MINI REVIEW published: 11 August 2020 doi: 10.3389/fendo.2020.00540 Immune System Remodelling by Prenatal Betamethasone: Effects on β-Cells and Type 1 Diabetes David Perna-Barrull 1 , Anna Gieras 2 , Silvia Rodriguez-Fernandez 1 , Eva Tolosa 2 and Marta Vives-Pi 1* 1 Immunology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain, 2 Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Type 1 diabetes (T1D) is a multifactorial disease of unknown aetiology. Studies focusing on environment-related prenatal changes, which might have an influence on the development of T1D, are still missing. Drugs, such as betamethasone, are used during this critical period without exploring possible effects later in life. Betamethasone can interact with the development and function of the two main players in T1D, the immune system and the pancreatic β-cells. Short-term or persistent changes in any of these two players may influence the initiation of the autoimmune reaction against β-cells. In this Edited by: review, we focus on the ability of betamethasone to induce alterations in the immune Teresa Rodriguez-Calvo, system, impairing the recognition of autoantigens. At the same time, betamethasone Helmholtz Zentrum München, Germany affects β-cell gene expression and apoptosis rate, reducing the danger signals that will Reviewed by: attract unwanted attention from the immune system. These effects may synergise to Guoqiang Gu, hinder the autoimmune attack. In this review, we compile scattered evidence to provide Vanderbilt University, United States a better understanding of the basic relationship between betamethasone and T1D, laying Barak Blum, University of Wisconsin-Madison, the foundation for future studies on human cohorts that will help to fully grasp the role of United States betamethasone in the development of T1D. *Correspondence: Keywords: prenatal betamethasone, Type 1 diabetes, immune system, β cell, glucocorticoid Marta Vives-Pi mvives@igtp.cat Specialty section: BETAMETHASONE AS AN EMERGING ENVIRONMENTAL This article was submitted to FACTOR IN T1D Diabetes: Molecular Mechanisms, a section of the journal Type 1 diabetes (T1D) is an autoimmune disease caused by the selective destruction of insulin- Frontiers in Endocrinology producing β-cells. The trigger, however, remains unknown. Postnatal environmental determinants Received: 25 May 2020 have been thoroughly studied as risk factors (1, 2) but a crucial phase for the immune system Accepted: 03 July 2020 development, the late prenatal stage, has been poorly investigated. Specifically, the interaction Published: 11 August 2020 of drugs commonly used during late pregnancy with T1D and the pancreatic β-cells remains Citation: unexplored. Nonetheless, some studies reveal the importance of the prenatal stage and the Perna-Barrull D, Gieras A, prematurity of the newborn in the development of T1D (3–5). An indirect demonstration of Rodriguez-Fernandez S, Tolosa E and how critical the in utero environment is in T1D development arises from the studies in twins: Vives-Pi M (2020) Immune System heterozygotic twins have an increased concordance of T1D when compared to non-twin siblings Remodelling by Prenatal Betamethasone: Effects on β-Cells (6, 7), underlining the potential relevance of prenatal factors and their influence in the development and Type 1 Diabetes. of autoimmunity. Front. Endocrinol. 11:540. Synthetic glucocorticoids, most often betamethasone, are routinely given to mothers at doi: 10.3389/fendo.2020.00540 risk of preterm birth between 24 and 34 weeks of gestation. A single course of prenatal Frontiers in Endocrinology | www.frontiersin.org 1 August 2020 | Volume 11 | Article 540 Perna-Barrull et al. Prenatal Betamethasone and Autoimmune Diabetes betamethasone reduces the occurrence and severity of respiratory A described effect of betamethasone is the increase in distress syndrome and improves the survival chances in leukocyte counts in peripheral blood after treatment (27), premature infants (8, 9). Another glucocorticoid used for lung similarly to the effects of natural glucocorticoids during stress maturation is dexamethasone and produces similar results on the (28). Accordingly, neutrophil number and percentage were newborn survivability (10). These synthetic glucocorticoids cross increased in human blood after betamethasone treatment (29), the placenta and accelerate foetal lung maturation, achieving correlating with the described neutrophil demargination into maximum benefit between 24 h and 7 days after administration the blood vessels (30–32). Moreover, in humans, betamethasone (11). Betamethasone is a poor substrate for the glucocorticoid reduces neutrophil motility and chemotaxis (33), and can affect inactivating enzyme 11beta-hydroxysteroid-dehydrogenase 2 metabolism and cytokine production, i.e., reducing interleukin (11βHSD2), therefore, its bioactivity in the foetus lasts for (IL)-8 and macrophage inflammatory protein alpha (MIP- several days (12) and it is known to exert long-lasting effects on 1α) release (34). The inflammatory capacity of neutrophils the hypothalamic-pituitary-adrenal (HPA) axis and cognition in is therefore reduced, as demonstrated in a lamb model of children (13, 14). lung inflammation after betamethasone treatment, where gene Glucocorticoids exert their effects by binding nuclear expression of IL-1, IL-6, IL-8, and CCL2 was suppressed (35). receptors that are ligand-dependent transcription factors. They can regulate gene transcription, either by direct binding to Monocytes DNA or by interacting with other transcription factors (15). Monocytes are circulating innate immune cells that can Glucocorticoid receptors (GR) are ubiquitously expressed; become antigen-presenting cells (APCs), either macrophages, however, due to the variation in the genomic location of GR or dendritic cells (DCs). Thus, reprogramming monocytes may binding, the transcriptional responses to glucocorticoids are cell lead to changes in both differentiated cells. Betamethasone has type-specific (16). Moreover, polymorphisms of the GR result an acute effect on the metabolism of monocytes, transiently in alterations in their responsiveness to glucocorticoids and in reducing the production, and the secretion of IL-6 and reactive gene expression (17, 18). In addition, human GR receptor can oxygen species. By contrast, the phagocytic activity of monocyte- be a target of endoncrine disruptors such as pesticides (19) that, derived APCs was not altered by betamethasone (36). In newborn in combination with antenatal glucocorticoids, could increase children with low weight at birth, prenatal betamethasone developmental neurotoxicity (20). administration induced a transient immunomodulatory effect The general effects of glucocorticoids administered during in monocytes, causing diminished IL-6 and IL-10 release and pregnancy have been thoroughly reviewed (21). Considering the downregulation of human leukocyte antigen DR (HLA-DR) overwhelming use of betamethasone as the treatment of choice expression (37). Moreover, the total number of monocytes was for respiratory distress syndrome in premature infants and the reduced by betamethasone (38). This effect was also assessed cell-specific response to glucocorticoids, in this review we will in vitro, demonstrating that glucocorticoids induce apoptosis dissect the specific effects of betamethasone on the main cellular in human monocytes (39). Nevertheless, these results are players in the context of T1D, namely immune cells and their controversial, and other authors reported that betamethasone targets, the β-cells of the pancreas. does not affect monocytes’ IL-6 production (40). DIRECT EFFECTS OF BETAMETHASONE Macrophages Macrophages are crucial in the initial damage to β-cells ON THE IMMUNE SYSTEM in T1D. These tissue-resident APCs contribute to initiate Several cell types of the immune system are involved in the specific immune responses (41). In macrophages, betamethasone development of T1D, and disturbances in the activity of these diminishes cytokine secretion (IL-8 and TNFα) (42) and cells, such as enhanced proinflammatory activity, can increase the impairs their ability for antigen presentation to T cells (43). risk to develop T1D (22). Below, the effect of betamethasone on These effects point to the induction of a regulatory profile different cell types of the immune system is detailed. in macrophages, similar as described in M2 macrophages (44). Indeed, dexamethasone induces the polarization of the Innate Immune Cells M2 phenotype (45). Moreover, it was recently reported that Prenatal administration of betamethasone can induce an dexamethasone increases the migration of macrophages by anti-inflammatory status in the newborn during the first CD26 overexpression, a membrane glycoprotein with enzymatic days after delivery (23), and this fact could be due to capabilities involved in inflammation, and this could contribute the immunomodulatory effects of betamethasone on innate to the egress of macrophages from inflamed tissue (46). immune cells. Dendritic Cells Neutrophils DCs are professional APCs with the ability to stimulate naïve Neutrophils have gained interest in T1D aetiology due to their T cells. In T1D, DCs are responsible for the presentation of participation in the initial steps of autoimmunity against β- β-cell autoantigens to T lymphocytes, initiating the adaptive cells (24). Moreover, neutrophils are part of the islet leukocytic autoimmune response against the insulin-producing cells. infiltrates of patients with T1D, and are accordingly reduced in Similarly to the observed effect of dexamethasone on this cell peripheral blood at disease onset (25, 26). type, DCs differentiated in vitro in the presence of betamethasone Frontiers in Endocrinology | www.frontiersin.org 2 August 2020 | Volume 11 | Article 540 Perna-Barrull et al. Prenatal Betamethasone and Autoimmune Diabetes failed to achieve a fully mature status, showing a reduced capacity after prenatal steroid treatment included pathogenic Vβ domains to stimulate the production of IL-17, a cytokine involved in (57, 58), so it is reasonable to speculate that betamethasone autoimmune responses, by T lymphocytes (32). Furthermore, will protect against T1D. In humans, betamethasone reduces the release of proinflammatory cytokines was reduced by this T lymphocyte proliferation capacity (40), thus reducing clonal drug in DCs. Betamethasone has been reported to induce expansion. Overall, T cells will have an impaired capacity of tolerogenic Langerhans DCs (LDCs) in the skin of patients interacting with β-cell antigens, thus contributing to prevent the with psoriasis (47) and atopic dermatitis, which in turn arrest autoimmune response. T helper (Th) 1 and Th2 responses (48). Similarly to the effects found in monocytes, human DCs differentiated with B Lymphocytes betamethasone showed a reduction of membrane expression of The role of B lymphocytes in the development of T1D is not costimulatory molecules, such as CD40 and CD86, accompanied completely understood. B cells produce autoantibodies to islet by a decrease in IL-12 secretion, an important cytokine antigens that, even if extremely useful as predictive biomarkers for Th1 responses. These effects resulted in tolerogenic for disease, do not appear pathogenic. Also, B cells are critical function in DCs and impaired ability to induce T lymphocyte as APCs during the first stages of autoimmunity in T1D (59). proliferation (39). Betamethasone has a deleterious effect on mature B cells of NOD mouse (32) and reduces their ability to produce antibodies, Natural Killer Cells specifically IgE and IgG (60, 61). Other glucocorticoids, such as Natural Killer cells (NKc) are effector lymphocytes of the innate dexamethasone, show a similar deleterious effect (62), affecting immune system. Their role in T1D is not completely understood, early precursor B cells, whereas mature B cells –IgD positive– but abnormalities in this cell type may contribute to trigger are resistant to glucocorticoid-induced apoptosis (63). The autoimmune reactions against β-cells (49). Little is known about reduction observed in antibody production could be the result the effects of betamethasone on NKc. Betamethasone tends to of impaired B cell receptor and Toll-like receptor 7 signalling, increase NKc activity in very preterm newborn babies (<32 since without these signals B cells cannot switch their Ig weeks of gestation), supporting the maturation of this cell type isotype, thus reducing their functionality. At the same time, B (40). However, other studies have reported that betamethasone cells have increased transcriptional activity of IL-10, amplifying reduces the number of NKc in newborn infants (50). In the immunomodulatory capacity of these cells induced by adults, NKc showed a reduced cytolytic activity after topical glucocorticoids (16). betamethasone administration (51). Adaptative Immune Cells EFFECTS OF BETAMETHASONE ON THE Innate immune cells are crucial in the first phases of autoimmune TARGET CELLS OF AUTOIMMUNE diseases, but the final effector cells are the adaptative immune DIABETES, THE ISLET β-CELLS system cells, T and B lymphocytes. Modulation of these cells can dampen or exacerbate an autoimmune reaction. β-cells are the insulin-producing cells of the islets of Langerhans. The autoimmune destruction of these cells is the ultimate cause T Lymphocytes of T1D. β-cells also have an active role in their own destruction, Betamethasone treatment results in T cell precursor apoptosis facilitating the interaction with the immune system, and and, to a lesser extent, of mature T cells. Transient reduction contributing to their own demise (64). Thus, the identification in thymus weight and thymocyte numbers have been described of changes induced by betamethasone may help to understand after prenatal betamethasone administration in mice (32, 52). the possible outcome of this drug in the context of T1D. In humans, the thymus of the foetus of mothers that were Studies performed in subjects with long term glucocorticoid prenatally treated with steroids showed delayed growth (53). treatment indicate that glucocorticoids can induce dysglycaemia, Moreover, a reduction of 20–30% of peripheral lymphocyte leading to diabetes (65, 66). Glucocorticoids increase insulin counts was observed in pregnant women after treatment with resistance (67) without affecting β-cell mass (68). On the other betamethasone, although this effect only lasted for 3 days (27, 38, hand, physiological endogenous levels of glucocorticoids are 54). Other glucocorticoids, like dexamethasone, have comparable necessary for maintaining the regulation of insulin secretion effects on lymphocytes after prenatal treatment (55). In newborn by β-cells (69). Moreover, prenatal glucocorticoids support the children, a similar effect on lymphocyte counts has been maturation of β-cells by enhancing their glucose sensitivity due described, mainly affecting CD4+ T lymphocytes (56). Data on to increased expression of Glut2 and Gck genes and by reducing lymphocyte counts are still controversial, since a different study apoptosis, similarly as the overexpression of surfactant proteins reported an increase in CD3+ T lymphocytes in very preterm induced by glucocorticoids helps with the maturation of the newborn babies (<32 gestational weeks) after betamethasone foetal lungs (70). In a similar way, prenatal glucocorticoids treatment (50). Prenatal betamethasone administered to the enhance insulin secretion in rats due to the overexpression of experimental model of T1D, the non-obese diabetic (NOD) Gck, Slca2, and Ins2 genes in β-cells, despite β-cell mass is mouse, resulted in long-lasting changes in the T Cell Receptor smaller than in non-treated animals (71). Experimental data (TCR) Vβ repertoire that persisted into adulthood (32). demonstrate that prenatal betamethasone reduces the risk of Importantly, the TCR Vβ families that diminished in frequency developing T1D in the NOD mice (57), correlating to altered Frontiers in Endocrinology | www.frontiersin.org 3 August 2020 | Volume 11 | Article 540 Perna-Barrull et al. Prenatal Betamethasone and Autoimmune Diabetes FIGURE 1 | Effects of prental betamethasone on β-cells and the immune system of the newborn. Created with BioRender.com. expression of genes related to metabolism and autoimmunity in rheumatoid arthritis (79, 80). Betamethasone, like other synthetic β-cells. In a previous study we reported a reduction of Ccl2 gene glucocorticoids, can reduce cytokine production and release, expression in β-cells, which may lead to a reduced recruitment thereby inhibiting specific immune responses and blocking the of macrophages and monocytes. Moreover, an increase in Gad1 initiation of an autoimmune attack to β-cells (2). Dampening gene expression, could promote tolerance to β-cells in NOD the autoimmune reaction can be the most efficient form of mice (32). Recent studies in other T1D experimental models preventing T1D, and it might be a consequence of the impaired indicate that short-term treatment with betamethasone during functionality of innate and adaptative immune cells (Figure 1). late pregnancy does not affect β-cell metabolism in later life On the one side, betamethasone diminishes the proinflammatory (72, 73). Glucocorticoid signalling can also cause epigenetic action of innate immune cells (neutrophils, macrophages, and modifications in these cells. In fact, glucocorticoids impair the NK cells). On the other side, this drug induces a tolerogenic methylation of the DNA by altering the enzymes responsible for antigen presentation in macrophages and DCs, limiting the this process. Moreover, the prenatal period is a very sensitive possibilities to activate autoreactive T lymphocytes in the lymph phase during which the epigenome shows heightened plasticity to nodes. In turn, lymphocytes are also affected by betamethasone, methylation modifications and these changes can be accumulated as aforementioned. T lymphocytes reduce their proliferation throughout life (74). Important β-cell functions, such as insulin capacity, decreasing the number of cells that can kill the β- secretion and islet cell mass homeostasis, are controlled by cells. At the same time, prenatal treatment critically reduces epigenetic mechanisms (75), and glucocorticoids can modify the number of developing thymocytes and induces a skewed the epigenome of β-cells inducing changes that can affect TCR repertoire towards T cells with less affinity to β-cell their function in adults (76), altering the efficiency of glucose autoantigens (57). This fact will impair autoreactivity when metabolism (77, 78). APCs expose β-cell autoantigens in Major Histocompatibility Complex (MHC) molecules. Moreover, in the presence of betamethasone, T lymphocytes tend to differentiate to Th2 HOW CAN BETAMETHASONE AFFECT rather than autoimmunity-prone Th1 or Th17 cells (81), and THE INTERPLAY BETWEEN THE IMMUNE it has been demonstrated that glucocorticoids exposure during SYSTEM AND β-CELLS? foetal development can alter the HPA axis, impairing CD8+ T lymphocytes function later in life, making them less responsive T1D is a multifactorial disease with complex interactions between against viral antigens (82), or blunting cortisol response against the immune system and the pancreatic β-cells. Glucocorticoids rhinovirus (83). In this sense, concerns have been raised about are potent immune suppressors and are commonly used multiple doses of prenatal betamethasone, including an increased in patients with autoimmune diseases such as psoriasis or susceptibility to infections in children (84, 85). B cell precursors Frontiers in Endocrinology | www.frontiersin.org 4 August 2020 | Volume 11 | Article 540 Perna-Barrull et al. Prenatal Betamethasone and Autoimmune Diabetes TABLE 1 | Studies on the effect of betamethasone in the immune system and impact on T1D. Species/substrates Main findings Expected effect on T1D References Human ↓ NKc cytolytic capacity Protective (49) Human ↓ IgE synthesis by B cells Neutral (59) Human ↑ Insulin resistance (long-term) Neutral (80) No effect in T1D prevalence (long-term) Human ↑ T1D Hazard ratio after glucocorticoid treatment ↑ Risk (81) Human ↑ Neutrophils Protective (27) ↓ Basophils, CD3+CD4+, and CD3+CD8+ T cells Human (adult monocytes) ↓ DCs costimulatory molecules Protective (37) ↓ IL-12p70 ↓ Th1 activation Human (adult skin cells) ↓ LDCs costimulatory molecules and HLA-DR Protective (45) ↓ Proinflammatory cytokines No effects in IL-10 secretion or ILT3 expression Human (cord blood of preterm babies) ↑ NKc activity (<32 weeks gestation) Protective (38) ↓ Lymphocyte proliferation No effect in IL-6 secretion Human (cord blood) ↓ IL-6, IL-8 and TNFα secretion by macrophages Protective (40) Human (newborn and adult) ↓ migration and motility of newborn’s neutrophils Neutral (31) No effects in adult’s neutrophils Human (newborn) ↓ IL-8 and CCL3 secretion from neutrophils Protective (33) Human (newborn) ↓ HLA-DR expression on monocytes Protective (35) ↓ IL-6 and IL-10 in plasma Human (newborn) ↑ CD3+ T cells and monocytes ↓ NKc ↑ Risk (48) Human (newborn) ↓ CD4+ and CD25+ T lymphocytes Protective (54) Human (pregnant women) ↑ Leukocytes and granulocytes Neutral (25) ↓ Lymphocytes Human (pregnant women) ↑ Leukocytes Neutral (36) ↓ Lymphocytes and monocytes Human (pregnant women) ↑ Neutrophils Neutral (52) ↓ Lymphocytes Mouse (NOD) ↓ Immunogenicity ↑ Tolerance Protective (30) Mouse (NOD) ↓ T1D incidence ↓ Diabetogenic Vβ TCR Protective (55) Mouse ↓ Impaired antigen presentation by macrophages Protective (41) Mouse ↓ Th1 and Th2 induction by LDCs Protective (46) Mouse ↑ Apoptosis of thymocytes ↓ Thymus weight ↑ Risk (50) Sheep ↓ IL-1, IL-6, IL-8, CCL2, and TLR4 expression Protective (33) Sheep ↓ IL-6 and ROS from monocytes Protective (34) Sheep No long-term effects Neutral (69) Improves preterm delivery adverse effects Sheep No impairment of insulin sensitivity ↑ Insulin signalling pathway Neutral (71) Rabbit ↓ B cells IgG+ Neutral (58) CCL, C-C motif ligand; HLA, human leukocyte antigen; ILT3, immunoglobulin-like transcript 3; IL, interleukin; IgE, immunoglobulin E; IgG, immunoglobulin G; LDCs, Langerhans dendritic cells of the skin; NKc, Natural killer cells; ROS, reactive oxygen species; T1D; type 1 diabetes; TCR, T cell receptor; Th, T helper; TLR, toll like receptor; TNF, tumour necrosis factor. are also affected by betamethasone, showing reduced antibody to interactions between the immune system and β-cell reduce production (63). However, how these effects altogether might β-cell immunogenicity, hindering their direct interaction with influence the development of T1D is not yet known. Taken immune system cells (32). This could help to avoid the activation together, these alterations suggest a rather positive effect leading of stray cytotoxic T cells with affinity to β-cell autoantigens. How to T1D protection, but this effect could depend, among other long this effect is maintained is unknown, but it is reasonable factors, on the concentration, and duration of the prenatal to speculate that prenatal betamethasone could reprogramme treatment. In addition, β-cell changes induced by betamethasone some aspects of β-cell function until adult life, without affecting may enhance this protective effect. Especially, β-cell maturation their intrinsic capacities as described for insulin secretion (86). and the acquisition of an apoptosis-resistant phenotype may be Furthermore, glucocorticoid stimulation also induces epigenetic key factors in thwarting undesired autoimmune reactions (70). changes in the precursor β-cells (76), and this could be the Moreover, alterations found in the expression of genes related main actor behind the long-term effects observed after prenatal Frontiers in Endocrinology | www.frontiersin.org 5 August 2020 | Volume 11 | Article 540 Perna-Barrull et al. Prenatal Betamethasone and Autoimmune Diabetes administration of betamethasone. We have summarised those stage as well as in its consequences in the adulthood phase. studies that used betamethasone in their research (Table 1), Glucocorticoids have shown a plethora of effects, which depend focusing on their findings in the context of the immune system on the duration of the treatment, the route of administration, the and β-cells, and the expected effect these changes would have on target tissue, etc. The key message of this review is that prenatal T1D. Further studies are needed to reveal the long-term effects betamethasone affects the immune system cells, and these of prenatal betamethasone treatment in the immune system and alterations may have long-term consequences. Simultaneously, T1D (87). betamethasone also alters β-cells towards a less immunogenic phenotype and could induce epigenetic modifications in immune FUTURE PERSPECTIVES cells and β-cell precursors. Considering these effects, it is tempting to speculate that betamethasone may act as a protective The effectiveness of glucocorticoids has been demonstrated for agent against human T1D when administered shortly before birth a wide range of immunologically related diseases. However, or in the perinatal period. Future immunological, metabolic, their effects during the prenatal period, both in the immune and epidemiological studies, together with the extrapolation system and the target tissue of T1D, are not fully characterised. of data from other glucocorticoids like dexamethasone, will Expanding the understanding of how they can affect self- shed light on the unanswered questions related to this tolerance and T1D could contribute to reduce the increasing prenatal treatment. incidence of this and other autoimmune diseases. Another key point is to determine whether the effects of glucocorticoid treatment found in immune system cells could result from AUTHOR CONTRIBUTIONS changes induced in hematopoietic stem cells, thus explaining DP-B and MV-P wrote the manuscript. AG, SR-F, and ET the alterations found in many immune cell types. Further participated in the literature review, and edited the manuscript studies are required to dissect the exact mechanism and the while adding additional insights. All authors read and approved magnitude of these changes in the immune system and β- the final version of the manuscript. cells, because other factors, such as maternal nutrition or stress during pregnancy, could also veil betamethasone effects (88). Finally, epidemiological studies are needed to explore FUNDING the effect of prenatal betamethasone on T1D. Finding pieces of evidence of the precise effects of betamethasone in T1D This work has been funded by the German Research Council development could lead to improved neonatal care, with (KFO296). DP-B was granted by DiabetesCero Foundation. special focus on children with higher genetic risk to suffer from T1D. ACKNOWLEDGMENTS CONCLUSION The authors thank Dr. Marta Murillo, Dr. Joan Bel, Dr. Federico Vázquez, and Prof. Manel Puig-Domingo, from University Knowledge about betamethasone action on the immune system Hospital Germans Trias i Pujol, for fruitful discussions. Special is currently increasing, but it is very limited in the prenatal thanks to DiabetesCero Foundation for their support. REFERENCES 7. Kumar D, Gemayel NS, Deapen D, Kapadia D, Yamashita PH, Lee M, et al. North-American twins with IDDM: genetic, etiological, and 1. Esposito S, Toni G, Tascini G, Santi E, Berioli MG, Principi N. 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Impact of prematurity for pancreatic islet and beta-cell conflict of interest. development. J Endocrinol. (2018) 238:R161–71. doi: 10.1530/JOE-18-0021 Copyright © 2020 Perna-Barrull, Gieras, Rodriguez-Fernandez, Tolosa and Vives-Pi. Conflict of Interest: MV-P holds a patent that relate to immunotherapy for This is an open-access article distributed under the terms of the Creative Commons T1D and is co-founder of Ahead Therapeutics S.L. SR-F is part-time employed Attribution License (CC BY). The use, distribution or reproduction in other forums at Ahead Therapeutics S.L. The authors have no other relevant affiliations or is permitted, provided the original author(s) and the copyright owner(s) are credited financial involvement with any organization or entity with a financial interest in or and that the original publication in this journal is cited, in accordance with accepted financial conflict with the subject matter or materials discussed in the manuscript academic practice. No use, distribution or reproduction is permitted which does not apart from those disclosed. comply with these terms. Frontiers in Endocrinology | www.frontiersin.org 9 August 2020 | Volume 11 | Article 540