Immune System


Immune system

Like other vertebrates teleost fish developed the means to protect or defend themselves from anything detected as a potential risk. This ability is mediated by defence mechanisms, essentially a set of cells and secreted factors that work in a complex and sophisticated manner: the immune system. For the purpose of this manual, this complex subject will be summarised for a general audience. The term “defence” is used broadly referring to all the mechanisms and tools that organisms use to protect from external insults such as pathogens (virus, bacteria, fungi or parasites), as well as chemicals, foreign molecules and even other animals action. In this sense, one of the immune system main properties is to distinguish “self” from “no self or foreign” (antigen), and to eliminate the later through the induction of a variety of mechanisms. In general terms the immune system is the response of the hosts to an antigen (Ag), which conversely, to be considered such, it must be capable of stimulating an immunological response. The mechanism of recognition would have been originated with the formation of “cell receptors” associated to surface molecules capable of binding to other molecules on the surface of other cells. This simple mechanism evolved into the vast complexity of the immune response. While the initial recognition of a specific Ag  is mainly done by cells belonging to the lymphocytes lineage, additional accessory cells are needed for antigen processing and presentation, as well as secreted mediators, or cytokines, required  for the proliferation, interaction and regulation of immune cells. The immune response is traditionally divided into two categories: innate (natural or non-specific) and acquired (adaptive, anticipatory, specific). Recently, the later has started to be referred to as “combinatorial response”. From an evolutionary point of view, fish seem to represent the transition between the innate immune response and the appearance of the more complex acquired immune response. Most of the known immune organs, tissues and functions in mammals have homologue structures and functions in fish, although structurally less complex, which may be related to a more limited or less effective response, lower antibody variability or to a relatively poorer immune memory response. The fish kidney, thymus, gills, liver, spleen, skin and digestive tract are involved in the processes of the immune system (link to haematopoietic system), the head kidney playing the major part in the immune function, harbouring many immune cell types involved in phagocytosis, antigen processing, immunoglobulin production and immune memory.  

Innate immunity

The innate response represents the earliest defence mechanism present in all living forms from the time of birth. It is inducible by foreign molecules and reacts rapidly providing the ability to recognize and destroy particles recognised as non self. The characteristic of “non-specificity”, allows it to react independently of the recognition or previous contacts with the potential invader. The innate response relies on the recognition of constitutional products of the organisms that have been preserved over the course of evolution, mediated by receptor proteins called PRRs (“pathogen or pattern recognition receptors”), which distinguish infectious no self, from non- infectious self. This mechanism well characterised in higher vertebrates is present in fish where PRRs and orthologous cytokines are functional and more complex to that found in invertebrates. Cell response includes physical barriers formed by intact epithelia and the secreted mucus that covers the skin, gills and digestive tract, preventing organisms and other aggressive agents from entering freely; and more specialized cells such as monocytes/macrophages, granulocytes and non-specific cytotoxic cells (equivalent to mammalian natural killer or NK cells), which can eliminate or ingest them. These cells are recruited towards the infection site by means of chemokines, cytokines, proteins responsible for the intercellular communication that regulates both the cytokine secreting cells, as well as other types of cells. Cytokines induce the activation of membrane receptors, cell proliferation and differentiation, chemotaxis, and even modulation of antibody or immunoglobulin secretion, among other functions. The humoral response uses a variety of proteins and glycoproteins that destroy or inhibit the growth or development of infectious organisms, including for example, antibacterial peptides, proteases, complement system, transferrins, C-reactive protein, lysozymes and interferon (IFN) and its inducible antiviral proteins.  

Acquired immunity

The acquired, adaptive, anticipatory, combinatorial or specific immune response is an inducible non-immediate response, described as “specific” because it is only effective against the particular foreign agent that triggered its reaction. In general it could be said that the acquired immunity comes to action when the first defensive barriers through the innate response have not been enough of fully effective in preventing an infection. The acquired system is based on the selective recognition of the Ag and has the potential to launch two types of response: humoral (by B lymphocytes) and cell-mediated (T lymphocytes) and has the advantage of a memory component. The humoral response is based on the recognition of the antigen by means of antibodies (Ab) or “immunoglobulins” (Ig), which bond specifically to a single type of  antigen. The process by which an antigen activates a single type of B cells is known as the “clonal selection”. That is, when the Ag is recognized by a naïve B lymphocyte and a number of other cell types, these cells undergo a process of cell proliferation (clonal expansion) until there are enough cells to develop an adequate response, ultimately leading to Ab-producing plasma cells. Thus, it is the Ag that selects the cell clone specifically capable of fixing it, and once synthesized the secreted Ab circulate in the bloodstream and different body fluids where they bind specifically to the Ag that induced their formation. They can work by activating the complement system, agglutinating bacteria, opsonizing antigens, acting as a helper antibody or releasing histamine, or directly neutralising the pathogen. Teleost fish have different immunoglobulins (IgM, IgD, IgH and IgT), of which IgM has been studied most. The T lymphocytes (helpers and cytotoxic) play a central role in regulating the immune response, by actively participating in various functions involving secretion, recognition and activation, but they also take part directly in the destruction of aggressive agents. Immunological memory provides the host that has been previously challenged and recovered from a given pathogen, with an effective state of “preventive alert” against subsequent contact with the same pathogen harbouring the same Ag. Memory B or T cells are part of a populations of lymphoid cells capable of generating an efficient and faster “secondary” immune response, a stronger reaction to subsequent challenges with a pathogen carrying an antigen that has already been encountered. Specificity and memory, distinguish acquired and innate immune systems. The immune system normally works efficiently but like any other, is vulnerable to factors that may depress it affecting the response. Inherent (intrinsic) or external (extrinsic) factors may also alter the behaviour and development of the immune response. Intrinsic factors are those such as age, weight, sex, nutritional or sanitary condition or stage of development; extrinsic factors are related to seasonal change (light and temperature), water quality or salinity, for example. As fish are poikilothermic, temperature variations are critical, and the optimum temperature for an adequate response is that of the environment in which the species normally develops. Within the species normal temperature window, the higher the temperature, the shorter the induction phase and the greater the immune response can be. Conversely, at low temperatures, the induction phase is longer and there is a reduction in the antibody concentration or even complete lack of response. In summary, the main function of the immune response is to eliminate the antigen through a variety of cellular and humoral mechanisms. The relative importance of the two kinds of response (innate and acquired) varies, and they are also affected by different factors. It is important to highlight that although the division between innate and acquired immunity serves for the description of a complex system, both responses work together by interacting and regulating each other. Additionally to the inherent and normal physiological processes, the immune system is essentially vulnerable as well to the acute or chronic cumulative effect of stress. Fish, like other organisms, are able to respond positively to stress by means of physiological and behavioural reactions to adapt to the new situation (eustress). However, when the stress-causing stimulus is very acute or persistent, it exceeds the ability to adjust (distress), reducing some defence reactions such as phagocytosis, inflammatory response or tissue repair, and ultimately leading to “immunosuppression”, facilitating the invasion by infectious agents. Some pathogens moreover can also induce immunosuppression, e.g. through complex mechanisms of evasion in certain viral infections or by secreting modulators that prevent an effective immune response, as with some parasites.

Further reading:

– The Laboratory Fish (2000) Gary K Ostrander (Ed). Chapters 14 and 26 (by David B Powell), Academic Press. ISBN: 978-0-12-529650-2.

-Developmental & Comparative Immunology, Volume 43, Issue 2, (2014) Immunity to infectious diseases of fish. Edited by Miodrag Belosevic and Geert F. Wiegertjes.

– Fletcher, Thelma C, and Secombes, Christopher J (2010) Immunology of Fish. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000520.pub2]