uprightdoc wrote:
Although they lack a lymphatic system, the brain and cord don't have a unqiue immune system. They use they same white blood cell system as the rest of the body.
Inflammation is a key culprit and many things from injuries to infections can cause inflammation. But there is much more to neurodegenerative diseases, much of it involves basic physics, nothing more. It's the impact of physics on physiology that sets up the neurodegenerative process.
Dr F are you sure that is what you think?
The CNS definitely has a lymphatic system and you have spoken about it before. The lymph system is spoken about in Angelique Corthals, "Multiple Sclerosis (MS) is not a disease of the immune system," The Quarterly Review of Biology 86:4 (December 2011).
http://www.jstor.org/discover/10.1086/6 ... 2826242283
and;
http://www.eurekalert.org/pub_releases/ ... um=twitter
The issues of a dysfunctional immune system inside and outside the BBB are likely to go hand in glove with the Flanagan Hypothesis of physics and physiology in neuro-de-generative disease BUT cannot happen without each other!!
;)
Nigel
What prompted my comment above was the tireless work of a friend who spent time looking into the immune system or lymph system of the brain;
""Upright Doc
Although they lack a lymphatic system, the brain and cord don't have a unqiue immune system."
I've just pulled together some basic descriptions of glial cells, particularly the microglial cells that shows that this is a very different immune system than on the other side of BBB. Interestingly, with all the research on the role of vitamin D in the non-CNS side of the BBB, I can find little on what it does in the CNS, though I would expect it to be similar.
The discussion here seems to be about where discussions of its role in immunity was about 10-15 years ago in the rest of the body. It was simply not recognized that vitamin D as a regulatory hormone was what was directing all of this. Could be different. There may be some other hormone in the CNS, but I think that is not likely to be the case.
Regulation of innate immune responses in the brain
Serge Rivest
Abstract
Microglial cells are the main innate immune cells of the complex cellular structure of the brain. These cells respond quickly to pathogens and injury, accumulate in regions of degeneration and produce a wide variety of pro-inflammatory molecules. These observations have resulted in active debate regarding the exact role of microglial cells in the brain and whether they have beneficial or detrimental functions. Careful targeting of these cells could have therapeutic benefits for several types of trauma and disease specific to the central nervous system. This Review discusses the molecular details underlying the innate immune response in the brain during infection, injury and disease.
Wiki (I've highlighted things that are parallel to what vitamin D does in the body. Again, I suspect that this is all under the control of VitD, but there seems to be little research on that and all the immunological functions that are attributed here to microglial cells are likely to be directed by calcitriol within them, rather than the cells themselves, at least at the molecular level.)
Glial cells, sometimes called neuroglia or simply glia (Greek γλία, γλοία "glue"; pronounced in English as either /ˈɡliːə/ or /ˈɡlaɪə/), are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain and peripheral nervous system.[1]
As the Greek name implies, glia are commonly known as the glue of the nervous system; however, this is not fully accurate. Neuroscience currently identifies four main functions of glial cells:
To surround neurons and hold them in place,
To supply nutrients and oxygen to neurons,
To insulate one neuron from another,
To destroy pathogens and remove dead neurons.
During early embryogenesis glial cells direct the migration of neurons and produce molecules that modify the growth of axons and dendrites.
Glia have a role in the regulation of repair of neurons after injury. In the CNS (Central Nervous System), glia suppress repair. Glial cells known as astrocytes enlarge and proliferate to form a scar and produce inhibitory molecules that inhibit regrowth of a damaged or severed axon. In the PNS (Peripheral Nervous System), glial cells known as Schwann cells promote repair.
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system (CNS).
The brain and spinal cord are considered "immune privileged" organs in that they are separated from the rest of the body by a series of endothelial cells known as the blood–brain barrier, which prevents most infections from reaching the vulnerable nervous tissue. In the case where infectious agents are directly introduced to the brain or cross the blood–brain barrier, microglial cells must react quickly to decrease inflammation and destroy the infectious agents before they damage the sensitive neural tissue. Due to the unavailability of antibodies from the rest of the body (few antibodies are small enough to cross the blood brain barrier), microglia must be able to recognize foreign bodies, swallow them, and act as antigen-presenting cells activating T-cells. Since this process must be done quickly to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS.[5]
Functions
Microglial cells fulfill a variety of different tasks within the CNS mainly related to both immune response and maintaining homeostasis. The following are some of the major known functions carried out by these cells.
Scavenging
In addition to being very sensitive to small changes in their environment, each microglial cell also physically surveys its domain on a regular basis. This action is carried out in the ameboid and resting states. While moving through its set region, if the microglial cell finds any foreign material, damaged cells, apoptotic cells, neural tangles, DNA fragments, or plaques it will activate and phagocytose the material or cell. In this manner microglial cells also act as "housekeepers" cleaning up random cellular debris.[7] During developmental wiring of the brain, microglial cells play a large role removing unwanted excess cellular matter. Post development, the majority of dead or apoptotic cells are found in the cerebral cortex and the subcortical white matter. This may explain why the majority of ameboid microglial cells are found within the "fountains of microglia" in the cerebral cortex.[12]
Phagocytosis
The main role of microglia, phagocytosis, involves the engulfing of various materials. Engulfed materials generally consist of cellular debris, lipids, and apoptotic cells in the non-inflamed state, and invading virus, bacteria, or other foreign materials in the inflamed state. Once the microglial cell is "full" it stops phagocytic activity and changes into a relatively non-reactive gitter cell.
Cytotoxicity
In addition to being able to destroy infectious organisms through cell to cell contact via phagocytosis, microglia can also release a variety of cytotoxic substances. Microglia in culture secrete large amounts of H2O2 and NO in a process known as ‘respiratory burst'. Both of these chemicals can directly damage cells and lead to neuronal cell death. Proteases secreted by microglia catabolise specific proteins causing direct cellular damage, while cytokines like IL-1 promote demyelination of neuronal axons. Finally, microglia can injure neurons through NMDA receptor-mediated processes by secreting glutamate and aspartate. Cytotoxic secretion is aimed at destroying infected neurons, virus, and bacteria, but can also cause large amounts of collateral neural damage. As a result, chronic inflammatory response can result in large scale neural damage as the microglia ravage the brain in an attempt to destroy the invading infection.[4]
Antigen presentation
As mentioned above, resident non-activated microglia act as poor antigen presenting cells due to their lack of MHC class I/II proteins. Upon activation they rapidly uptake MHC class I/II proteins and quickly become efficient antigen presenters. In some cases, microglia can also be activated by IFN-γ to present antigens, but do not function as effectively as if they had undergone uptake of MHC class I/II proteins. During inflammation, T-cells cross the blood–brain barrier thanks to specialized surface markers and then directly bind to microglia in order to receive antigens. Once they have been presented with antigens, T-cells go on to fulfill a variety of roles including pro-inflammatory recruitment, formation of immunomemories, secretion of cytotoxic materials, and direct attacks on the plasma membranes of foreign cells.[4][7]
Synaptic stripping
In a phenomenon first noticed in spinal lesions by Blinzinger and Kreutzberg in 1968, post-inflammation microglia remove the branches from nerves near damaged tissue. This helps promote regrowth and remapping of damaged neural circuitry.[4]
Promotion of repair
Post-inflammation, microglia undergo several steps to promote regrowth of neural tissue. These include synaptic stripping, secretion of anti-inflammatory cytokines, recruitment of neurons and astrocytes to the damaged area, and formation of gitter cells. Without microglial cells regrowth and remapping would be considerably slower in the resident areas of the CNS and almost impossible in many of the vascular systems surrounding the brain and eyes.[4][6]
Extracellular signaling
A large part of microglial cell's role in the brain is maintaining homeostasis in non-infected regions and promoting inflammation in infected or damaged tissue. Microglia accomplish this through an extremely complicated series of extracellular signaling molecules which allow them to communicate with other microglia, astrocytes, nerves, T-cells, and myeloid progenitor cells. As mentioned above the cytokine IFN-γ can be used to activate microglial cells. In addition, after becoming activated with IFN-γ, microglia also release more IFN-γ into the extracellular space. This activates more microglia and starts a cytokine induced activation cascade rapidly activating all nearby microglia. Microglia-produced TNF-α causes neural tissue to undergo apoptosis and increases inflammation. IL-8 promotes B-cell growth and differentiation, allowing it to assist microglia in fighting infection. Another cytokine, IL-1, inhibits the cytokines IL-10 and TGF-β, which downregulate antigen presentation and pro-inflammatory signaling. Additional dendritic cells and T-cells are recruited to the site of injury through the microglial production of the chemotactic molecules like MDC, IL-8, and MIP-3β. Finally, PGE2 and other prostanoids help prevent chronic inflammation by inhibiting microglial pro-inflammatory response and downregulating Th1 (T-helper cell) response.[7]
Role in chronic neuroinflammation
The word neuroinflammation has come to stand for chronic, central nervous system (CNS) specific, inflammation-like glial responses that may produce neurodegenerative symptoms such as plaque formation, dystrophic neurite growth, and excessive tau phosphorylation.[16] It is important to distinguish between acute and chronic neuroinflammation. Acute neuroinflammation is generally caused by some neuronal injury after which microglia migrate to the injured site engulfing dead cells and debris.[16] The term neuroinflammation generally refers to more chronic, sustained injury when the responses of microglial cells contribute to and expand the neurodestructive effects, worsening the disease process.[16]
When microglia are activated they take on an amoeboid shape and they alter their gene expression. Altered gene expression leads to the production of numerous potentially neurotoxic mediators. These mediators are important in the normal functions of microglia and their production is usually decreased once their task is complete.[17] In chronic neuroinflammation, microglia remain activated for an extended period during which the production of mediators is sustained longer than usual.[17] This increase in mediators contributes to neuronal death.[17]
Neuroinflammation is distinct from inflammation in other organs, but does include some similar mechanisms such as the localized production of chemoattractant molecules to the site of inflammation.[17] The following list contains a few of the numerous substances that are secreted when microglia are activated:
Cytokines
Microglia activate the proinflammatory cytokines IL-1α, IL-1β and TNF-α in the CNS.[17] Cytokines play a potential role in neurodegeneration when microglia remain in a sustained activated state.[17] Direct injection of the cytokines IL-1α, IL-1β and TNF-α into the CNS result in local inflammatory responses and neuronal degradation.[17] This is in contrast with the potential neurotrophic (inducing growth of neurons) actions of these cytokines during acute neuroinflammation.[17]
Chemokines
Chemokines are cytokines that stimulate directional migration of inflammatory cells in vitro and in vivo.[17] Chemokines are divided into four main subfamilies: C, CC, CXC, and CX3C. Microglial cells are sources of some chemokines and express the monocyte chemoattractant protein-1 (MCP-1) chemokine in particular.[17] Other inflammatory cytokines like IL-1β and TNF-α, as well as bacterial-derived lipopolysaccharide (LPS) may stimulate microglia to produce MCP-1, MIP-1α, and MIP-1β.[17] Microglia can express CCR3, CCR5, CXCR4, and CX3CR1 in vitro.[17] Chemokines are proinflammatory and therefore contribute to the neuroinflammation process.[17]"
