Leptin and the hygieneaffluence hypothesis in autoimmunity

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Fewer infections and more autoimmunity, observed in affluent countries, lead us to postulate the so-called "leptin hypothesis" to explain this phenomenon (42). During the past century, in the industrialized world, the incidence of infections has diminished greatly because of improved hygienic conditions, better nutrition, vaccination, and the use of antibiotics (42). Interestingly, in affluent and more-developed societies, epidemio-logical studies have revealed a parallel increase in the incidence of autoimmune diseases, whereas these diseases have become less common in less-developed nations. Thus, susceptibility to infection and autoimmunity appear to be inversely related (42). Several factors other than nutrition might contribute to this relationship, such as the environment, genetic background, other hormones, stress, and exposure to specific pathogens (Fig. 1). Nevertheless, changes in diet and calorie intake and, subsequently, serum leptin concentrations should be taken into account to explain the complex network connecting nutritional status and susceptibility to autoimmune and infectious diseases (42) (Fig. 1). Animal studies provide support for this concept. In some murine models of systemic lupus erythematosus (SLE), T1D, and EAE, the induction and progression of disease can be prevented by starvation and/or reduced calorie intake, or by

Insulin Resistance Images
  1. 1. Schematic representation of the pleiotropic effects of leptin in immunity and pathogenesis of autoimmune responses. Leptin secreted by adipose tissue is involved in thymic homeostasis and prevention of apoptosis, naïve T-cell proliferation/IL-2 secretion, acute phase response, innate immunity, and angiogenesis. More specifically, on adaptive immunity, leptin favors the switch toward Th1 immunity by inhibiting Th2 cytokine release. The effect of leptin on TRegs is still under investigation. These pleiotropic actions of leptin may contribute to the different autoimmune vs infectious disease susceptibility observed in affluent countries together with the contribution of environmental, genetic, and neuroendocrine factors. Th, T helper; TRegs, regulatory T-cells.
  2. 1. Schematic representation of the pleiotropic effects of leptin in immunity and pathogenesis of autoimmune responses. Leptin secreted by adipose tissue is involved in thymic homeostasis and prevention of apoptosis, naïve T-cell proliferation/IL-2 secretion, acute phase response, innate immunity, and angiogenesis. More specifically, on adaptive immunity, leptin favors the switch toward Th1 immunity by inhibiting Th2 cytokine release. The effect of leptin on TRegs is still under investigation. These pleiotropic actions of leptin may contribute to the different autoimmune vs infectious disease susceptibility observed in affluent countries together with the contribution of environmental, genetic, and neuroendocrine factors. Th, T helper; TRegs, regulatory T-cells.

administering nutrients such as polyunsaturated fatty acids, which are able to reduce the inflammatory response and leptin secretion (42). In humans, a similar observation has been reported by Bruining, who described an increased incidence of T1D at younger ages in affluent countries, where affluence is associated with increased postnatal growth and abundant nutrition (43). More specifically, children that developed diabetes had a greater gain in BMI in the first year of life compared with healthy siblings and the early presence of autoantibodies specific for pancreatic islet tyrosine phosphatase (IA-2). Leptin, with its pleiotropic functions, including the promotion of Th1 responses, reduction of the apoptotic rate of thymocytes, reversal of acute-starvation-induced immunosuppression, and induction of expression of adhesion molecules (e.g., ICAM-1 and CD49b [integrin 2]) (Fig. 1), is a good candidate for contributing to the pathogenesis and maintenance of autoimmunity in genetically predisposed individuals. Conversely, malnutrition and nutritional deficiency might protect individuals from autoimmunity by lowering circulating leptin concentrations, but predispose to infections, such as candidi-asis, tuberculosis, pneumonia, and bacterial and viral diarrhea. Last but not least, the most common form of human obesity, characterized by hyperleptinemia causing central and peripheral leptin resistance, is associated with an increased frequency of infections (Fig. 1) (42). In this context, leptin receptor desensitization is perceived by T-cells as a condition of leptin deficiency, leading to immune dysfunction in a similar manner to malnutrition and genetic leptin deficiency.

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