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home:pathogenesis:innate_immunity [01.12.2020] – [Immune suppression] sallieqhome: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>long:19400860}})) Located in the nucleus of a variety of cells, the Vitamin D nuclear receptor (VDR)  +The innate immune response is the body's first line of defense against and a non-specific way for responding to bacterial pathogens.(({{pmid>long:19400860}})) Located in the nucleus of a variety of cells, the Vitamin D nuclear receptor (VDR)  
-plays a crucial, often under-appreciated, role in the innate immune response. [[http://journal.frontiersin.org/article/10.3389/fimmu.2013.00148/full|The vitamin D receptor and T cell function]]+plays a crucial, often under-appreciated, role in the innate immune response. [[https://journal.frontiersin.org/article/10.3389/fimmu.2013.00148/full|The vitamin D receptor and T cell function]]
  
-When functioning properly, the VDR transcribes between hundreds(({{pubmed>long:20736230}})) and thousands of genes(({{pubmed>long:16002434}})) including those for the proteins known as the antimicrobial peptides. Antimicrobial peptides are "the body's natural antibiotics," crucial for both prevention and clearance of infection.(({{pubmed>long:11807545}})) The VDR also expresses the TLR2 receptor, which is expressed on the surface of certain cells and recognizes foreign substances. +When functioning properly, the VDR transcribes between hundreds(({{pmid>long:20736230}})) and thousands of genes(({{pmid>long:16002434}})) including those for the proteins known as the antimicrobial peptides. Antimicrobial peptides are "the body's natural antibiotics," crucial for both prevention and clearance of infection.(({{pmid>long:11807545}})) The VDR also expresses the TLR2 receptor, which is expressed on the surface of certain cells and recognizes foreign substances. 
  
 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 1,25-dihydroxyvitamin D (1,25-D) agonizes or activates the Receptor. 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 1,25-dihydroxyvitamin D (1,25-D) agonizes or activates the Receptor.
  
-Greater than 36 types of tissue have been identified as having a Vitamin D Receptor.(({{pubmed>long:18689389}}))+Greater than 36 types of tissue have been identified as having a Vitamin D Receptor.(({{pmid>long:18689389}}))
  
 Another component of the innate immune response is the release of inflammatory cytokines. The result is what medicine calls inflammation, which generally leads to an increase in symptoms.  Another component of the innate immune response is the release of inflammatory cytokines. The result is what medicine calls inflammation, which generally leads to an increase in symptoms. 
  
-Adenosine: an endogenous regulator of innate immunity.  (({{pubmed>long:14698282}}))+Adenosine: an endogenous regulator of innate immunity.  (({{pmid>long:14698282}}))
  
 Before the Human Microbiome Project, scientists couldn't link bacteria to inflammatory diseases. But with the advent of DNA sequencing technology, scientists have detected many of the bacteria capable of generating an inflammatory response. All diseases of unknown etiology are inflammatory diseases. Before the Human Microbiome Project, scientists couldn't link bacteria to inflammatory diseases. But with the advent of DNA sequencing technology, scientists have detected many of the bacteria capable of generating an inflammatory response. All diseases of unknown etiology are inflammatory diseases.
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 ===== Research ===== ===== Research =====
  
-Modern vaccinations, fear of germs and obsession with hygiene are depriving the immune system of the information input upon which it is dependent. ....and may lead to increased incidences of allergies and autoimmune diseases.  (({{pubmed>long:9540269}})) +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://www.sciencedirect.com/science/article/pii/S0160289616303324|Science Direct]]  
 + 
 +Modern vaccinations, fear of germs and obsession with hygiene are depriving the immune system of the information input upon which it is dependent. ....and may lead to increased incidences of allergies and autoimmune diseases.  (({{pmid>long:9540269}})) 
  
 Country kids had more, and more-diverse, bacteria on their skin, with a particularly high abundance of Acinetobacter—a genus of microbes in the Proteobacteria phylum that are commonly found on plants. The researchers further found that children with more Acinetobacter on their skin had more leukocytes in their bloodstream and that these cells were much more capable of producing the anti-inflammatory cytokine IL-10 compared with the leukocytes of urban kids. [[https://www.the-scientist.com/news-opinion/the-influence-of-soil-on-human-health-66885|influence of soil on human health]]   Country kids had more, and more-diverse, bacteria on their skin, with a particularly high abundance of Acinetobacter—a genus of microbes in the Proteobacteria phylum that are commonly found on plants. The researchers further found that children with more Acinetobacter on their skin had more leukocytes in their bloodstream and that these cells were much more capable of producing the anti-inflammatory cytokine IL-10 compared with the leukocytes of urban kids. [[https://www.the-scientist.com/news-opinion/the-influence-of-soil-on-human-health-66885|influence of soil on human health]]  
  
-Insulin gives an extra boost to the immune system  (({{pubmed>long:30174303}})) +Insulin gives an extra boost to the immune system  (({{pmid>long:30174303}})) 
  
-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.  (({{pubmed>long:28791487}})) +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.  (({{pmid>long:28791487}})) 
  
-Glucose homeostasis, nutrition and infections during critical illness  (({{pubmed>long:28082192}})) +Glucose homeostasis, nutrition and infections during critical illness  (({{pmid>long:28082192}})) 
  
-Adenosine is an important molecule that exerts control on the immune system, by signaling through receptors lying on the surface of immune cells.   (({{pubmed>long:27557887}})) +Adenosine is an important molecule that exerts control on the immune system, by signaling through receptors lying on the surface of immune cells.   (({{pmid>long:27557887}})) 
  
 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>long:26963409}}))+Recent data also suggests butyrate suppresses TNF-α, IL-6, and myeloperoxidase activity by preventing NF-κΒ activation in Kupffer cells.(({{pmid>long:26963409}}))
  
  
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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>long:17139284}}))+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>long:17139284}}))
  
 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 "native" ligands, which are also the two main forms of vitamin D in the human body: 25-hydroxyvitamin D (25-D) and 1,25-dihydroxyvitamin D (1,25-D). Non-native or exogenous ligands can also inactivate or activate a nuclear receptor, depending on its molecular structure. 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 "native" ligands, which are also the two main forms of vitamin D in the human body: 25-hydroxyvitamin D (25-D) and 1,25-dihydroxyvitamin D (1,25-D). Non-native or exogenous ligands can also inactivate or activate a nuclear receptor, depending on its molecular structure.
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 <blockquote>Vitamin D/VDR have multiple critical functions in regulating the response to intestinal homeostasis, tight junctions, pathogen invasion, commensal bacterial colonization, antimicrobe peptide secretion, and mucosal defense.... The involvement of Vitamin D/VDR in anti-inflammation and anti-infection represents a newly identified and highly significant activity for VDR. <blockquote>Vitamin D/VDR have multiple critical functions in regulating the response to intestinal homeostasis, tight junctions, pathogen invasion, commensal bacterial colonization, antimicrobe peptide secretion, and mucosal defense.... The involvement of Vitamin D/VDR in anti-inflammation and anti-infection represents a newly identified and highly significant activity for VDR.
  
-//**Jun Sun**// (({{pubmed>long:20639756}}))</blockquote>+//**Jun Sun**// (({{pmid>long:20639756}}))</blockquote>
  
  
  
-When activated by 1,25-D, the Vitamin D Receptor (also called the calcitriol receptor) transcribes thousands of genes.(({{pubmed>long:16002434}})) It is commonly known that the VDR functions in regulating calcium metabolism.(({{pubmed>long:11500311}})) It is becoming increasingly clear, however, that the clinically accepted role of the Vitamin D metabolites, that of regulating calcium homeostasis, is just a small subset of the functions actually performed by these hormones.+When activated by 1,25-D, the Vitamin D Receptor (also called the calcitriol receptor) transcribes thousands of genes.(({{pmid>long:16002434}})) It is commonly known that the VDR functions in regulating calcium metabolism.(({{pmid>long:11500311}})) It is becoming increasingly clear, however, that the clinically accepted role of the Vitamin D metabolites, that of regulating calcium homeostasis, is just a small subset of the functions actually performed by these hormones.
 ==== Transcription of antimicrobial peptides ==== ==== Transcription of antimicrobial peptides ====
  
-One of the VDR's key functions is the transcription of antimicrobial peptides.(({{pubmed>long:15322146}})) (({{pubmed>long:15985530}})) //See [[#antimicrobial_peptides|below]].//+One of the VDR's key functions is the transcription of antimicrobial peptides.(({{pmid>long:15322146}})) (({{pmid>long:15985530}})) //See [[#antimicrobial_peptides|below]].//
  
  
 ==== Other antimicrobial activity of the VDR ==== ==== Other antimicrobial activity of the VDR ====
  
-Additionally, when the VDR is activated, TLR2 is expressed.(({{pubmed>long:17290304}})) TLR2 is a receptor, which is expressed on the surface of certain cells and recognizes native or foreign substances, and passes on appropriate signals to the cell and/or the nervous system.+Additionally, when the VDR is activated, TLR2 is expressed.(({{pmid>long:17290304}})) TLR2 is a receptor, which is expressed on the surface of certain cells and recognizes native or foreign substances, and passes on appropriate signals to the cell and/or the nervous system.
  
-When activated TLR2 allows the immune system to recognize gram-positive bacteria, including //Staphylococcus aureus//(({{pubmed>long:11067888}})) (({{pubmed>long:15731086}})) //Chlamydia pneumoniae//(({{pubmed>long:17145941}})) and //Mycoplasma pneumoniae//.(({{pubmed>long:15843573}})) TLR2 also protects from intracellular infections such as //Mycobacteria tuberculosis.//(({{pubmed>long:19442756}}))+When activated TLR2 allows the immune system to recognize gram-positive bacteria, including //Staphylococcus aureus//(({{pmid>long:11067888}})) (({{pmid>long:15731086}})) //Chlamydia pneumoniae//(({{pmid>long:17145941}})) and //Mycoplasma pneumoniae//.(({{pmid>long:15843573}})) TLR2 also protects from intracellular infections such as //Mycobacteria tuberculosis.//(({{pmid>long:19442756}}))
  
  
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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," crucial for both prevention and clearance of infection. AMPs are broad-spectrum, responding to pathogens in a non-specific manner.(({{pubmed>long:11807545}}))+The antimicrobial peptides (AMPs), of which there are hundreds, are families of proteins, which have been called "the body's natural antibiotics," crucial for both prevention and clearance of infection. AMPs are broad-spectrum, responding to pathogens in a non-specific manner.(({{pmid>long:11807545}}))
  
-For example, consider cathelicidin, a protein transcribed by the VDR, which not unlike a Swiss Army knife, has many different functions. Because it can be differentially spliced, the cathelicidin protein itself can respond to a range of very different microbial challenges. In humans, the cathelicidin antimicrobial peptide gene encodes an inactive precursor protein (hCAP18) that is processed to release a 37amino-acid peptide (LL-37) from the C-terminus. LL-37 is susceptible to proteolitic processing by a variety of enzymes, generating many different cathelicidin-derived peptides, each of which has specific targets. For example, LL-37 is generated in response to //Staphylococcus aureus//, yet LL-37 represents 20% of the cathelicidin-derived peptides, with the smaller peptides being much more abundant and able to target even more diverse microbial forms.(({{pubmed>long:19817855}}))+For example, consider cathelicidin, a protein transcribed by the VDR, which not unlike a Swiss Army knife, has many different functions. Because it can be differentially spliced, the cathelicidin protein itself can respond to a range of very different microbial challenges. In humans, the cathelicidin antimicrobial peptide gene encodes an inactive precursor protein (hCAP18) that is processed to release a 37amino-acid peptide (LL-37) from the C-terminus. LL-37 is susceptible to proteolitic processing by a variety of enzymes, generating many different cathelicidin-derived peptides, each of which has specific targets. For example, LL-37 is generated in response to //Staphylococcus aureus//, yet LL-37 represents 20% of the cathelicidin-derived peptides, with the smaller peptides being much more abundant and able to target even more diverse microbial forms.(({{pmid>long:19817855}}))
  
 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>long:30978238}}))+Cathelicidin is a “fire alarm”, generating protective NLRP3-dependent airway epithelial cell inflammatory responses (({{pmid>long:30978238}}))
  
-The full extent by which microbes interfere with AMP expression is the subject of a rapidly growing body of research.(({{pubmed>long:18717821}})) (({{pubmed>long:15695583}})) (({{pubmed>long:15953032}})) +The full extent by which microbes interfere with AMP expression is the subject of a rapidly growing body of research.(({{pmid>long:18717821}})) (({{pmid>long:15695583}})) (({{pmid>long:15953032}})) 
  
 ==== 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, are priceless in stimulation the immune system.   Whey proteins and numerous growth factors that regulate insulin secretion, differentiation of intestine epithelium cells, and also tissue restoration, are priceless in stimulation the immune system. 
  
-Lactoferrin shows the most comprehensive pro-health properties: antioxidative, anticancer, immune stimulative and even chemopreventive. Also peptides and amino acids formed from casein and whey proteins possess immune stimulative activity. The most valuable proteins, i.e. lactoferrin, immune globulins, lactoperoxidase and lisozyme, together with bioactive peptides, are resistant to pepsin and trypsin activity. This is why they maintain their exceptional biological activity.   (({{pubmed>long:24720113}})) +Lactoferrin shows the most comprehensive pro-health properties: antioxidative, anticancer, immune stimulative and even chemopreventive. Also peptides and amino acids formed from casein and whey proteins possess immune stimulative activity. The most valuable proteins, i.e. lactoferrin, immune globulins, lactoperoxidase and lisozyme, together with bioactive peptides, are resistant to pepsin and trypsin activity. This is why they maintain their exceptional biological activity.   (({{pmid>long:24720113}})) 
 ==== 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>long:18809937}})) It diminishes HIV replication and can inactivate cytomegalovirus, herpes simplex virus, vesicular stomatitis virus and adenovirus.(({{pubmed>long:19817855}})) In addition to killing both gram positive and gram-negative bacteria, human beta-defensins HBD-1, HDB-2, and HBD-3 have also been shown to kill the opportunistic yeast species //Candida albicans//.(({{pubmed>long:18809937}})) Cathelicidin also possesses antiviral and antifungal activity.(({{pubmed>long:16630942}})) (({{pubmed>long:17023499}}))+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>long:18809937}})) It diminishes HIV replication and can inactivate cytomegalovirus, herpes simplex virus, vesicular stomatitis virus and adenovirus.(({{pmid>long:19817855}})) In addition to killing both gram positive and gram-negative bacteria, human beta-defensins HBD-1, HDB-2, and HBD-3 have also been shown to kill the opportunistic yeast species //Candida albicans//.(({{pmid>long:18809937}})) Cathelicidin also possesses antiviral and antifungal activity.(({{pmid>long:16630942}})) (({{pmid>long:17023499}}))
  
 In other words, there is a reason why this group of proteins are named anti//microbial// peptides rather than anti//bacterial// peptides. In other words, there is a reason why this group of proteins are named anti//microbial// peptides rather than anti//bacterial// peptides.
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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's disease – can act as an antimicrobial peptide, having antimicrobial activity against eight common microorganisms, including //Streptococcus//, //Staphylococcus aureus//, and //Listeria//.(({{pubmed>long:20209079}})) This led study author Rudolph E. Tanzi, PhD to conclude that amyloid beta is "the brain's protector." However, a 2010 study suggests that toxic levels of amyloid beta "dramatically suppresses VDR expression." This suggests that overexpression of amyloid beta serves the interests of at least some microbes.(({{pubmed>long:20966550}})) //[[home:diseases:alzheimers_dementia#amyloid_proteins_the_hallmark_of_alzheimer_s_are_produced_in_response_to_infection|Read more]]//.+  * **amyloid beta (amyloid-β)** – In a seminal 2010 study, a team of Harvard researchers showed that amyloid beta – the hallmark of Alzheimer's disease – can act as an antimicrobial peptide, having antimicrobial activity against eight common microorganisms, including //Streptococcus//, //Staphylococcus aureus//, and //Listeria//.(({{pmid>long:20209079}})) This led study author Rudolph E. Tanzi, PhD to conclude that amyloid beta is "the brain's protector." However, a 2010 study suggests that toxic levels of amyloid beta "dramatically suppresses VDR expression." This suggests that overexpression of amyloid beta serves the interests of at least some microbes.(({{pmid>long:20966550}})) //[[home:diseases:alzheimers_dementia#amyloid_proteins_the_hallmark_of_alzheimer_s_are_produced_in_response_to_infection|Read more]]//.
   * **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 "powerful force" in protecting the body against infection. This is evidenced by the fact that the Alu short interspersed element (SINE), which transcribes the vitamin D receptor binding element (VDRE), has been evolutionarily conserved for 55-60 million years, but not prior.(({{pubmed>long:19607716}})) The differences in this pathway between humans/primates and other mammals call into question animal models that try to emulate the vitamin D system and indeed the immune system.+The TLR2/1 and cathelicidin-vitamin D pathway has long played a "powerful force" in protecting the body against infection. This is evidenced by the fact that the Alu short interspersed element (SINE), which transcribes the vitamin D receptor binding element (VDRE), has been evolutionarily conserved for 55-60 million years, but not prior.(({{pmid>long:19607716}})) The differences in this pathway between humans/primates and other mammals call into question animal models that try to emulate the vitamin D system and indeed the immune system.
  
 ===== 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/nutrient allocation. According to Rainer Straub [2], insulin resistance caused by pro-inflammatory cytokines is a physiological way of the immune system to usurp energy/nutrients during acute stress from the rest of the organism because immune cells themselves do not become insulin resistant.  (({{pubmed>long:26427038}})) +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/nutrient allocation. According to Rainer Straub [2], insulin resistance caused by pro-inflammatory cytokines is a physiological way of the immune system to usurp energy/nutrients during acute stress from the rest of the organism because immune cells themselves do not become insulin resistant.  (({{pmid>long:26427038}})) 
  
  
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 =====Inflammation ===== =====Inflammation =====
  
-Another component of the innate immune response is inflammation, the universal initial response of the organism to any injurious agent.(({{pubmed>long:20540037}})) Inflammation is a systemic physiological process fundamental for survival.(({{pubmed>long:20388071}})) The identification of bacteria and other pathogens triggers the release of inflammatory cytokines. These cytokines include interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), and Nuclear Factor-kappa B (NF-kappaB). Cytokines are regulatory proteins, such as the interleukins and lymphokines, that are released by cells of the immune system and act as intercellular mediators in the generation of an immune response. The result is what medicine calls inflammation, which generally leads to an increase in symptoms.+Another component of the innate immune response is inflammation, the universal initial response of the organism to any injurious agent.(({{pmid>long:20540037}})) Inflammation is a systemic physiological process fundamental for survival.(({{pmid>long:20388071}})) The identification of bacteria and other pathogens triggers the release of inflammatory cytokines. These cytokines include interferon-gamma, tumor necrosis factor-alpha (TNF-alpha), and Nuclear Factor-kappa B (NF-kappaB). Cytokines are regulatory proteins, such as the interleukins and lymphokines, that are released by cells of the immune system and act as intercellular mediators in the generation of an immune response. The result is what medicine calls inflammation, which generally leads to an increase in symptoms.
  
 ==== Th1/Th17 inflammation ==== ==== Th1/Th17 inflammation ====
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 <blockquote>An inflammatory immune response—one of the body’s primary means to protect against infection—defines multiple established infectious causes of chronic diseases, including some cancers. Inflammation also drives many chronic conditions that are still classified as (noninfectious) autoimmune or immune-mediated (e.g., systemic lupus erythematosus, rheumatoid arthritis, Crohn’s disease). Both [the innate and adaptive immune systems] play critical roles in the pathogenesis of these inflammatory syndromes. Therefore, inflammation is a clear potential link between infectious agents and chronic diseases. <blockquote>An inflammatory immune response—one of the body’s primary means to protect against infection—defines multiple established infectious causes of chronic diseases, including some cancers. Inflammation also drives many chronic conditions that are still classified as (noninfectious) autoimmune or immune-mediated (e.g., systemic lupus erythematosus, rheumatoid arthritis, Crohn’s disease). Both [the innate and adaptive immune systems] play critical roles in the pathogenesis of these inflammatory syndromes. Therefore, inflammation is a clear potential link between infectious agents and chronic diseases.
  
-//**Siobhán M. O'Connor** et al.// (({{pubmed>long:16836820}}))</blockquote>+//**Siobhán M. O'Connor** et al.// (({{pmid>long:16836820}}))</blockquote>
  
  
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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, antifungals, and anti-pyreutics. While interfering with the inflammatory response typically reduces immunopathology and makes a patient feel less symptomatic in the near term, doing so allows the bacteria which cause chronic disease to proliferate. 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, antifungals, and anti-pyreutics. While interfering with the inflammatory response typically reduces immunopathology and makes a patient feel less symptomatic in the near term, doing so allows the bacteria which cause chronic disease to proliferate.
  
-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 //Mycobacterium tuberculosis//.(({{pubmed>long:18544042}})) (({{pubmed>long:12852719}})) (({{pubmed>long:15216471}})) Another effect of the use of TNF blockers is to break or reduce the formation of granuloma, one of the body's mechanisms to control bacterial pathogens.(({{pubmed>long:16322600}})) +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 //Mycobacterium tuberculosis//.(({{pmid>long:18544042}})) (({{pmid>long:12852719}})) (({{pmid>long:15216471}})) Another effect of the use of TNF blockers is to break or reduce the formation of granuloma, one of the body's mechanisms to control bacterial pathogens.(({{pmid>long:16322600}})) 
  
 ===== Commensal microbes ===== ===== Commensal microbes =====
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 <mainarticle> [[home:othertreatments:probiotics|Probiotics and commensal bacteria]]</article> <mainarticle> [[home:othertreatments:probiotics|Probiotics and commensal bacteria]]</article>
  
-The host innate immune defense system is highly active in healthy tissue.(({{pubmed>long:20514045}}))  Commensal bacteria can activate innate immune responses.(({{pubmed>long:19161412}})) (({{pubmed>long:12960260}}))+The host innate immune defense system is highly active in healthy tissue.(({{pmid>long:20514045}}))  Commensal bacteria can activate innate immune responses.(({{pmid>long:19161412}})) (({{pmid>long:12960260}}))
  
 ===== 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.  (({{pubmed>long:000}}))   (({{pubmed>long:9540269}})) +The surprising finding of science is that home and hospital environments can be less supportive of human health than the outdoors.  exposure to environmental microbes helps protect against allergies and other inflammatory diseases   (({{pmid>long:9540269}})) [[https://www.the-scientist.com/news-opinion/the-influence-of-soil-on-human-health-66885|Exposure to environmental microbes helps protect against allergies and other inflammatory diseases]] 
  
 Environmental pollution, both visible and invisible, many palliative medications, and increasingly this century the cellular level radiation from wifi devices, are interfering with the capacity of the innate immune system to create the defensive molecules necessary to control intracellular infections Environmental pollution, both visible and invisible, many palliative medications, and increasingly this century the cellular level radiation from wifi devices, are interfering with the capacity of the innate immune system to create the defensive molecules necessary to control intracellular infections
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 +<nodisp>
 ===== Notes and comments ===== ===== Notes and comments =====
  
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 <blockquote>Vitamin D, Vitamin D Receptor, and Macroautophagy in Inflammation and Infection <blockquote>Vitamin D, Vitamin D Receptor, and Macroautophagy in Inflammation and Infection
  
-http://tiny.cc/9xtyw+https://tiny.cc/9xtyw
  
  
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-http://www.reuters.com/article/2011/04/22/us-biogen-tysabri-idUSTRE73L2WN20110422+https://www.reuters.com/article/2011/04/22/us-biogen-tysabri-idUSTRE73L2WN20110422
  
  
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 </blockquote> </blockquote>
  
-  * [[http://diss.kib.ki.se/2005/91-7140-270-5/thesis.pdf|AMPs and proteins in innate immunity]] - 2005 thesis from Karolinksa+  * [[https://diss.kib.ki.se/2005/91-7140-270-5/thesis.pdf|AMPs and proteins in innate immunity]] - 2005 thesis from Karolinksa
  
 <blockquote>Cell Microbiol. 2010 Nov;12(11):1648-65. doi: 10.1111/j.1462-5822.2010.01497.x. Epub 2010 Jul 20. <blockquote>Cell Microbiol. 2010 Nov;12(11):1648-65. doi: 10.1111/j.1462-5822.2010.01497.x. Epub 2010 Jul 20.
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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://www.ncbi.nlm.nih.gov/pmc/articles/PMC2970753/?tool=pubmed+https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2970753/?tool=pubmed
  
 **"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://www.ncbi.nlm.nih.gov/pmc/articles/PMC1784003/?tool=pubmed+https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1784003/?tool=pubmed
  
 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, CD14, or TLR2 in human keratinocytes, while CYP27B1-deficient mice failed to increase CD14 expression following wounding. The functional consequence of these observations was confirmed by demonstrating that 1,25D3 enabled keratinocytes to recognize microbial components through TLR2 and respond by cathelicidin production. Thus, we demonstrate what we believe to be a previously unexpected role for vitamin D3 in innate immunity, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection. 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, CD14, or TLR2 in human keratinocytes, while CYP27B1-deficient mice failed to increase CD14 expression following wounding. The functional consequence of these observations was confirmed by demonstrating that 1,25D3 enabled keratinocytes to recognize microbial components through TLR2 and respond by cathelicidin production. Thus, we demonstrate what we believe to be a previously unexpected role for vitamin D3 in innate immunity, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection.
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 <blockquote>In Vivo Activation of the Intracrine Vitamin D Pathway in Innate Immune Cells and Mammary Tissue during a Bacterial Infection. <blockquote>In Vivo Activation of the Intracrine Vitamin D Pathway in Innate Immune Cells and Mammary Tissue during a Bacterial Infection.
-http://www.ncbi.nlm.nih.gov/pubmed/21124742+https://www.ncbi.nlm.nih.gov/pubmed/21124742
  
  
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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."(({{pubmed>long:19809501}}))+"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."(({{pmid>long:19809501}}))
  
  
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 Hydrogen sulfide: a marker of inflammation: Hydrogen sulfide: a marker of inflammation:
-http://www.eurekalert.org/pub_releases/2010-08/tpco-reg082010.php +https://www.eurekalert.org/pub_releases/2010-08/tpco-reg082010.php 
-http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2010.05556.x/full+https://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2010.05556.x/full
  
  
-In a 2008 paper, Liu lists the different pattern recognition receptors in humans.(({{pubmed>long:19000576}}))+In a 2008 paper, Liu lists the different pattern recognition receptors in humans.(({{pmid>long:19000576}}))
 {{:home:pathogenesis:patternrecognition.png?nolink|}} {{:home:pathogenesis:patternrecognition.png?nolink|}}
  
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-Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells(({{pubmed>long:20414208}}))+Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells(({{pmid>long:20414208}}))
 {{:home:pathogenesis:screen_shot_2010-09-05_at_4.06.56_pm.png|}} {{:home:pathogenesis:screen_shot_2010-09-05_at_4.06.56_pm.png|}}
  
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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/differentiate into macrophages and dendritic cells to elicit an immune response       * 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/differentiate into macrophages and dendritic cells to elicit an immune response
  
-=====  References =====+=====  References =====</nodisp> 
home/pathogenesis/innate_immunity.1578866986.txt.gz · Last modified: 01.12.2020 by sallieq
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