**2. Innate and adaptive immunity**

The immune system of vertebrates is commonly divided into two main complementary parts, innate and adaptive immunity, the bridge between which is critical for an efficient and effective immune response.

The innate immune system is evolutionary the most primitive, where there is non-specific response to a broad class of antigens. The haematopoietic cells involved include macrophages, dendritic cells, mast cells, neutrophils, eosinophils, NK cells and NKT cells. Although 1908 Nobel Prize winner, Elie Metchnikoff, first described an important role for the innate immune system [30], it is only now being recognised as a critical regulator of human inflammatory disease. Innate immunity involves the recognition of infected cells through surface recognition receptors. These are termed pattern recognition receptors (PRRs) which recognise pathogen associated molecular patterns (PAMPs) unique to non-vertebrate cells, including bacteria and fungi. They are also on internal vesicle membranes for recognition of viral ssRNA and dsRNA and for distinguishing lysed bacterial components [31]. Cytotoxic innate lymphocytes can lyse abnormal or infected cells through the release of cytotoxic granules containing perforin or granzymes, and antigen presenting cells (APCs) can be activated by the innate immune system to present pathogen antigens on their surface. Once activated they will migrate to secondary lymph organs to present their antigen to T cells, and in so doing also activate the adaptive immune system response [32, 33]. The innate immune system therefore functions through a combination of cellular defences and humoral components to defend against nonspecific antigens before activating B and T cells, triggering an adaptive immune response. Speed is the main advantage of innate immunity, with a protective inflammatory response being generated within minutes of pathogen exposure.

Another part of innate immunity is the complement system, which is made up of several small proteins that have been synthesised in the liver and circulate in the blood as active precursors that when stimulated are proteolytically cleaved to release cytokines, leading to a cascade of reactions, ultimately resulting in complement activation or fixation [34]. As the name suggests, they complement or enhance the ability of antibodies and phagocytic cells to clear damaged or diseased cells by promoting inflammation and attack of the cell membrane of the pathogen. Antibodies, generated by the adaptive immune system, can activate the complement system.

Adaptive immunity, sometimes referred to as acquired immunity, is highly specialised and helps to protect the body by recognising antigens, whether they are foreign to the host's immune system (exogenous), produced by intracellular bacteria or viruses (intracellular) or produced by the host (autoantigen). The adaptive immune system also remembers previously encountered antigens, leading to quicker response times [35]. T and B lymphocytes are the main cells mediating adaptive immunity, with T cells being further divided into the cytotoxic CD8 T cells and CD4 T cells that constitute several classes of what are commonly referred to as "helper T cells". These cell have produced highly specific receptors for recognition of hundreds or even thousands of antigens through genetic recombination, and this facilitates pathogen specific immunologic effectors pathways, the generation of immunological memory and the regulation of host immune homoeostasis [36].

CD8 T cells recognise infected cells through interaction of T cell receptors with antigens presented by major histocompatibility complex (MHC) class I on the infected cell. The target cell is then killed by the release of cytotoxins, such as perforin and

granzymes, from the CD8 T cell [28]. CD4 T cells, on the other hand, recognise antigens presented in the context of MHC II on an APC. Binding to MHC II molecules activates CD4 T cells to release cytokines, which can stimulate CD8 T cells, macrophages and B cells to form an immune response (reviewed in [37]). They can, for example, release cytokines as instructors to CD8 T cells to release cytotoxins, or to B cells to produce pathogen specific antibodies. They therefore instigate and shape adaptive immune responses dependent on the cytokines they release. These can be mainly Th1, or inflammatory, in nature, such as IFN-γ and IL-12, responsible for the control of intracellular pathogens, or polarised to a more anti-inflammatory Th2 response, where cytokines such as IL-4, IL-5 or IL-13 are produced [38, 39]. A disturbance in this Th1/Th2 response can have severe consequences, be they more Th2 in nature, driving asthma and allergy, or Th1 driven, resulting in autoimmune diseases, including MS (reviewed in [40]). A couple of the more recently identified CD4 T cells subsets include Th17 cells that are characterised by production of IL-17 and IL-23, and have been linked to inflammatory diseases, and T regulatory (Treg) cells, which are important in maintaining homeostasis and tolerance of the immune system [41–43]. Tregs express the transcription factor FoxP3 which is essential for their development and function [44–46]. In humans, mutations in FOXP3 have been found to result in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, providing evidence that anomalies of Tregs can cause autoimmune disease and allergy [47].

During production of the T cell receptor (TCR) on T cells and B cell receptor (BCR) on B cells, random genetic recombination events can lead to receptors being produced that are specific to autoantigens [48, 49]. To prevent reaction to self, cells undergo central and peripheral tolerance events through which autoreactive cells are apoptotically removed, first in the primary lymphoid organs of the thymus (T cell) and bone marrow (B cell), and if this fails, in the secondary lymphoid organs after cells migrate to the periphery [49]. Self-reactive antibodies account for 55–75% of all antibodies expressed by early immature B cells, including polyreactive and anti-nuclear specificities [49]. However, it is estimated that the majority of newly produced B cells do not reach maturity, and during central and peripheral tolerance most of the self-reactive B cells are removed. If both selection processes fail in T or B cells, this will result in T and B cells able to react with the body's own cells and tissues. These events lead to autoimmune disease.
