Thursday, June 30, 2016

BtB#7: Immune cells of Central Nervous System


In a blog post long ago, I had commented that the central nervous system is immunologically isolated from rest of the body. In the post, I mainly focussed on talking about the need for an isolated system. In the event of inflammation and breach of BBB (Blood Brain Barrier), many different peripheral immune cells are allowed access to the brain. Under normal circumstances, most of the immunological functions are managed by cells exclusive to CNS. Very recently, it has been shown that CNS has a lymphatic system of its own. That means a lot of things that we assumed about CNS immunology is wrong and new research will be needed to rectify older theories.

Fig 1: Cells of CNS.
The CNS cells are divisible to into 2 different basic types- Neuronal cells and Glial cells. Glia refers to "cementing material". Earlier it was thought that glial cells are simply supporting cells and doesn't have any much function. Studies have proven otherwise. The glial cells are classified into 3 types
  • Microglia
  • Macroglia
  • Others

Of all the cells, Microglia is considered as the innate immune cell and first and line of defence. Astrocytes were thought of as a cell of importance in neuronal regulation. However, most recent findings conclude that they are important in regulating microglia and function as an immune modulator. Thus they too are included as Immune cells (at least in part) of CNS.


Fig 3: Structure of Microglia.
Microglia is originally derived from yolk sac during the developmental stage and is exclusively maintained in CNS. In the case of depletion of the microglia, they can be derived from peripheral myeloid cells. The microglia forms roughly 10–15% of all cells found within the brain. They can be identified by flow cytometry using phenotype CD11b+, CD45low.

Microglia in the brain exists in 2 possible forms- (i) Ramified or (ii) Activated. Everything described in the literature is one of the 2 forms or an intermediate state.

Table 1: Factors involved in activation of Microglia.
Ramified microglia are simply resting microglial cells. They are identified by their long thin branching processes and a small cellular body. It has been noted that each microglia has a micro-territory where it works and scans for damage. They are immunologically inactive (They possess very low MHC I/II molecules on their surface). The branching process moves very rapidly around the environment (estimated speed of 1.5 µm/min). These cells are extremely sensitive to changes in the environment. Microglia can be activated several factors. The factors are categorised into 2 types- "Off signal" and "On signal". Other than the innate molecules molecules such as LPS and toxins can activate microglia. In the event of a neural damage, the microglial cells are rapidly activated. The cells become motile, and using amoeboid-like movements and immediately surround the site of damage. If the damage persists and cells begin to die or degenerate microglial cells undergo further differentiation and assume the role of phagocytes.

Fig 4: Microglial functions. Source
Microglia offers several functions in CNS such as scavenging, phagocytosis, neuronal repair. Even on a day to day basis, several types of cellular debris accumulates in the brain. These are cleared up the microglial cells. One important function is neuronal repair. After an inflammatory event the microglia clears up the cellular mess and induces neuronal repair. This is achieved by secreting anti inflammatory cytokines, recrutiment of astroglial cells and promoting building of neuronal cell network. This is achieved through a mechasnim called as synaptic stripping. Microglia physically interacts with injured neurons and remove synapses which can extend to removing entire dendritic trees (depending on extent of damage). This allows proper reforming of new synapse and connections.

Microglia via its interaction with neuronal cells is recognised to play inportant roles in Mental health, memory formation and neurogenesis. Microglial dysregulation is considered as one of the important factors involved in Behavioral disorders and conditions such as Alzheimers (Lack of phagocytic activity leading to accumulation of Aβ Proteins).

Fig 5: CD4+ T cells interaction with microglia. Source
Just like Monocytes, and macrophages, microglia can have a range of phenotypes depending on their microenvironment. These are refferred as polarisation states. Microglia polarization states can be one of the following- classical activation (M1), alternative activation (M2a), type II alternative activation (M2b) or acquired deactivation (M2c). This polarisation can be achieved through interaction with different types of molecules or cells. For example, interaction with Th1 and Th17 cells leads to a more M1 like state. Th2 and Treg can influence M2 like. See Fig 5.


Fig 6: Neuron-Microglia and Astrocyte
Microglia Signaling Pathways. Source
As already explained astrocytes are not classicaly considered as immune cells. More recently it has however become clear that astrocytes control the microglial activity and the reverse is also true. It's a two way signalling system and both of them are also in direct contact with neurons.

Astrocytes form roughly about 40% of the glial cells and are the main supporting cells of Neurons. They are derived from the neuroepithelial cells during development. Their major role in structural (supporting neurons, formation of BBB), metabolic support for neurons (Regulation of ion concentration, fuel supply) and modulate synaptic transmission.

Immunologically, Microglia constantly communicates with astroglia via a 2 way signal. For example, Microgllia can be activated by ROS/RNS which can be controlled by Astroglia through soluble anti oxidant factors (thus controlling microglia activation). Another example, astroglia constantly removes K+ ions which otherwise leads to activation of microglia.

Table 2: Astrocyte-produced molecules and
immune functions. Source
In the event of chronic microglia activation, microglia can produce excessive quantitites of TNF-α. The excessive TNF-α then dampens the ability of astrocyte to uptake glutamate thereby leading to accumulation and neuronal toxicity (Excitotoxicity). I'm basically illutsrating some examples to imply that astrocytes and microglia immunologically talk to each other. Astrocytes can produce a variety of cytokines which mediates a variety of effects. Table 2 is a summation of molecules that exert or regulate pro-inflammatory functions.

To summarise, microglia are the primary immune cells of the CNS regulated mainly by astroglial cells. I really like this idea, "If Microglia is the police, Astroglia polices the police". Microglia and astroglia manages the immunology show within CNS, and only when help is needed does it allow peripheral cells to further participate.

      Louveau, Antoine et al. "Structural And Functional Features Of Central Nervous System Lymphatic Vessels". Nature 523.7560 (2015): 337-341.

Derecki, Noël C., James C. Cronk, and Jonathan Kipnis. "The Role Of Microglia In Brain Maintenance: Implications For Rett Syndrome". Trends in Immunology 34.3 (2013): 144-150.

Sofroniew, Michael V. "Astrocyte Barriers To Neurotoxic Inflammation". Nature Reviews Neuroscience 16.5 (2015): 249-263.

Shih, A. Y. "Policing The Police: Astrocytes Modulate Microglial Activation". Journal of Neuroscience 26.15 (2006): 3887-3888.