One theory of immune regulation involves homeostasis between T-helper 1 (Th1) and Thelper 2 (Th2) activity. The Th1/Th2 hypothesis arose from 1986 research suggesting mouse T-helper cells expressed differing cytokine patterns. This hypothesis was adapted to human immunity, with Th1- and Th2-helper cells directing different immune response pathways. Th1 cells drive the type-1 pathway (“cellular immunity”) to fight viruses and other intracellular pathogens, eliminate cancerous cells, and stimulate delayed-type hypersensitivity (DTH) skin reactions. Th2 cells drive the type-2 pathway (“humoral immunity”) and up-regulate antibody production to fight extracellular organisms; type 2 dominance is credited with tolerance of xenografts and of the fetus during pregnancy. Overactivation of either pattern can cause disease, and either pathway can down-regulate the other. But the hypothesis has major inconsistencies; human cytokine activities rarely fall into exclusive proTh1 or -Th2 patterns. The non-helper regulatory T cells, or the antigen-presenting cells (APC), likely influence immunity in a manner comparable to Th1 and Th2 cells. Many diseases previously classified as Th1 or Th2 dominant fail to meet the set criteria. Experimentally, Th1 polarization is readily transformed to Th2 dominance through depletion of intracellular glutathione, and vice versa. Mercury depletes glutathione and polarizes toward Th2 dominance. Several nutrients and hormones measurably influence Th1/Th2 balance, including plant sterols/ sterolins, melatonin, probiotics, progesterone, and the minerals selenium and zinc. The longchain omega-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) significantly benefit diverse inflammatory and autoimmune conditions without any specific Th1/Th2 effect. Th1/Th2-based immunotherapies, e.g., T-cell receptor (TCR) peptides and interleukin-4 (IL4) injections, have produced mixed results to date. (Altern Med Rev 2003;8(3):223-246)

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Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease.

Obesity increases morbidity and mortality through its multiple effects on nearly every human system. However, the various aspects of the association between obesity and infection have not been reviewed. Thus, we reviewed the relevant literature focusing on clinical aspects of this association. Obesity has a clear but not yet precisely defined effect on the immune response through a variety of immune mediators, which leads to susceptibility to infections. Data on the incidence and outcome of specific infections, especially community-acquired infections, in obese people are so far limited. The available data suggest that obese people are more likely than people of normal weight to develop infections of various types including postoperative infections and other nosocomial infections, as well to develop serious complications of common infections. Large prospective studies are required to further define the burden of infectious morbidity and mortality conferred by obesity.

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Obesity and infection

The interactions between obesity and infectious diseases have recently received increasing recognition as emerging data have indicated an association between obesity and poor outcome in pandemic H1N1 influenza infection. Obesity is an established risk factor for surgical-site infections, nosocomial infections, periodontitis and skin infections. Several studies indicate that acute pancreatitis is more severe in the obese. Data are controversial and limited as regards the association between obesity and the risk and outcome of community-acquired infections such as pneumonia, bacteremia and sepsis and obesity and the course of HIV infection. As the cause-effect relationship between obesity and infection remains obscure in many infectious diseases, further studies are warranted. The consequences of obesity may have substantial effects on the global burden of infectious diseases.

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Obesity and the risk and outcome of infection

Lack of adequate macronutrients or selected micronutrients, especially zinc, selenium, iron, and the antioxidant vitamins, can lead to clinically significant immune deficiency and infections in children. Undernutrition in critical periods of gestation and neonatal maturation and during weaning impairs the development and differentiation of a normal immune system. Infections are both more frequent and more often become chronic in the malnourished child. Recent identification of genetic mechanisms is revealing critical pathways in the gastrointestinal immune response. New studies show that the development of tolerance, control of inflammation, and response to normal mucosal flora are interrelated and linked to specific immune mechanisms. Nutrients act as antioxidants and as cofactors at the level of cytokine regulation. Protein calorie malnutrition and zinc deficiency activate the hypothalamic-pituitary-adrenal axis. Increased circulating levels of glucocorticoids cause thymic atrophy and affect hematopoiesis. Chronic undernutrition and micronutrient deficiency compromise cytokine response and affect immune cell trafficking. The combination of chronic undernutrition and infection further weakens the immune response, leading to altered immune cell populations and a generalized increase in inflammatory mediators. Obesity caused by excess nutrition or excess storage of fats relative to energy expenditure is a form of malnutrition that is increasingly seen in children. Leptin is emerging as a cytokine-like immune regulator that has complex effects in both overnutrition and in the inflammatory response in malnutrition. Because the immune system is immature at birth, malnutrition in childhood might have long-term effects on health.

Iconographies supplémentaires de l'article : Mechanisms of nutrient modulation of the immune response

Almost all nutrients in the diet play a crucial role in maintaining an "optimal" immune response, such that deficient and excessive intakes can have negative consequences on immune status and susceptibility to a variety of pathogens. Iron and vitamin A deficiencies and protein-energy malnutrition are highly prevalent worldwide and are important to the public health in terms of immunocompetence. There are also nutrients (i.e., glutamine, arginine, fatty acids, vitamin E) that provide additional benefits to immunocompromised persons or patients who suffer from various infections. The remarkable advances in immunology of recent decades have provided insights into the mechanisms responsible for the effects of various nutrients in the diet on specific functions in immune cells. In this review, we will present evidence and proposed mechanisms for the importance of a small group of nutrients that have been demonstrated to affect host resistance to infection will be presented. An inadequate status of some of these nutrients occurs in many populations in the world (i.e., vitamin A, iron, and zinc) where infectious disease is a major health concern. We will also review nutrients that may specifically modulate host defense to infectious pathogens (long-chain polyunsaturated n-3 fatty acids, vitamin E, vitamin C, selenium, and nucleotides). A detailed review of the effect of long-chain polyunsaturated n-3 fatty acids on host defense is provided as an example of how the disciplines of nutrition and immunology have been combined to identify key mechanisms and propose nutrient-directed management of immune-related syndromes.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.71.1.16

Nutrients and their role in host resistance to infection.

Despite widespread nutrient deficiencies, a substantial proportion of the MIDAS cohort exhibits obesity, which has been linked to immune dysregulation in other clinical settings. Herein, the effects of obesity on immune function, disease progression, and mortality were evaluated longitudinally in 125 HIV-1-seropositive drug users, with comparison measures in 148 HIV-1-seronegative controls. Data were collected at a community clinic from 1992 to 1996, before administration of highly active antiretroviral therapy. Results indicated that overweight/obesity, defined as body mass index (BMI; kg/m2) > or =27, was evident in 18% of the HIV-1-seropositive patients and 29% of the seronegative patients. At baseline, no significant immunologic differences were observed among lean, nonobese, and obese groups. Over an 18-month period, 60.5% of the nonobese HIV-1-seropositive patients exhibited a 25% decline in CD4 cell count, compared with 18% of the obese patients (p<.004). During the follow-up period, 38% of the lean and 13% of the nonobese study subjects died of HIV-1-related causes. Measurements of BMI were inversely associated with progression to death, independent of CD4 count <200 cells/mm3 (p<.02). These data suggest that mild-to-moderate obesity in HIV-1-infected chronic drug users does not impair immune function and is associated with better HIV-1-related survival.

When obesity is desirable: a longitudinal study of the Miami HIV-1-infected drug abusers (MIDAS) cohort.

An important role for selenium in human immunodeficiency virus (HIV) disease has been proposed. Decreased selenium levels, as found in persons with HIV infection or AIDS, are sensitive markers of disease progression. Selenium deficiency, an independent predictor of mortality in both HIV-1-infected adults and children, is an essential micronutrient that is associated with an improvement of T cell function and reduced apoptosis in animal models. In addition, adequate selenium may enhance resistance to infections through modulation of interleukin (IL) production and subsequently the Th1/Th2 response. Selenium supplementation up-regulates IL-2 and increases activation, proliferation, differentiation, and programmed cell death of T helper cells. Moreover, selenium supplementation may down-regulate the abnormally high levels of IL-8 and tumor necrosis factor-alpha observed in HIV disease, which has been associated with neurologic damage, Kaposi's sarcoma, wasting syndrome, and increased viral replication. Together, these findings suggest a new mechanism through which selenium may affect HIV-1 disease progression.

Selenium and Interleukins in Persons Infected with Human Immunodeficiency Virus Type 1

Our recent studies have demonstrated that in early HIV-1 infection, elevation of plasma immunoglobulin E (IgE) levels precedes the decline of CD4 cell count and is influenced by vitamin E status. In order to further investigate the role of IgE elevation in HIV-1 infection, we determined IgE levels in HIV-1-seropositive and -seronegative intravenous drug users (IDUs) (n = 38), in relationship to cellular and humoral immune function, liver enzymes, and vitamin E status. To examine the possible impact of the route of HIV-1 infection on IgE levels, comparisons between the cohorts of the HIV-1-seropositive and -seronegative IDUs and homosexual men (n = 45) were also conducted. All HIV-1-seropositive participants had significantly higher (P = 0.003) IgE levels than the HIV-1-seronegative subjects. The HIV-1-seropositive IDUs, moreover, demonstrated significantly higher (P = 0.01) IgE levels than HIV-1-seropositive homosexual men, despite similar CD4 cell counts. Stepwise regression analysis was used to evaluate the possible variables contributing to the IgE variation. HIV-1 status (P = 0.0009), intravenous drug use (P = 0.014), CD8 cell counts (P = 0.0001), plasma level of vitamin E (P = 0.006), and alcohol intake (P = 0.047) were significant, accounting for 71% of the IgE elevation. These findings suggest that IgE may serve as a sensitive marker to reflect the evolution of HIV-1 disease in individuals from different risk groups.

Immunoglobulin E levels in relationship to HIV-1 disease, route of infection, and vitamin E status.

Impaired neuroprotection resulting from oxidative stress has been implicated in neurodegeneration in a number of pathologic conditions of the brain, including both subcortical and cortical type dem ...

Neuroprotection in HIV-positive drug users: Implications for antioxidant therapy

With the exception of hemolytic anemia, the potential hematological toxicity of antiretrovirals (ARV) and combination treatments in HIV treated individuals has not been well established. We report, for the first time, hematological toxicity defined as thrombocytosis in 9% of the HIV+ patients receiving highly active antiretroviral treatment (HAART) being followed in a nutritional clinical trial. Participants were evaluated every 6 months during a 2-year period (1998-2000) and blood drawn for biochemical, hematological and immunological parameters. NK cells were negatively correlated with platelet counts in the total cohort (P = 0.018) and persistently elevated with ARVT. Chronic thrombocytosis was associated with significantly lower NK percentages (P = 0.005). Twenty-five percent of the patients with thrombocytosis developed a cardiovascular disease. Together, these results support the proposal that HAART may increase the risk of hematological dysfunction and impact the risk of cardiovascular disease.

M. J. Miguez-Burbano

Papers

When obesity is desirable: a longitudinal study of the Miami HIV-1-infected drug abusers (MIDAS) cohort.

Selenium and Interleukins in Persons Infected with Human Immunodeficiency Virus Type 1

Immunoglobulin E levels in relationship to HIV-1 disease, route of infection, and vitamin E status.

Neuroprotection in HIV-positive drug users: Implications for antioxidant therapy

Development of thrombocytosis in HIV+ drug users: impact of antiretroviral therapy