presented.

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Ana says

It’s great that the nutritional yeast works for you. That may be an excellent choice, and much less expensive, I might add. Yeast, however, can be allergenic for people with mold sensitivities. Also, some people with gut problems are quite sensitive to yeast products. My allergies to mold and yeast came well before the low b12. As healthy as yeast products are for many people, I wouldn’t take a chance. The methyl B12 shots work for me.

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Jenn says

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