leptin and Immunologic-Deficiency-Syndromes

Topics: Adaptive Immunity; Animals; Autoimmune Diseases; Communicable Diseases; Humans; Immunity, Innate; Immunologic Deficiency Syndromes; Leptin; Malnutrition

Leptin is a 16 kDa protein mainly produced by adipose tissue in proportion to adipose tissue mass. Originally thought to be a satiety factor, leptin is a pleiotropic molecule. In addition to playing a role in energy regulation, leptin also regulates endocrine and immune functions. Both the structure of leptin and that of its receptor suggest that leptin might be classified as a cytokine. The secondary structure of leptin has similarities to the long-chain helical cytokines family, which includes interleukin 6 (IL-6), IL-11, CNTF, and LIF, and the leptin receptor is homologous to the gp-130 signal-transducing subunit of the IL-6-type cytokine receptors. Leptin plays a role in innate and acquired immunity. Leptin levels increase acutely during infection and inflammation, and may represent a protective component of the host response to inflammation. More important, leptin deficiency increases susceptibility to infectious and inflammatory stimuli and is associated with dysregulation of cytokine production. Leptin deficiency also causes a defect in hematopoiesis. Leptin regulates T cells responses, polarizing Th cells toward a Th1 phenotype. Low leptin levels occurring during starvation mediate the neuroendocrine and immune dysfunction of starvation.

Topics: Animals; Humans; Immunity; Immunologic Deficiency Syndromes; Leptin; Nutrition Disorders; Obesity

In much of the developing world, severe malnutrition is the most prevalent cause of immunodeficiency and affects up to 50% of the population in some impoverished communities. As yet, we do not know how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will behave in populations with immunodeficiency caused by malnourishment. Interestingly, researchers are now speculating that, in some instances, a defective cellular immune system could paradoxically be a protective factor against severe disease in certain patients contracting SARS-CoV and SARS-CoV-2. This could be linked to the absence of T-cell activation. Based on available information presented here, it is plausible that the hyperimmune response, and subsequent cytokine storm often associated with severe coronavirus disease 2019 (COVID-19), could be "counteracted" by the defective immune response seen in individuals with malnutrition-induced leptin deficiency. In this paper, we proposed a theory that although those with malnutrition-linked leptin deficiency are at risk of SARS-CoV-2 infection, they are at lower risk of developing severe COVID-19.

Topics: Antibody Formation; Body Mass Index; COVID-19; COVID-19 Vaccines; Cytokine Release Syndrome; Developing Countries; Disease Susceptibility; Humans; Immunity, Cellular; Immunogenicity, Vaccine; Immunologic Deficiency Syndromes; Leptin; Lymphocyte Activation; Malnutrition; Models, Biological; Obesity; Protein-Energy Malnutrition; Risk; SARS-CoV-2; Severity of Illness Index; T-Lymphocytes

A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined.. We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives.. Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency.. The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.

Topics: Adult; Age of Onset; Basal Metabolism; Body Composition; Child; Diagnosis, Differential; Female; Genotype; Humans; Hyperphagia; Hypogonadism; Immunologic Deficiency Syndromes; Leptin; Lymphocyte Count; Male; Metabolism, Inborn Errors; Mutation; Obesity; Pedigree; Phenotype; Receptors, Cell Surface; Receptors, Leptin

There is a finely tuned interplay between immune and neuroendocrine systems. Metabolic disturbances like obesity will have serious consequences on immunity both at the cellular and at the cytokine expression levels. Our in vivo results confirm the immune deficiency of ob/ob mice, leptin deficient and massively obese, characterized by a reduced Ag-specific T cell proliferation after keyhole limpet hemocyanin immunization. In this report, we show that dendritic cells (DCs), major APCs involved in T lymphocyte priming, are affected in obese mice. Both their function and their steady-state number are disturbed. We demonstrate that DCs from ob/ob mice are less potent in stimulation of allogenic T cells in vitro. This impaired functionality is not associated with altered expression of phenotypic markers but with the secretion of immunosuppressive cytokines such as TGF-beta. Moreover, we show increased in vivo steady-state number of epidermal DCs in ob/ob mice, which is not due to a migratory defect. The ob/ob mice are characterized by the absence of functional leptin, a key adipokine linking nutrition, metabolism, and immune functions. Interestingly, intradermal injection of leptin is able to restore epidermal DC number in obese mice. Thus, DCs might be directly sensitive to metabolic disturbances, providing a partial explanation of the immunodeficiency associated with obesity.

Topics: Animals; Cell Movement; Cytokines; Dendritic Cells; Epidermis; Female; Immunologic Deficiency Syndromes; Langerhans Cells; Leptin; Mice; Mice, Obese; Obesity; T-Lymphocytes; Transforming Growth Factor beta

The present study was designed to assess the effect of maternal undernutrition, during gestation and lactation, on the neuroendocrine [hypothalamo-pituitary-adrenal (HPA)]-immune axis response to endotoxin (LPS) administration. For this purpose, 21-day-old male rats from both well-nourished (WN) and undernourished (UN) mothers were examined 2 h after injection (i.p.) of vehicle alone (VEH) or containing LPS (130 microg/kg BW). Circulating levels of glucose (GLU), ACTH, corticosterone (B), tumor necrosis factor-alpha (TNFalpha) and leptin were explored. The results indicate that: (a) mother body weight was significantly (p < 0.05) reduced, as a consequence of UN, at the second and third weeks of pregnancy; (b) no differences in basal glycemia were found in the two groups of pups, and LPS treatment did not induce hypoglycemia, in either group; (c) basal plasma ACTH, B and TNFalpha levels were similar in the two groups, and LPS-induced ACTH, B and TNFalpha secretions, although severalfold higher than respective VEH values (p < 0.05) in pups from WN mothers, were fully (ACTH and B) and partially (TNFalpha) abolished in products from UN mothers; (d) both mean body weights and basal plasma leptin levels were significantly (p < 0.05) lower in pups from UN than from WN mothers, and LPS administration did not modify plasma leptin values in products from both groups. In addition, results of dispersed total adrenal cells incubated in vitro indicate that: (a) both basal and ACTH (22 pM)-induced B secretion were significantly (p < 0.05) lower in cells from UN than WN pups, and (b) leptin (100 nM) was able to inhibit partially ACTH-stimulated B output by adrenal gland (AG) cells from WN pups; however, it failed to inhibit ACTH-stimulated glucocorticoid release by AG cells from UN pups. The present results indicate that undernutrition in mothers, during the very critical periods of gestation and lactation, induces in their male pups at weaning: (a) reduced circulating leptin levels and body weight values; (b) metabolic adaptation to normal carbohydrate metabolism; (c) hyporesponsiveness of the HPA and immune (TNFalpha) axes during endotoxemia, and (d) leptin resistance at the adrenocortical level. This study strongly supports that undernutrition of mothers results in neuroendocrine immune dysfunction of their pups; however, adrenal resistance to the inhibitory effect of leptin on glucocorticoid output is developed, probably as an adaptive mechanism to counteract unfavor

Topics: Adaptation, Physiological; Adrenal Glands; Adrenocorticotropic Hormone; Animals; Animals, Suckling; Blood Glucose; Body Weight; Corticosterone; Female; Gestational Age; Hypothalamo-Hypophyseal System; Immunologic Deficiency Syndromes; Lactation; Leptin; Lipopolysaccharides; Male; Maternal-Fetal Exchange; Neuroimmunomodulation; Nutrition Disorders; Pituitary-Adrenal System; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Rats; Rats, Inbred F344; Tumor Necrosis Factor-alpha; Weaning