<p>Among food allergies, peanut has attracted the most research attention because the allergy is typically lifelong, often severe and potentially fatal. Furthermore, other than epinephrine, there are no treatments available to date. A decade of research has provided a great deal of insight into the factors that promote and regulate the <em>development </em>of allergic responses. However, less in known about the factors involved in the <em>elicitation</em> of the most common and severe manifestation of peanut allergy, namely anaphylaxis. The research in this thesis centers on the investigation of cellular and molecular pathways leading to peanut-induced anaphylaxis (PIA) as well as potential therapeutic targets. Specifically presented are: i) the development and characterization of a mouse model of PIA (Chapter 2), ii) the role of molecules including histamine, leukotrienes (LT) and platelet-activating factor (PAF) (Chapter 3) and, iii) the relative contribution of mast cells, basophils and macrophages as well as IgE and IgG₁(Chapter 4). Our data show that oral sensitization to peanut in C57BL/6 mice generated local and systemic markers of type-2 immunity that was associated with robust and consistent clinical anaphylaxis following antigen challenge. In this context, concurrent blockade of PAF and histamine receptors markedly decreases the severity of these reactions. Moreover, they demonstrate that distinctive immune effector pathways involving activation of mast cells (via IgE and IgG₁) and macrophages (via IgG₁) cooperate to elicit a broad range of systemic reactions to peanut. These findings highlight that concomitant and progressive recruitment of immune-effector pathways leads to a full range of anaphylactic reactions and therefore, therapeutic strategies for PIA may need to target several pathways or, alternatively shared components within these pathways. Combination therapy blocking both PAF and histamine may represent such as a therapeutic approach.</p> / Doctor of Philosophy (Medical Science)

The enteric nervous system (ENS) is an incredibly complex neural network that is extensively integrated within the neuroimmunoendocrine system through countless signalling pathways that have yet to be fully characterized. In the last decade we have discovered that many more neurotransmitters are at work in the ENS than was originally thought. This opens up new avenues of research into physiological phenomena traditionally thought to be associated only with the central nervous system, such as NMDA receptor-induced excitotoxicity, and how these may influence immune interactions. In particular, the kynurenine pathway of the tryptophan catabolism produces many neuro-active and immuno-active constituents whose effects are unknown in the ENS but are of great consequence in many neurodegenerative disorders of the CNS. Our study hypothesized that co-culture of the enteric neurons with mast cells would increase neuronal survival through kynurenic acid production in quinolinic acid (QUIN)-induced excitotoxic conditions. This study developed a novel in vitro co-culture system of enteric neurons and glia grown from murine longitudinal muscle-myenteric plexus tissue and bone marrow-derived mast cells. In addition, a pipeline in image analysis software CellProfiler was designed and optimized in order to reduce human bias and error in subsequent immunocytochemical image analysis. Furthermore, we identified the genetic expression of subunits of the NMDA glutamate receptor in cultured enteric neurons via PCR, which suggests that these cultured neurons may be susceptible to excitotoxicity. PCR analysis of cultured mast cells seemed to indicate that our cultured mast cells do not express KAT-III, the enzyme needed to produce the neuroprotective KYNA. Overall, co-culture with mast cells seemed to decrease neuronal survival. This project developed a novel methodology for the in vivo study of mast cell-nerve interactions, and lays the groundwork for future studies in excitotoxicity in the ENS. / Thesis / Master of Science (MSc) / The enteric nervous system is a vast web of nerves and immune cells that innervates the gut and interacts with the central nervous system through the gut-brain axis. An important mediator in this system is the mast cell, a type of immune cell often involved in protective responses to venoms and allergens. Intriguingly, in normal physiological conditions these cells are in close contact with nerves in the periphery, despite their potential to release damaging constituents. While mast cells are well-known for inciting inflammation and releasing toxic granules, they can also synthesize and release potentially beneficial neuroactive compounds, such as neurotransmitters or growth factors. The aim of this study was to characterize mast cell-nerve interactions in neurotoxic conditions, to see if the proximity of mast cells to nerves might serve a neuroprotective purpose.

PhD Dissertation / Obesity is a major risk factor for type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), and is attributed to excess energy intake in comparison to energy expenditure. Therapeutics that reduce energy intake in obesity have limited efficacy, with weight loss typically reaching less than 10% of initial body mass, leading to efforts to uncover new therapies that may increase energy expenditure. Unlike lipid-storing white adipose tissue, brown and beige adipose tissues undergo futile cycling, oxidizing lipids and carbohydrates thereby increasing energy expenditure. With obesity, the metabolic activity of brown and beige adipose tissue is reduced, suggesting that restoring adipose tissue thermogenesis may represent a new means to enhance energy expenditure. Previous studies in mice have shown that peripheral serotonin synthesis by the enzyme tryptophan hydroxylase 1 (Tph1) inhibits adipose tissue thermogenesis and contributes to the development of obesity, insulin resistance and NAFLD. However, the primary Tph1 expressing tissue(s) inhibiting adipose tissue futile cycling is not known. In this thesis, we genetically removed Tph1 in mast cells of mice and discovered that this elevated beige adipose tissue activity protecting mice from developing high-fat diet induced obesity, insulin resistance and NAFLD. In contrast to these findings, genetic deletion of Tph1 in adipocytes did not result in protection from obesity, suggesting that mast cells are the primary source of serotonin that inhibits white adipose tissue thermogenesis. Lastly, to determine the importance of adipose tissue thermogenesis in mediating the beneficial metabolic effects of reduced Tph1, mice were housed at thermoneutrality, blocking the requirement for adipose tissue thermogenesis. Under these conditions, mice lacking Tph1 had comparable brown and beige adipose tissue metabolic activity, energy expenditure and adiposity, however, surprisingly, were still protected from insulin resistance and NAFLD. The studies in this dissertation have discovered that mast cell Tph1 is critical for inhibiting adipose tissue thermogenesis and that serotonin plays an important role in promoting NAFLD, independently of its inhibitory effects on adipose tissue thermogenesis. Collectively, these findings further define the roles of serotonin in regulating whole-body energy metabolism, providing critical clues and mechanistic insights for potential therapies to mitigate metabolic diseases. / Dissertation / Doctor of Philosophy (Medical Science) / Obesity, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) can develop when caloric intake exceeds expenditure. In contrast to lipid-storing white fat, brown and beige fat burn calories. Serotonin is a hormone that reduces the burning of calories in fat, therefore finding ways to inhibit its effects on fat tissue without altering serotonin in the brain may lead to new therapies for obesity and other related diseases. In this thesis, we examined potential sources of serotonin that might inhibit the burning of calories in adipose tissue of mice. By reducing the synthesis of serotonin in a white blood cell called mast cells, but not fat cells, mice were protected from obesity, pre-diabetes and NAFLD due to increased activity of beige fat. Moreover, when we kept mice in a warm environment, thus reducing the need for mice to burn calories in brown and beige fat, this eliminated the effects of serotonin to promote obesity, but not pre-diabetes and NAFLD. These studies have identified how serotonin generated from mast cells inhibits the burning of calories in adipose tissue, a finding that may lead to new therapies for obesity, T2D and NAFLD.

Mast cells stem from the bone marrow and migrate via the blood as mast cell progenitors. Upon arrival in peripheral tissues, they develop into mast cells. These rare immune cells have numerous granules that contain large amounts of pro-inflammatory mediators. Mast cells accumulate at certain sites in the asthmatic lung, and once activated they release mediators that are thought to induce symptoms. In mouse models of allergic airway inflammation, the increase in lung mast cells in asthma can be mimicked and is mainly caused by the recruitment of mast cell progenitors to the lung. However, whether other types of lung inflammation stimulate the recruitment of mast cell progenitors to the lung was unknown until now. Here, using a murine model of influenza A virus infection, this type of virus was demonstrated to trigger an extensive recruitment of mast cell progenitors to the lung, most likely through the induction of VCAM-1 expression in the lung endothelium. Thereafter, some influenza-induced mast cell progenitors developed into an intermediate mast cell stage before they matured into mast cells. However, upon the resolution of inflammation, the mast cells that accumulated in the lung upon influenza infection were gradually lost. Because the recruitment of mast cell progenitors started early after influenza infection, the role of innate immune signals in inducing the recruitment of mast cell progenitors was addressed. The intranasal administration of either Poly I:C or IL-33 was sufficient to induce an increase in lung mast cell progenitors in a TLR3- or ST2-dependent fashion. However, the influenza-induced recruitment of mast cell progenitors to the lung occurred independently of TLR3 and ST2. VAAT/SLC10A4 is a member of the solute carrier family of proteins that is expressed in nerve cells and mast cells. In this study, murine VAAT was localized to mast cell granules and regulated the IgE/antigen-mediated release of granule-associated mediators and ATP. However, the absence of VAAT did not affect IgE/antigen-mediated de novo synthesis of cytokines and lipid mediators. Additionally, mice lacking VAAT had attenuated passive cutaneous anaphylaxis reactions and scratched less frequently in response to compound 48/80 injections, suggesting that VAAT regulates reactions for which mast cells are implicated in vivo.

Although the physiological consequences of Notch signaling in hematopoiesis have been extensively studied, the differential effects of individual notch cleavage products remain to be elucidated. Given that a disintegrin and metalloproteinase 10 (ADAM10) is a critical regulator of Notch and that its deletion is embryonically lethal, we generated transgenic mice that overexpress ADAM10 at early stages of lymphoid and myeloid development (A10Tg). ADAM10 transgene expression alters hematopoiesis post-hematopoietic Lineage-Sca-1+c-kit+ (LSK) subset differentiation but prior to lineage commitment of progenitor populations. This results in delayed T cell development, abrogated B2 cell development, and dramatic expansion of functionally active myeloid derived suppressor cells (MDSCs) in A10Tg mice. Given ADAM10’s role in Notch signaling, we hypothesized that the observed hematopoietic alterations may be a consequence of perturbed Notch signaling. In fact, blockade of ADAM10 (S2) rescues B cell development and reduces myeloid cells in A10Tg LSKs. Inhibition of γ-secretase (S3) in wild type (WT) LSKs results in enhanced myelopoiesis, mimicking the phenotype of A10Tg mice. Collectively, these findings indicate that the differential cleavage of Notch into S2 and S3 products regulated by ADAM10 is critical for hematopoietic cell-fate determination. Albeit arising in a tumor-free host, A10Tg MDSCs are functionally and phenotypically analogous to tumor-derived MDSCs. A10Tg MDSCs inhibit T cell activation in vitro, and inhibit adoptive immunotherapy (AIT) of metastatic melanoma in vivo, which can be reversed with MDSC depletion. Intriguingly, A10Tg mice are resistant to parasitic infection upon inoculation of Nippostrongylus brasiliensis. However, depletion of MDSCs abrogates this response, while adoptive transfer (AT) of MDSCs into WT mice increases their resistance. This polarized activity of MDSCs is heavily dependent upon interaction with mast cells (MCs). In fact, B16 melanoma cells metastasize more rapidly in WT mice infused with MDSCs when compared to MC-deficient mice (Kit Wsh/Wsh), with or without MDSC AT. Parallel to B16 progression, the ability of MDSCs to promote anti-Nb immunity is significantly diminished in MC-deficient (Kit Wsh/Wsh) mice even with MDSC AT. This augmentation of MDSC activity in the presence of MCs is further corroborated by in vitro co-culture assays that demonstrate a synergistic increase in cytokine production. Furthermore, MDSCs preferentially migrate to the liver in a MC-dependent manner. This interaction is mediated by MC-released histamine. In fact, MDSCs express histamine receptors (HR) and histamine induces MDSC survival, proliferation, and activation. We demonstrate that MDSC activity is abrogated with histamine blockade. Moreover, in humans, allergic patients present with an increase in MDSC population, and MDSCs purified from a stage I breast cancer patient exhibit increased survival in the presence of histamine. Taken together, our studies indicate that MCs and MC-released histamine are critical for the observed functional duality of MDSCs, ranging from immunosuppressive to immunosupportive, depending on the disease state.

Mast cells play a critical role in both acute and chronic inflammation and mature in peripheral tissues from bone marrow-derived progenitors that circulate in the blood as immature precursors. Mast cell progenitors are likely to encounter the serum-borne bioactive sphingolipid metabolite, sphingosine-1-phosphate (S1P), during migration to target tissues. Mast cells developed from human cord blood-derived progenitors cultured with stem cell factor (SCF) alone express intragranular tryptase (MCT), the phenotype predominant in the lung. S1P accelerated the development of cord blood-derived mast cells (CB-MCs) and strikingly increased the numbers of mast cells expressing chymase. These mast cells have functional FcepsilonRI, and similar to skin mast cells that express both tryptase and chymase (MCTC), also express CD88, the receptor for C5a, and are activated by anaphylatoxin C5a and the secretagogue compound 48/80. S1P induced release of IL-6, a cytokine known to promote development of functionally mature MCTC, from cord blood cultures containing adherent macrophages, and from highly purified macrophages, but not from macrophage-depleted CB-MCs. In contrast, S1P stimulated secretion of the chemokine, monocyte chemoattractant protein 1 (MCP-1/CCL2), from these macrophage-depleted and purified CB-MCs.

L’allergie de type I, une réaction de type hypersensibilité immédiate (HIS), a considérablement augmenté au cours des dernières décades dans les pays industrialisés. Le rôle des lymphocytes T régulateurs (Treg) dans le contrôle des maladies allergiques a été récemment apprécié. Cependant, il n’existe actuellement aucune connaissance précise si et comment les CD4+ Treg peuvent réguler l’allergie de type I. Le but du projet était d’étudier la contribution de cellules Treg dans le contrôle de l’allergie de type I chez la souris et chez l’homme. En utilisant un modèle murin d’HSI aux protéines de lait de vache, ß-lactoglobuline(BLG), nous avons montré que l’absence de Treg augmentait les réponses des cytokines Th1et Th2 et des anticorps IgE, IgG1 et IgG2a spécifique de la BLG. De plus, l’absence de Treg a augmenté la sévérité de l’anaphylaxie chez les souris sensibilisées lors de l’épreuve orale avec la BLG, avec une augmentation concomitante de la protéase des mastocytes muqueux 1(mMCP-1) dans le sérum. La contribution des cellules Treg dans un modèle murin d’anaphylaxie systémique passive (PSA) a été également étudiée. Une anaphylaxie plus sévère a été observée chez les souris déficientes en CHM de classe II ainsi que chez des souris B6 traitées avec un anti-CD4. En revanche, la déplétion sélective des Foxp3+ Treg chez des souris Tg DEREG n’a pas d’effet sur l’anaphylaxie.La capacité des Treg à contrôler la dégranulation des basophiles a été étudiée chez l’homme. Les données préliminaires ont montré que les Treg ont été incapables de contrôler la dégranulation des basophiles chez les donneurs sains. En revanche, une légère mais reproductible down-regulation de la dégranulation/activation des basophiles a été observée dans l’allergie induite par les médicaments chez l’homme. Dans l’ensemble, notre travail met en évidence un nouveau rôle encore non identifié des Treg dans le contrôle de l’HSI et souligne que chez la souris et l’homme, les Treg peuvent dans certaines conditions, limiter la sévérité de l’HSI en agissant sur les mastocytes et/ou basophiles effecteurs / Type I allergy, an immediate type hypersensitivity reaction (ITH), has dramatically increased during the past decades affecting up to 30% of the population in industrialized countries. The role of regulatory T cells (Treg) in the control of allergic diseases has been recently appreciated. However, there is currently no precise knowledge of whether and howCD4+ Treg can regulate type I allergy. The aim of this project was to investigate the contribution of Treg in the control of type I allergy. Using a murine model of ITH to cow’s milk protein the ß-lactoglobulin (BLG), we showed that lack of Treg increased BLG-specific Th2 and Th1 cytokine response and BLG-specific IgE, IgG1 and IgG2a antibodies.Furthermore, absence of Treg enhanced the severity of the anaphylaxis with concomitant increase in serum mucosal mast cell protease 1 (mMCP-1) in sensitized mice upon oral challenge with BLG. Furthermore, we investigated the contribution of Treg in a murine model of passive systemic anaphylaxis (PSA). More sever anaphylaxis was observed in both MHCclass II KO mice and after anti-CD4 mAb treatment. Alternatively, selective depletion of Foxp3+ Treg in DEREG Tg mice did not show changes in anaphylaxis.The capacity of Treg to control basophils degranulation was investigated in humans. Preliminary data showed that Treg were unable to control basophils degranulation in healthy donors. In contrast, a slight butreproducible downregulation of basophils activation/ degranulation was observed in allergic individuals. Taken together, our work points out to a novel as yet unidentified role of Treg in the control of ITH and emphasizes that both mouse and human Treg can, in certain conditions, limit the severity of ITH by acting on mast cells and/or basophils effectors of ITH

Hodgkin lymphoma (HL) is a heterogeneous condition varying from engaging one single lymph node site to a widespread condition. The prognosis with contemporary treatment is excellent for the vast majority. However, the treatment might cause severe late adverse effects in a proportion of the affected individuals. We evaluated all children and adolescents diagnosed in Sweden and registered in the Swedish Childhood Cancer Register over a period of 25 years. The incidence has been stable and the overall survival (OS) is very good, comparable to the best results in the world. Approximately ten percent encountered a relapse, but even after relapse the chances of survival were good. During the study period there were no detectable changes in survival estimates. The use of radiotherapy has decreased. Epstein Barr virus (EBV) and numbers of eosinophils, mast cells and macrophages in the tumors were investigated in 98 cases. Young children were more likely to express EBV. In patients with advanced disease the mast cell and macrophage counts were higher and they also had more affected laboratory parameters. Patients with Nodular Lymphocyte Predominant Hodgkin Lymphoma did not express EBV in the tumor, had significantly lower numbers of eosinophils, mast cells and macrophages and less affected laboratory parameters compared to classical HL. Outcome and clinical presentation were investigated in a cohort of children, adolescents and young adults in Sweden and Denmark and treatment in pediatric and adult departments was compared. OS and event-free survival (EFS) did not differ between the three age groups nor between pediatric and adult treatment. However, the Danish pediatric patients had lower EFS, which corresponded to less use of radiotherapy. Adolescents and young adults shared similar characteristics, while children presented differently with less advanced disease and male preponderance. Hospitalization rates and outpatient visits after end of treatment were evaluated to see whether the excess need of resources described in the literature is evenly distributed among the survivors or whether it is limited to a smaller group. Most of the patients had a low burden of health care use and the relapsing patients were the main drivers of the excess need.

Die Anaphylaxie, eine potentiell lebensbedrohliche Reaktion, kann durch Kofaktoren beeinflusst werden. ACE-Inhibitoren, ß-Blocker und Acetylsalicylsäure (ASS) werden häufig in der Therapie von Herz-Kreislauferkrankungen eingesetzt. In der vorliegenden Arbeit wurde überprüft, ob diese anaphylaktische Reaktionen begünstigen. Das Modell der passiv systemischen Anaphylaxie (PSA) wurde speziell angepasst, um die Behandlung einer Herz-Kreislauf-Therapie nachzubilden. Die orale Gabe von Metoprolol oder Ramipril verstärkte die Anaphylaxie geringfügig. Die Kombination der Medikamente steigerte die Anaphylaxie deutlich, was im Modell der passiv kutanen Anaphylaxie (PCA) bestätigt werden konnte. Gleichzeitig waren Mastzellmediatoren im Serum der Tiere erhöht. Die Inkubation muriner Mastzellen (MZ) mit den Medikamenten, steigerte die FcεRI-vermittelten Histaminfreisetzung in vitro. ASS-Vorbehandlung der Mäuse verstärkte die Ausprägung der PSA und der PCA, was mit einer Steigerung von MZ-Mediatoren im Serum assoziiert war. Die FcεRI-induzierte Histaminfreisetzung muriner MZ wurde hingegen nach ASS-Inkubation gehemmt, was auf einen indirekten Mechanismus hinweist. Die Reduktion der Prostaglandine (PG) durch ASS ist mit einer gesteigerten Leukotriensynthese verbunden. Der Leukotrienantagonist Montelukast konnte die, durch ASS verstärkte, PSA nicht mildern, was zeigt, dass dieser Effekt unabhängig von Leukotrienen ist. PGE2 kann die MZ-Degranulation über EP1-EP4-Rezeptoren modulieren. Tatsächlich schwächten EP3- und EP4-Rezeptoragonisten die durch ASS gesteigerte Anaphylaxie ab. PGE2 nimmt somit eine wichtige Rolle in der pro-anaphylaktischen Wirkung von ASS ein. Zusammenfassend wurde erstmals gezeigt, dass Metoprolol und Ramipril die Anaphylaxie über eine Steigerung der MZ-Reaktivität verstärken. ASS hingegen erhöht anaphylaktische Reaktionen über einen indirekt steigernden Effekt auf die MZ. PGE2 ist zumindest teilweise an der pro-anaphylaktischen Wirkung von ASS beteiligt. / Cofactors contribute to the severity of anaphylaxis, a potential life-threatening hypersensitivity reaction. ACE-inhibitors, ß-blockers and acetylsalicylic acid (asa) are frequently used drugs in cardiovascular therapy. Whether they affect systemic anaphylactic reactions has been addressed within this thesis. To this aim, the passive systemic anaphylaxis model (PSA) was employed here and specially designed to mimic a long term treatment in cardiovascular therapy. The data demonstrate that oral treatment of mice with ramipril or metoprolol alone slightly aggravated anaphylaxis. However, the combination clearly potentiated anaphylactic reactions, which was also confirmed in the passive cutaneous anaphylaxis model (PCA). In line with this, elevated amounts of mast cell (MC) mediators were detected in mice sera upon combined drug treatment. In vitro, FcεRI-mediated histamine release of murine MCs was likewise enhanced by the respective drugs. Pre-treatment of mice with asa aggravated the symptoms of PSA and PCA; simultaneously MC-mediators in sera were elevated. In contrast, FcεRI-mediated histamine release of MCs was reduced by asa in vitro, pointing to an indirect mechanism. Asa reduces prostaglandins (PGs) and increases leukotriene synthesis. The leukotriene antagonist montelukast failed to attenuate PSA, aggravated by asa, suggesting that the pro-anaphylactic effect of asa might be independent of leukotrienes. PGE2 can modulate MC degranulation via EP1-EP4 receptor. Indeed, EP3 and EP4 receptor agonists alleviated anaphylaxis enhanced by asa. Therefore PGE2 might play an important role in the pro-anaphylactic effect of asa. In conclusion, the data demonstrate for the first time that metoprolol and ramipril exacerbate anaphylactic symptoms by a direct increase in MC reactivity. In contrast, asa aggravates anaphylactic reactions by priming MCs through an indirect mechanism. PGE2 is at least partly involved in this process.

Les récepteurs activés par les proliférateurs de peroxysomes (PPARs) sont des facteurs de transcription impliqués dans la régulation du métabolisme lipidique et de la tolérance au glucose. Les PPARs contrôlent également l’inflammation associée à de multiples pathologies, dont la polyarthrite rhumatoide. Dans les travaux présentés dans ce manuscrit, nous avons comparé les potentialités anti-arthritiques, dans un modèle expérimental, de deux agonistes synthétiques de haute affinité pour deux isotypes de PPARs, PPARα et PPARγ. Nous avons démontré qu’un traitement avec un agoniste sélectif de PPARγ, la pioglitazone, en plus de diminuer la sévérité de l’arthrite expérimentale, réduisait la perte osseuse inflammatoire en préservant la micro-architecture osseuse. Nous avons mis en évidence que PPARγ, d’une part, régulait l’expression locale et systémique de l’interleukine-17 et de RANKL, et que, d’autre part, il inhibait l’expression du facteur de transcription RORγt, acteur majeur de la voie IL-17/Th17. Les animaux déficients pour PPARγ nous ont permis de confirmer son rôle majeur dans le développement du processus arthritique. En effet, ces animaux présentent tous et de façon spontanée une arthrite associée à une augmentation du nombre de mastocytes capables de produire l’IL-17 et leur propre facteur de différenciation, le SCF dans la synoviale inflammatoire. Enfin, nous avons discuté le lien possible entre l'arthrite inflammatoire et la mastocytose à la lumière de l’étude d’un cas clinique d’un patient atteint de polyarthrite rhumatoïde concomitante à une mastocytose systémique / Peroxisome proliferator-activated receptors (PPARs) are transcription factors implicated in lipid metabolism and glucose tolerance. Once activated by specific agonists, PPARs control inflammation associated with numerous diseases, notably Rheumatoid arthritis. The first study presented here aim to compare the anti-arthritic potency of two high-affinity synthetic agonists for PPARα and PPARγ in an experimental model. Then we focused on the effect of pioglitazone, a high-affinity synthetic agonists for PPARγ, and demonstrated that a per os treatment with this agonist not only reduced experimental arthritis but also inhibited partly inflammation-related bone loss by preserving bone microarchitecture. We pointed out that PPARγ, on one hand, regulated local and systemic expression of interleukine-17 (IL-17) and RANKL and on the other hand, inhibited expression of transcription factor RORγt, a main regulator of IL-17/Th17 pathway. Study of mice deficient for PPARγ confirmed its major role in the development of the arthritic process since these mice developed spontaneously arthritis. Of interest arthritis in these mice is associated with increased number of synovial mast cells able to produce IL-17 and their own differenciation factor, the SCF. Finally, we discussed the possible link between inflammatory arthritis and mastocytosis in a case report of a patient suffering from rheumatoid arthritis concomitant to systemic mastocytosis