Leptin's metabolic and immune functions can be uncoupled at the ligand/receptor interaction level.

The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. We here provide genetic and biochemical evidence that the metabolic and immune functions of leptin can be uncoupled at the receptor level. First, homozygous mutant fatt/fatt mice carry a spontaneous splice mutation causing deletion of the leptin receptor (LR) immunoglobulin-like domain (IGD) in all LR isoforms. These mice are hyperphagic and morbidly obese, but display only minimal changes in size and cellularity of the thymus, and cellular immune responses are unaffected. These animals also displayed liver damage in response to concavalin A comparable to wild-type and heterozygous littermates. Second, treatment of healthy mice with a neutralizing nanobody targeting IGD induced weight gain and hyperinsulinaemia, but completely failed to block development of experimentally induced autoimmune diseases. These data indicate that leptin receptor deficiency or antagonism profoundly affects metabolism, with little concomitant effects on immune functions.

Minor differences in body condition and immune status between avian influenza virus-infected and noninfected mallards: a sign of coevolution?

Wildlife pathogens can alter host fitness. Low pathogenic avian influenza virus (LPAIV) infection is thought to have negligible impacts on wild birds; however, effects of infection in free-living birds are largely unstudied. We investigated the extent to which LPAIV infection and shedding were associated with body condition and immune status in free-living mallards (Anas platyrhynchos), a partially migratory key LPAIV host species. We sampled mallards throughout the species' annual autumn LPAIV infection peak, and we classified individuals according to age, sex, and migratory strategy (based on stable hydrogen isotope analysis) when analyzing data on body mass and five indices of immune status. Body mass was similar for LPAIV-infected and noninfected birds. The degree of virus shedding from the cloaca and oropharynx was not associated with body mass. LPAIV infection and shedding were not associated with natural antibody (NAbs) and complement titers (first lines of defense against infections), concentrations of the acute phase protein haptoglobin (Hp), ratios of heterophils to lymphocytes (H:L ratio), and avian influenza virus (AIV)-specific antibody concentrations. NAbs titers were higher in LPAIV-infected males and local (i.e., short distance) migrants than in infected females and distant (i.e., long distance) migrants. Hp concentrations were higher in LPAIV-infected juveniles and females compared to infected adults and males. NAbs, complement, and Hp levels were lower in LPAIV-infected mallards in early autumn. Our study demonstrates weak associations between infection with and shedding of LPAIV and the body condition and immune status of free-living mallards. These results may support the role of mallards as asymptomatic carriers of LPAIV and raise questions about possible coevolution between virus and host.

The neuro-immune pathophysiology of central and peripheral fatigue in systemic immune-inflammatory and neuro-immune diseases

Many patients with systemic immune-inflammatory and neuro-inflammatory disorders, including depression, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, cancer, cardiovascular disorder, Parkinson's disease, multiple sclerosis, stroke, and chronic fatigue syndrome/myalgic encephalomyelitis, endure pathological levels of fatigue. The aim of this narrative review is to delineate the wide array of pathways that may underpin the incapacitating fatigue occurring in systemic and neuro-inflammatory disorders. A wide array of immune, inflammatory, oxidative and nitrosative stress (O&NS), bioenergetic, and neurophysiological abnormalities are involved in the etiopathology of these disease states and may underpin the incapacitating fatigue that accompanies these disorders. This range of abnormalities comprises: increased levels of pro-inflammatory cytokines, e.g., interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF) α and interferon (IFN) α; O&NS-induced muscle fatigue; activation of the Toll-Like Receptor Cycle through pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns, including heat shock proteins; altered glutaminergic and dopaminergic neurotransmission; mitochondrial dysfunctions; and O&NS-induced defects in the sodium-potassium pump. Fatigue is also associated with altered activities in specific brain regions and muscle pathology, such as reductions in maximum voluntary muscle force, downregulation of the mitochondrial biogenesis master gene peroxisome proliferator-activated receptor gamma coactivator 1-alpha, a shift to glycolysis and buildup of toxic metabolites within myocytes. As such, both mental and physical fatigue, which frequently accompany immune-inflammatory and neuro-inflammatory disorders, are the consequence of interactions between multiple systemic and central pathways.

Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut–brain pathways

The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut–brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when “comorbid” with depression.

Immune response of greenback flounder Rhombosolea tapirina after exposure to contaminanted marine sediment and diet

Non-specific immune response of greenback flounder, Rhombosolea tapirina, exposed to contaminated marine sediments was examined. Reference sediments from Port Sorell and contaminated sediments from Deceitful Cove, Tasmania, Australia were investigated. Hatchery-reared flounder were exposed to reference sediment, contaminated sediment or contaminated sediment and diet for 6 weeks. Phagocytic capacity and lysozyme response in flounder were examined on cessation of exposure trial. Significant differences were found in phagocyticcapacity and lysozyme response between treatments. Exposure to contaminated sediment, irrespective of diet or benthic disturbance elicited inhibition of phagocytic efficiency in flounder. Disturbance of contaminated sediment stimulated lysozyme activity. The immuneresponse in flounder indicates potential immunotoxicity of sediment from Deceitful Cove.