The Natural Immune System

4.1. Natural killer cells: history and current status

Natural killer (NK) cells are a major component of the immune system, which play important roles in host defences against cancer and microbial infections. NK cells are distinct from T or B lymphocytes, with a characteristic morphology of large granular cells, and can be readily identified by characteristic cell surface molecules. They have the ability to recognise and rapidly kill a wide array of tumour cells and also virus-infected normal cells. NK cytotoxic activity can be strongly augmented by interferon, interleukin-2, and other cytokines. NK cells are major producers of some cytokines, especially interferon gamma [41]; they produce a neutrophil-activat-ing factor and upregulate polymorphonuclear leukocytes to kill Candida albicans [42].

4.2. The reticuloendothelial system

During the nineteenth century varied cell types, which acted in host defence by phagocytos-ing foreign invaders were grouped collectively into the reticuloendothelial system (RES). The depression or blockage of the granulopoetic activity of this system has attracted considerable attention. Gadolinium chloride (GdCl3), depresses RES activity and selectively suppresses or eliminates the large Kupffer cells. Kupffer cell blockade modifies the immune response, exerts protective effects on anaphylactic and endotoxic/septic shock, and decreases the liver-damaging effects of several hepatotoxins and ischaemic reperfusion. Recent studies have elucidated the mechanisms by which GdCI ,-induced Kupffer cell blockade protects against a variety of hepa-totoxic processes [43],

4.3. Effector mechanisms of natural immunity

Evolutionary approaches to the investigation of innate immune mechanisms has shown that monoclonal antibodies to human adhesion molecules react with earthworm, leech and sipuncu-lan leukocytes. Many CD markers common to vertebrate leukocytes, especially to macrophages and natural killer cells are expressed. In earthworms, only those leukocytes which are positive are active as killers in cytotoxic responses, whereas larger, primarily phagocytic leukocytes are negative. The evolution of complement can be traced from sea urchins to the teleosts and tetrapods, exhibiting at each level a corresponding increase in the numbers of complement components and duplications in complement pathways. Invertebrates and vertebrates seem to possess common signalling molecules e.g. neuropeptides. These signalling molecules are immunomodulators in circulating blood. In vertebrates, release occurs during stress that triggers the hypothalamo-hypophyseal-adrenal (HPA) axis. Neuropeptides are conserved messengers that regulate innate immune responses in invertebrates and in humans. The evidence suggests that the cross talk between nervous and immune systems has an ancient evolutionary origin, which is essential to homeostasis [7],

4.4. Natural immune activation

Multiple recognition molecules are involved representing numerous structural families including, several lectin families, pentraxins, leucine-rich repeats, many members of the IgSF, integrins, scavenger receptors and the seven transmembrane receptor family. Invading pathogens exhibit a range of different repeating epitopes. Host molecules express a variety of receptors capable of recognising these epitopes and act in a combinatorial manner which confers specificity to the host response. The large number, diversity, and ancient evolutionary origin of these receptors argues for the essential nature of their functions. While providing a first line of defence against invading pathogens is clearly crucial for organism survival, evidence is accumulating that these same receptors also participate in essential physiological functions [44],

4.5. Signaling in natural killer cells

NK cells have the ability to recognize tumour- and virus-associated ligands. These cells express CD16, the low-affinity Fc receptor (FcR) for IgG. NK cells do not have a single type of receptor through which they recognize antigens. Rather, clonal subpopulations of NK cells differ in their expression of receptors that recognize a variety of ligands on target cells throughout the body. NK cell binding of these ligands initiates signalling cascades within the NK cell that control its response to the target [45].

4.6. Toll-like receptors

Macrophages are central in orchestrating the innate immune response to infection, which is not a trivial task: they must be able to discriminate microbes from self, and then initiate a proper response. The discovery of the Toll-like receptor (TLR) family of pattern-recognition receptors has provided insight into this kind of recognition. TLRs are expressed on macrophages and other innate immune cells, where they collaborate to read the molecular fingerprint of different microbes and initiate inflammatory signalling pathways. The TLR family is important in infectious diseases, and there is also evidence that they may play a role in autoimmunity and degenerative diseases in the central nervous system [46],

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