GS as a condition associated with prevalent gluten-induced activation of innate, rather than adaptive, immune responses in the absence of detectable changes in mucosal barrier function.
Awesome read on the immune system and cancer. Specifically, the acid/base environment in the local cancer bed and its effects on the immune system and therapies.
only abstract available here to general public. Opiates suprress the immune system. This is an important point in the fight against cancer. Cancer is, in part, the result of signficant immune imbalance. In this study of patients with Renal Cell Cancer, melatonin + IL-2 was found to counter this immunosuppressive effect of morphine to increase partial response and to increase the 3 year survival.
the lack of immunologic control is recognized as a hallmark of cancer currently
Programmed death-1 (PD-1) and its ligand PD-L1 play a key role in tumor immune escape and the formation of tumor microenvironment, closely related with tumor generation and development
Blockading the PD-1/PD-L1 pathway could reverse the tumor microenvironment and enhance the endogenous antitumor immune responses.
environmental factors, living habits, genetic mutations, dysfunction of the immune system and so on
special tumor immune microenvironment
cytotoxic T lymphocyte-associated antigen 4 (CLTA-4), Programmed death-1 (PD-1) and its ligands PD-L1 (B7H1) and PD-L2 (B7-DC)
CTLA-4 regulates T cell activity in the early stage predominantly, and PD-1 mainly limits the activity of T-cell in the tumor microenvironment at later stage of tumor growth
It is produced predominately by antigen-simulated CD4+ T cells, while it can also be produced by CD8+ cells, natural killer (NK) cells, and activated dendritic cells (DC)
IL-2 is an important factor for the maintenance of CD4+ regulatory T cells
plays a critical role in the differentiation of CD4+ T cells into a variety of subsets
It can promote CD8+ T-cell and NK cell cytotoxicity activity, and modulate T-cell differentiation programs in response to antigen, promoting naive CD4+ T-cell differentiation into T helper-1 (Th1) and T helper-2 (Th2) cells while inhibiting T helper-17 (Th17) differentiation
Of note, Tregs, which act to dampen the immune response, constitutively express high levels of α chain
IL-2Rα is unique to IL-2 and is expressed by a number of immune cells including T regulatory cells (Treg), activated CD4+ and CD8+T cells, B cells, mature DCs, endothelial cells
some investigators evaluated the efficacy of regimens containing low-dose IL-2
IL-2 can promote the activation and cell growth of T and NK cells
Unfortunately, not all of patients would benefit from targeted therapy and nearly all patients who initially respond to targeted inhibitors inevitably develop acquired resistance to the treatment
IL-2 also stimulates T-regulatory cells that constitutively express CTLA-4 and can suppress immune reactions. Hence, IL-2 might enhance antitumor reactivity in the presence of CTLA-4 blockade
both HD and low-dose IL-2 therapy preferentially induce the expansion of CD4+CD25+Foxp3+ Treg and the Treg level remains elevated after each cycle of HD IL-2 therapy
Due to rapid elimination and metabolism via the kidney, IL-2 has a short serum half-life of several minutes
HD IL-2-induced severe toxicities including vascular leak syndrome (VLS), pulmonary edema, hypotension, and heart toxicities
not well understood, but it is felt to be a combination of both heat-induced necrosis and of protein inactivation (e.g., repair enzymes) as opposed to DNA damage
alterations in tumor cytoskeletal and membrane structures, which disrupt cell motility and intracellular signal transduction
A common explanation for HT-enhancement of RT and CT involves inhibition of homologous recombination repair of double-strand DNA breaks, preventing cells from repairing sub-lethal damage
it does appear to inhibit rejoining of RT-induced DNA breaks more than is commonly observed after RT alone
HT damages cells and enhances RT and CT sensitivity as a function of both temperature and duration of treatment
as temperature or duration increase, the rate of cell killing also increases
At temperatures above 42 °C, tumor vasculature is damaged, resulting in decreased blood flow
Cancer cells are particularly vulnerable to heating; in vivo studies have shown that temperatures in the range of 40–44 °C cause more selective damage to tumor cells
cancerous blood vessels are chaotic, leaky, and inefficient
selective cytotoxic effect on tumor cells include inhibition of key cancer cell-signaling pathways such as AKT, inducing apoptosis, suppression of cancer stem cell proliferation, and others
increase in immunological attacks against tumors after HT, which were believed to be achieved through activation of HSPs and subsequent modulation of the innate and adaptive immune responses against tumor cells
HT does lead to activation of the immune system and HSP-induced cell death through modification of the tumor cell surface
These HSPs and tumor antigens are taken up by dendritic cells and macrophages and go on to induce specific anti-tumor immunity
In vivo studies demonstrate HT-enhancement of NK cell activity, and HT has been shown to increase neutrophilic granulocytes with anti-tumor activity
it has become increasingly clear that HT results in immune stimulation, through both direct heat-mediated cell killing as well as innate and adaptive immune system modulation
The term hyperthermia is used in this review to refer to heating within the clinically accepted range of 40–45 °C
temperatures above 42.5–43 °C the exposure time can be halved with each 1 °C increase while maintaining equivalent cell killing
gradual heating at 43 °C for 1 h worked through an apoptotic pathway
affect approximately 5 to 8 % of the US population
the incidence and prevalence of autoimmune diseases are rising
Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) account for the majority of the patients with autoimmune diseases
Autoimmune diseases are characterized by a breakdown of mechanisms that allow the immune system to distinguish between self and nonself and maintain immunologic self-tolerance
Tregs, which are important in the maintenance of peripheral immune tolerance.
Several subtypes of Tregs exist, the most well studied being CD4+ cells that express high-level CD25 and the transcription factor forkhead box P3 (FOXP3)
Treg deficiency or dysfunction is associated with autoimmune disease
In clinical studies, decreased levels of circulating CD25+CD4+ T cells have been reported in patients with autoimmune disease
These data have led to the hypothesis that augmentation of Tregs may be a useful therapeutic strategy in autoimmune disease
Treg augmentation has resulted in clinical improvements in numerous animal models of autoimmune diseases
the administration of in vitro expanded CD4+CD25highCD127-Tregs has been found to be safe and may help to preserve β-cell function in children with T1D
ability of IL-2 to augment the numbers and function of CD4+ Tregs.
Great article. Immune dysfunction plays role in autoimmune disease and cancer. Treg cells sit at the center of autoimmunity. This artice highlights the different uses: low dose IL2 therapy to augment Tregs and reduce autoinflammation and high dose IL2 to augment Treg cells in the fight against cancer.
Another incredible read on the mechanism behind the action of melatonin. From the immune stimulating of NK, T lymphocytes...to the decrease int he Tregs and cancer associated fibroblasts in the TME.
MENK increased the infiltration of M1-type macrophages, natural killer cells, CD8+ T cells, CD4+ T cells, and dendritic cells into the TME, and decreased the proportion of myeloid inhibitory cells and M2-type macrophages. Plays particular role in preventing immune escape and immune dysfunction paramount to cancer metastasis
play a role during the initial chemotactic response of neutrophils shortly after infection
following vitamin C supplementation, a 20% increase in neutrophil chemotactic activity was observed
also contributes to the phagocytosis and killing of microbes by neutrophils
low levels of vitamin C occurring in high-stress situations
maturation, proliferation, and viability of T cells have all been shown to be upregulated by the presence of normal physiologic concentrations of vitamin C
Vitamin C has been shown to directly affect the number of Igs released from B cells
vitamin C among healthy young adult males showed a significant increase in serum levels of IgA, IgG, and IgM
effects of high-dose vitamin C on cytokine levels in cancer patients, finding decreased amounts of the cytokines Interleukin-1 alpha (IL-1 alpha), IL-2, IL-8, and tumor necrosis factor-alpha (TNF-alpha) after high-dose vitamin C infusion
when vitamin C was supplemented with vitamin E in healthy adults, it increased the production of cytokines IL-1 beta and TNF-alpha
vitamin C acts to modulate the levels of cytokines to prevent them from fluctuating in either direction
vitamin C also acts as an important antioxidant to the cells of the immune system.
human leukocytes, neutrophils, in particular, possess the ability to transport the oxidized form of vitamin C across its membrane to use as a defense mechanism against ROS produced during an immune response
Vitamin C also can recover other endogenous antioxidants in the body such as vitamin E and glutathione, returning them to their active state
vitamin C can decrease the activation of NF-kB
can reduce harmful nitrogen-based compounds such as N-nitrosamines and nitrosamides, both of which are carcinogenic
subjects taking oral vitamin C supplementation saw a 60% to 90% reduction in oxidative stress compared to a placebo control
subjects infused with vitamin C alone had a 516% increase in glutathione levels compared to subjects not provided the 500 mg daily supplementation
hydroxylating proline and lysine
mature and stabilize the tissue of a healing wound
healing
oral surgery
improved soft tissue regeneration
vitamin C increases the mRNA levels of type I and type III collagen in the human dermis
Studies have demonstrated that those with low levels of vitamin C are at a significantly higher risk of respiratory infection compared to those with normal levels
viral cold duration was reduced by about 8% in adults and 13.5% in children using prophylactic daily doses of 200 mg of oral vitamin C
prophylactically supplementing vitamin C decreases the risk of infection with respiratory viruses such as the common cold
combined with probiotics, oral vitamin C supplementation showed a 33% decrease in the incidence of respiratory tract infections in preschool-age children [
high-dose oral supplementation of vitamin C managed to prevent or reduce symptoms if taken before or just after the onset of cold- or flu-like symptoms
improvements in oxygen saturation and decreased IL-6 levels (a marker of inflammation) in the treatment group compared to the control group
8 g doses of oral vitamin C
there is a negative correlation between age and serum levels of vitamin C
Patients with COVID-19 will likely also experience depletion in serum levels of vitamin C as a direct result of the upregulation of the immune system to combat the infection
Colunga et al. suggested that oral vitamin C can be combined with oral Quercetin, an antiviral flavonoid, to improve Quercetin’s ability to block viral membrane fusion of SARS-CoV-2
high doses of 1-2 g/day of oral vitamin C could prevent other upper respiratory infections
It appears vitamin C supplementation by itself does not provide a striking benefit in preventing COVID-19 infection for those without a deficiency
Flawed statement. What is normal? Vitamin D.
Many variables effect levels and dose, including the two compartment kinetics and absorption.
Hiedra et al. were able to show decreases in inflammatory biomarkers, such as D-dimer and ferritin
some evidence to support that prophylactic use of vitamin C helps reduce the severity of respiratory infection symptoms once a subject has already been infected
oral vitamin C in combination with zinc provided the largest amount of antibody titers 42 days
linear relationship between days of vitamin C therapy and survival duration
other studies were unable to find any definitive improvement concerning therapy with vitamin C
Either these studies are designed to fail or the authors are lacking some basic understanding of pharmacokinetics and pharmacodynamics with vitamin C.
Fowler et al. aimed to see if a high-dose vitamin C infusion would benefit patients affected by ARDS, but they were unable to conclude that vitamin C infusion, compared to a placebo, could decrease vascular inflammation and damage in ARDS
They are kind of make the point from my earlier note.
continuous vitamin C infusion at a rate of 60 mg/kg/day for four days decreased the need for mechanical ventilation and vasopressor use but had no significant effect on overall mortality
Again, designed to fail or ignorance designed the study which failed
Carr et al. suggested that high-dose IV vitamin C is most effective when treating sepsis as septic patients receiving the normal daily recommendations through diet still showed decreased vitamin C levels
High-dose IV vitamin C treatment has also been shown by Kakodkar et al. to decrease syndecan-1, an endothelial glycocalyx that contributes to mortality in septic patients
combined with hydrocortisone and thiamine, septic patients treated with 1.5 g of IV vitamin C every six hours showed a distinct decrease in their SOFA scores and none of the patients treated developed organ failure
combined with hydrocortisone and thiamine, septic patients treated with 1.5 g of IV vitamin C every six hours showed a distinct decrease in their SOFA scores and none of the patients treated developed organ failure
reduced overall mortality
reduced overall mortality
propose the use for high-dose vitamin C to aid in the treatment of septic shock-induced hypotension
treatment of severe sepsis using a high dose (up to 200 mg/kg/day) of IV vitamin C was explored in phase I, a double-blind, randomized, placebo-controlled trial by Fowler et al. [75]. Their findings included a reduction in SOFA scores and decreased vascular injury compared to a placebo control group, all while showing minimal adverse side effects
Benefits of progesterone, are in part, due to its function on the immune system. Progesterone shown to decrease T cell activity, macrophage activity and NK cell activity. Aside, NK cell activity has been found to be increased in those with recurrent first trimester miscarriages and progesterone defects. So, low progesterone allows for a rise in NK cell activity and inflammation that is detrimental to a developing pregnancy. If that is the case in pregnancy, what about the rest of the body?
insulin resistance leads to excess FFA, obesity and activation of the innate immune signaling. This uses TLR4 and stimulates NF-KappaB transcription. The result is inflammation and associated inflammatory disease conditions.
Dysfunctions of the innate immune system, in the gastrointestinal system, in children with autism found. LPS found to be involved. Again, revealing a gut-brain connection in autism.