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home:pathogenesis:innate_immunity [01.12.2020] – [Immune suppression] sallieq | home:pathogenesis:innate_immunity [09.14.2022] (current) – external edit 127.0.0.1 | ||
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===== Introduction ===== | ===== Introduction ===== | ||
- | The innate immune response is the body's first line of defense against and a non-specific way for responding to bacterial pathogens.(({{pubmed> | + | The innate immune response is the body's first line of defense against and a non-specific way for responding to bacterial pathogens.(({{pmid> |
- | plays a crucial, often under-appreciated, | + | plays a crucial, often under-appreciated, |
- | When functioning properly, the VDR transcribes between hundreds(({{pubmed> | + | When functioning properly, the VDR transcribes between hundreds(({{pmid> |
The body controls activity of the VDR through regulation of the vitamin D metabolites. 25-hydroxyvitamin D (25-D) antagonizes or inactivates the Receptor while 1, | The body controls activity of the VDR through regulation of the vitamin D metabolites. 25-hydroxyvitamin D (25-D) antagonizes or inactivates the Receptor while 1, | ||
- | Greater than 36 types of tissue have been identified as having a Vitamin D Receptor.(({{pubmed> | + | Greater than 36 types of tissue have been identified as having a Vitamin D Receptor.(({{pmid> |
Another component of the innate immune response is the release of inflammatory cytokines. The result is what medicine calls inflammation, | Another component of the innate immune response is the release of inflammatory cytokines. The result is what medicine calls inflammation, | ||
- | Adenosine: an endogenous regulator of innate immunity. | + | Adenosine: an endogenous regulator of innate immunity. |
Before the Human Microbiome Project, scientists couldn' | Before the Human Microbiome Project, scientists couldn' | ||
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===== Research ===== | ===== Research ===== | ||
- | Modern vaccinations, | + | Those with a high intellectual capacity (hyper brain) possess overexcitabilities in various domains that may predispose them to certain psychological disorders as well as physiological conditions involving elevated sensory, and altered immune and inflammatory responses (hyper body). [[https:// |
+ | |||
+ | Modern vaccinations, | ||
Country kids had more, and more-diverse, | Country kids had more, and more-diverse, | ||
- | Insulin gives an extra boost to the immune system | + | Insulin gives an extra boost to the immune system |
- | Results indicate a relationship between muscular TLR4, p-AMPK and NF-κB content and insulin sensitivity. The study also highlights that in situations of insulin resistance, such as in diabetic subjects, metformin treatment may prevent attenuation of activation of the inflammatory pathway. | + | Results indicate a relationship between muscular TLR4, p-AMPK and NF-κB content and insulin sensitivity. The study also highlights that in situations of insulin resistance, such as in diabetic subjects, metformin treatment may prevent attenuation of activation of the inflammatory pathway. |
- | Glucose homeostasis, | + | Glucose homeostasis, |
- | Adenosine is an important molecule that exerts control on the immune system, by signaling through receptors lying on the surface of immune cells. | + | Adenosine is an important molecule that exerts control on the immune system, by signaling through receptors lying on the surface of immune cells. |
An exciting area of recent investigation has arisen from the discovery that SCFA play a role in regulating the immune system and inflammatory response. Early work at the turn of this century had demonstrated the potential role of butyrate in immune regulation when it was shown that butyrate inhibits nuclear factor kappa β (NF-κΒ) activation in macrophages and also inhibits histone deacetylation (HDAc) in acute myeloid leukemia. | An exciting area of recent investigation has arisen from the discovery that SCFA play a role in regulating the immune system and inflammatory response. Early work at the turn of this century had demonstrated the potential role of butyrate in immune regulation when it was shown that butyrate inhibits nuclear factor kappa β (NF-κΒ) activation in macrophages and also inhibits histone deacetylation (HDAc) in acute myeloid leukemia. | ||
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Whether SCFA act as a signal to induce tolerance to the host-associated microbiome or directly reduce inflammatory responses remains to be fully elucidated. SCFA do appear able to reduce the responsiveness of lamina propria macrophages to commensal bacteria, via nitric oxide, IL-6, and IL-12 independent of FFAR signaling, to induce tolerance. | Whether SCFA act as a signal to induce tolerance to the host-associated microbiome or directly reduce inflammatory responses remains to be fully elucidated. SCFA do appear able to reduce the responsiveness of lamina propria macrophages to commensal bacteria, via nitric oxide, IL-6, and IL-12 independent of FFAR signaling, to induce tolerance. | ||
- | Recent data also suggests butyrate suppresses TNF-α, IL-6, and myeloperoxidase activity by preventing NF-κΒ activation in Kupffer cells.(({{pubmed> | + | Recent data also suggests butyrate suppresses TNF-α, IL-6, and myeloperoxidase activity by preventing NF-κΒ activation in Kupffer cells.(({{pmid> |
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It is commonly accepted that most ligands, approximately 95% to 98%, inactivate the nuclear receptors. Since the nuclear receptors play a significant role in the immune response, this factor alone may explain why so many drugs and substances found in food and drink are immunosuppressive. | It is commonly accepted that most ligands, approximately 95% to 98%, inactivate the nuclear receptors. Since the nuclear receptors play a significant role in the immune response, this factor alone may explain why so many drugs and substances found in food and drink are immunosuppressive. | ||
- | Because the expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases which explains why the molecular targets of approximately 13% of FDA approved drugs are nuclear receptors.(({{pubmed> | + | Because the expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases which explains why the molecular targets of approximately 13% of FDA approved drugs are nuclear receptors.(({{pmid> |
Different cell types have different nuclear receptors. One of the nuclear receptors seen in immune cells is the Vitamin D Receptor (VDR). The VDR has two endogenous or " | Different cell types have different nuclear receptors. One of the nuclear receptors seen in immune cells is the Vitamin D Receptor (VDR). The VDR has two endogenous or " | ||
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< | < | ||
- | //**Jun Sun**// (({{pubmed> | + | //**Jun Sun**// (({{pmid> |
- | When activated by 1,25-D, the Vitamin D Receptor (also called the calcitriol receptor) transcribes thousands of genes.(({{pubmed> | + | When activated by 1,25-D, the Vitamin D Receptor (also called the calcitriol receptor) transcribes thousands of genes.(({{pmid> |
==== Transcription of antimicrobial peptides ==== | ==== Transcription of antimicrobial peptides ==== | ||
- | One of the VDR's key functions is the transcription of antimicrobial peptides.(({{pubmed> | + | One of the VDR's key functions is the transcription of antimicrobial peptides.(({{pmid> |
==== Other antimicrobial activity of the VDR ==== | ==== Other antimicrobial activity of the VDR ==== | ||
- | Additionally, | + | Additionally, |
- | When activated TLR2 allows the immune system to recognize gram-positive bacteria, including // | + | When activated TLR2 allows the immune system to recognize gram-positive bacteria, including // |
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===== Antimicrobial peptides ===== | ===== Antimicrobial peptides ===== | ||
- | The antimicrobial peptides (AMPs), of which there are hundreds, are families of proteins, which have been called "the body's natural antibiotics," | + | The antimicrobial peptides (AMPs), of which there are hundreds, are families of proteins, which have been called "the body's natural antibiotics," |
- | For example, consider cathelicidin, | + | For example, consider cathelicidin, |
AMPs have been documented to kill bacteria and disrupt their function through the following modes of action: | AMPs have been documented to kill bacteria and disrupt their function through the following modes of action: | ||
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Two of the more significant families of AMPs are cathelicidin and the beta-defensins. Of these two families, cathelicidin is the most common. | Two of the more significant families of AMPs are cathelicidin and the beta-defensins. Of these two families, cathelicidin is the most common. | ||
- | Cathelicidin is a “fire alarm”, generating protective NLRP3-dependent airway epithelial cell inflammatory responses (({{pubmed> | + | Cathelicidin is a “fire alarm”, generating protective NLRP3-dependent airway epithelial cell inflammatory responses (({{pmid> |
- | The full extent by which microbes interfere with AMP expression is the subject of a rapidly growing body of research.(({{pubmed> | + | The full extent by which microbes interfere with AMP expression is the subject of a rapidly growing body of research.(({{pmid> |
==== Recent research into valuable proteins ==== | ==== Recent research into valuable proteins ==== | ||
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Whey proteins and numerous growth factors that regulate insulin secretion, differentiation of intestine epithelium cells, and also tissue restoration, | Whey proteins and numerous growth factors that regulate insulin secretion, differentiation of intestine epithelium cells, and also tissue restoration, | ||
- | Lactoferrin shows the most comprehensive pro-health properties: antioxidative, | + | Lactoferrin shows the most comprehensive pro-health properties: antioxidative, |
==== Antimicrobial peptides target fungi and viruses ==== | ==== Antimicrobial peptides target fungi and viruses ==== | ||
- | The antimicrobial peptides play a role in mitigating the virulence of the virome and other non-bacterial infectious agents. In addition to its antibacterial activity, alpha-defensin human neutrophil peptide-1 inhibits HIV and influenza virus entry into target cells.(({{pubmed> | + | The antimicrobial peptides play a role in mitigating the virulence of the virome and other non-bacterial infectious agents. In addition to its antibacterial activity, alpha-defensin human neutrophil peptide-1 inhibits HIV and influenza virus entry into target cells.(({{pmid> |
In other words, there is a reason why this group of proteins are named anti// | In other words, there is a reason why this group of proteins are named anti// | ||
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There are now several examples of substances believed to cause disease, which have since been proven to be part of host defense. | There are now several examples of substances believed to cause disease, which have since been proven to be part of host defense. | ||
- | * **amyloid beta (amyloid-β)** – In a seminal 2010 study, a team of Harvard researchers showed that amyloid beta – the hallmark of Alzheimer' | + | * **amyloid beta (amyloid-β)** – In a seminal 2010 study, a team of Harvard researchers showed that amyloid beta – the hallmark of Alzheimer' |
* **certain human prion proteins** | * **certain human prion proteins** | ||
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===== Evolutionarily conserved ===== | ===== Evolutionarily conserved ===== | ||
- | The TLR2/1 and cathelicidin-vitamin D pathway has long played a " | + | The TLR2/1 and cathelicidin-vitamin D pathway has long played a " |
===== Energy consumption ===== | ===== Energy consumption ===== | ||
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It has become clear in recent years that pretty much any immune cell in our body undergoes, upon its activation, a metabolic shift resembling the Warburg effect originally described for cancer cells. Immune cells increase glucose consumption and produce a significant portion of ATP by glycolysis ending with lactate even under oxygenated conditions; increased glycolysis is required for the generation of intermediate metabolites associated with the activation of the immune cell. | It has become clear in recent years that pretty much any immune cell in our body undergoes, upon its activation, a metabolic shift resembling the Warburg effect originally described for cancer cells. Immune cells increase glucose consumption and produce a significant portion of ATP by glycolysis ending with lactate even under oxygenated conditions; increased glycolysis is required for the generation of intermediate metabolites associated with the activation of the immune cell. | ||
- | Increased energy consumption by immune cells requires a metabolic adaptation of the whole organism. During trauma or infection, the organism vitally depends on the immune system, which is therefore privileged in energy/ | + | Increased energy consumption by immune cells requires a metabolic adaptation of the whole organism. During trauma or infection, the organism vitally depends on the immune system, which is therefore privileged in energy/ |
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=====Inflammation ===== | =====Inflammation ===== | ||
- | Another component of the innate immune response is inflammation, | + | Another component of the innate immune response is inflammation, |
==== Th1/Th17 inflammation ==== | ==== Th1/Th17 inflammation ==== | ||
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< | < | ||
- | // | + | // |
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While inflammation is associated with disease, inflammation often serves an invaluable role as the immune system fights off chronic pathogens. Numerous medications artificially suppress inflammation including anti-TNF drugs, interferon, corticosteroids, | While inflammation is associated with disease, inflammation often serves an invaluable role as the immune system fights off chronic pathogens. Numerous medications artificially suppress inflammation including anti-TNF drugs, interferon, corticosteroids, | ||
- | The release of cytokines appears to be essential for recovery after an infection. One study found that the cytokine TNF-alpha – which is blocked by anti-TNF drugs – is necessary for the proper expression of acquired specific resistance following infection with // | + | The release of cytokines appears to be essential for recovery after an infection. One study found that the cytokine TNF-alpha – which is blocked by anti-TNF drugs – is necessary for the proper expression of acquired specific resistance following infection with // |
===== Commensal microbes ===== | ===== Commensal microbes ===== | ||
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< | < | ||
- | The host innate immune defense system is highly active in healthy tissue.(({{pubmed> | + | The host innate immune defense system is highly active in healthy tissue.(({{pmid> |
===== Immune suppression ===== | ===== Immune suppression ===== | ||
- | The surprising finding of science is that home and hospital environments can be less supportive of human health than the outdoors. | + | The surprising finding of science is that home and hospital environments can be less supportive of human health than the outdoors. |
Environmental pollution, both visible and invisible, many palliative medications, | Environmental pollution, both visible and invisible, many palliative medications, | ||
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| | ||
+ | < | ||
===== Notes and comments ===== | ===== Notes and comments ===== | ||
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< | < | ||
- | http:// | + | https:// |
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- | http:// | + | https:// |
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</ | </ | ||
- | * [[http:// | + | * [[https:// |
< | < | ||
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Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling | Mycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling | ||
- | http:// | + | https:// |
**"our findings clearly demonstrate that TLR2/1 signalling regulates antibacterial autophagy pathway through functional vitamin D3 receptor activation and cathelicidin expression in human primary monocytes." | **"our findings clearly demonstrate that TLR2/1 signalling regulates antibacterial autophagy pathway through functional vitamin D3 receptor activation and cathelicidin expression in human primary monocytes." | ||
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Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D–dependent mechanism | Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D–dependent mechanism | ||
- | http:// | + | https:// |
An essential element of the innate immune response to injury is the capacity to recognize microbial invasion and stimulate production of antimicrobial peptides. We investigated how this process is controlled in the epidermis. Keratinocytes surrounding a wound increased expression of the genes coding for the microbial pattern recognition receptors CD14 and TLR2, complementing an increase in cathelicidin antimicrobial peptide expression. These genes were induced by 1,25(OH)2 vitamin D3 (1,25D3; its active form), suggesting a role for vitamin D3 in this process. How 1,25D3 could participate in the injury response was explained by findings that the levels of CYP27B1, which converts 25OH vitamin D3 (25D3) to active 1,25D3, were increased in wounds and induced in keratinocytes in response to TGF-β1. Blocking the vitamin D receptor, inhibiting CYP27B1, or limiting 25D3 availability prevented TGF-β1 from inducing cathelicidin, | An essential element of the innate immune response to injury is the capacity to recognize microbial invasion and stimulate production of antimicrobial peptides. We investigated how this process is controlled in the epidermis. Keratinocytes surrounding a wound increased expression of the genes coding for the microbial pattern recognition receptors CD14 and TLR2, complementing an increase in cathelicidin antimicrobial peptide expression. These genes were induced by 1,25(OH)2 vitamin D3 (1,25D3; its active form), suggesting a role for vitamin D3 in this process. How 1,25D3 could participate in the injury response was explained by findings that the levels of CYP27B1, which converts 25OH vitamin D3 (25D3) to active 1,25D3, were increased in wounds and induced in keratinocytes in response to TGF-β1. Blocking the vitamin D receptor, inhibiting CYP27B1, or limiting 25D3 availability prevented TGF-β1 from inducing cathelicidin, | ||
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< | < | ||
- | http:// | + | https:// |
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- | "As mentioned above, prion protein is not only confined to the nervous system, but instead ubiquitously found in many other cells and tissues, and the physiological role for this protein are still enigmatic. In a previous study, it was reported that human keratinocytes express PrPc in vitro and during inflammatory skin disease [18]. Although that previous work was focusing on prion infectivity routes, our current findings on increased expression of PrP during wounding, together with the observation of its antimicrobial activity, clearly indicate that PrPs could have a previously undisclosed role in host defense. In this context, experiments with PrP deficient animals in infection models should be valuable in order to further delineate a possible role of PrP in innate defense." | + | "As mentioned above, prion protein is not only confined to the nervous system, but instead ubiquitously found in many other cells and tissues, and the physiological role for this protein are still enigmatic. In a previous study, it was reported that human keratinocytes express PrPc in vitro and during inflammatory skin disease [18]. Although that previous work was focusing on prion infectivity routes, our current findings on increased expression of PrP during wounding, together with the observation of its antimicrobial activity, clearly indicate that PrPs could have a previously undisclosed role in host defense. In this context, experiments with PrP deficient animals in infection models should be valuable in order to further delineate a possible role of PrP in innate defense." |
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Hydrogen sulfide: a marker of inflammation: | Hydrogen sulfide: a marker of inflammation: | ||
- | http:// | + | https:// |
- | http:// | + | https:// |
- | In a 2008 paper, Liu lists the different pattern recognition receptors in humans.(({{pubmed> | + | In a 2008 paper, Liu lists the different pattern recognition receptors in humans.(({{pmid> |
{{: | {{: | ||
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- | Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells(({{pubmed> | + | Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells(({{pmid> |
{{: | {{: | ||
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* monocytes – several roles: (1) replenish resident macrophages and dendritic cells under normal states, and (2) in response to inflammation signals, monocytes can move quickly (approx. 8-12 hours) to sites of infection in the tissues and divide/ | * monocytes – several roles: (1) replenish resident macrophages and dendritic cells under normal states, and (2) in response to inflammation signals, monocytes can move quickly (approx. 8-12 hours) to sites of infection in the tissues and divide/ | ||
- | ===== References ===== | + | ===== References =====</ |