The Immune System: An Explainer
When we catch a cold, get an infection, or otherwise become sick, our bodies use a natural defense mechanism called the immune system to fight off what’s attacking us. The immune system has two ways of responding1. The first, called innate immunity, involves physical and chemical barriers like the skin and saliva, as well as many different types of cells that “eat” and destroy whatever is causing the trouble. While this innate response happens very quickly, then the downside is that it’s not very specific, and the immune cells can damage healthy parts of the body while trying to gobble up the foreign invaders. In order to specifically target particular offenders, the body uses its second way of responding: the adaptive immune system. This response can take days or weeks to develop but is also able to remember what the foreign invader looked like, so if it attacks again a targeted reaction can occur faster than the first time. To acquire this immunity against a particular foreign substance, the body uses two types of cells that act in different ways: T cells (which develop in an organ called the thymus, that’s where the “T” comes from) and B cells (which mature in the bone marrow, hence the “B”).
These two cell types are able to attack so specifically because each one recognizes a particular structure, called an antigen, on a foreign substance. For instance, one T cell might recognize a certain part of an influenza virus, while another could recognize a specific part of a bacterium; the same situation also holds true for B cells. The T and B cells travel around between different lymphoid tissues (organs like the spleen, tonsils, and lymph nodes, the last which are spread throughout the body) until they encounter their particular antigen. Once activated by their antigen, the T and B cells leave the lymph tissues and work in different ways to fight off the foreign invader (Figure 1).
T cells come in many varieties, but the two major types are cytotoxic and helper. Cytotoxic T cells (sometimes referred to as CD8+ T cells due to a particular identifier on their surface) travel to the disease site to search for cells that also bear the antigen that activated them, and destroy them. Helper T cells (sometimes referred to as CD4+ T cells), as the name might suggest, help activate other parts of the immune system. There are many subtypes of helper T cells that activate different types of responses; for instance, some promote the cytotoxic T cell response, while others activate B cells. Another kind of CD4+ T cell called regulatory cells actually tells the immune system, not to attack2.
Unlike T cells, B cells do not destroy their target. Instead, once they are activated by their antigen and T helper cells, they mature into plasma cells that produce antibodies, proteins that recognize the same antigen as the B cell. These antibodies essentially enhance the innate immune system and act in several ways, including neutralizing toxins, signaling to other immune cells that a cell should be attacked and destroyed, or activating complement. Complement is a group of proteins (not cells) that make up yet another arm of the immune system. These complement proteins can recruit immune cells or directly kill foreign cells themselves1.
T and B Cells in Autoimmune Encephalitis
So what happens in autoimmune encephalitis (AE)? In this and other autoimmune diseases, the body mistakenly recognizes part of itself as a foreign invader and mounts an attack. Scientists believe that AE starts when a tumor or virus causes proteins from neurons to be exposed to the immune system. The proteins get picked up by immune cells outside the brain that go on to activate T and B cells in lymphoid tissue. These activated cells then make their way into the brain where they cause AE3,4. Which cells are responsible for causing the disease depends on what antigen sets off the immune response.
In cases where the antigen comes from inside a cell, cytotoxic T cells are the culprits. When proteins from inside neurons like Hu, Yo, or Ma2 are the antigens, that usually indicates that the immune system first encountered the proteins in a cancerous tumor, which can express proteins from all sorts of cell types (this cancer association is why these antibodies and diseases are called “onconeural,” or “paraneoplastic”). Cytotoxic T cells fighting the tumor can make their way into the brain and kill neurons5. This cell death is likely part of the reason why patients with these diseases have poor recovery. Antibodies from B cells that have matured into plasma cells can also be produced in response to the tumor, but they do not contribute to AE symptoms6.
Antibodies do have a strong role in producing AE symptoms when the antigen comes from the outside surface of a neuron, like the NMDA receptor for instance. These antibodies can still be formed in reaction to a tumor, but this is less common. Research on NMDAR encephalitis, in particular, has revealed the presence of B cells and antibody-secreting plasma cells in the brain7,8. Because the antibodies have access to the surface proteins they target, they can bind to them and interfere with their function. In the case of NMDAR encephalitis, it’s thought that the antibodies cause the receptors, which normally are exposed to the outside of the cell, to be taken back inside so that they can’t function properly. Once the antibodies are gone the receptors can return to the cell surface, reversing many of the symptoms9. Unlike diseases in which the antibodies target intracellular proteins, in NMDAR encephalitis there are few to no cytotoxic T cells in the brain or neuronal death5,7,8. But while there are little to no cytotoxic T cells, there have been reports of helper T cells around blood vessels in the brain, including one type called Th17 that act to enhance the immune response10.
In other cases of encephalitis with antibodies again a cell surface protein, such as LGI1, CASPR2, or GABA receptors, the precise immune reaction is less certain and in some ways seems to be a little different from NMDAR encephalitis. B cells and plasma cells are still found in the brain, and antibodies also play a major role in causing symptoms5,11. For instance, antibodies against the GABAB receptor block it from functioning, while antibodies against LGI1 can disrupt interactions between proteins and lead to a decrease in AMPA receptors12. The involvement of T cells is unclear and may vary depending on the disease-causing antibody. For example, cytotoxic and helper T cells have been found in the brain of anti-GABAB receptor patients11, while few T cells were found in anti-VGKC-complex patients5. In addition, scientists sometimes observe signs of complement, the protein arm of the immune system that can kill cells5,6. In line with the presence of cytotoxic T cells and complement, neuronal loss is sometimes reported5,13.
Overall, the type of immune response the body produces appears to be dependent on the specific antigen. In general, diseases with antibodies that target intracellular proteins like Hu, Yo, or Ma2 involve cytotoxic T cells that kill neurons. In contrast, diseases with antibodies that target cell surface proteins like NMDAR, LGI1, and GABAR involve B cells in symptom production. In this second category, the role of T cells and complement may vary depending on the particular antigen.
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- Parkin, J. & Cohen, B. An overview of the immune system. Lancet 357, 1777–1789 (2001).
- Corthay, A. How do regulatory T cells work? Scand. J. Immunol. 70, 326–336 (2009).
- Venkatesan, A. & Adatia, K. Anti-NMDA-Receptor Encephalitis: From Bench to Clinic. ACS Chem. Neurosci. 8, 2586–2595 (2017).
- Dalmau, J. NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: The 2016 Cotzias Lecture. Neurology 87, 2471–2482 (2016).
- Bien, C. G. et al. Immunopathology of autoantibody-associated encephalitides: Clues for pathogenesis. Brain 135, 1622–1638 (2012).
- Damato, V., Balint, B., Kienzler, A. K. & Irani, S. R. The clinical features, underlying immunology, and treatment of autoantibody-mediated movement disorders. Mov. Disord. 33, 1376–1389 (2018).
- Martinez-Hernandez, E. et al. Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology 77, 589–593 (2011).
- Tüzün, E. et al. Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. Acta Neuropathol. 118, 737–743 (2009).
- Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091–1098 (2008).
- Zeng, C. et al. Th17 cells were recruited and accumulated in the cerebrospinal fluid and correlated with the poor prognosis of anti-NMDAR encephalitis. Acta Biochim. Biophys. Sin. (Shanghai). 50, 1266–1273 (2018).
- Golombeck, K. S. et al. Evidence of a pathogenic role for CD8 + T cells in anti-GABA B receptor limbic encephalitis. Neurol. Neuroimmunol. NeuroInflammation 3, 1–8 (2016).
- Dalmau, J. & Graus, F. Antibody-mediated encephalitis. N. Engl. J. Med. 378, 840–851 (2018).
- Shin, Y.-W. et al. Treatment strategies for autoimmune encephalitis. Ther. Adv. Neurol. Disord. 11, 1–19 (2018).
Figure 1 created with BioRender