Innate immunity, our sentinel

December 20, 2016

Have you ever wondered why you stay healthy while your friends are sick with a flu? Or why you are not sick all the time when the microbes are all around us? You can thank to your innate immune system, the first line of defence against all sort of pathogens. The role of the innate immunity was long underestimated but now it is becoming clear that it is an important process without which the evolutionary more developed adaptive response couldn’t exist.

So how does the innate immune system work? Everyone knows that the blood contains red blood cells, white blood cells and platelets with a distinct but important functions (Fig. 1). The red blood cells carry oxygen so our tissues do not suffocate; the white cells counteract and fight pathogens so we are not sick; and the platelets stop bleeding by clumping and clotting blood vessels.

Figure 1: Types of cells in the blood.

Ok, so far so good, but from now on the things are getting more complicated. There are several types of white cells or also known as leukocytes including lymphocytes, granulocytes, and monocytes, and even though they are all rounded and contains nucleus, they have distinct functions. Lymphocytes are cells of the adaptive immunity and comprises B and T cells. Both B and T cells have a big nuclei and they can live for years. B cells are the main cells producing antibodies which are specific against pathogens while T cells help to orchestrate the innate and adaptive responses. Consequently, the adaptive immune response takes days or weeks to be activated (Fig. 2). So if we relied solely on the adaptive immunity, we would be very sick by the time our bodies have produced the antibodies. And it is within this time when the innate immune response takes place.

                   Figure 2: The cells of the immune system and time needed for their activation after infection.

The cells of the innate immune system, granulocytes and monocytes, are short lived cells that circulate in the blood or reside in the tissues. Granulocytes are white cells with a typically segmented nuclei and presence of granules in the cytoplasm containing distinct antimicrobial enzymes. Monocytes, on the other hand, have a kidney shaped nuclei with no granules in the cytoplasm. Upon activation, blood monocytes mature into macrophages moving to the specific tissues.

Figure 3: Phagocytosis of bacteria by a phagocytic cell.

The most prominent characteristics of innate cells is their ability to phagocytose and to destruct the pathogen within a short period of time. Phagocytosis is an important process by which cell take up a pathogen and then by the action of distinct enzymes the microbe is eliminated within the cell (Fig. 3). During this process, the cells also release molecules, called chemokines, which attract more immune cells to the site of the infection to help fighting the invading pathogens. However, after resolution of the infection, the immune cells die and we can observe the result of this whole process as a pus. Furthermore, the innate immune cells migrate to the lymph nodes where they activate T cells and T cells consequently activate B cells and thus antibody production which helps to fight the pathogens during later stages of the infection. So the innate immune system function as the first barricade: it blocks or slow down invading microbes, it also alerts the cells of adaptive immune system, and it also informs which type of weaponry to mount.

But how is it possible that the immune cells recognize the pathogens and they do not attack our own cells and tissues? The immune cells indeed recognize our tissues as well as a wide variety of pathogens ranging from viruses to bacteria and fungi. But the innate response is only triggered when specialized pattern recognition receptors aka PRRs recognize specific parts of pathogens termed as pathogen-associated molecular patterns or PAMPs (Fig. 4).

PAMPs are evolutionary conserved components of pathogens that are essential for their structure, survival and propagation such as bacterial carbohydrates (lipopolysaccharide, lipoteichoic acid), proteins (flagellin) and nucleic acids (viral dsRNA, bacterial DNA). PAMPs are also structures that do not naturally occurred in our body or they are modified so that they are distinct from the “self”. However, researcher recently described a new class of antigens that is produced by our own cells and it can trigger immune response. These antigens were termed as danger-associated molecular patterns or DAMPs and they are released by cells that underwent a cellular damage and thus DAMPs act as an internal stress signals. But the exact mechanism of action is not yet completely understood as does the possible links to diseases.

Figure 4: Recognition of a PAMP via a cellular PRR (TLR, Toll-like receptor).

PRRs are germline-encoded receptors that are abundantly expressed by immune cells and to a lesser degree by other non-immune cells such as skin cells. PRRs are a superfamily of many groups of receptors which have different structures, recognize distinct PAMPs but their main function is activation of immune responses (Fig. 5). In the cell, PRRs trigger signaling cascades that leads to activation of transcription factors: nuclear factor κ B (NFκB) and interferon regulatory factors (IRFs), which then initiate transcription of immune genes. NFκB is the key regulator of proinflammatory responses during bacterial infections while IRFs provide an antiviral response by induction type I interferons.

          Figure 5: One group of PRRs, Toll-like receptors (TLR) and their respective PAMPs.

In an ideal scenario then, the innate immune response will halt the infection even before we feel under the weather. So even though the innate immunity is often referred to as a primitive system, it is a powerful and complicated machinery that we are just beginning to appreciate.