Turning Up The Heat: Immune Brinksmanship In The Acute-phase Response

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Abstract
The acute-phase response (APR) is a systemic response to severe trauma, infection, and cancer, although many of the numerous cytokine-mediated components of the APR are incompletely understood. Some of these components, such as fever, reduced availability of iron and zinc, and nutritional restriction due to anorexia, appear to be stressors capable of causing harm to both the pathogen and the host. We review how the host benefits from differences in susceptibility to stress between pathogens and the host. Pathogens, infected host cells, and neoplastic cells are generally more stressed or vulnerable to additional stress than the host because: a) targeted local inflammation works in synergy with APR stressors; b) proliferation/growth increases vulnerability to stress; c) altered pathogen physiology results in pathogen stress or vulnerability; and d) protective heat shock responses are partially abrogated in pathogens since their responses are utilized by the host to enhance immune responses. Therefore, the host utilizes a coordinated system of endogenous stressors to provide additional levels of defense against pathogens. This model of immune brinksmanship can explain the evolutionary basis for the mutually stressful components of the APR.

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Restless legs syndrome – Theoretical roles of inflammatory and immune mechanisms

Theories for restless legs syndrome (RLS) pathogenesis include iron deficiency, dopamine dysregulation and peripheral neuropathy. Increased prevalence of small intestinal bacterial overgrowth (SIBO) in controlled studies in RLS and case reports of post-infectious RLS suggest potential roles for inflammation and immunological alterations.

A literature search for all conditions associated with RLS was performed. These included secondary RLS disorders and factors that may exacerbate RLS. All of these conditions were reviewed with respect to potential pathogenesis including reports of iron deficiency, neuropathy, SIBO, inflammation and immune changes. A condition was defined as highly-associated if there was a prevalence study that utilized an appropriate control group. Small case reports were recorded but not included as definite RLS-associated conditions.

Fifty four diseases, syndromes and conditions have been reported to cause and/or exacerbate RLS. Of these, 38 have been reported to have a higher prevalence than age-matched controls, 9 have adequate sized reports and have general acceptance as RLS-associated conditions and 7 have been reported in case report form. Overall, 42 of the 47 RLS-associated conditions (89%) have also been associated with inflammatory and/or immune changes. In addition, 43% have been associated with peripheral iron deficiency, 40% with peripheral neuropathy and 32% with SIBO. Most of the remaining conditions have yet to be studied for these factors.

The fact that 95% of the 38 highly-associated RLS conditions are also associated with inflammatory/immune changes suggests the possibility that RLS may be mediated or affected through these mechanisms. Inflammation can be responsible for iron deficiency and hypothetically could cause central nervous system iron deficiency-induced RLS. Alternatively, an immune reaction to gastrointestinal bacteria or other antigens may hypothetically cause RLS by a direct immunological attack on the central or peripheral nervous system.

Fig. 1. Potential interplay of pathologic factors in secondary RLS. Abbreviations: RLS: restless legs syndrome; Inflam & Immune: inflammation and/or altered immunity; SIBO: small intestinal bacterial overgrowth; Neuropathy: peripheral neuropathy.

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Fig. 2.  [26], [55], [56] and [125] of hepcidin synthesis in the setting of inflammation and theoretical consequences for developing CNS iron deficiency and subsequent RLS. Hepcidin is the main hormone involved in regulation of iron levels and has been shown to be produced by the liver in humans and in the brain in animal models. Increased hepcidin levels lead to iron deficiency. Interleukin-6 is the main cytokine that can increase hepcidin levels. Lipopolysaccharides which are breakdown products of gram negative bacteria stimulate hepcidin synthesis. Hypoxia also stimulates hepcidin synthesis. Hepcidin binds to ferroportin on human choroid plexus cells and decrease availability of iron for the CNS. Not shown – Bacteria may also utilize iron and cause iron deficiency.57 Abbreviations: LPS: lipopolysaccharides.

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Table 1. Iron deficiency, small intestinal bacterial overgrowth (SIBO), inflammation and/or immunological alterations and peripheral neuropathy in conditions associated with restless legs syndrome (RLS). References are categorized as either: a controlled study (CS); an observational case series (OS); a laboratory study (LS) which uses defined assays but does not have a control group; or a review article (RA). Highly-associated conditions are defined as RLS conditions shown to have a statistically higher prevalence than controls. This table does not include seven single case reports associated with RLS (see result section).

Additional abbreviations: ADHD: attention-deficit/hyperactivity disorder; COPD: chronic obstructive pulmonary disease; NS: not studied.

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