The immune system, defined in the simplest terms, is the system in our bodies that defends us against infectious disease. However, our immune systems are far more complex. Not only does it defend us against pathogens, it is also responsible for protecting us against cancer, initiating allergy symptoms, and determining the state of our general health. The Immune system itself is like a miniature world in our bodies, and it is populated with various immune cells that are supported by the cells making up the tissues and organs of the body. Each type of immune cell has its own specialized function. Some are good at fighting infectious bodies “hand to hand” like soldiers, while others are specialized at scouting, intelligence and recruiting other cell types during battle. During an immune response, the cells of the surrounding tissues also play their roles and, much like civilians in war, they fight, warn others, or die as a result of the battles. I will do my best to introduce you to this exciting world in simple terms. Sections: Self and Non-self Generation of Immune Cells Where are Immune Cells Located? Induction of an Immune Response Innate Immune Responses Adaptive Immune Responses Innate and Adaptive Interplay Self and Non-self To put it quite simply, the Immune System is designed to protect you. Immunologist refer to the body often as “self”. This includes all the products of the body ranging from your tissues to the smallest secreted molecules. Life forms and molecules that interact with your body are considered “non-self”. The non-self life forms are parasites, bacteria and viruses as well as friendly intestinal bacteria. Common non-self molecules that we often encounter are food, pollen and chemical substances from our environments (like drugs, cleaning products and hygienic products)1. The Generation of Immune Cells Cells of the immune system are born from hematopoietic stem cells found deep in the bone marrow. Hematopoietic stem cells are immortal, capable of generating daughter cells, called progenitors that will later give rise to different type of immune cells. There are two main types of progenitors created, the myeloid progenitors and the lymphoid progenitors2. Cells of Myeloid Progenitors Monocytes/macrophages, Dendritic cells Neutrophils Eosinophils Basophils Mast cells Cells of the Lymphoid Progenitors NK cells T cells B cells Dendritic cells3 Where Are the Immune Cells Located? For immunologists, the mammalian body is divided into three main regions: the primary lymphoid areas, the secondary lymphoid areas and the periphery. Primary Lymphoid Areas The primary lymphoid areas include the bone marrow and the thymus. The bone marrow, as we mentioned, is the site of immune cell generation2. The thymus, on the other hand, is the location of T cell development4. Lymphoid progenitor populations travel there from the bone marrow and produce a population of immature thymocytes. It is these thymocytes that give rise to the varied T cell populations. Secondary Lymphoid Areas The secondary lymphoid areas include the adenoids, tonsils, spleen, lymph nodes and lymphoid follicles found in the gastrointestinal system and the mucosa (areas adjacent to a mucus membrane). These areas house lymphocytes and support the development of an adaptive immune responses5-7. Periphery The periphery includes all regions that are not included in the primary and secondary lymphoid areas. This includes areas like the skin, brain, joints, muscles and gastrointestinal/mucosal areas surrounding lymphoid follicles. The Induction of an Immune Response In order for an immune response to be initiated, there must be some kind of danger. This is a fairly simple idea, but it leads to the question: How is danger defined by the immune system? This question is actually one of the most exciting topics of immunology today. Simply put, danger is sensed by the immune system through two main avenues: the recognition of a pathogen-associated molecular pattern (PAMP)8 or through the release of cell molecules associated with trauma which are called danger-associated molecular patterns (DAMPs) or alarmins9. Examples of PAMPs would be cell wall lipoproteins of bacteria and an example of DAMPs would be ATP (adenosine triphosphate), a nucleotide used as an energy source in cells10. PAMPs and DAMPs are recognized by the cells of the immune system and non-immune cells, through receptors located at the cell surface or internally8,9. PAMPs are also recognized by several non-cellular systems as well11,12. This recognition initiates the very first processes of an immune response called the innate immune response. Innate Immune Responses Immune cells, non-immune cells and non-cellular systems all participate in initiating an innate immune response. Why is it called “innate”? It’s innate because it depends on intrinsic systems that are built into your body to recognize danger and there is no learning or adaptation involved. Receptors of the Innate Immune Response In order to detect PAMPs or DAMPs, cells need tools to recognize them. These tools are protein receptors that can be found on the cell surface as well as internally. In general, they are called pattern recognition receptors or PRRs. These receptors come in families consisting of multiple members. Receptors that recognize PAMPs include the Toll-like receptors (TLRs), the C-type lectin receptors (CLRs), the NOD-like receptors (NLRs), RIG-I-like receptors (RLRs)8 and invariant T cell receptors13,14. DAMP receptors are not so clear-cut. TLRs have been implicated15 as well as the receptor for advanced glycation endproducts (RAGE)15. Also the purinergic receptors that recognize ATP would also fall into this category10. Toll-like Receptors These receptors are found on most cells of the body. They recognize a variety patterns associated with a number of pathogens including virus-associated nucleic acids; bacterial-associated cell wall components, protein, ribosomal RNA and DNA; and protozoan-associated proteins8. The majority is found extracellularly, but a number are also found intracellularly. When stimulated they activate the transcription factor NFκB, which is essential for activating a cell’s immune functions and set off a signal cascade via MAP kinase (a phosphorylating enzyme)8. C-type Lectin Receptors These receptors are specialized in recognizing carbohydrate structures, such as the sugar mannose, which is a common component of fungal cell walls16. Thus, these receptors are found on the cell surface. Though much of the literature involves their expression on immune cells, reports of CLR variants on non-immune cells can also be found17. On the phagocytic cells, it is known that they can participate in endocytosis, the engulfment of particles or pathogens and respiratory burst16. Some also appear to initiate signal cascades similar to TLRs leading to NFκB and MAP kinase activation, but it also appears that they can work in concert with TLRs, enhancing or inhibiting their function16. NOD-like Receptors These receptors are found in the cytoplasm of cells. Traces of their expression is found in most organs of the body18 and it is probably safe to say that most immune cells express at least some members of the NLR family. These receptors are designed to detect intracellular bacteria and, possibly, endogenous stress molecules and allow the cell to produce one of the most potent inflammatory mediators, Interleukin (IL)-1β19. RIG-I-like Receptors Like NLRs, RLRs are also found in the cytoplasm of a cell. Instead of detecting bacterial products, these receptors help detect viral infection20. They do this by binding to RNA produced during viral replication. Working together with nucleic-acid detecting TLRs, they lead to NFκB, MAP kinase activation and activation of Interferon regulatory factor (IRF) transcription factors20. The IRF transcription factors are necessary to produce cytokines specialized for the control of viral infections. Cytokines are small, secreted proteins used as messengers between cells, which alert surrounding immune cells about danger. Non-immune Cells in Innate Immunity Areas of the body that come in contact with the outside world (skin, gastrointestinal and mucosal areas) are covered with an epithelial layer. Epithelial layers are composed mainly of cells called epithelial cells. These cells form an anatomical barrier and they have their own immune functions. When exposed to DAMPs or PAMPs, epithelial cells produce inflammatory cytokines 21. The cells of the epithelial layer are often the main cells involved in the first detection of pathogens and/or danger. The majority of cells in the body also have this capacity. Other cell types like muscle cells, adipocytes and fibroblasts are all outfitted with receptors to detect PAMPs and DAMPs8,22. Just like citizens of a city, they will alert the authorities if there are any problems.