Neuroinflammation Simplified – The Link Between the Immune System and The Brain- Dr Sanil Rege
Dr Sanil Rege’s talk on Neuroinflammation. In a previous article, he spoke about a young girl with mania who was found to have anti-neuronal antibodies and responded to immunosuppressants. In this talk, he explains the link between the immune system and the brain and how the brain can be ‘attacked by one’s own immune system under certain conditions.
Getting to know the Immune System
The Phagocyte will eat the bacterium first or an antigen. It will then take parts of these antigens to the surface and take it to a T lymphocyte – mainly the T-helper cell – and present the antigen to the T cell, but it usually does this in the context of the MHC which is a multihistocompatability complex. The T helper cell then gets activated. It will then bring in other B cells. B cells are essentially two types – the plasma cell, which produces antibodies and the memory cell, which will recognise similar antigens for the future so that it does not have to go through all of these steps again. This is the basics of the immune system.
The 4 Types of T Cells
- Th17 – extracellular bacteria, fungi, and autoimmunity
- Th1 – intracellular pathogens and autoimmunity
- iTreg – immune tolerance, lymphocyte homeostasis, and regulation of immune responses
- Th2 – extracellular parasites, allergy, and asthma
I would like to bring your attention to this one, the iTreg cells, because what we do know is that hormones such as thyroxine, lithium for example, vitamin D, is known to regulate these iTreg cells.
Activation of Autoimmunity
We’re exposed to oxidative stress all the time and we know that the mitochondrion is the energy powerhouse of the cell, particularly important in the brain, and it is particularly susceptible to oxidative stress because it does not contain much glutathione, which is necessary to prevent oxidative stress damage.
So what tends to happen is if the mitochondria are attacked and at the same time sort of break down then we tend to get things called damage-associated molecular patterns (DAMP’s) or pathogen-associated molecular patterns.
Now, pathogen-associated molecular patterns (PAMP’s) are of course when we have an infection, but damage associated molecular patterns are basically our own antigens that were initially cryptic, hidden from the immune system, are actually now exposed – look different to the body, so they start getting attacked.
Once that happens it binds to the Toll-like receptors… once the toll-like receptors are activated it sends off a cascade, and the cascade ends with the enhancing of the nuclear factor kappa beta, and this is the same factor that is enhanced by lithium. The NF-kB results in the release of self-antigens, immunogenic epitopes and proinflammatory cytokines. There is then a T and B cell response.
Autoimmune Reaction in the Brain
So we know that when there are immunogenic epitopes that are released in the body the body can start fighting them. Now sometimes there is a concept of molecular mimicry, which means certain antigens or certain foreign antigens even look like certain parts of the body so we can get cross-reaction.
Now if we look at the tight junction. The blood-brain barrier essentially consists of the astrocytes – these are the foot processes, we’ve got the endothelial cell and the tight junction. For many years the blood-brain barrier was considered to be impenetrable, but what we do know now is that there are very sophisticated pathways that actually connect the peripheral system with the CNS. There are gaps in the blood-brain barrier as well, so there can be easy transmission between the two.
Once T and B cells are activated they can interact with the endothelial system and pass through the barrier to the brain. This can then trigger off an immune system response within the CNS, which can be automatically amplified. When that happens, one of the key elements is the B cells part can pass through and can actually produce brain reactive antibodies. Then what happens is that the antibodies can act as four distinct mechanisms:
- Block neurotransmitter binding
- Enhance receptor activity
- Block ion channels
- Intracellular interference – can go through a process of apoptosis (programmed cell death)
Impact of Neuroinflammation on Mitochondria and Oligodendrocytes
Microglia receive inflammatory signals from the periphery which then reach the brain. Activated microglia, in turn, initiates an inflammatory cascade releasing cytokines, chemokines, inflammatory mediators, and reactive nitrogen and oxygen species (RNS and ROS) induces mutual activation of astroglia, thereby amplifying inflammatory signals within the CNS.
Cytokines, induce the enzyme, IDO (indolamine 2,3 dioxygenase), which breaks down Tryptophan, the primary precursor of 5-HT, into quinolinic acid (QUIN), a potent NMDA agonist and stimulator of Glutamate (GLU) release.
Excessive glutamate is associated with multiple effects such as decreased BDNF expression, excitotoxicity, and apoptosis. The oligodendrocytes which play a key role in the formation of myelin are particularly susceptible resulting in demyelination.
Want to learn more? Check out the other articles in the neuroimmunology section of the archives.
- Q & A Session on Neuroinflammation in Psychiatry – Dr. Sanil Rege
- The Neurobiology of Trauma and PTSD Phenotypes – Dr Sanil Rege
- Clozapine Mechanism of Action and Augmentation Strategy – Dr Sanil Rege
- Pathogenesis and Diagnostic Indicators for Antiphospholipid Syndrome (APS) in Psychiatry-Dr Sanil Rege
- Antiphospholipid Syndrome and the Brain (Neuropsychiatric Manifestations of APS) – Dr Sanil Rege
- Techniques to Prepare For the EMQ and Critical Analysis (MCQ) Problems – RANZCP Written Exam-Dr Sanil Rege
- Passing the Modified Essay (MEQ) and Critical Essay (CEQ) Exam- RANZCP- Dr Sanil Rege
- Essential Mental Models for A Psychiatrist – The Art of Complex Problem Solving- Dr Sanil Rege
- Observed Clinical Activity (OCA) and MEQ – Passing the RANZCP Exam- Dr Sanil Rege
- Sanil Rege on Education and Entrepreneurship – Podcast
- A Summary of 3 Important Autoimmune Neuropsychiatric Disorders for Psychiatrists – Dr Sanil Rege
- What is Regression Analysis in Critical Appraisal? – Dr Sanil Rege
- Principles of Entrepreneurship and Innovation in Medicine – Dr Sanil Rege
- The Power of Serendipity and Multidisciplinary Learning in Medicine – Solving a Complex Clinical Case- Dr Sanil Rege
- How To Appraise A Systematic Review and Meta Analysis in Clinical Practice- Dr Sanil Rege
- Psychiatric Formulation and Management- Tips and Techniques- Dr Sanil Rege
- Psychiatry Exams – What’s the Right Mindset?- Dr Sanil Rege
- Psychiatry Trainee to Consultant Psychiatrist – Skills Breakdown- Dr Sanil Rege
- From Psychiatry Trainee to Consultant Psychiatrist – Stages of Training for the RANZCP Exams- Dr Sanil Rege
- From Psychiatry Trainee to Consultant Psychiatrist- Dr Sanil Rege