Autoimmune disorders

The immune system enhances robustness of the host system against broad range of pathogenic perturbations. It has to be able to react against a greater variety of pathogens within the resource limitations of the host system. The major constraint in immune system is resource limitation. Host immune systems must cope with an infinite variety of pathogens using finite number of T cells. Antigen processing and trimming is an effective mechanism that enables recognition of a broader range of pathogens using limited numbers of T cells. The trade-off is increased risk of misrecogni-tion of a pathogen associated signature with the host's tissues. At the same time, resource limitation forces the system to take activation-triggered maturation of adaptive immune cells, rather than making themselves ready to be dispatched immediately. It is conceivable that this requirement has imposed selective pressures that have shaped the global structure of the immune system. A typical architecture of a bow-tie, or hour-glass, comprises conserved and efficient core processes with diverse and redundant input and output processes [1, 71]. The host immune system encompasses a nested tandem bow-tie architecture which can be observed in TLR signaling in innate immunity [58], processing and recognition of MHC-peptides between APC and T cells, and convergence of signaling from various cells into CD4+ T cells to foster polarized proliferation involving a complex cytokine network [57].

The most relevant issue in the current context is the bow tie structure of antigen presentation and recognition. In this process, various exogenous materials are captured by antigen presenting cells (APCs) through phagocytosis, macropinocytosis, and fluid phase endocytosis; also it expresses a broad range of receptors that induce receptor-mediated endo-cytosis. Exogenous materials captured undergo peptide processing to be loaded onto MHC II followed by trimming. The size of loaded peptides on MHC II ranges between 13-17 [72], and only a core of short peptides of 9-10 amino acids epitope binds to a receptor on CD4+ helper T cells [73]. A proper binding of TCR to MHC II activates signal transduction path ways, triggering cytokine secretion and polarization. MHC Class I is yet another bow-tie structure where a huge variety of peptides of endogenous origin are processed for loading and trimming on MHC I with the length of 8-10 amino acids and recognized by CD8+ T cells [74]. While this mechanism enabled robust host adaptive immune response to a broad range of pathogens, it is fragile against misrecognition so that, in some cases, molecular signature for pathogens and that of host tissue systems can be misrecognized that may trigger autoimmune reactions.

Some autoimmune diseases are now identified as infection-triggered, such as Crohn's disease (CD), which is an intestine autoimmune disease that causes chronic inflammation. Recently, it was shown that inflammation induced by bacterial infection triggers chronic inflammation, and mutation of NOD2 increases disease susceptibility [75, 76]. Extensive concentration of bacteria such as Mycobacterium paratuberculosis and Listeria monocytogenes has been observed by biopsy of CD patients using 16S rDNA PCR and DNA hybridization analysis [77]. Such infection-triggered autoimmune disorders are not specific to Crohn's disease reflecting the inherent fragility of the immune system where antigen patterns presented for immune reaction are sufficiently similar to the host's own signature, causing the immune system to react against the self [78]. The MHC antigen presentation and receptor system is the core of the bow-tie architecture, and so a breach in this system seriously affects its functionality. Dilated cardiomyopathy is associated with cardiotropic virus infection triggering dendritic cell-induced autoimmune heart failure [79]. It has been argued that the broad range of autoimmune disorders discussed above as well as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and others, are due to multiple exposures to pathogenic bacteria and virus [80]. This class of autoimmune diseases can be attributed to breaches of the immune response against pathogens, by which invaded pathogens trigger a sustained immune response by molecular mimicry [78], possibly with TCR-dependent bystander activation [80].

Chlamydia pneumoniae has been found to associate with atherosclerosis [81, 82]. Chlamydia was found to infect lymphocytes and monocytes to escape host immune reactions and to proliferate [83]. Promotions of atherosclerosis due to Chlamydia may be due to its ability to transform macrophage into foam cells as well as possible autoimmune reactions [84]

as similarity between Chlamydia external membrane protein and human cardio-muscle myosin has been identified [85].

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