Kigure 3, The neuroiinmune regulatory circuit.

During evolution (he neuroendocrine system has been super-imposed onto I he hi i sic regulatory circuit outlined above. The CNS, via the pituitary gland now controls systemically the competence signal for all organs and tissues that amounts to effective growth control of the organi-sm. Adhesion molecules and cytokines remain in control of the local (e.g. positional) regulation or the systemic competence signal. The target organs/tissues provide feedback signals to the neuroendocrine system via innervation and by soluble mediators, such as hormones and cytokines. The neuroimmune regulatory circuitry is fundamental for the development and function of higher animals for their entire life cycle, !t e^eits physiological regulation and also fundamental to host defence, including regeneration and healing.

ing DC's to provide the needed costimulatory second signals for T lymphocyte activation. These discoveries brought the innate immune system attention, but it was chiefly framed as a supporter for the adaptive immune response.

2.4. An in ¬°eg rated system with expanded functions

Increasingly, investigators have viewed ihe immune system as a highly complex and integrated system, which communicates with the body in which it resides and self, non-self discrimination is less the issue, rather action is determined by the context of the interaction. Tan her [18], considers that the question of 'context' has been interpreted narrowly by some as being established at birth or shortly after, while for others (including Cohen, Coutinho, Grossman and Mat/.inger) the context is ever changing. The search to understand activation has Ibcussed increasingly on, I) ihe nature of signals, which are ancillary to antigen recognition in the adaptive immune response, 2) the functional structure of the immune system in which they operate and 3) the relationships between the clonally selected T and B lymphocytes of the adaptive response and the mediators of the evolutionarily ancient innate immune response. Recognition of phylogenetic and functional relationships between the innate and adaptive immune systems has led to the concept of a more integrated immune system with a wider scope of function. Matzinger in particular, in defining the context of activation as "danger" rather than the discrimination between self and non-self, assigned the decision-making role for activation to the phagocytic APC. This proposal was supported by her observation that necrotic but not healthy or apoptotic cells released factors which could activate dendritic cells in vitro [35],

2.5. LPS at the core of innate immune research

The recently reviewed [36] long history of endotoxin study, provides a continuous thread (a fuse really) that starts before Metchnikoff with Hippocrates and informs our current concept of innate immunity. Beutler's and Rietschel's story of innate immune sensing focussing on microbial 'endotoxin' which in time became synonymous with lipopolysaccharide (LPS) a protein-free product from Gram-negative bacteria, cites three major milestones in the quest to understand how microbes create disease: the identification of endotoxin as a definable chemical species, the identification of soluble, host-derived mediators of toxicity (e.g., tumour necrosis factor, TNF) coupled with the idea that toxicity and protection were not readily separable, and recently the identification of the LPS receptor itself, providing evidence that many microbial toxins share mechanisms of action similar to endotoxin.

Additional bacterial components including some from Gram-positive bacteria exhibit endo-toxin-like biological effects in mammals among them lipopeptides, lipoteichoic acid double-stranded RNA and unmethylated DNA with CpG motifs, and all are recognized by paralogous receptors [36,37],


Epithelial tissues and granulocytes express numerous antimicrobial peptides called defensins and cathelicidins. These molecules were recognised initially for their broad-spectrum antimicrobial properties. However, now they are known to play a role in both the regulatory and effector arms of the innate immune system. These peptides modulate bacterial adherence ; complement activation ; fibrinolysis; steroid synthesis; mast cell activation; monocyte, neutrophil, mast cell, T cell and immature dendritic cell chemoattraction; cytokine expression; cytotoxicity; cell proliferation; angiogenesis; protease inhibitor synthesis; keratinocyte differentiation; proteoglycan synthesis; phagocytosis and Ca+2 mobilisation. Genes of the adaptive immune system encoding immunoglobulins and T cell receptors undergo a series of genetic amplifications and rearrangements. Homologous events involving genes of the innate immune system can be seen as generating a protective diversity promoting survival of a population or species. The mechanisms for this "genome instability" in innate immunity genes remain to be elucidated [38].

3.2. Endogenous cytoprotective mechanisms

Endogenous cytoprotective mechanisms protect the mammalian host against various forms of injury and noxious stimuli. Since these mechanisms are activated upon encountering potentially cytotoxic conditions, Haem-oxygenase and the heat shock response confer protection against a broad array of cytotoxic stimuli. The activation of the anti-oxidant pathways is critical to survival in an aerobic environment. Hypoxia inducible factor is a key transcription factor that directs the expression of genes necessary for adaptation to hypoxia and/or ischemia. Nitric oxide is a ubiquitous molecule that impacts a number of biological, physiological and pathophysiological processes [39],

3.3. Bile acids and natural resistance

Bacterial endotoxin is toxic, when given parenterally but is harmless upon oral administration. In naturally occurring entero-endotoxaemic diseases (e.g. shock due to sepsis or to other causes), endotoxin is known to absorb from the intestinal tract. If the common bile duct of rats was chronically cannulated (bile deprived animals) orally administered endotoxin was absorbed from the intestinal tract and provoked shock. This absorption was prevented by sodium deoxycholate or by natural bile. Bile acids split the endotoxin macromolecule into non-toxic fragments. This detoxifying detergent action of bile plays a significant role in host defence against infectious agents with a lipoprotein outer structure (e.g. "big" viruses). This represents a physico-chemical defence system. Bile deficiency and the consequent endotoxaemia are important components in the pathogenesis of certain diseases, such as sepsis, intestinal syndrome of radiation disease, hepato-renal syndrome, parvovirus infection, herpes, psoriasis, atherosclerosis, etc. Finally, bile acids may be used for the prevention and/or therapy of some clinical conditions such as the hepato-renal syndrome and psoriasis [40],

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