DIAB-6020; No. of Pages 8 diabetes research and clinical practice xxx (2014) xxx–xxx
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Review
Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis? S. Ziai a,b, A. Coriati a,b, M.-S. Gauthier b, R. Rabasa-Lhoret a,b,c,d, M.V. Richter e,* a
Nutrition Department, Faculty of Medicine, Universite´ de Montre´al, Montre´al, Que´bec, Canada Institut de Recherches Cliniques de Montre´al (IRCM), Montre´al, Que´bec, Canada c Montreal Diabetes Research Centre (MDRC), Montre´al, Que´bec, Canada d Cystic Fibrosis Clinic, Centre Hospitalier de l’Universite´ de Montre´al (CHUM) & CHUM Research Center (CR-CHUM), Montre´al, Que´bec, Canada e Department of Medicine, Faculty of Medicine and Health Sciences, Universite´ de Sherbrooke, Sherbrooke, Que´bec, Canada b
article info
abstract
Article history:
Cystic fibrosis-related diabetes (CFRD) is the most frequent complication of cystic fibrosis
Received 8 November 2013
(CF) and associated with increased mortality. Why patients have an accelerated loss of lung
Received in revised form
function before the diagnosis of CFRD remains poorly understood. We reported that patients
20 January 2014
with or without CFRD had increased glucose excursions when compared to healthy peers.
Accepted 3 March 2014
Studies have demonstrated that patients with CF have increased glucose fluctuations and
Available online xxx
hyperglycemia and that this may affect the clinical course of CF and lead to lymphocyte
Keywords:
cytokine IL-17. The Th17 pathway is involved in CF lung inflammation, b-cell destruction in
dysfunction. T-helper 17 (Th17) lymphocytes produce and secrete the pro-inflammatory Cystic fibrosis-related diabetes
type 1 diabetes (T1D) and Th17 cells of patients with type 2 diabetes have increased
Hyperglycemia
production of IL-17 when compared to healthy peers. Also, regulatory T-cells (Tregs) have
Lung function
been shown to be dysfunctional and produce IL-17 in T1D. Furthermore, vitamin D can affect
Th17 cells
inflammation in CF, diabetes and the differentiation of lymphocytes. In this review, we
Regulatory T-cells
discuss the potential roles of hyperglycemia on Th17 cells, Tregs and IL-17 as a potential
IL-17 therapy
cause for accelerated lung function decline before CFRD and how this could be modulated by vitamin D or by directly intervening in the IL-17A pathway. # 2014 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CFRD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
000 000 000
* Corresponding author at: Service de pneumologie, De´partement de me´decine, Faculte´ de me´decine et des sciences de la sante´, Universite´ de Sherbrooke, 3001-12e Avenue Nord, Sherbrooke, Que´bec J1H 5N4, Canada. Tel.: +1 819 820 6868x14881. E-mail address: [email protected] (M.V. Richter). http://dx.doi.org/10.1016/j.diabres.2014.03.002 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
DIAB-6020; No. of Pages 8
2
diabetes research and clinical practice xxx (2014) xxx–xxx
3.1.
4.
5. 6.
1.
Helper T-cell subsets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. T-helper 17 (Th17) lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Regulatory T-cells (Tregs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How could Th17, IL-17 and Treg lymphocytes be implicated in lung function loss associated with CFRD? . 4.1. Proposed mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Could vitamin D affect Th17 and Treg cells? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Therapeutic potential of interventions in the IL-17A mediated pathway . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disease among individuals of European descent [1]. First described in North America in 1938 by Dr. Dorothy H. Andersen [2], CF affects one in every 3600 births in Canada [3]. In 1989, researchers discovered that CF is caused by a mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene mainly at position 508 (p.Phe508del) [4]. Since then, over 1900 other mutations have been found in the CFTR gene [5]. The CFTR gene is translated into a chloride channel and its absence or dysfunction causes excess intracellular sodium and water resorption [6]. Consequently, people with CF have an accumulation of thick mucus in various organs such as the lungs and the pancreas, often have recurrent lung infections, exocrine insufficiency and in most cases, ultimately die from lung disease [7,8]. With more aggressive nutritional interventions and antibiotic treatments, the median life expectancy of individuals with CF in Canada has steadily risen to 48,5 years of age in 2011 [3]. This increase led to the emergence of numerous new complications including CF-related diabetes (CFRD) [1,9].
2.
CFRD
CFRD is an important complication that affects approximately 20% of adults between 18 and 20 years old with CF in Canada [3]. CFRD is a unique type of diabetes that differs from type 1 (T1D) and type 2 diabetes mellitus (T2D) but shares some common similarities [10]. On one hand, the main cause of death in patients with CFRD is respiratory failure whereas patients with T1D and T2D most often die of cardiovascular disease [10,11]. On the other hand, CFRD is associated to a very significant decrease in insulin secretion [1,12], similar to that observed in T1D [10], caused by a decreased number of b-cells [13,14], atrophy and by important fibrosis and amyloidosis in the pancreas [15]. Similarly to what is observed in T2D, CFRD is preceded by a long phase of glucose intolerance characterized by progressive worsening of postprandial hyperglycemia [1,10]. Its presence in patients with CF is associated with worse lung (i.e. FEV1) and nutritional statuses (i.e. body mass index) and with increased mortality [12,16]. CFRD is also associated with an accelerated decline in lung functions years before its diagnosis [3,16]. Both the physiopathology of CFRD and the accelerated lung function decline before CFRD onset
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
000 000 000 000 000 000 000 000 000 000 000
are not fully understood but experimental evidence suggests that chronic inflammatory aspects might be involved [17]. In this review, we will discuss the potential roles of T-helper 17 (Th17) and regulatory T (Treg) cells and the pro-inflammatory interleukin-17A (IL-17A) in progressive lung function deterioration and hyperglycemia in CF.
3.
Inflammation
The CF inflammatory response in the lungs is dominated by neutrophil activation [18]. Both CF and diabetes are diseases with inflammatory components [7,19]. The thick mucus that accumulates in the lungs of patients with CF is frequently colonized by various bacteria including Pseudomonas aeruginosa and Staphylococcus aureus [20]. Neutrophils are then attracted by chemotaxis to the site of inflammation by formylated peptides such as formyl-methionine-leucine-phenylalanine produced by bacteria [21] and secrete oxidases and proteases in an attempt to clear the pathogens [18]. This neutrophil response is excessive and contributes to lung tissue damage and eventually contributes to decreased lung function [18]. However, the presence of lymphocytes in the lungs of patients with CF suggests the involvement of adaptive immunity [22,23]. There are two main groups of lymphocytes: T cells and B cells. B cells produce antibodies while T cells are responsible for cellular immunity [24]. T cells are subdivided into cytotoxic T cells that kill intracellular pathogens and helper T cells that assist cytotoxic T cells and B cells by secreting cytokines [25,26].
3.1.
Helper T-cell subsets
Several T-cell subsets have been identified of which T-helper 1 (Th1), T-helper 2 (Th2) and Th17 cells are the main groups [26]. While on one hand, Th1 lymphocytes are involved in the clearance of intracellular pathogens, on the other hand, Th2 cells play an important role in the humoral response to extracellular pathogens [26]. In CF, in 2001, Hubeau et al. found increased levels of T cells in the airway mucosa of individuals with the disease [22]. Subsequent studies demonstrated that a Th1-dominated inflammatory response was associated with better lung function in patients with CF [27] and that those infected by Pseudomonas had elevated levels of Th2 cells, IL-4 and IL-13 in their bronchoalveolar lavage fluids versus patients that were
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
DIAB-6020; No. of Pages 8 diabetes research and clinical practice xxx (2014) xxx–xxx
not infected [28]. Accordingly, the levels of these cytokines were inversely correlated with lung function [28]. Lymphocytes are also implicated in the physiopathology of diabetes. T1D is an autoimmune disease primarily caused by the destruction of insulin producing pancreatic b-cells mainly by cytotoxic T and Th1 lymphocytes [29]. Taken together, helper T cells are involved in both the inflammatory response in the lungs of patients with CF and also in pancreatic b-cell destruction in T1D. Although it remains to be experimentally verified, helper T cells may thus represent a mechanistic link between decreased lung functions and the development of CFRD.
3.1.1.
T-helper 17 (Th17) lymphocytes
In the past decade, much attention has been given to a specific subtype of T-helper cells called Th17 cells. This subset cells mainly produces IL-17A as well as IL-17F, IL-21 and IL-22 [30] and aid in eliminating pathogens not adequately handled by Th1 and Th2 cells and fungi [26]. Elevated levels of the proinflammatory cytokine IL-17A have been implicated in the physiopathology of many autoimmune diseases including rheumatoid arthritis (RA), multiple sclerosis and T1D [29,31,32]. IL-17A binds IL-17-receptor A and is expressed in various cell types [32] including human bronchial epithelial cells [33]. Other immune cells such as the gdT cells and natural killer T cells have also been shown to produce IL-17A [34]. Studies in mice have demonstrated that Th17 cells and IL17A are involved in the pulmonary immune response against bacteria by stimulating the secretion of CXCL8 and IL-6 from epithelial cells, cytokines that recruit and activate neutrophils [35]. Furthermore, IL-17A was shown to increase the expression of mucins (MUC5AC, MUC5B) in human tracheobronchial epithelial cells in vitro [36]. In individuals with CF, increased production of mucins is thought to contribute to the generation of the thick mucus observed in the lungs [37]. Studies have found elevated levels of IL-17A and Th17 cells in the sputum and the lungs of patients with CF when compared to healthy controls [33,34,38]. It has also been reported that IL-17A can exacerbate inflammatory responses in the lungs of patients with CF [39,40]. In 2011, Brodlie and colleagues measured increased levels of IL-17A in the lungs of 43 patients with compared to 35 subjects with pulmonary hypertension. In the same study, when human bronchial epithelial cells were stimulated with IL-17A, the authors observed increased production of IL-8, IL-6 and granulocytemacrophage colony-stimulating factor (GM-CSF), cytokines known to activate and recruit neutrophils [41]. In CF, macrophages also contribute to neutrophil recruitment and activation involved in lung disease by producing IL-6 and IL-8 [42]. Another study, in 2007 by Dubin et al., suggested that the bacteria trapped in the thick mucous in the lungs of people with CF could activate dendritic cells. These dendritic cells could then produce IL-23 that would recruit Th17 cells. Th17 cells would then produce IL-17A that would recruit neutrophils. Th17 cells could have an exaggerated response in the presence of IL-23 because this cytoking stabilizes them [43]. A recent study by Tan et al. demonstrated the importance of the Th17 pathway in early pathogenesis of CF by detecting elevated levels of IL-17+ cells in newly diagnosed children with CF [34]. In 2013, Tiriniger et al. demonstrated that levels of
3
IL-17A inversely correlated with FEV1 of patients with CF [44]. These studies clearly suggest that the Th17 pathway and IL17A are both involved in CF airway inflammation and might contribute to the chronic neutrophil recruitment in CF lungs (Fig. 1). Studies also suggest a role for IL-17 in the development of T1D [29,31] and that suppressing the Th17 pathway could help in preventing T1D [45]. More recently, Yaochite et al. reported an association between IL-17 levels and the degree of pancreatic inflammation in streptozotocin (STZ) treated mice [46], suggesting the potential role of IL-17 in pancreatic b-cell destruction in this animal model of T1D. However, in other studies, IL-17 was not implicated in the physiopathology of T1D [47,48]. This discrepancy might be due to the fact that different methods were used to study the implication of IL-17 in T1D. For instance, in some studies the injection of adjuvants containing Mycobacterium [47] and RNA interference were used to examine the role of IL-17 in the development of T1D in NOD mice [46] while in the others T-cell vaccination was used [45]. The potential contributing role of IL-17 in the development of T1D has also been explored in humans. Firstly, in 2010, Honkanen et al. observed increased levels of IL-17 in peripheral blood of children with T1D and a pro-apoptotic effect of this cytokine on human islets in vitro [49]. A few years later, another research team isolated peripheral blood from 50 patients with T1D and 30 healthy control subjects, exposed their isolated helper T cells to auto-antibodies of pancreatic bcells and observed that patients with T1D had a greater proportion of IL-17 when compared to healthy control subjects [50]. They also observed increased IL-17 mRNA levels in the pancreas of two deceased patients with T1D when compared to levels in three deceased subjects without T1D [50]. These studies suggest that targeting Th17 cells and IL-17 could potentially prevent the destruction of pancreatic b-cells. T2D is associated with obesity and is characterized by insulin resistance and dysfunctional b-cells which lead to hyperglycaemia [51]. Individuals with T2D have increased plasma levels of IL-6 and IL-1b, two cytokines associated with Th17 differentiation [52–54]. In 2011, Jagannathan-Bogdan et al. reported increased numbers of Th17 cells and secretion of IL-17 and interferon g (IFN-g) in the peripheral blood of individuals with T2D compared to healthy individuals [55], suggesting that IL-17 could also be involved in the physiopathology of this type of diabetes.
3.1.2.
Regulatory T-cells (Tregs)
Tregs are a subset of T cells that help in the suppression of excessive effector T-cell responses and maintain a balance between anti-inflammatory and pro-inflammatory responses [56]. Tregs express the transcription factor Foxp3 in addition to producing the anti-inflammatory cytokine IL-10 [57,58]. When this balance is perturbed, auto-immune diseases such as rheumatoid arthritis and multiple sclerosis can develop [59]. Furthermore, Treg cells can dedifferentiate into Foxp3 cells and become pro-inflammatory [60]. For example, in the presence of IL-6 and IL-1b, Treg cells can differentiate into Th17 cells and produce IL-17 thus underscoring the plasticity between these T-cell subsets [61]. A study by Marwaha et al. reported that Treg cells of patients with T1D expressed IL-17 and were inefficient at
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
DIAB-6020; No. of Pages 8
4
diabetes research and clinical practice xxx (2014) xxx–xxx
Fig. 1 – Effects of intrinsic CFTR-related defects in epithelial cells and lymphocytes on IL-17A production, neutrophil activation and recruitement, the roles of other immune cells (dendritic cells and macrophages) in this vicious inflammatory cycle and the possible effects on pancreatic b cells and insulin secretion.
suppressing exaggerated immune responses [62]. This was subsequently confirmed by other groups in streptozotocin mice and in humans where elevated levels of dysfunctional Treg cells that were unable to attenuate inflammatory responses were reported [63,64]. Dysfunctional Treg cells that become Th17 cells and produce IL-17 have also been reported in the auto-immune disease psoriasis [65]. Moreover, a study conducted in patients with T2D also suggested an implication of dysfunctional Treg cells producing IL-17 in this disease [55]. In summary, even though Th1 and Th2 cells probably modulate lung inflammation in patients with CF, Th17 cells and IL-17A seem to perpetuate neutrophil infiltration into the lungs and contribute to lung damage. Also, Th17 and dysfunctional Treg cells as well as IL-17A are involved in b cell destructions in T1D and possibly the physiopathology of T2D. Altogether, this suggests that the Th17 pathway could be involved both in lung function loss as well as hyperglycemia in CF.
4. How could Th17, IL-17 and Treg lymphocytes be implicated in lung function loss associated with CFRD? 4.1.
Proposed mechanism
Compared to healthy counterparts, hyperglycemia and glucose fluctuations are present not only in patients with CFRD and in patients with CF who are pre-diabetic but also in
patients who are considered as having normal glucose tolerance [1,66,67]. While hyperglycemia may exacerbate the clinical course of CF by inducing immune reactivity [17], studies in mice demonstrated that lymphocytes responded in an exaggerated fashion to hyperglycaemia [68] and that CFTR dysfunction in T cells can lead to aberrant immune responses [69]. In addition, as mentioned above, Th17 cells and the proinflammatory cytokine IL-17 are implicated in CF as well as in hyperglycemia and Treg cells are thought to be dysfunctional in T1D and possibly T2D. Thus, the hyperglycemia and glucose fluctuations observed in patients with CF without diabetes might negatively impact lymphocyte subsets such as Th17 and Treg cells and increase their production of IL-17A perpetuating a vicious cycle of abnormal immune responses by these cells and deteriorate hyperglycemia and glucose fluctuations (Fig. 2). The evidence suggests that the impaired glucose conditions in patients with CF with and without CFRD could promote hyperactive responses of lymphocytes without a functional CFTR by increasing the proportions of IL-17producing Th17 and dysfunctional Tregs cells. Although a study has demonstrated CFTR / mice with allergic bronchopulmonary aspergillosis have decreased percentages of CD4+ Foxp3+ T-cells [70], Treg cells have not yet been examined in CFRD but it may be plausible that this important T-cell subtype involved in immune regulation would be influenced by CFTR dysfunction, hyperglycemia and glucose fluctuations. The increased amount of IL-17 produced by these skewed T-cells could travel to the lungs and, combined with bacterial
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
DIAB-6020; No. of Pages 8 diabetes research and clinical practice xxx (2014) xxx–xxx
5
CFRD and they suggested that, because vitD is associated to improved insulin secretion and sensitivity, decreased levels observed in CF could contribute to glucose abnormalities [74]. In rodent models, vitD modulates insulin synthesis and secretion [75] and in humans, observational studies (crosssectional and longitudinal) report a link between low serum levels of the active form of vitD (25(OH)D) and diabetes [75–77]. Furthermore, vitD receptors (VDR) are expressed in various immune cells including dendritic cells, B cells and T cells and their levels increase in proliferating lymphocytes [78]. Research has shown that 1,25-dihydroxyvitamin D favors Treg cell development by modulating dendritic cells and also by targeting the T cells and thus promoting FoxP3 expression by binding to its response element (VDRE) in the gene’s promoter [78,79]. VitD can also suppress IL-17 production via its direct transcriptional suppression and inhibit Th17 development in vitro [80]. Therefore, vitD can also modulate Th17 and Treg cells dysregulation and influence lung damage and hyperglycemia in CF. In addition, other nutrients including polyunsaturated fatty acids and vitamin A could also affect Th17 and Treg cells as well as hyperglycemia [81–84]. Further studies are needed to explore the effects of these nutrients on these cell types and the development of CFRD.
4.3. Therapeutic potential of interventions in the IL-17A mediated pathway
Fig. 2 – Proposed mechanism of the vicious cycle by which hyperglycemia, glucose fluctuations and non-optimal vitamin D levels in non-diabetic and pre-diabetic patients with cystic fibrosis could lead to lymphocyte dysfunction, increased circulating IL-17A levels, pancreatic dysfunction and the decrease in lung functions years before cystic fibrosis-related diabetes onset.
infections, perpetuate neutrophilic inflammation, lung tissue damage and consequently lead to a decrease in lung functions before the onset and during CFRD. In addition, these abnormalities could also play a role in CFRD at the level of the pancreatic b-cell favoring hyperglycemia and thus initiating a vicious cycle (Fig. 2).
4.2.
Could vitamin D affect Th17 and Treg cells?
Besides vitamin D’s (vitD) classical role in bone metabolism [71], it also affects lung function in CF as well as diabetes. In 2008, Wolfenden et al. found a positive association between levels of vitD (25(OH)D) and percent predicted FEV1 in 185 patients with CF [72]. Despite regular supplementation, most patients with CF still display suboptimal vitD levels [73]. In 2011, Pincikova et al. associated suboptimal levels of vitD to
As previously mentioned the IL-17A pathway is implicated in the physiopathology of many immune diseases. Recently, clinical trials in RA and psoriasis using drugs to block the IL17A pathway have shown promising results. In RA, 237 patients were recruited to a randomized, double-blind, placebo-controlled, dose finding phase II trial using secukinumab, a monoclonal antibody that binds specifically to human IL-17A. Compared to the placebo, the Disease Activity Score in 28 joints (DAS28) score and C-reactive protein (CRP) levels were improved after 16 weeks in participants taking higher doses of secukinumab [85]. Two phase III trials are currently underway exploring safety and efficacy of secukinumab for RA management [86]. Two other compounds to block the IL-17 pathway have been used in clinical trials with patients with moderate-tosevere psoriasis. In these two short term randomized, doubleblind, placebo-controlled, dose-ranging phase II trials, brodalumab, a human IL-17 receptor antibody, and ixekizumab, a human monoclonal antibody against IL-17A, demonstrated an improvement of the Psoriasis area and severity index (PASI) by 75% in a majority (77–82%) of patients compared to placebo [87,88]. Of note, none of these trials verified the effect of these drugs on blood glucose. A study published by Mueller et al. in 2010 demonstrated that inhibiting IL-17E decreases the production of Th2 cytokines by T-cells in CF. These authors injected a recombinant adeno-associated virus 1 intramuscularly expressing the soluble receptor for IL-17E into CFTR / mice and they observed a decrease in IL-4 and IL-13 production in CD4+ T-cells [89]. Therefore, targeting IL-17A directly with an antibody or with a receptor could possibly decrease the production of other cytokines such as IL-4, IL-13, IL-6 and IL-8
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
DIAB-6020; No. of Pages 8
6
diabetes research and clinical practice xxx (2014) xxx–xxx
and decrease airway inflammation in CF. However, as phase II trials in humans suggest that one of the most frequent side effects of the drugs is upper respiratory infection [86–88], their usage in CF will await an understanding of pulmonary infection risks associated with these drugs. In summary, non-optimal levels of, vitD are frequently observed in patients with CF and might promote inappropriate immune responses of Th17 and Treg cells and in turn, possibly contribute to decreased lung functions, hyperglycemia as well as the emergence of CFRD. Future studies are needed to explore the relationship between nutrients, T cell populations and lung inflammation as well as CFRD although one study has already examined vitD and CFRD [74]. Moreover, therapies targeting IL-17A have been studied in RA and psoriasis and could also be beneficial in CF.
5.
Conclusions
[2]
[3]
[4]
[5]
[6] [7] [8]
CFRD is an important complication of CF that is preceded by a long pre-diabetic phase associated with unexplained accelerated loss of lung functions [16]. There is some evidence that Th17 cells and dysfunctional Treg lymphocytes producing IL17 could be implicated both in lung damage, perpetuating the excessive pulmonary inflammatory process, and in b-cell dysfunction, providing a potential link between these two key and frequent abnormalities in CF [38–41,44–51]. Lymphocytes are susceptible to hyperglycemia [68,69] but also to nonoptimal levels of vitD which could both trigger the abnormal immune response observed in CF [68,69,78–80]. Human data in CF supporting interventions targeting glucose fluctuations, hyperglycemia, IL-17A and/or vitD deficiency are however lacking but this field requires attention of researchers and healthcare providers because of its potential to improve CF patients’ health.
[9] [10]
[11] [12]
[13]
[14]
[15]
6.
Conflicts of Interest [16]
There is no conflict of interest. [17]
Acknowledgments S.Z. has a Banting and Best Graduate scholarship from the Canadian Institutes of Health Research and A.C. holds the Jacques-Gauthier scholarship from the Institut de recherches cliniques de Montre´al (IRCM). R.R-L. is a senior scholar of the FRQ-S (Fonds de Recherches qu Que´bec en sante´) and holds the J-A De Se`ve research chair. M.R. is a junior 2 scholar of the FRQ-S and M-S.G. is a fellow of the Canadian Diabetes Association. This work was funded by a team grant from Cystic Fibrosis Canada.
[18]
[19]
[20]
[21]
references
[1] Costa M, Potvin S, Hammana I, Malet A, Berthiaume Y, Jeanneret A, et al. Increased glucose excursion in cystic
[22]
fibrosis and its association with a worse clinical status. J Cyst Fibros 2007;6:376–83. Andersen DH, Hodges RG. Celiac syndrome; genetics of cystic fibrosis of the pancreas, with a consideration of etiology. Am J Dis Child 1946;72:62–80. Cystic Fibrosis Canada. Canadian Cystic Fibrosis Registry 2011 Annual Report; 2013 CF Statistics. http:// www.cysticfibrosis.ca/en/aboutCysticFibrosis/CfStatistics [accessed 24.08.13]http://www.cysticfibrosis.ca/en/ publications/CanadianCysticFibrosisRegistry. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066–73. The Hospital for Sick Children. Cystic Fibrosis Mutation Database; 2011, http://www.genet.sickkids.on.ca/cftr/ [accessed 24.08.13]. Berdiev BK, Qadri YJ, Benos DJ. Assessment of the CFTR and ENaC association. Mol Biosyst 2009;5:123–7. Quinton PM. Cystic fibrosis: lessons from the sweat gland. Physiology (Bethesda) 2007;22:212–25. Moyer K, Balistreri W. Hepatobiliary disease in patients with cystic fibrosis. Curr Opin Gastroenterol 2009;25:272–8. Dodge JA, Morrison G. Diabetes mellitus in cystic fibrosis: a review. J R Soc Med 1992;85(Suppl. 19):25–8. Costa M, Potvin S, Berthiaume Y, Gauthier L, Jeanneret A, Lavoie A, et al. Diabetes: a major co-morbidity of cystic fibrosis. Diabetes Metab 2005;31:221–32. Nathan DM. Long-term complications of diabetes mellitus. N Engl J Med 1993;328:1676–85. Bismuth E, Laborde K, Taupin P, Velho G, Ribault V, Jennane F, et al. Glucose tolerance and insulin secretion, morbidity, and death in patients with cystic fibrosis. J Pediatr 2008;152:540–5. Soejima K, Landing BH. Pancreatic islets in older patients with cystic fibrosis with and without diabetes mellitus: morphometric and immunocytologic studies. Pediatr Pathol 1986;6:25–46. Iannucci A, Mukai M, Johnson D, Burke B. Endocrine pancreas in cystic fibrosis: an immunohistochemical study. Hum Pathol 1984;15:278–84. Couce M, O’Brien TD, Moran A, Roche PC, Butler PC. Diabetes mellitus in cystic fibrosis is characterized by islet amyloidosis. J Clin Endocrinol Metab 1996;81:1267–72. Lanng S, Thorsteinsson B, Nerup J, Koch C. Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis. Eur J Pediatr 1992;151:684–7. Stalvey MS, Brusko TM, Mueller C, Wasserfall CH, Schatz DA, Atkinson MA, et al. CFTR mutations impart elevated immune reactivity in a murine model of cystic fibrosis related diabetes. Cytokine 2008;44:154–9. Hayes E, Pohl K, McElvaney NG, Reeves EP. The cystic fibrosis neutrophil: a specialized yet potentially defective cell. Arch Immunol Ther Exp (Warsz) 2011;59:97–112. Romeo GR, Lee J, Shoelson SE. Metabolic syndrome, insulin resistance, and roles of inflammation – mechanisms and therapeutic targets. Arterioscler Thromb Vasc Biol 2012;32:1771–6. Rogers GB, Hoffman LR, Doring G. Novel concepts in evaluating antimicrobial therapy for bacterial lung infections in patients with cystic fibrosis. J Cyst Fibros 2011;10:387–400. Anton P, O’Connell J, O’Connell D, Whitaker L, O’Sullivan GC, Collins JK, et al. Mucosal subepithelial binding sites for the bacterial chemotactic peptide, formyl-methionylleucyl-phenylalanine (FMLP). Gut 1998;42:374–9. Hubeau C, Le Naour R, Abely M, Hinnrasky J, Guenounou M, Gaillard D, et al. Dysregulation of IL-2 and IL-8 production
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
DIAB-6020; No. of Pages 8 diabetes research and clinical practice xxx (2014) xxx–xxx
[23] [24]
[25]
[26]
[27] [28] [29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37] [38]
[39]
[40]
[41]
[42]
[43]
in circulating T lymphocytes from young cystic fibrosis patients. Clin Exp Immunol 2004;135:528–33. Moss RB. Lymphocytes in cystic fibrosis lung disease: a tale of two immunities. Clin Exp Immunol 2004;135:358–60. Widmaier EP, Raff H, Strang KT. Defense mechanisms of the body. In: Vander’s Human Physiology. New York: McGraw-Hill; 2006: 712. Schepers K, Arens R, Schumacher TN. Dissection of cytotoxic and helper T cell responses. Cell Mol Life Sci 2005;62:2695–710. Jager A, Kuchroo VK. Effector and regulatory T-cell subsets in autoimmunity and tissue inflammation. Scand J Immunol 2012;72:173–84. Aujla SJ, Dubin PJ, Kolls JK. Th17 cells and mucosal host defense. Semin Immunol 2007;19:377–82. Dubin PJ, Kolls JK. Th17 cytokines and mucosal immunity. Immunol Rev 2008;226:160–71. Roep BO, Peakman M, Diabetogenic. T lymphocytes in human Type 1 diabetes. Curr Opin Immunol 2011;23: 746–53. Louten J, Boniface K, de Waal Malefyt R. Development and function of TH17 cells in health and disease. J Allergy Clin Immunol 2009;123:1004–11. Emamaullee JA, Davis J, Merani S, Toso C, Elliott JF, Thiesen A, et al. Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice. Diabetes 2009;58:1302–11. Zhang X, Angkasekwinai P, Dong C, Tang H. Structure and function of interleukin-17 family cytokines. Protein Cell 2011;2:26–40. McAllister F, Henry A, Kreindler JL, Dubin PJ, Ulrich L, Steele C, et al. Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis. J Immunol 2005;175:404–12. Tan HL, Regamey N, Brown S, Bush A, Lloyd CM, Davies JC. The Th17 pathway in cystic fibrosis lung disease. Am J Respir Crit Care Med 2011;184:252–8. Nembrini C, Marsland BJ, Kopf M, IL-17-producing. T cells in lung immunity and inflammation. J Allergy Clin Immunol 2009;123:986–94. quiz 95–6. Chen Y, Thai P, Zhao YH, Ho YS, DeSouza MM, Wu R. Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J Biol Chem 2003;278:17036–43. Quinton PM. Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis. Lancet 2008;372:415–7. Decraene A, Willems-Widyastuti A, Kasran A, De Boeck K, Bullens DM, Dupont LJ. Elevated expression of both mRNA and protein levels of IL-17A in sputum of stable Cystic Fibrosis patients. Respir Res 2010;11:177. Roussel L, Rousseau S. IL-17 primes airway epithelial cells lacking functional Cystic Fibrosis Transmembrane conductance Regulator (CFTR) to increase NOD1 responses. Biochem Biophys Res Commun 2009;391:505–9. Mizunoe S, Shuto T, Suzuki S, Matsumoto C, Watanabe K, Ueno-Shuto K, et al. Synergism between interleukin (IL)-17 and toll-like receptor 2 and 4 signals to induce IL-8 expression in cystic fibrosis airway epithelial cells. J Pharmacol Sci 2012;118:512–20. Brodlie M, McKean MC, Johnson GE, Anderson AE, Hilkens CM, Fisher AJ, et al. Raised interleukin-17 is immunolocalised to neutrophils in cystic fibrosis lung disease. Eur Respir J 2011;37:1378–85. Gwyer Findlay E, Hussell T. Macrophage-mediated inflammation and disease: A focus on the lungs. Mediators Inflamm 2012;2012:140937. Dubin PJ, McAllister F, Kolls JK. Is cystic fibrosis a Th17 disease? Inflamm Res 2007;56:221–7.
[44] Tiringer K, Treis A, Fucik P, Gona M, Gruber S, Renner S, et al. A Th17- and Th2-skewed cytokine profile in cystic fibrosis lungs represents a potential risk factor for Pseudomonas aeruginosa infection. Am J Respir Crit Care Med 2013;187:621–9. [45] Wang M, Yang L, Sheng X, Chen W, Tang H, Sheng H, et al. T-cell vaccination leads to suppression of intrapancreatic Th17 cells through Stat3-mediated RORgammat inhibition in autoimmune diabetes. Cell Res 2011;21:1358–69. [46] Yaochite JN, Caliari-Oliveira C, Davanso MR, Carlos D, Ribeiro Malmegrim KC, Ribeiro de Barros Cardoso C, et al. Dynamic changes of the Th17/Tc17 and regulatory T cell populations interfere in the experimental autoimmune diabetes pathogenesis. Immunobiology 2012. [47] Joseph J, Bittner S, Kaiser FM, Wiendl H, Kissler S. IL-17 silencing does not protect nonobese diabetic mice from autoimmune diabetes. J Immunol 2012;188:216–21. [48] Nikoopour E, Schwartz JA, Huszarik K, Sandrock C, Krougly O, Lee-Chan E, et al. Th17 polarized cells from nonobese diabetic mice following mycobacterial adjuvant immunotherapy delay type 1 diabetes. J Immunol 2010;184:4779–88. [49] Honkanen J, Nieminen JK, Gao R, Luopajarvi K, Salo HM, Ilonen J, et al. IL-17 immunity in human type 1 diabetes. J Immunol 2010;185:1959–67. [50] Arif S, Moore F, Marks K, Bouckenooghe T, Dayan CM, Planas R, et al. Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated beta-cell death. Diabetes 2011;60:2112–9. [51] Tahrani AA, Bailey CJ, Del Prato S, Barnett AH. Management of type 2 diabetes: new and future developments in treatment. Lancet 2011;378:182–97. [52] Andriankaja OM, Barros SP, Moss K, Panagakos FS, DeVizio W, Beck J, et al. Levels of serum interleukin (IL)-6 and gingival crevicular fluid of IL-1beta and prostaglandin E(2) among non-smoking subjects with gingivitis and type 2 diabetes. J Periodontol 2009;80:307–16. [53] Osborn O, Brownell SE, Sanchez-Alavez M, Salomon D, Gram H, Bartfai T. Treatment with an Interleukin 1 beta antibody improves glycemic control in diet-induced obesity. Cytokine 2008;44:141–8. [54] Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immun 2007;8:942–9. [55] Jagannathan-Bogdan M, McDonnell ME, Shin H, Rehman Q, Hasturk H, Apovian CM, et al. Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol 2011;186:1162–72. [56] Geiger TL, Tauro S. Nature and nurture in Foxp3(+) regulatory T cell development, stability, and function. Hum Immunol 2012;73:232–9. [57] Brusko TM, Putnam AL, Bluestone JA. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol Rev 2008;223:371–90. [58] Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151–64. [59] Torgerson TR. Regulatory T cells in human autoimmune diseases. Springer Semin Immunopathol 2006;28:63–76. [60] Gao Y, Lin F, Su J, Gao Z, Li Y, Yang J, et al. Molecular mechanisms underlying the regulation and functional plasticity of FOXP3(+) regulatory T cells. Genes Immun 2012;13:1–13.
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
7
DIAB-6020; No. of Pages 8
8
diabetes research and clinical practice xxx (2014) xxx–xxx
[61] Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008;29: 44–56. [62] Marwaha AK, Crome SQ, Panagiotopoulos C, Berg KB, Qin H, Ouyang Q, et al. Cutting edge: Increased IL-17-secreting T cells in children with new-onset type 1 diabetes. J Immunol 2010;185:3814–8. [63] Zhen Y, Sun L, Liu H, Duan K, Zeng C, Zhang L, et al. Alterations of peripheral CD4+ CD25+ Foxp3+ T regulatory cells in mice with STZ-induced diabetes. Cell Mol Immunol 2012;9:75–85. [64] Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 2005;54:92–9. [65] Bovenschen HJ, van de Kerkhof PC, van Erp PE, Woestenenk R, Joosten I, Koenen HJ. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol 2011;131:1853–60. [66] Dobson L, Sheldon CD, Hattersley AT. Conventional measures underestimate glycaemia in cystic fibrosis patients. Diabet Med 2004;21:691–6. [67] Anzeneder L, Kircher F, Feghelm N, Fischer R, Seissler J. Kinetics of insulin secretion and glucose intolerance in adult patients with cystic fibrosis. Horm Metab Res 2011;43:355–60. [68] Maciver NJ, Jacobs SR, Wieman HL, Wofford JA, Coloff JL, Rathmell JC. Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. J Leukoc Biol 2008;84:949–57. [69] Mueller C, Braag SA, Keeler A, Hodges C, Drumm M, Flotte TR. Lack of cystic fibrosis transmembrane conductance regulator in CD3+ lymphocytes leads to aberrant cytokine secretion and hyperinflammatory adaptive immune responses. Am J Respir Cell Mol Biol 2011;44:922–9. [70] Iannitti RG, Carvalho A, Cunha C, De Luca A, Giovannini G, Casagrande A, et al. Th17/Treg imbalance in murine cystic fibrosis is linked to indoleamine 2,3-dioxygenase deficiency but corrected by kynurenines. Am J Respir Crit Care Med 2013;187:609–20. [71] Martin TR, Pistorese BP, Chi EY, Goodman RB, Matthay MA. Effects of leukotriene B4 in the human lung. Recruitment of neutrophils into the alveolar spaces without a change in protein permeability. J Clin Invest 1989;84:1609–19. [72] Wolfenden LL, Judd SE, Shah R, Sanyal R, Ziegler TR, Tangpricha V. Vitamin D and bone health in adults with cystic fibrosis. Clin Endocrinol (Oxf) 2008;69:374–81. [73] Stephenson A, Brotherwood M, Robert R, Atenafu E, Corey M, Tullis E. Cholecalciferol significantly increases 25hydroxyvitamin D concentrations in adults with cystic fibrosis. Am J Clin Nutr 2007;85:1307–11. [74] Pincikova T, Nilsson K, Moen IE, Fluge G, Hollsing A, Knudsen PK, et al. Vitamin D deficiency as a risk factor for cystic fibrosis-related diabetes in the Scandinavian Cystic Fibrosis Nutritional Study. Diabetologia 2011;54:3007–15.
[75] Rosen CJ, Adams JS, Bikle DD, Black DM, Demay MB, Manson JE, et al. The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev 2012;33:456–92. [76] Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 2007;92:2017–29. [77] George PS, Pearson ER, Witham MD. Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta-analysis. Diabet Med 2012;29:e142–50. [78] Van Belle TL, Gysemans C, Mathieu C. Vitamin D in autoimmune, infectious and allergic diseases: a vital player? Best Pract Res Clin Endocrinol Metab 2011;25: 617–32. [79] Kang SW, Kim SH, Lee N, Lee WW, Hwang KA, Shin MS, et al. 1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. J Immunol 2012;188:5276–82. [80] Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc 2012;71:50–61. [81] Nkondjock A, Receveur O. Fish-seafood consumption, obesity, and risk of type 2 diabetes: an ecological study. Diabetes Metab 2003;29:635–42. [82] Monk JM, Jia Q, Callaway E, Weeks B, Alaniz RC, McMurray DN, et al. Th17 cell accumulation is decreased during chronic experimental colitis by (n-3) PUFA in Fat-1 mice. J Nutr 2012;142:117–24. [83] Kim CH. Regulation of FoxP3 regulatory T cells and Th17 cells by retinoids. Clin Dev Immunol 2008;416910. [84] Manolescu DC, Sima A, Bhat PV. All-trans retinoic acid lowers serum retinol-binding protein 4 concentrations and increases insulin sensitivity in diabetic mice. J Nutr 2010;140:311–6. [85] Genovese MC, Durez P, Richards H, Supronik J, Dokoupilova E, Mazurov V, et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 2013;72:863–9. [86] Kellner H. Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential. Ther Adv Musculoskel Dis 2013;5:141–52. [87] Papp KA, Leonardi C, Menter A, Ortonne JP, Krueger JG, Kricorian G, et al. Brodalumab as an anti-interleukin-17receptor antibody for psoriasis. N Engl J Med 2012;366: 1181–9. [88] Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 2012;366:1190–9. [89] Mueller C, Keeler A, Bragg S, Menz T, Tang Q, Flotte TR. Modulation of exaggerated-IgE allergic response by gene transfer-mediated antagonism of IL-13 and IL-17e. Mol Ther 2010;18:511–8.
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
Contents available at ScienceDirect
Diabetes Research and Clinical Practice journ al h ome pa ge : www .elsevier.co m/lo cate/diabres
Review
Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis? S. Ziai a,b, A. Coriati a,b, M.-S. Gauthier b, R. Rabasa-Lhoret a,b,c,d, M.V. Richter e,* a
Nutrition Department, Faculty of Medicine, Universite´ de Montre´al, Montre´al, Que´bec, Canada Institut de Recherches Cliniques de Montre´al (IRCM), Montre´al, Que´bec, Canada c Montreal Diabetes Research Centre (MDRC), Montre´al, Que´bec, Canada d Cystic Fibrosis Clinic, Centre Hospitalier de l’Universite´ de Montre´al (CHUM) & CHUM Research Center (CR-CHUM), Montre´al, Que´bec, Canada e Department of Medicine, Faculty of Medicine and Health Sciences, Universite´ de Sherbrooke, Sherbrooke, Que´bec, Canada b
article info
abstract
Article history:
Cystic fibrosis-related diabetes (CFRD) is the most frequent complication of cystic fibrosis
Received 8 November 2013
(CF) and associated with increased mortality. Why patients have an accelerated loss of lung
Received in revised form
function before the diagnosis of CFRD remains poorly understood. We reported that patients
20 January 2014
with or without CFRD had increased glucose excursions when compared to healthy peers.
Accepted 3 March 2014
Studies have demonstrated that patients with CF have increased glucose fluctuations and
Available online xxx
hyperglycemia and that this may affect the clinical course of CF and lead to lymphocyte
Keywords:
cytokine IL-17. The Th17 pathway is involved in CF lung inflammation, b-cell destruction in
dysfunction. T-helper 17 (Th17) lymphocytes produce and secrete the pro-inflammatory Cystic fibrosis-related diabetes
type 1 diabetes (T1D) and Th17 cells of patients with type 2 diabetes have increased
Hyperglycemia
production of IL-17 when compared to healthy peers. Also, regulatory T-cells (Tregs) have
Lung function
been shown to be dysfunctional and produce IL-17 in T1D. Furthermore, vitamin D can affect
Th17 cells
inflammation in CF, diabetes and the differentiation of lymphocytes. In this review, we
Regulatory T-cells
discuss the potential roles of hyperglycemia on Th17 cells, Tregs and IL-17 as a potential
IL-17 therapy
cause for accelerated lung function decline before CFRD and how this could be modulated by vitamin D or by directly intervening in the IL-17A pathway. # 2014 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CFRD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
000 000 000
* Corresponding author at: Service de pneumologie, De´partement de me´decine, Faculte´ de me´decine et des sciences de la sante´, Universite´ de Sherbrooke, 3001-12e Avenue Nord, Sherbrooke, Que´bec J1H 5N4, Canada. Tel.: +1 819 820 6868x14881. E-mail address: [email protected] (M.V. Richter). http://dx.doi.org/10.1016/j.diabres.2014.03.002 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
DIAB-6020; No. of Pages 8
2
diabetes research and clinical practice xxx (2014) xxx–xxx
3.1.
4.
5. 6.
1.
Helper T-cell subsets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. T-helper 17 (Th17) lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Regulatory T-cells (Tregs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How could Th17, IL-17 and Treg lymphocytes be implicated in lung function loss associated with CFRD? . 4.1. Proposed mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Could vitamin D affect Th17 and Treg cells? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Therapeutic potential of interventions in the IL-17A mediated pathway . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction
Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disease among individuals of European descent [1]. First described in North America in 1938 by Dr. Dorothy H. Andersen [2], CF affects one in every 3600 births in Canada [3]. In 1989, researchers discovered that CF is caused by a mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene mainly at position 508 (p.Phe508del) [4]. Since then, over 1900 other mutations have been found in the CFTR gene [5]. The CFTR gene is translated into a chloride channel and its absence or dysfunction causes excess intracellular sodium and water resorption [6]. Consequently, people with CF have an accumulation of thick mucus in various organs such as the lungs and the pancreas, often have recurrent lung infections, exocrine insufficiency and in most cases, ultimately die from lung disease [7,8]. With more aggressive nutritional interventions and antibiotic treatments, the median life expectancy of individuals with CF in Canada has steadily risen to 48,5 years of age in 2011 [3]. This increase led to the emergence of numerous new complications including CF-related diabetes (CFRD) [1,9].
2.
CFRD
CFRD is an important complication that affects approximately 20% of adults between 18 and 20 years old with CF in Canada [3]. CFRD is a unique type of diabetes that differs from type 1 (T1D) and type 2 diabetes mellitus (T2D) but shares some common similarities [10]. On one hand, the main cause of death in patients with CFRD is respiratory failure whereas patients with T1D and T2D most often die of cardiovascular disease [10,11]. On the other hand, CFRD is associated to a very significant decrease in insulin secretion [1,12], similar to that observed in T1D [10], caused by a decreased number of b-cells [13,14], atrophy and by important fibrosis and amyloidosis in the pancreas [15]. Similarly to what is observed in T2D, CFRD is preceded by a long phase of glucose intolerance characterized by progressive worsening of postprandial hyperglycemia [1,10]. Its presence in patients with CF is associated with worse lung (i.e. FEV1) and nutritional statuses (i.e. body mass index) and with increased mortality [12,16]. CFRD is also associated with an accelerated decline in lung functions years before its diagnosis [3,16]. Both the physiopathology of CFRD and the accelerated lung function decline before CFRD onset
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
. . . . . . . . . . .
000 000 000 000 000 000 000 000 000 000 000
are not fully understood but experimental evidence suggests that chronic inflammatory aspects might be involved [17]. In this review, we will discuss the potential roles of T-helper 17 (Th17) and regulatory T (Treg) cells and the pro-inflammatory interleukin-17A (IL-17A) in progressive lung function deterioration and hyperglycemia in CF.
3.
Inflammation
The CF inflammatory response in the lungs is dominated by neutrophil activation [18]. Both CF and diabetes are diseases with inflammatory components [7,19]. The thick mucus that accumulates in the lungs of patients with CF is frequently colonized by various bacteria including Pseudomonas aeruginosa and Staphylococcus aureus [20]. Neutrophils are then attracted by chemotaxis to the site of inflammation by formylated peptides such as formyl-methionine-leucine-phenylalanine produced by bacteria [21] and secrete oxidases and proteases in an attempt to clear the pathogens [18]. This neutrophil response is excessive and contributes to lung tissue damage and eventually contributes to decreased lung function [18]. However, the presence of lymphocytes in the lungs of patients with CF suggests the involvement of adaptive immunity [22,23]. There are two main groups of lymphocytes: T cells and B cells. B cells produce antibodies while T cells are responsible for cellular immunity [24]. T cells are subdivided into cytotoxic T cells that kill intracellular pathogens and helper T cells that assist cytotoxic T cells and B cells by secreting cytokines [25,26].
3.1.
Helper T-cell subsets
Several T-cell subsets have been identified of which T-helper 1 (Th1), T-helper 2 (Th2) and Th17 cells are the main groups [26]. While on one hand, Th1 lymphocytes are involved in the clearance of intracellular pathogens, on the other hand, Th2 cells play an important role in the humoral response to extracellular pathogens [26]. In CF, in 2001, Hubeau et al. found increased levels of T cells in the airway mucosa of individuals with the disease [22]. Subsequent studies demonstrated that a Th1-dominated inflammatory response was associated with better lung function in patients with CF [27] and that those infected by Pseudomonas had elevated levels of Th2 cells, IL-4 and IL-13 in their bronchoalveolar lavage fluids versus patients that were
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
DIAB-6020; No. of Pages 8 diabetes research and clinical practice xxx (2014) xxx–xxx
not infected [28]. Accordingly, the levels of these cytokines were inversely correlated with lung function [28]. Lymphocytes are also implicated in the physiopathology of diabetes. T1D is an autoimmune disease primarily caused by the destruction of insulin producing pancreatic b-cells mainly by cytotoxic T and Th1 lymphocytes [29]. Taken together, helper T cells are involved in both the inflammatory response in the lungs of patients with CF and also in pancreatic b-cell destruction in T1D. Although it remains to be experimentally verified, helper T cells may thus represent a mechanistic link between decreased lung functions and the development of CFRD.
3.1.1.
T-helper 17 (Th17) lymphocytes
In the past decade, much attention has been given to a specific subtype of T-helper cells called Th17 cells. This subset cells mainly produces IL-17A as well as IL-17F, IL-21 and IL-22 [30] and aid in eliminating pathogens not adequately handled by Th1 and Th2 cells and fungi [26]. Elevated levels of the proinflammatory cytokine IL-17A have been implicated in the physiopathology of many autoimmune diseases including rheumatoid arthritis (RA), multiple sclerosis and T1D [29,31,32]. IL-17A binds IL-17-receptor A and is expressed in various cell types [32] including human bronchial epithelial cells [33]. Other immune cells such as the gdT cells and natural killer T cells have also been shown to produce IL-17A [34]. Studies in mice have demonstrated that Th17 cells and IL17A are involved in the pulmonary immune response against bacteria by stimulating the secretion of CXCL8 and IL-6 from epithelial cells, cytokines that recruit and activate neutrophils [35]. Furthermore, IL-17A was shown to increase the expression of mucins (MUC5AC, MUC5B) in human tracheobronchial epithelial cells in vitro [36]. In individuals with CF, increased production of mucins is thought to contribute to the generation of the thick mucus observed in the lungs [37]. Studies have found elevated levels of IL-17A and Th17 cells in the sputum and the lungs of patients with CF when compared to healthy controls [33,34,38]. It has also been reported that IL-17A can exacerbate inflammatory responses in the lungs of patients with CF [39,40]. In 2011, Brodlie and colleagues measured increased levels of IL-17A in the lungs of 43 patients with compared to 35 subjects with pulmonary hypertension. In the same study, when human bronchial epithelial cells were stimulated with IL-17A, the authors observed increased production of IL-8, IL-6 and granulocytemacrophage colony-stimulating factor (GM-CSF), cytokines known to activate and recruit neutrophils [41]. In CF, macrophages also contribute to neutrophil recruitment and activation involved in lung disease by producing IL-6 and IL-8 [42]. Another study, in 2007 by Dubin et al., suggested that the bacteria trapped in the thick mucous in the lungs of people with CF could activate dendritic cells. These dendritic cells could then produce IL-23 that would recruit Th17 cells. Th17 cells would then produce IL-17A that would recruit neutrophils. Th17 cells could have an exaggerated response in the presence of IL-23 because this cytoking stabilizes them [43]. A recent study by Tan et al. demonstrated the importance of the Th17 pathway in early pathogenesis of CF by detecting elevated levels of IL-17+ cells in newly diagnosed children with CF [34]. In 2013, Tiriniger et al. demonstrated that levels of
3
IL-17A inversely correlated with FEV1 of patients with CF [44]. These studies clearly suggest that the Th17 pathway and IL17A are both involved in CF airway inflammation and might contribute to the chronic neutrophil recruitment in CF lungs (Fig. 1). Studies also suggest a role for IL-17 in the development of T1D [29,31] and that suppressing the Th17 pathway could help in preventing T1D [45]. More recently, Yaochite et al. reported an association between IL-17 levels and the degree of pancreatic inflammation in streptozotocin (STZ) treated mice [46], suggesting the potential role of IL-17 in pancreatic b-cell destruction in this animal model of T1D. However, in other studies, IL-17 was not implicated in the physiopathology of T1D [47,48]. This discrepancy might be due to the fact that different methods were used to study the implication of IL-17 in T1D. For instance, in some studies the injection of adjuvants containing Mycobacterium [47] and RNA interference were used to examine the role of IL-17 in the development of T1D in NOD mice [46] while in the others T-cell vaccination was used [45]. The potential contributing role of IL-17 in the development of T1D has also been explored in humans. Firstly, in 2010, Honkanen et al. observed increased levels of IL-17 in peripheral blood of children with T1D and a pro-apoptotic effect of this cytokine on human islets in vitro [49]. A few years later, another research team isolated peripheral blood from 50 patients with T1D and 30 healthy control subjects, exposed their isolated helper T cells to auto-antibodies of pancreatic bcells and observed that patients with T1D had a greater proportion of IL-17 when compared to healthy control subjects [50]. They also observed increased IL-17 mRNA levels in the pancreas of two deceased patients with T1D when compared to levels in three deceased subjects without T1D [50]. These studies suggest that targeting Th17 cells and IL-17 could potentially prevent the destruction of pancreatic b-cells. T2D is associated with obesity and is characterized by insulin resistance and dysfunctional b-cells which lead to hyperglycaemia [51]. Individuals with T2D have increased plasma levels of IL-6 and IL-1b, two cytokines associated with Th17 differentiation [52–54]. In 2011, Jagannathan-Bogdan et al. reported increased numbers of Th17 cells and secretion of IL-17 and interferon g (IFN-g) in the peripheral blood of individuals with T2D compared to healthy individuals [55], suggesting that IL-17 could also be involved in the physiopathology of this type of diabetes.
3.1.2.
Regulatory T-cells (Tregs)
Tregs are a subset of T cells that help in the suppression of excessive effector T-cell responses and maintain a balance between anti-inflammatory and pro-inflammatory responses [56]. Tregs express the transcription factor Foxp3 in addition to producing the anti-inflammatory cytokine IL-10 [57,58]. When this balance is perturbed, auto-immune diseases such as rheumatoid arthritis and multiple sclerosis can develop [59]. Furthermore, Treg cells can dedifferentiate into Foxp3 cells and become pro-inflammatory [60]. For example, in the presence of IL-6 and IL-1b, Treg cells can differentiate into Th17 cells and produce IL-17 thus underscoring the plasticity between these T-cell subsets [61]. A study by Marwaha et al. reported that Treg cells of patients with T1D expressed IL-17 and were inefficient at
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
DIAB-6020; No. of Pages 8
4
diabetes research and clinical practice xxx (2014) xxx–xxx
Fig. 1 – Effects of intrinsic CFTR-related defects in epithelial cells and lymphocytes on IL-17A production, neutrophil activation and recruitement, the roles of other immune cells (dendritic cells and macrophages) in this vicious inflammatory cycle and the possible effects on pancreatic b cells and insulin secretion.
suppressing exaggerated immune responses [62]. This was subsequently confirmed by other groups in streptozotocin mice and in humans where elevated levels of dysfunctional Treg cells that were unable to attenuate inflammatory responses were reported [63,64]. Dysfunctional Treg cells that become Th17 cells and produce IL-17 have also been reported in the auto-immune disease psoriasis [65]. Moreover, a study conducted in patients with T2D also suggested an implication of dysfunctional Treg cells producing IL-17 in this disease [55]. In summary, even though Th1 and Th2 cells probably modulate lung inflammation in patients with CF, Th17 cells and IL-17A seem to perpetuate neutrophil infiltration into the lungs and contribute to lung damage. Also, Th17 and dysfunctional Treg cells as well as IL-17A are involved in b cell destructions in T1D and possibly the physiopathology of T2D. Altogether, this suggests that the Th17 pathway could be involved both in lung function loss as well as hyperglycemia in CF.
4. How could Th17, IL-17 and Treg lymphocytes be implicated in lung function loss associated with CFRD? 4.1.
Proposed mechanism
Compared to healthy counterparts, hyperglycemia and glucose fluctuations are present not only in patients with CFRD and in patients with CF who are pre-diabetic but also in
patients who are considered as having normal glucose tolerance [1,66,67]. While hyperglycemia may exacerbate the clinical course of CF by inducing immune reactivity [17], studies in mice demonstrated that lymphocytes responded in an exaggerated fashion to hyperglycaemia [68] and that CFTR dysfunction in T cells can lead to aberrant immune responses [69]. In addition, as mentioned above, Th17 cells and the proinflammatory cytokine IL-17 are implicated in CF as well as in hyperglycemia and Treg cells are thought to be dysfunctional in T1D and possibly T2D. Thus, the hyperglycemia and glucose fluctuations observed in patients with CF without diabetes might negatively impact lymphocyte subsets such as Th17 and Treg cells and increase their production of IL-17A perpetuating a vicious cycle of abnormal immune responses by these cells and deteriorate hyperglycemia and glucose fluctuations (Fig. 2). The evidence suggests that the impaired glucose conditions in patients with CF with and without CFRD could promote hyperactive responses of lymphocytes without a functional CFTR by increasing the proportions of IL-17producing Th17 and dysfunctional Tregs cells. Although a study has demonstrated CFTR / mice with allergic bronchopulmonary aspergillosis have decreased percentages of CD4+ Foxp3+ T-cells [70], Treg cells have not yet been examined in CFRD but it may be plausible that this important T-cell subtype involved in immune regulation would be influenced by CFTR dysfunction, hyperglycemia and glucose fluctuations. The increased amount of IL-17 produced by these skewed T-cells could travel to the lungs and, combined with bacterial
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
DIAB-6020; No. of Pages 8 diabetes research and clinical practice xxx (2014) xxx–xxx
5
CFRD and they suggested that, because vitD is associated to improved insulin secretion and sensitivity, decreased levels observed in CF could contribute to glucose abnormalities [74]. In rodent models, vitD modulates insulin synthesis and secretion [75] and in humans, observational studies (crosssectional and longitudinal) report a link between low serum levels of the active form of vitD (25(OH)D) and diabetes [75–77]. Furthermore, vitD receptors (VDR) are expressed in various immune cells including dendritic cells, B cells and T cells and their levels increase in proliferating lymphocytes [78]. Research has shown that 1,25-dihydroxyvitamin D favors Treg cell development by modulating dendritic cells and also by targeting the T cells and thus promoting FoxP3 expression by binding to its response element (VDRE) in the gene’s promoter [78,79]. VitD can also suppress IL-17 production via its direct transcriptional suppression and inhibit Th17 development in vitro [80]. Therefore, vitD can also modulate Th17 and Treg cells dysregulation and influence lung damage and hyperglycemia in CF. In addition, other nutrients including polyunsaturated fatty acids and vitamin A could also affect Th17 and Treg cells as well as hyperglycemia [81–84]. Further studies are needed to explore the effects of these nutrients on these cell types and the development of CFRD.
4.3. Therapeutic potential of interventions in the IL-17A mediated pathway
Fig. 2 – Proposed mechanism of the vicious cycle by which hyperglycemia, glucose fluctuations and non-optimal vitamin D levels in non-diabetic and pre-diabetic patients with cystic fibrosis could lead to lymphocyte dysfunction, increased circulating IL-17A levels, pancreatic dysfunction and the decrease in lung functions years before cystic fibrosis-related diabetes onset.
infections, perpetuate neutrophilic inflammation, lung tissue damage and consequently lead to a decrease in lung functions before the onset and during CFRD. In addition, these abnormalities could also play a role in CFRD at the level of the pancreatic b-cell favoring hyperglycemia and thus initiating a vicious cycle (Fig. 2).
4.2.
Could vitamin D affect Th17 and Treg cells?
Besides vitamin D’s (vitD) classical role in bone metabolism [71], it also affects lung function in CF as well as diabetes. In 2008, Wolfenden et al. found a positive association between levels of vitD (25(OH)D) and percent predicted FEV1 in 185 patients with CF [72]. Despite regular supplementation, most patients with CF still display suboptimal vitD levels [73]. In 2011, Pincikova et al. associated suboptimal levels of vitD to
As previously mentioned the IL-17A pathway is implicated in the physiopathology of many immune diseases. Recently, clinical trials in RA and psoriasis using drugs to block the IL17A pathway have shown promising results. In RA, 237 patients were recruited to a randomized, double-blind, placebo-controlled, dose finding phase II trial using secukinumab, a monoclonal antibody that binds specifically to human IL-17A. Compared to the placebo, the Disease Activity Score in 28 joints (DAS28) score and C-reactive protein (CRP) levels were improved after 16 weeks in participants taking higher doses of secukinumab [85]. Two phase III trials are currently underway exploring safety and efficacy of secukinumab for RA management [86]. Two other compounds to block the IL-17 pathway have been used in clinical trials with patients with moderate-tosevere psoriasis. In these two short term randomized, doubleblind, placebo-controlled, dose-ranging phase II trials, brodalumab, a human IL-17 receptor antibody, and ixekizumab, a human monoclonal antibody against IL-17A, demonstrated an improvement of the Psoriasis area and severity index (PASI) by 75% in a majority (77–82%) of patients compared to placebo [87,88]. Of note, none of these trials verified the effect of these drugs on blood glucose. A study published by Mueller et al. in 2010 demonstrated that inhibiting IL-17E decreases the production of Th2 cytokines by T-cells in CF. These authors injected a recombinant adeno-associated virus 1 intramuscularly expressing the soluble receptor for IL-17E into CFTR / mice and they observed a decrease in IL-4 and IL-13 production in CD4+ T-cells [89]. Therefore, targeting IL-17A directly with an antibody or with a receptor could possibly decrease the production of other cytokines such as IL-4, IL-13, IL-6 and IL-8
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
DIAB-6020; No. of Pages 8
6
diabetes research and clinical practice xxx (2014) xxx–xxx
and decrease airway inflammation in CF. However, as phase II trials in humans suggest that one of the most frequent side effects of the drugs is upper respiratory infection [86–88], their usage in CF will await an understanding of pulmonary infection risks associated with these drugs. In summary, non-optimal levels of, vitD are frequently observed in patients with CF and might promote inappropriate immune responses of Th17 and Treg cells and in turn, possibly contribute to decreased lung functions, hyperglycemia as well as the emergence of CFRD. Future studies are needed to explore the relationship between nutrients, T cell populations and lung inflammation as well as CFRD although one study has already examined vitD and CFRD [74]. Moreover, therapies targeting IL-17A have been studied in RA and psoriasis and could also be beneficial in CF.
5.
Conclusions
[2]
[3]
[4]
[5]
[6] [7] [8]
CFRD is an important complication of CF that is preceded by a long pre-diabetic phase associated with unexplained accelerated loss of lung functions [16]. There is some evidence that Th17 cells and dysfunctional Treg lymphocytes producing IL17 could be implicated both in lung damage, perpetuating the excessive pulmonary inflammatory process, and in b-cell dysfunction, providing a potential link between these two key and frequent abnormalities in CF [38–41,44–51]. Lymphocytes are susceptible to hyperglycemia [68,69] but also to nonoptimal levels of vitD which could both trigger the abnormal immune response observed in CF [68,69,78–80]. Human data in CF supporting interventions targeting glucose fluctuations, hyperglycemia, IL-17A and/or vitD deficiency are however lacking but this field requires attention of researchers and healthcare providers because of its potential to improve CF patients’ health.
[9] [10]
[11] [12]
[13]
[14]
[15]
6.
Conflicts of Interest [16]
There is no conflict of interest. [17]
Acknowledgments S.Z. has a Banting and Best Graduate scholarship from the Canadian Institutes of Health Research and A.C. holds the Jacques-Gauthier scholarship from the Institut de recherches cliniques de Montre´al (IRCM). R.R-L. is a senior scholar of the FRQ-S (Fonds de Recherches qu Que´bec en sante´) and holds the J-A De Se`ve research chair. M.R. is a junior 2 scholar of the FRQ-S and M-S.G. is a fellow of the Canadian Diabetes Association. This work was funded by a team grant from Cystic Fibrosis Canada.
[18]
[19]
[20]
[21]
references
[1] Costa M, Potvin S, Hammana I, Malet A, Berthiaume Y, Jeanneret A, et al. Increased glucose excursion in cystic
[22]
fibrosis and its association with a worse clinical status. J Cyst Fibros 2007;6:376–83. Andersen DH, Hodges RG. Celiac syndrome; genetics of cystic fibrosis of the pancreas, with a consideration of etiology. Am J Dis Child 1946;72:62–80. Cystic Fibrosis Canada. Canadian Cystic Fibrosis Registry 2011 Annual Report; 2013 CF Statistics. http:// www.cysticfibrosis.ca/en/aboutCysticFibrosis/CfStatistics [accessed 24.08.13]http://www.cysticfibrosis.ca/en/ publications/CanadianCysticFibrosisRegistry. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066–73. The Hospital for Sick Children. Cystic Fibrosis Mutation Database; 2011, http://www.genet.sickkids.on.ca/cftr/ [accessed 24.08.13]. Berdiev BK, Qadri YJ, Benos DJ. Assessment of the CFTR and ENaC association. Mol Biosyst 2009;5:123–7. Quinton PM. Cystic fibrosis: lessons from the sweat gland. Physiology (Bethesda) 2007;22:212–25. Moyer K, Balistreri W. Hepatobiliary disease in patients with cystic fibrosis. Curr Opin Gastroenterol 2009;25:272–8. Dodge JA, Morrison G. Diabetes mellitus in cystic fibrosis: a review. J R Soc Med 1992;85(Suppl. 19):25–8. Costa M, Potvin S, Berthiaume Y, Gauthier L, Jeanneret A, Lavoie A, et al. Diabetes: a major co-morbidity of cystic fibrosis. Diabetes Metab 2005;31:221–32. Nathan DM. Long-term complications of diabetes mellitus. N Engl J Med 1993;328:1676–85. Bismuth E, Laborde K, Taupin P, Velho G, Ribault V, Jennane F, et al. Glucose tolerance and insulin secretion, morbidity, and death in patients with cystic fibrosis. J Pediatr 2008;152:540–5. Soejima K, Landing BH. Pancreatic islets in older patients with cystic fibrosis with and without diabetes mellitus: morphometric and immunocytologic studies. Pediatr Pathol 1986;6:25–46. Iannucci A, Mukai M, Johnson D, Burke B. Endocrine pancreas in cystic fibrosis: an immunohistochemical study. Hum Pathol 1984;15:278–84. Couce M, O’Brien TD, Moran A, Roche PC, Butler PC. Diabetes mellitus in cystic fibrosis is characterized by islet amyloidosis. J Clin Endocrinol Metab 1996;81:1267–72. Lanng S, Thorsteinsson B, Nerup J, Koch C. Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis. Eur J Pediatr 1992;151:684–7. Stalvey MS, Brusko TM, Mueller C, Wasserfall CH, Schatz DA, Atkinson MA, et al. CFTR mutations impart elevated immune reactivity in a murine model of cystic fibrosis related diabetes. Cytokine 2008;44:154–9. Hayes E, Pohl K, McElvaney NG, Reeves EP. The cystic fibrosis neutrophil: a specialized yet potentially defective cell. Arch Immunol Ther Exp (Warsz) 2011;59:97–112. Romeo GR, Lee J, Shoelson SE. Metabolic syndrome, insulin resistance, and roles of inflammation – mechanisms and therapeutic targets. Arterioscler Thromb Vasc Biol 2012;32:1771–6. Rogers GB, Hoffman LR, Doring G. Novel concepts in evaluating antimicrobial therapy for bacterial lung infections in patients with cystic fibrosis. J Cyst Fibros 2011;10:387–400. Anton P, O’Connell J, O’Connell D, Whitaker L, O’Sullivan GC, Collins JK, et al. Mucosal subepithelial binding sites for the bacterial chemotactic peptide, formyl-methionylleucyl-phenylalanine (FMLP). Gut 1998;42:374–9. Hubeau C, Le Naour R, Abely M, Hinnrasky J, Guenounou M, Gaillard D, et al. Dysregulation of IL-2 and IL-8 production
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
DIAB-6020; No. of Pages 8 diabetes research and clinical practice xxx (2014) xxx–xxx
[23] [24]
[25]
[26]
[27] [28] [29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37] [38]
[39]
[40]
[41]
[42]
[43]
in circulating T lymphocytes from young cystic fibrosis patients. Clin Exp Immunol 2004;135:528–33. Moss RB. Lymphocytes in cystic fibrosis lung disease: a tale of two immunities. Clin Exp Immunol 2004;135:358–60. Widmaier EP, Raff H, Strang KT. Defense mechanisms of the body. In: Vander’s Human Physiology. New York: McGraw-Hill; 2006: 712. Schepers K, Arens R, Schumacher TN. Dissection of cytotoxic and helper T cell responses. Cell Mol Life Sci 2005;62:2695–710. Jager A, Kuchroo VK. Effector and regulatory T-cell subsets in autoimmunity and tissue inflammation. Scand J Immunol 2012;72:173–84. Aujla SJ, Dubin PJ, Kolls JK. Th17 cells and mucosal host defense. Semin Immunol 2007;19:377–82. Dubin PJ, Kolls JK. Th17 cytokines and mucosal immunity. Immunol Rev 2008;226:160–71. Roep BO, Peakman M, Diabetogenic. T lymphocytes in human Type 1 diabetes. Curr Opin Immunol 2011;23: 746–53. Louten J, Boniface K, de Waal Malefyt R. Development and function of TH17 cells in health and disease. J Allergy Clin Immunol 2009;123:1004–11. Emamaullee JA, Davis J, Merani S, Toso C, Elliott JF, Thiesen A, et al. Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice. Diabetes 2009;58:1302–11. Zhang X, Angkasekwinai P, Dong C, Tang H. Structure and function of interleukin-17 family cytokines. Protein Cell 2011;2:26–40. McAllister F, Henry A, Kreindler JL, Dubin PJ, Ulrich L, Steele C, et al. Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis. J Immunol 2005;175:404–12. Tan HL, Regamey N, Brown S, Bush A, Lloyd CM, Davies JC. The Th17 pathway in cystic fibrosis lung disease. Am J Respir Crit Care Med 2011;184:252–8. Nembrini C, Marsland BJ, Kopf M, IL-17-producing. T cells in lung immunity and inflammation. J Allergy Clin Immunol 2009;123:986–94. quiz 95–6. Chen Y, Thai P, Zhao YH, Ho YS, DeSouza MM, Wu R. Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J Biol Chem 2003;278:17036–43. Quinton PM. Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis. Lancet 2008;372:415–7. Decraene A, Willems-Widyastuti A, Kasran A, De Boeck K, Bullens DM, Dupont LJ. Elevated expression of both mRNA and protein levels of IL-17A in sputum of stable Cystic Fibrosis patients. Respir Res 2010;11:177. Roussel L, Rousseau S. IL-17 primes airway epithelial cells lacking functional Cystic Fibrosis Transmembrane conductance Regulator (CFTR) to increase NOD1 responses. Biochem Biophys Res Commun 2009;391:505–9. Mizunoe S, Shuto T, Suzuki S, Matsumoto C, Watanabe K, Ueno-Shuto K, et al. Synergism between interleukin (IL)-17 and toll-like receptor 2 and 4 signals to induce IL-8 expression in cystic fibrosis airway epithelial cells. J Pharmacol Sci 2012;118:512–20. Brodlie M, McKean MC, Johnson GE, Anderson AE, Hilkens CM, Fisher AJ, et al. Raised interleukin-17 is immunolocalised to neutrophils in cystic fibrosis lung disease. Eur Respir J 2011;37:1378–85. Gwyer Findlay E, Hussell T. Macrophage-mediated inflammation and disease: A focus on the lungs. Mediators Inflamm 2012;2012:140937. Dubin PJ, McAllister F, Kolls JK. Is cystic fibrosis a Th17 disease? Inflamm Res 2007;56:221–7.
[44] Tiringer K, Treis A, Fucik P, Gona M, Gruber S, Renner S, et al. A Th17- and Th2-skewed cytokine profile in cystic fibrosis lungs represents a potential risk factor for Pseudomonas aeruginosa infection. Am J Respir Crit Care Med 2013;187:621–9. [45] Wang M, Yang L, Sheng X, Chen W, Tang H, Sheng H, et al. T-cell vaccination leads to suppression of intrapancreatic Th17 cells through Stat3-mediated RORgammat inhibition in autoimmune diabetes. Cell Res 2011;21:1358–69. [46] Yaochite JN, Caliari-Oliveira C, Davanso MR, Carlos D, Ribeiro Malmegrim KC, Ribeiro de Barros Cardoso C, et al. Dynamic changes of the Th17/Tc17 and regulatory T cell populations interfere in the experimental autoimmune diabetes pathogenesis. Immunobiology 2012. [47] Joseph J, Bittner S, Kaiser FM, Wiendl H, Kissler S. IL-17 silencing does not protect nonobese diabetic mice from autoimmune diabetes. J Immunol 2012;188:216–21. [48] Nikoopour E, Schwartz JA, Huszarik K, Sandrock C, Krougly O, Lee-Chan E, et al. Th17 polarized cells from nonobese diabetic mice following mycobacterial adjuvant immunotherapy delay type 1 diabetes. J Immunol 2010;184:4779–88. [49] Honkanen J, Nieminen JK, Gao R, Luopajarvi K, Salo HM, Ilonen J, et al. IL-17 immunity in human type 1 diabetes. J Immunol 2010;185:1959–67. [50] Arif S, Moore F, Marks K, Bouckenooghe T, Dayan CM, Planas R, et al. Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated beta-cell death. Diabetes 2011;60:2112–9. [51] Tahrani AA, Bailey CJ, Del Prato S, Barnett AH. Management of type 2 diabetes: new and future developments in treatment. Lancet 2011;378:182–97. [52] Andriankaja OM, Barros SP, Moss K, Panagakos FS, DeVizio W, Beck J, et al. Levels of serum interleukin (IL)-6 and gingival crevicular fluid of IL-1beta and prostaglandin E(2) among non-smoking subjects with gingivitis and type 2 diabetes. J Periodontol 2009;80:307–16. [53] Osborn O, Brownell SE, Sanchez-Alavez M, Salomon D, Gram H, Bartfai T. Treatment with an Interleukin 1 beta antibody improves glycemic control in diet-induced obesity. Cytokine 2008;44:141–8. [54] Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immun 2007;8:942–9. [55] Jagannathan-Bogdan M, McDonnell ME, Shin H, Rehman Q, Hasturk H, Apovian CM, et al. Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol 2011;186:1162–72. [56] Geiger TL, Tauro S. Nature and nurture in Foxp3(+) regulatory T cell development, stability, and function. Hum Immunol 2012;73:232–9. [57] Brusko TM, Putnam AL, Bluestone JA. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol Rev 2008;223:371–90. [58] Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151–64. [59] Torgerson TR. Regulatory T cells in human autoimmune diseases. Springer Semin Immunopathol 2006;28:63–76. [60] Gao Y, Lin F, Su J, Gao Z, Li Y, Yang J, et al. Molecular mechanisms underlying the regulation and functional plasticity of FOXP3(+) regulatory T cells. Genes Immun 2012;13:1–13.
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
7
DIAB-6020; No. of Pages 8
8
diabetes research and clinical practice xxx (2014) xxx–xxx
[61] Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008;29: 44–56. [62] Marwaha AK, Crome SQ, Panagiotopoulos C, Berg KB, Qin H, Ouyang Q, et al. Cutting edge: Increased IL-17-secreting T cells in children with new-onset type 1 diabetes. J Immunol 2010;185:3814–8. [63] Zhen Y, Sun L, Liu H, Duan K, Zeng C, Zhang L, et al. Alterations of peripheral CD4+ CD25+ Foxp3+ T regulatory cells in mice with STZ-induced diabetes. Cell Mol Immunol 2012;9:75–85. [64] Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 2005;54:92–9. [65] Bovenschen HJ, van de Kerkhof PC, van Erp PE, Woestenenk R, Joosten I, Koenen HJ. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol 2011;131:1853–60. [66] Dobson L, Sheldon CD, Hattersley AT. Conventional measures underestimate glycaemia in cystic fibrosis patients. Diabet Med 2004;21:691–6. [67] Anzeneder L, Kircher F, Feghelm N, Fischer R, Seissler J. Kinetics of insulin secretion and glucose intolerance in adult patients with cystic fibrosis. Horm Metab Res 2011;43:355–60. [68] Maciver NJ, Jacobs SR, Wieman HL, Wofford JA, Coloff JL, Rathmell JC. Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. J Leukoc Biol 2008;84:949–57. [69] Mueller C, Braag SA, Keeler A, Hodges C, Drumm M, Flotte TR. Lack of cystic fibrosis transmembrane conductance regulator in CD3+ lymphocytes leads to aberrant cytokine secretion and hyperinflammatory adaptive immune responses. Am J Respir Cell Mol Biol 2011;44:922–9. [70] Iannitti RG, Carvalho A, Cunha C, De Luca A, Giovannini G, Casagrande A, et al. Th17/Treg imbalance in murine cystic fibrosis is linked to indoleamine 2,3-dioxygenase deficiency but corrected by kynurenines. Am J Respir Crit Care Med 2013;187:609–20. [71] Martin TR, Pistorese BP, Chi EY, Goodman RB, Matthay MA. Effects of leukotriene B4 in the human lung. Recruitment of neutrophils into the alveolar spaces without a change in protein permeability. J Clin Invest 1989;84:1609–19. [72] Wolfenden LL, Judd SE, Shah R, Sanyal R, Ziegler TR, Tangpricha V. Vitamin D and bone health in adults with cystic fibrosis. Clin Endocrinol (Oxf) 2008;69:374–81. [73] Stephenson A, Brotherwood M, Robert R, Atenafu E, Corey M, Tullis E. Cholecalciferol significantly increases 25hydroxyvitamin D concentrations in adults with cystic fibrosis. Am J Clin Nutr 2007;85:1307–11. [74] Pincikova T, Nilsson K, Moen IE, Fluge G, Hollsing A, Knudsen PK, et al. Vitamin D deficiency as a risk factor for cystic fibrosis-related diabetes in the Scandinavian Cystic Fibrosis Nutritional Study. Diabetologia 2011;54:3007–15.
[75] Rosen CJ, Adams JS, Bikle DD, Black DM, Demay MB, Manson JE, et al. The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev 2012;33:456–92. [76] Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 2007;92:2017–29. [77] George PS, Pearson ER, Witham MD. Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta-analysis. Diabet Med 2012;29:e142–50. [78] Van Belle TL, Gysemans C, Mathieu C. Vitamin D in autoimmune, infectious and allergic diseases: a vital player? Best Pract Res Clin Endocrinol Metab 2011;25: 617–32. [79] Kang SW, Kim SH, Lee N, Lee WW, Hwang KA, Shin MS, et al. 1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. J Immunol 2012;188:5276–82. [80] Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc 2012;71:50–61. [81] Nkondjock A, Receveur O. Fish-seafood consumption, obesity, and risk of type 2 diabetes: an ecological study. Diabetes Metab 2003;29:635–42. [82] Monk JM, Jia Q, Callaway E, Weeks B, Alaniz RC, McMurray DN, et al. Th17 cell accumulation is decreased during chronic experimental colitis by (n-3) PUFA in Fat-1 mice. J Nutr 2012;142:117–24. [83] Kim CH. Regulation of FoxP3 regulatory T cells and Th17 cells by retinoids. Clin Dev Immunol 2008;416910. [84] Manolescu DC, Sima A, Bhat PV. All-trans retinoic acid lowers serum retinol-binding protein 4 concentrations and increases insulin sensitivity in diabetic mice. J Nutr 2010;140:311–6. [85] Genovese MC, Durez P, Richards H, Supronik J, Dokoupilova E, Mazurov V, et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 2013;72:863–9. [86] Kellner H. Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential. Ther Adv Musculoskel Dis 2013;5:141–52. [87] Papp KA, Leonardi C, Menter A, Ortonne JP, Krueger JG, Kricorian G, et al. Brodalumab as an anti-interleukin-17receptor antibody for psoriasis. N Engl J Med 2012;366: 1181–9. [88] Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 2012;366:1190–9. [89] Mueller C, Keeler A, Bragg S, Menz T, Tang Q, Flotte TR. Modulation of exaggerated-IgE allergic response by gene transfer-mediated antagonism of IL-13 and IL-17e. Mol Ther 2010;18:511–8.
Please cite this article in press as: Ziai S, et al. Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?. Diabetes Res Clin Pract (2014), http://dx.doi.org/10.1016/j.diabres.2014.03.002
