Chronic immune activation

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Abstract: The conclusion of this paper is that non-communicable diseases such as the psychiatric disorders, neurological diseases, autoimmune diseases and other diseases associated with immune system upregulation but not deemed to be autoimmune, such as cardiovascular disease, cancer, type 2 diabetes, porphyria and many others, all arise as a consequence of chronic, aberrant activation of an immune system response which is driven by the transcription factor, nuclear factor kappa beta (NF-kB).

One of the principal functions of the NF-kB immune response is to control intracellular pathogens which establish latency within cells. To achieve this, reactive oxygen species (ROS), such as hydroxyl radical, which are destructive to these pathogens, are generated inside cells. In addition, the cell membrane receptors which are used by these pathogens to gain entry into cells are reduced in number, desensitised, or blocked by antibodies, causing these cells to become hypofunctional. To compensate for this, receptors on other cells may become hyperfunctional.

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Many of the diseases which are known to be associated with a chronically activated NF-kB driven immune response are also associated with an above average incidence of infection with specific pathogens. I have compiled a list of those pathogens which appear to be most important. They are herpes simplex virus-1, herpes simplex virus-2, human herpes virus-6, cytomegalovirus (herpes family), Epstein-Barr virus (herpes family), varicella zoster (herpes family), mycobacteria, Borna virus, enteroviruses, hepatitis C virus, human papilloma virus, Borrelia bacterium, Toxoplasma gondii protozoon, human endogenous retroviruses, mycoplasma pneumoniae bacterium, Chlamydia pneumoniae bacterium, Helicobacter pylori bacterium, JC virus, Candida albicans fungus and intestinal worms.

This list reveals a crucially important fact. Except for Candida and worms, all these infectious organisms are obligate intracellular parasites which are known to establish latency within cells and can persist in a dormant state for years without causing illness. 

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Enzymes are frequently seen to be autoantigens in autoimmune diseases and are attacked by antibodies generated by B-cells. About a third of enzymes utilise a metal co-factor, very often iron, which may produce ROS, including hydroxyl radicals. However, virtually all of the enzyme autoantigens I have studied are metalloenzymes which use transition metal ions as a co-factor. The only exception I am aware of is glutamic acid decarboxylase, which utilises pyridoxal phosphate (vitamin B6) as a co-factor and is often an autoantigen in type 1 diabetes. This means that it is the metal or a product of the chemical reactivity of the metal which is attracting the attention of the immune system. The products may be ROS or alterations to the enzymes, co-factors or substrates caused by reactions with ROS. Examples of metalloenzyme autoantigens in autoimmune diseases include thyroid peroxidase (iron in heme) in thyroiditis, tyrosinase (copper) in vitiligo, transglutaminase (manganese) in coeliac disease and cytochrome P450 (iron in heme) in Addison’s disease. The cytochrome P450 superfamily of enzymes are frequent targets of the immune system, with CYPc21 and CYPc17 both antigens in Addison’s disease, CYPc17 and CYPscc in premature menopause, CYPc17 in gonadal failure, CYP1a2 and CYP2a6 in autoimmune polyglandular syndrome type1 and CYP1a2 in halothane hepatitis.




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