It’s brain awareness week!

Hello all!  I wanted to take a few minutes to write something for the brain awareness week. This is important to me because my research focusses on understanding the role of the immune system in the brain. For a very long time, the brain was thought to be an “immune privileged” organ i.e., it was thought that the brain is protected from all the peripheral insults and that it is “divorced” from the rest of the body. In 2015, it was shown that there exists certain lymphatic vessels that connect the CNS to the rest of the body (1). The lymphatic system carries immune cells through a network of vessels and tissues; it connects the bloodstream and tissues in order to remove dead cells and other debris. The discovery of the new “glymphatic system” has opened new avenues to study the connection between the brain and the rest of the body. This is especially helpful in understanding the role of the peripheral immune system on the CNS during infections, injury, and other disease insults.

glymphatic system
Old lymphatic system (left) and newly discovered lymphatic system in the CNS (right). Source: University of Virginia Health System

My work focusses on a specific cell type in the brain known as microglia which are are the resident macrophages of the CNS (they eat up and clear out the bad stuff in the brain like dead cells and mis-folded proteins). Microglia are the only known immune cells of the brain. Compared to all that’s known about the cells of our body’s immune system (B cells, T cells, NK cells, neutrophils, basophils, Treg cells, MDSCs, TH1, TH2, and many many more with several subtypes of each cell), it is safe to say that cells of the CNS are poorly understood. My efforts are focussed towards understanding the role of microglial cells in neurodegenerative diseases such as Alzheimer’s Diseases (AD) , Parkinson’s Disease (PD), Multiple Sclerosis (MS), etcetera. These diseases are characterized by mis-folded proteins that aggregate in the different regions of the brain tissues causing the neurons to degenerate and eventually die. The microglial cells in these disorders play a major role in disease progression by regulating many pathways involved in cell-cell communication, cell survival, and cell death. This is a relatively new and an exciting area of study with many missing links and questions to be answered. I will try my best to keep this space alive with updates and stories! In the meantime, here’s a fun read on Leonardo da Vinci’s contributions to neuroscience: http://www.sciencedirect.com/science/article/pii/S0166223600021214

And here’s a 1504-1506 drawing of the human brain by da Vinci:

Leonardo da Vinci's contributions to neuroscience
In the upper figure, the three ventricles are labeled imprensiva (anterior ventricle, corresponding to the paired lateral ventricles), senso comune (third ventricle), and memoria (posterior or fourth ventricle). Below the ventricles, seven pairs of cranial nerves are shown. The lower figure shows a human head in an exploded view, with the skull raised over the brain and from the head. Source: 

Sources:

  1. Louveau A, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–341. doi: 10.1038/nature14432.
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The Biology of Vaccination

I was never too involved in the vaccination debate until I came to the United States. Back home in India, the majority of us seem to be grateful to science for being able to wipe out dreadful diseases like MMR (mumps-measles-rubella) and polio, and prevent the lifelong suffering of thousands of people. A friend recently mentioned that his mother refused to vaccinate him as a child when she observed escalated fever-like-symptoms every time he got an immunization shot. This is one small example of a widespread scientific ignorance that lures people into believing in absurd anti-vax propaganda.

Let’s talk about the biology of vaccination. A vaccine is a weakened form of a disease-causing agent that boosts the immune system and provides protection against natural infection. This “agent” may be an altered form of the infection or its less dangerous close relative. A vaccine is usually combined with an adjuvant – a chemical that enhances the immune response. Prior to vaccination, a process known as variolation remained popular in the 17th and 18th century. In this, scab material taken from a mild form of smallpox was inoculated through the skin to curb the disease. Variolation was in no way harmless and therefore ceased to be in use when safer alternatives were sought. The history of vaccination is one of the most interesting stories in the field of science and medicine. Edward Jenner (the father of Immunology) – after having observed that milkmaids exposed to cowpox were protected from smallpox disease,  treated the locals with cowpox scabs and successfully prevented the occurrence of smallpox.

So how does vaccination work? I have briefly talked about the two main kinds of immune responses in one of my earlier posts. Further, acquired immunity consists of antibody (humoral) response and cell-mediated response that involves various types of white blood cells (WBCs) like macrophages, dendritic cells, T-lymphocytes and B-lymphocytes. When an infectious agent enters the body, chemicals called chemokines and cytokines recruit WBCs to the area of infection. The pathogen is broken down into its constituent proteins by Antigen-Presenting Cells (APCs) and is then “presented” to the helper T-lymphocytes (CD4+ T cells). These lymphocytes actively mediate protective immunity.

In humoral immunity, the receptors on B-cells recognize specific antigenic proteins, get activated and multiply to make hundreds of identical cells. Upon maturation, these plasma cells release a large number of antibodies that are specific to the antigen. This rapid increase in the number of antibodies is sufficient to eliminate the pathogen. Apart from the B-cells, cytotoxic T-cells (CD8+ T cells) also induce an immune response by directly destroying antigens that are presented by the APCs.

Primary exposure to pathogen via vaccine and secondary exposure to pathogen via infection - Sequence of events.
Primary exposure to pathogen via vaccine and secondary exposure to pathogen via infection – Sequence of events with respect to humoral immunity. Cell-mediated immunity works similarly through cytotoxic T cells – Activated cytotoxic T cells directly destroys the antigen. (Not shown) — CLICK TO ENLARGE —

When the infection is cleared, the immune response reduces and so does the number of antibodies and cytotoxic T-cells. During this time, some of the T- and B-cells become memory cells and preserve their antigen-specific surface receptor. These cells stick around in our serum and wait for a subsequent attack by the same pathogen. This is the crux of vaccination.

When our body is invaded by the same pathogen again, these memory cells immediately proliferate and release surplus of specific antibodies against it. This secondary response is faster and involves a greater number of cells, and is therefore more effective than the primary response. Vaccination establishes a pool of memory cells that are specific to the antigen and prepares the body in case of future infection. Therefore, when a weakened form of the pathogen is intentionally administered to us, our body develops an “actively acquired immunity” for a quicker and a more efficient secondary response.

Antibody response during primary and secondary exposure
Antibody response during primary and secondary exposure

The milkmaids from Edward Jenner’s anecdote had acquired an active immunity for smallpox virus because they were previously infected by the cowpox virus (both poxviruses, members of the Poxviridae family) due to their occupation. Also, when my friends mother observed an escalated fever-like symptoms after the vaccine shot, it was merely the body’s primary immune response to the infection – completely normal and a sign of an actively functioning immune system.

Though the science of vaccination is pretty forthright, many concern arises regarding its safety, constituents, production and side-effects. It is important to understand that every immune system is unique due to which every person may respond differently to different vaccines. Many of the health and safety claims (with respect to autism, mercury, formaldehyde, and so on) have already been debunked extensively by reputed scientific sources. Also, parents choosing not to vaccinate their kids against the government’s decision are endangering the rest of the community. Herd immunity works when the larger part of the population is resistant to a pathogen providing protection to those without immunity thereby preventing an outbreak. And finally, if you’re against vaccination due to your religious beliefs, please pack up and leave.

Interestingness –

  1. How the anti-vaccine movement is endangering lives
  2. The dangerous consequences of anti-vaccine propaganda in one map
  3. Understanding Herd Immunity
  4. 9 vaccination myths busted. With science!

Memory response of Natural Killer cells

The beauty of our immune system lies in the diversity of the cells involved in the responses triggered by a range of pathogens. These responses can be broadly classified into two groups: innate immune response, which is mainly a non-specific first line of defence, and adaptive immune response, which is acquired over the lifetime of all vertebrates and contains highly differentiated cells that are specific to the antigen. These cells are capable of recognizing the antigens upon secondary exposure and therefore contribute to the memory of the immune system.

Until now, natural killer (NK) cells were considered to be a significant part of the innate immune system participating in non-specific responses. These cells play important functional roles against tumor cells and virus infected cells, through their cytolytic activity. Like T and B cells of the adaptive immunity, NK cells do not express RAG (recombination-activating gene) proteins that are required for assembling the antigen specific receptors on the cells. Based on this concept, RAG knockout mice are common model organism to study cell-mediated immune responses as they lack a functional adaptive system.

Figure 1 - Rag1/2 knockout mouse lacks memory
Figure 1 – Rag1/2 knockout mouse lacks memory

Contact hypersensitivity (CHS) is another significant experimental model used to study cell-mediated immune function in the context of memory.1 In this, epidermal cells that are exposed to haptens (compounds that modifies proteins and elicit an immune response) exhibit a delayed-type hypersensitivity reaction. It was first shown by O’Leary et al.2 that Rag2 knockout mice exhibited hapten induced CHS due to NK cells, thus confirming the role of NK cells in memory responses.

Figure 2 - Hapten induced Rag2 knockout mouse exhibited CHS
Figure 2 – Hapten induced Rag2 knockout mouse exhibited CHS

So how did O’Leary et al. confirm that it was indeed NK cells that was responsible for inducing hypersensitivity and not other cell types of the innate immune system? As shown in Fig. 2 above, Rag2 knockout mouse that is incapable of producing mature T and B cells still reacted to the hapten. However, Rag2/II2rg double knockout mice did not exhibit the hypersensitivity reaction when exposed to haptens. These double knockout mice lack NK cells along with T and B cells. Moreover, the Rag2 deficient mice that were treated with anti-NK 1.1 antibody (binds to receptors on NK cells and prevents activity) also showed no hypersensitivity response to the haptens. The wild type mice treated with anti-NK 1.1 antibody exhibited CHS due to the activity of T and B cells.

The study of immune responses is still a new and exciting field with many unanswered questions and unknown terrains yet to be discovered. This novel insight on NK cells possessing adaptive immune-like responses and its role in memory could be significant in designing next generation vaccines against a range of pathogens.

References:

  1. Gaspari AA, Katz SI. Contact hypersensitivity. Current Protocols in Immunology. 2001 Chapter 4, Unit 4 2.
  2. O’Leary, J.G. , Goodarzi, M. , Drayton, D.L. & von Andrian, U.H. T cell- and B cell- independent adaptive immunity mediated by natural killer cells. Nature Immunology. 7, 507–516 (2006).