The term cirrhosis-associated immune dysfunction refers to the main syndromic abnormalities of immune function, immunodeficiency and systemic inflammation that are present in cirrhosis. The course of advanced cirrhosis, regardless of its aetiology, is complicated by cirrhosis-associated immune dysfunction and this constitutes the pathophysiological hallmark of an increased susceptibility to bacterial infection, distinctive of the disease. Cirrhosis impairs the homeostatic role of the liver in the systemic immune response. Damage to the reticulo-endothelial system compromises the immune surveillance function of the organ and the reduced hepatic synthesis of proteins, involved in innate immunity and pattern recognition, hinders the bactericidal ability of phagocytic cells. Systemic inflammation, in form of activated circulating immune cells and increased serum levels of pro-inflammatory cytokines, is the result of persistent episodic activation of circulating immune cells from damage-associated molecular patterns, released from necrotic liver cells and, as cirrhosis progresses, from pathogen-associated molecular patterns, released from the leaky gut. Cirrhosis-associated immune dysfunction phenotypes switch from predominantly "pro-inflammatory" to predominantly "immunodeficient" in patients with stable ascitic cirrhosis and in patients with severely decompensated cirrhosis and extra-hepatic organ failure (e.g. acute-on-chronic liver failure), respectively. These cirrhosis-associated immune dysfunction phenotypes represent the extremes of a spectrum of reversible dynamic events that take place during the course of cirrhosis. Systemic inflammation can affect the functions of tissue somatic cells and modify the clinical manifestation of cirrhosis. The best characterized example is the contribution of systemic inflammation to the haemodynamic derangement of cirrhosis, which correlates negatively with prognosis.

This study examines the potential role of transforming growth factor beta (TGF-beta) in the regulation of human T lymphocyte proliferation, and proposes that TGF-beta is an important autoregulatory lymphokine that limits T lymphocyte clonal expansion, and that TGF-beta production by T lymphocytes is important in T cell interactions with other cell types. TGF-beta was shown to inhibit IL-2-dependent T cell proliferation. The addition of picograms amounts of TGF-beta to cultures of IL-2-stimulated human T lymphocytes suppressed DNA synthesis by 60-80%. A potential mechanism of this inhibition was found. TGF-beta inhibited IL-2-induced upregulation of the IL-2 and transferrin receptors. Specific high-affinity receptors for TGF-beta were found both on resting and activated T cells. Cellular activation was shown to result in a five- to sixfold increase in the number of TGF-beta receptors on a per cell basis, without a change in the affinity of the receptor. Finally, the observations that activated T cells produce TGF-beta mRNA and that TGF-beta biologic activity is present in supernatants conditioned by activated T cells is strong evidence that T cells themselves are a source of TGF-beta. Resting T cells were found to have low to undetectable levels of TGF-beta mRNA, while PHA activation resulted in a rapid increase in TGF-beta mRNA levels (within 2 h). Both T4 and T8 lymphocytes were found to make mRNA for TGF-beta upon activation. Using both a soft agar assay and a competitive binding assay, TGF-beta biologic activity was found in supernatants conditioned by T cells; T cell activation resulted in a 10-50-fold increase in TGF-beta production. Thus, TGF-beta may be an important antigen-nonspecific regulator of human T cell proliferation, and important in T cell interaction with other cell types whose cellular functions are modulated by TGF-beta.

Intestinal bacterial overgrowth and translocation, both common in cirrhosis with ascites, may lead to the activation of monocytes and lymphocytes, increased levels of proinflammatory cytokines, and enhanced synthesis of nitric oxide present in cirrhosis. Bacterial endotoxin promotes the synthesis of lipopolysaccharide (LPS)-binding protein (LBP), and forms a LPS-LBP complex that binds to CD14. This study was designed to evaluate LBP levels and their correlation to the immune response and the hemodynamic status in cirrhotic patients. Plasma LBP, endotoxin, soluble CD14 (sCD14), cytokines, renin, nitrites, and systemic vascular resistance were determined before and 4 weeks after norfloxacin or placebo in 102 cirrhotic patients and 30 controls. LBP was elevated in 42% of ascitic cirrhotic patients (15.7 ؎ 0.7 versus 6.06 ؎ 0.5 g/mL, P < .01). In 60% of high LBP patients, endotoxin was within normal range. Among ascitic patients, those with high LBP showed greater (P < .05) levels of sCD14, tumor necrosis factor ␣ (TNF-␣), interleukin 6 (IL-6), nitrites ؉ nitrates (NOx)/creatinine, and renin, and lower vascular resistance. In the cirrhotic patients with high LBP, norfloxacin normalized (P < .01) LBP (from 16.6 ؎ 0.5 to 5.82 ؎ 0.8 g/mL) and sCD14; reduced the level of cytokines, NOx/creatinine, and renin; and increased vascular resistance; but lacked effect in patients with normal LBP. Portal pressure was unchanged after norfloxacin in another group of 18 cirrhotic patients with high and 19 with normal LBP. In conclusion, the subset of ascitic cirrhotic patients with marked immune and hemodynamic derangement is identified by increased LBP levels. Amelioration of these abnormalities by norfloxacin suggests the involvement of enteric bacteria or their products in the triggering of the process. (HEPATOLOGY 2003;37:208-217.)

Human immunodeficiency virus (HIV)-1 infectivity requires actin-dependent clustering of host lipid raft–associated receptors, a process that might be linked to Rho guanosine triphosphatase (GTPase) activation. Rho GTPase activity can be negatively regulated by statins, a family of drugs used to treat hypercholesterolemia in man. Statins mediate inhibition of Rho GTPases by impeding prenylation of small G proteins through blockade of 3-hydroxy-3-methylglutaryl coenzyme A reductase. We show that statins decreased viral load and increased CD4+ cell counts in acute infection models and in chronically HIV-1–infected patients. Viral entry and exit was reduced in statin-treated cells, and inhibition was blocked by the addition of l-mevalonate or of geranylgeranylpyrophosphate, but not by cholesterol. Cell treatment with a geranylgeranyl transferase inhibitor, but not a farnesyl transferase inhibitor, specifically inhibited entry of HIV-1–pseudotyped viruses. Statins blocked Rho-A activation induced by HIV-1 binding to target cells, and expression of the dominant negative mutant RhoN19 inhibited HIV-1 envelope fusion with target cell membranes, reducing cell infection rates. We suggest that statins have direct anti–HIV-1 effects by targeting Rho.

Objective The aim of this study was to summarize evidence on the effectiveness of therapeutic exercise in Fibromyalgia Syndrome. Design Studies retrieved from the Cochrane Plus, PEDro, and Pubmed databases were systematically reviewed. Randomized controlled trials and meta-analyses involving adults with fibromyalgia were included. The primary outcomes considered in this systematic review were pain, global well-being, symptoms of depression, and health-related quality of life. Results Effects were summarized using standardized mean differences with 95% confidence intervals using a random effects model. This study provides strong evidence that physical exercise reduces pain (−1.11 [95% CI] −1.52; −0.71; overall effect p < 0.001), global well-being (−0.67 [95% CI] −0.89, −0.45; p < 0.001), and symptoms of depression (−0.40 [95% CI] −0.55, −0.24; p < 0.001) and that it improves both components of health-related quality of life (physical: 0.77 [95% CI] 0.47; 1.08; p < 0.001; mental: 0.49 [95% CI] 0.27; 0.71; p < 0.001). Conclusions This study concludes that aerobic and muscle strengthening exercises are the most effective way of reducing pain and improving global well-being in people with fibromyalgia and that stretching and aerobic exercises increase health-related quality of life. In addition, combined exercise produces the biggest beneficial effect on symptoms of depression.

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The most prevalent diseases of our time, non-communicable diseases (NCDs) (including obesity, type 2 diabetes, cardiovascular diseases and some types of cancer) are rising worldwide. All of them share the condition of an “inflammatory disorder”, with impaired immune functions frequently caused or accompanied by alterations in gut microbiota. These multifactorial maladies also have in common malnutrition related to physiopathology. In this context, diet is the greatest modulator of immune system–microbiota crosstalk, and much interest, and new challenges, are arising in the area of precision nutrition as a way towards treatment and prevention. It is a fact that the westernized diet (WD) is partly responsible for the increased prevalence of NCDs, negatively affecting both gut microbiota and the immune system. Conversely, other nutritional approaches, such as Mediterranean diet (MD), positively influence immune system and gut microbiota, and is proposed not only as a potential tool in the clinical management of different disease conditions, but also for prevention and health promotion globally. Thus, the purpose of this review is to determine the regulatory role of nutritional components of WD and MD in the gut microbiota and immune system interplay, in order to understand, and create awareness of, the influence of diet over both key components.