Objective
Obese adults have a greater risk of morbidity and mortality from infection with pandemic H1N1 influenza A virus (pH1N1). The objective of the present study was to elucidate the specific ...mechanisms by which obesity and overweight impact the cellular immune response to pH1N1.
Design and Methods
Peripheral blood mononuclear cells from healthy weight, overweight, and obese individuals were stimulated ex vivo with live pH1N1 and then markers of activation and function were measured using flow cytometry and cytokine secretion was measured using cytometric bead array assays.
Results
CD4+ and CD8+ T cells from overweight and obese individuals expressed lower levels of CD69, CD28, CD40 ligand, and interleukin‐12 receptor, as well as, produced lower levels of interferon‐γ and granzyme B, compared with healthy weight individuals, suggesting deficiencies in activation and function are indicated. Dendritic cells from the three groups expressed similar levels of major histocompatibility complex‐II, CD40, CD80, and CD86, as well as, produced similar levels of interleukin‐12.
Conclusions
The defects in CD4+ and CD8+ T cells may contribute to the increased morbidity and mortality from pH1N1 in obese individuals. These data also provide evidence that both overweight and obesity cause impairments in immune function.
In mammals, a family of five acyl-CoA synthetases (ACSLs), each the product of a separate gene, activates long chain fatty acids to form acyl-CoAs. Because the ACSL isoforms have overlapping ...preferences for fatty acid chain length and saturation and are expressed in many of the same tissues, the individual function of each isoform has remained uncertain. Thus, we constructed a mouse model with a liver-specific knock-out of ACSL1, a major ACSL isoform in liver. Eliminating ACSL1 in liver resulted in a 50% decrease in total hepatic ACSL activity and a 25–35% decrease in long chain acyl-CoA content. Although the content of triacylglycerol was unchanged in Acsl1L−/− liver after mice were fed either low or high fat diets, in isolated primary hepatocytes the absence of ACSL1 diminished the incorporation of 14Coleate into triacylglycerol. Further, small but consistent increases were observed in the percentage of 16:0 in phosphatidylcholine and phosphatidylethanolamine and of 18:1 in phosphatidylethanolamine and lysophosphatidylcholine, whereas concomitant decreases were seen in 18:0 in phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and lysophosphatidylcholine. In addition, decreases in long chain acylcarnitine content and diminished production of acid-soluble metabolites from 14Coleate suggested that hepatic ACSL1 is important for mitochondrial β-oxidation of long chain fatty acids. Because the Acsl1L−/− mice were not protected from developing either high fat diet-induced hepatic steatosis or insulin resistance, our study suggests that lowering the content of hepatic acyl-CoA without a concomitant decrease in triacylglycerol and other lipid intermediates is insufficient to protect against hepatic insulin resistance.
Abstract Background Diabetics are considered to be at high risk for complications from influenza infection and type 2 diabetes is a significant comorbidity of obesity. Obesity is an independent risk ...factor for complications from infection with influenza. Annual vaccination is considered the best strategy for protecting against influenza infection and it's complications. Our previous study reported intact antibody responses 30 days post vaccination in an obese population. This study was designed to determine the antibody response to influenza vaccination in type 2 diabetics. Methods Subjects enrolled were 18 or older without immunosuppressive diseases or taking immunosuppressive medications. A pre-vaccination blood draw was taken at time of enrollment, the subjects received the influenza vaccine and returned 28–32 days later for a post-vaccination blood draw. Height and weight were also obtained at the first visit and BMI was calculated. Antibody levels to the vaccine were determined by both ELISA and hemagglutination inhibition (HAI) assays. Results As reported in our previous work, obesity positively correlates with the influenza antibody response ( p = 0.02), while age was negatively correlated with antibody response ( p < 0.001). In both year 1 and year 2 of our study there was no significant difference in the percentage of the type 2 diabetic subjects classified as seroprotected or a responder to the influenza vaccine compared to the non-diabetic subjects. Conclusions These data are important because they demonstrate that diabetics, considered a high risk group during influenza season, are able to mount an antibody response to influenza vaccination that may protect them from influenza infection.
Abstract only
We have previously shown that obesity impairs expression of CD4
+
and CD8
+
T cell markers of activation and function. Obesity is associated with type II diabetes; however, not all ...obese individuals develop type II diabetes. Type II diabetes is associated with low levels of chronic inflammation and a higher prevalence of infections. The objective of our study was to elucidate the differences in the human cellular immune response between obese individuals with type II diabetes and obese individuals without type II diabetes. We stimulated peripheral blood mononuclear cells, obtained from obese individuals with and without type II diabetes,
ex vivo
with live pandemic influenza virus A and anti‐CD3/anti‐CD28 beads. Markers of activation, function, and signaling were measured using flow cytometry. We also measured three parameters of cellular glycolysis, including glycolytic rate, glycolytic capacity, and glycolytic reserve capacity, in T cells stimulated with or without anti‐CD3/anti‐CD28 bead stimulation and with or without insulin stimulation. We found significant differences between obese individuals with and without type II diabetes, demonstrating that metabolic disruptions in insulin signaling further increase immune dysfunction in obese adults.
Grant Funding Source
: NIH ROI
AI078090
and P30DK056350
Abstract only
Obese individuals are at greater risk of morbidity and mortality when infected with pandemic influenza. The underlying mechanism for the increased risk is unknown, although our work in ...a vaccinated obese population suggests an impaired immune response. Using a mouse model to study the immune response to influenza infection under conditions of diet‐induced obesity, we previously found reduced NK cell activity, impaired dendritric cell function, and failure of CD8
+
T cells to respond to virus. What could cause this seemingly global immune failure? One possibility is alterations in the highly suppressive T cell subset, regulatory T cells (Tregs). CD25
+
Foxp3
+
Tregs regulate nearly all aspects of the immune response, making them a plausible candidate for the impaired immunity in obese mice and likely obese humans. Diet‐induced obese and lean mice were infected with a mild dose of influenza A/PR/8/34. Obese mice had a greater number of Tregs in the lungs during the peak of the adaptive immune response. At an increased dose, obese mice had a greater percentage and number of Tregs in mediastinal lymph nodes. Further, Tregs isolated from obese mice were found to be less suppressive and more proliferative than those of lean mice. This data suggests that alterations in Treg distribution and function may be a novel, modifiable mechanism contributing to the impaired immune response and worse outcome to infection in the obese.
Grant Funding Source
: NORC DK56350
There are very limited data on mechanisms that mediate the obesity-associated and type II diabetes-associated impairments in immune function against viral infections, such as with the influenza ...virus. The purpose of this dissertation was to assess the humoral and cellular immune responses to the influenza virus, as well as to examine the effects of type II diabetes on T cell metabolism. This dissertation followed three aims. Aim 1 utilized a convenience sample to determine the antibody response to influenza vaccination in healthy weight, overweight, and obese adults at one and 11 months post vaccination. Higher body mass index (BMI) was associated with a greater decline in antibody titers to influenza strains at eleven months post vaccination, suggesting that overweight and obese individuals may not be as protected throughout the duration of the flu season compared to healthy weight individuals. Aim 2 consisted of a series of several studies comparing the cellular immune response to influenza virus in dendritic cells, cluster of differentiation (CD) 4+ T cells, and CD8+ T cells from healthy weight, overweight, and obese adults following ex vivo stimulation with live influenza virus. Although markers of dendritic cell activation and function remained intact, markers of T cell activation and function were significantly impaired in overweight and obese, compared to healthy weight adults. Together these data suggest that there would be significant deficiencies in the activation and cytotoxic function of CD8+ T cells, as well as in the activation and helper function of CD4+ T cells resulting from overweight and obesity. Aim 3 was an exploratory aim designed to generate preliminary data towards answering the question of how obesity with or without type II diabetes will affect T cell glucose metabolism. The data suggests that there are differences in glucose metabolism in unstimulated T cells from obese individuals with and without type II diabetes. The results of this dissertation indicate that both overweight and obesity impair the humoral and cellular immune response to influenza virus and that type II diabetes may alter T cell metabolism.
In mammals, a family of five acyl-CoA synthetases (ACSLs), each the product of a separate gene, activates long chain fatty
acids to form acyl-CoAs. Because the ACSL isoforms have overlapping ...preferences for fatty acid chain length and saturation
and are expressed in many of the same tissues, the individual function of each isoform has remained uncertain. Thus, we constructed
a mouse model with a liver-specific knock-out of ACSL1, a major ACSL isoform in liver. Eliminating ACSL1 in liver resulted
in a 50% decrease in total hepatic ACSL activity and a 25â35% decrease in long chain acyl-CoA content. Although the content
of triacylglycerol was unchanged in Acsl1 L â/â liver after mice were fed either low or high fat diets, in isolated primary hepatocytes the absence of ACSL1 diminished the
incorporation of 14 Coleate into triacylglycerol. Further, small but consistent increases were observed in the percentage of 16:0 in phosphatidylcholine
and phosphatidylethanolamine and of 18:1 in phosphatidylethanolamine and lysophosphatidylcholine, whereas concomitant decreases
were seen in 18:0 in phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and lysophosphatidylcholine. In addition,
decreases in long chain acylcarnitine content and diminished production of acid-soluble metabolites from 14 Coleate suggested that hepatic ACSL1 is important for mitochondrial β-oxidation of long chain fatty acids. Because the Acsl1 L â/â mice were not protected from developing either high fat diet-induced hepatic steatosis or insulin resistance, our study suggests
that lowering the content of hepatic acyl-CoA without a concomitant decrease in triacylglycerol and other lipid intermediates
is insufficient to protect against hepatic insulin resistance.
Recent reports suggest that obesity may be an independent risk factor for influenza A virus (IAV) H1N1 infection. Obese mice are also more susceptible to IAV infection. While many studies focus on ...the host immune response to IAV infection, few focus specifically on the response of lung epithelial cells, one of the primary targets for IAV infection. In an obese state, lung epithelial cells are exposed to serum containing high amounts of lipids, including fatty acids (FAs). A459 lung epithelial cells were used to test the hypothesis that lipid‐induced modifications would alter cellular responses to IAV infection. Cells were incubated for 24 hours with media containing a combination of the FAs palmitate, palmitoleate, stearate, and oleate, complexed to albumin, or control media without FAs, followed by infection with IAV. Cells incubated with FAs were found to have higher influenza viral titers compared with control cells. Concomitant with the higher titers, FA‐treated cells expressed higher levels of mRNA for the antiviral cytokines interferon (IFN)‐α and IFN‐β, and the proinflammatory cytokine interleukin‐6, likely in response to the higher viral load. These data suggest that lung epithelial cells in obese individuals may be more susceptible to viral infection due to exposure to FA‐rich serum and provide a novel mechanism for increased susceptibility to influenza infection due to obesity.
Patients with prostate cancer suffer significant sexual dysfunction after treatment which negatively affects them and their partners psychologically, and strain their relationships.
We convened an ...international panel with the aim of developing guidelines that will inform clinicians, patients and partners about the impact of prostate cancer therapies (PCT) on patients' and partners' sexual health, their relationships, and about biopsychosocial rehabilitation in prostate cancer (PC) survivorship.
The guidelines panel included international expert researchers and clinicians, and a guideline methodologist. A systematic review of the literature, using the Ovid MEDLINE, Scopus, CINAHL, PsychINFO, LGBT Life, and Embase databases was conducted (1995-2022) according to the Cochrane Handbook for Systematic Reviews of Interventions. Study selection was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Each statement was assigned an evidence strength (A-C) and a recommendation level (strong, moderate, conditional) based on benefit/risk assessment, according to the nomenclature of the American Urological Association (AUA). Data synthesis included meta-analyses of studies deemed of sufficient quality (3), using A Measurement Tool to Assess Systematic Reviews (AMSTAR).
Guidelines for sexual health care for patients with prostate cancer were developed, based on available evidence and the expertise of the international panel.
The guidelines account for patients' cultural, ethnic, and racial diversity. They attend to the unique needs of individuals with diverse sexual orientations and gender identities. The guidelines are based on literature review, a theoretical model of sexual recovery after PCT, and 6 principles that promote clinician-initiated discussion of realistic expectations of sexual outcomes and mitigation of sexual side-effects through biopsychosocial rehabilitation. Forty-seven statements address the psychosexual, relationship, and functional domains in addition to statements on lifestyle modification, assessment, provider education, and systemic challenges to providing sexual health care in PC survivorship.
The guidelines provide clinicians with a comprehensive approach to sexual health care for patients with prostate cancer.
The strength of the study is the comprehensive evaluation of existing evidence on sexual dysfunction and rehabilitation in prostate cancer that can, along with available expert knowledge, best undergird clinical practice. Limitation is the variation in the evidence supporting interventions and the lack of research on issues facing patients with prostate cancer in low and middle-income countries.
The guidelines document the distressing sexual sequelae of PCT, provide evidence-based recommendations for sexual rehabilitation and outline areas for future research. Wittmann D, Mehta A, McCaughan E, et al. Guidelines for Sexual Health Care for Prostate Cancer Patients: Recommendations of an International Panel. J Sex Med 2022;19:1655-1669.
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