Young and elderly patients with type 2 diabetes have optimal B cell responses to the seasonal influenza vaccine
Introduction
Type 2 diabetes (T2D) mellitus is a metabolic, inflammatory disease not associated with autoimmunity, but often characterized by obesity, hypertension, dyslipidemia, accelerated atherosclerosis and increased mortality [1], [2]. It is a common disease affecting >15 million Americans and is dramatically increasing in incidence [1], [2]. Inflammation in diabetes is thought to initiate in the visceral adipose tissue due to changes in fat metabolism occurring in individuals with abnormally large fat deposits consequent in most cases to hypernutrition [3], [4]. The local inflammatory response results in higher levels of pro-inflammatory saturated fatty acids, which serve as ligands for the Toll-like receptors TLR2 and TLR4 [5], [6]. TLRs activate the signaling pathways that culminate for example in activation of NF-κB, its translocation into the nucleus and release of pro-inflammatory cytokines [7], [8]. These cytokines, secreted by several immune and non-immune cells, are crucial regulators of the pathological inflammation that promotes and characterizes diabetes.
B cells are the first immune cells to infiltrate the expanding adipose tissues in response to hypernutrition, followed by T cells and macrophages [9]. B cells can be activated by products of altered lipolysis in the expanding adipose tissue to release pro-inflammatory cytokines, such as TNF-α and IL-6, or chemokines, such as IL-8, thus contributing in a significant way to systemic inflammation [2], [8].
T2D patients are at risk for infections due to influenza or for complications related to it [10], [11], [12]. Therefore annual influenza vaccination is recommended [10]. Viral and bacterial infections and consequent diseases are associated with increased morbidity and mortality in T2D patients, causing loss of metabolic control leading to an increase of glycosylated serum proteins, ketoacidosis which may result in an increased hospitalization rate and mortality rate, and prolonged complications [13], [14]. Studies assessing the clinical efficacy of influenza vaccination in T2D patients have provided incomplete and controversial results, which were attributed to the effects of confounding factors (age, duration of disease, co-morbidities, treatments, nutritional status and vaccination history [15], [16]). A few studies have shown clinical efficacy of influenza vaccination with reduction in health complications, hospitalization and deaths [17], [18], [19], [20]. However, less is known on the effects of influenza vaccination on lymphocyte populations of T2D patients. The few studies addressing this issue have measured T cell function in vaccinated young [11] and elderly [21] T2D patients as compared to healthy controls [11], [21] and have shown reduced [11] or similar [21] responses in patients versus controls. No studies have been conducted so far to evaluate the contribution of B cells to the influenza vaccine response in T2D patients.
In the present study we performed a detailed evaluation of B cell markers and function in T2D patients, vaccinated with influenza vaccine during the 2011–2012 season and determine the contribution of B cells and B cell-derived cytokines to the serum response in these individuals at risk for infections. It has previously been shown that elderly individuals have high levels of systemic inflammation [22], [23], [24] and we have shown that this negatively impacts the function of B cells [25]. We therefore hypothesized that the increased inflammation in T2D patients would also lead to decreased B cell function. Unexpectedly, we found normal in vivo and in vitro B cell responses, despite high levels of inflammation in these patients. We suggest that the innate immune system of T2D patients is beneficially hyperactivated, as we found elevated serum levels of bacterial lipopolysaccharide (LPS) and soluble (s)CD14, and we believe that these may not only counteract the negative effects of inflammation from increased TNF-α, IL-6 and CRP, but also to induce a direct stimulation of B cells. Moreover, T2D patients were all taking anti-inflammatory agents, such as Metformin, which blocks TNF-α signaling in all cells, including B cells.
Section snippets
Subjects
Experiments were conducted using blood from T2D patients and healthy volunteers of different ages after appropriate signed informed consent and were approved with IRB protocol #20070481. In every experiment, 37 healthy young, 28 healthy elderly, 14 diabetic young and 8 diabetic elderly were evaluated. Young individuals are 20–59 years of age, whereas elderly individuals are ≥60 years of age. All subjects at the time of enrollment were influenza-free, without symptoms associated with respiratory
Demographic characteristics and serological profile of the subjects in the study
Demographic characteristics and serological profile of the participants are in Table 1. We measured serum levels of the following markers of inflammation: TNF-α and IL-6, CRP, LPS, sCD14 and Adiponectin. Results show increased levels of serum IL-6, CRP, LPS and sCD14 in both young and elderly T2D patients as compared to healthy age-matched controls, and increased levels of TNF-α only in elderly T2D patients versus healthy controls. This can be due to the use of high doses of Metformin by young
Discussion and conclusions
So far, no studies have been performed to determine the contribution of B cells to the influenza vaccine response in T2D patients. Our results herein show for the first time that young and elderly T2D patients have normal in vivo and in vitro B cell responses. Previous studies, designed to evaluate the effect of diabetes on influenza vaccine-specific T cell responses, have shown controversial results, as these responses can be either affected [11] or not [21] by the disease.
We have previously
Acknowledgements
This study was supported by NIH AG-32576 (BBB).
We would like to express our gratitude to the people who participated in this study. We thank the personnel of the Department of Family Medicine and Common Health at the University of Miami Miller School of Medicine, in particular Dr. Robert Schwartz, chairman, Susie Batista (RN) for the recruitment of healthy volunteers and Isabel Alfonsin-Vittoria (LMHC) for the recruitment of patients with T2D; Dr. Sandra Chen-Walta, Employee Health Manager; and
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These authors contributed equally.