Academic literature on the topic 'Autoimmune pancreatiti'

Introduction. Isolated pancreatic and peripancreatic tuberculosis is a challenging diagnosis due to its rarity and variable presentation. Pancreatic tuberculosis can mimic pancreatic carcinoma. Similarly, autoimmune pancreatitis can appear as a focal lesion resembling pancreatic malignancy. Endoscopic ultrasound-guided fine needle aspiration provides an effective tool for differentiating between benign and malignant pancreatic lesions. The immune processes involved in immunoglobulin G4 related systemic diseases and tuberculosis appear to have some similarities.Case Report. We report a case of a 59-year-old Southeast Asian male who presented with fever, weight loss, and obstructive jaundice. CT scan revealed pancreatic mass and enlarged peripancreatic lymph nodes. Endoscopic ultrasound-guided fine needle aspiration confirmed the presence ofmycobacterium tuberculosis. Patient also had high immunoglobulin G4 levels suggestive of autoimmune pancreatitis. He was started on antituberculosis medications and steroids. Clinically, he responded to treatment. Follow-up imaging showed findings suggestive of chronic pancreatitis.Discussion. Pancreatic tuberculosis and autoimmune pancreatitis can mimic pancreatic malignancy. Accurate diagnosis is imperative as unnecessary surgical intervention can be avoided. Endoscopic ultrasound-guided fine needle aspiration seems to be the diagnostic test of choice for pancreatic masses. Long-term follow-up is warranted in cases of chronic pancreatitis.

Autoimmune pancreatitis is a rare form of chronic pancreatitis of presumed autoimmune etiology. Due to significant overlap in clinical and imaging characteristics, misdiagnosis as a pancreatic malignancy is common. As a result, a significant number of patients undergo a major pancreatic resection, associated with considerable morbidity, for a disease process that generally responds well to corticosteroid therapy. In the past ten years, important advances have been made in understanding the disease. Several diagnostic criteria have been developed to aid in diagnosis. Despite this, pancreatic resection may still be required in a subset of patients to reliably exclude pancreatic malignancy and establish a definite diagnosis of autoimmune pancreatitis. This article aimed to define the role of surgery in autoimmune pancreatitis, if any. For this purpose, published case series of patients with a diagnosis of autoimmune pancreatitis, based on the histopathological examination of surgical specimens, were reviewed and patients’ clinical, radiological and serological details were assessed. At the end, histopathologic examinations of patients who underwent pancreatic resection at our department in the last 10 years were retrospectively reviewed in order to identify patients with autoimmune pancreatitis and assess their clinical characteristics.

Background: Immunoglobulin G4 (IgG4)-related diseases are a group of diseases characterized by enlargement of the affected organs, elevation of serum IgG4, massive infiltration of affected organs with lymphocytes and plasma cells with IgG4 positivity and tissue fibrosis. Type I autoimmune pancreatitis is one form of IgG4-related disease. For IgG4-related diseases, various localizations are described for up to 10% of malignancies. The aim of our study was to examine IgG4 serum levels and pancreatic tissue with respect to the simultaneous presence of autoimmune pancreatitis in patients with pancreatic cancer. Methods: IgG4 serum levels were examined In 106 patients with histologically confirmed pancreatic cancer. The level of 135 mg/dl was considered as the normal value. Pancreatic tissue was histologically examined with respect to the presence of markers of autoimmune pancreatitis. Results: A higher IgG4 level than the cut-off value of 135 mg/dl was proven in 11 patients with pancreatic cancer. Of these 11 patients, 7 had levels twice the normal limit (65.6%). Autoimmune pancreatitis was diagnosed in these individuals. In the case of 1 patient, it was basically an unexpected finding; another patient was initially diagnosed with autoimmune pancreatitis. Repeated biopsy of the pancreas at the time of diagnosis did not confirm the presence of tumour structures, therefore steroid therapy was started. At a check-up 6 months after starting steroid therapy, the condition of the patient improved subjectively and IgG4 levels decreased. However, endosonographically, malignancy was suspected, which was subsequently confirmed histologically. This patient also demonstrated an IgG4 level twice the normal limit. Conclusion: IgG4-related diseases can be accompanied by the simultaneous occurrence of malignancies, which also applies to autoimmune pancreatitis. Chronic pancreatitis is considered a risk factor for pancreatic cancer. It cannot be reliably confirmed whether this also applies to autoimmune pancreatitis. In accordance with other works, however, it is evident that, despite the described high sensitivity and specificity for IgG4 elevation in the case of autoimmune pancreatitis, even levels twice the normal limit are demonstrable in some individuals with pancreatic cancer, without the presence of autoimmune pancreatitis. We believe that patients with IgG4-related disease, including autoimmune pancreatitis, must be systematically monitored with respect to the potential presence of malignancy.

Abstract Context.—Autoimmune pancreatitis is an uncommon, inflammatory disease of the pancreas that presents with clinical features, such as painless jaundice and a pancreatic mass, similar to those caused by pancreatic cancer. Patients with autoimmune pancreatitis frequently have elevated serum immunoglobulin G fraction 4 (IgG4) levels, and their pancreatic tissue may show IgG4-positive plasma cell infiltration. It is imperative to differentiate autoimmune pancreatitis from pancreatic cancer because autoimmune pancreatitis typically responds to corticosteroid treatment. A previous Japanese study reported that serum IgG4 greater than 135 mg/dL was 97% specific and 95% sensitive in predicting autoimmune pancreatitis. Objective.—To prospectively measure serum IgG4 levels in pancreatic cancer patients to ascertain whether increased levels might be present in this North American population. Design.—We collected blood samples and phenotypic information on 71 consecutive pancreatic cancer patients and 103 healthy controls who visited our clinics between October 2004 and April 2006. IgG4 levels were determined using a single radial immunodiffusion assay. A serum IgG4 level greater than 135 mg/dL was considered elevated. Results.—Five cancer patients had IgG4 elevation, with a mean serum IgG4 level of 160.8 mg/dL. None of our cancer patients with plasma IgG4 elevation demonstrated evidence of autoimmune pancreatitis. One control subject demonstrated elevated serum IgG4 unrelated to identified etiology. Conclusions.—As many as 7% of patients with pancreatic cancer have serum IgG4 levels above 135 mg/dL. In patients with pancreatic mass lesions and suspicion of cancer, an IgG4 level measuring between 135 and 200 mg/dL should be interpreted cautiously and not accepted as diagnostic of autoimmune pancreatitis without further evaluation.

Autoimmune pancreatitis is a rare but important differential diagnosis from pancreatic cancer. This autoimmune disease can mimic pancreatic cancer by its clinical symptoms, including weight loss and jaundice. Furthermore imaging findings may include a mass of the pancreas. Here we present the case of a 67-year-old male patient diagnosed with autoimmune pancreatitis but showing the well-known symptoms of pancreatic cancer. This emphasizes the difficulties of histological findings and the importance of the correct diagnostic process.

Background. Autoimmune pancreatitis (AIP) often mimics pancreatic cancer. The diagnosis of both conditions is difficult preoperatively let alone when they coexist. Several reports have been published describing pancreatic cancer in the setting of AIP.Case Report. The case of a 53-year-old man who presented with abdominal pain, jaundice, and radiological features of autoimmune pancreatitis, with a “sausage-shaped” pancreas and bulky pancreatic head with portal vein impingement, is presented. He had a normal serum IgG4 and only mildly elevated Ca-19.9. Initial endoscopic ultrasound-(EUS-) guided fine-needle aspiration (FNA) of the pancreas revealed an inflammatory sclerosing process only. A repeat EUS guided biopsy following biliary decompression demonstrated both malignancy and features of autoimmune pancreatitis. At laparotomy, a uniformly hard, bulky pancreas was found with no sonographically definable mass. A total pancreatectomy with portal vein resection and reconstruction was performed. Histology revealed adenosquamous carcinoma of the pancreatic head and autoimmune pancreatitis and squamous metaplasia in the remaining pancreas.Conclusion. This case highlights the diagnostic and management difficulties in a patient with pancreatic cancer in the setting of serum IgG4-negative, Type 2 AIP.

Autoimmune pancreatitis (AIP) was first used to describe cases of pancreatitis with narrowing of the pancreatic duct, enlargement of the pancreas, hyper-γ-globulinaemia, and antinuclear antibody (ANA) positivity serologically. The main differential diagnosis, is pancreatic cancer, which can be ruled out through radiological, serological, and histological investigations. The targets of ANA in patients with autoimmune pancreatitis do not appear to be similar to those found in other rheumatological diseases, as dsDNA, SS-A, and SS-B are not frequently recognized by AIP-related ANA. Other disease-specific autoantibodies, such as, antimitochondrial, antineutrophil cytoplasmic antibodies or diabetes-specific autoantibodies are virtually absent. Further studies have focused on the identification of pancreas-specific autoantigens and reported significant reactivity to lactoferrin, carbonic anhydrase, pancreas secretory trypsin inhibitor, amylase-alpha, heat-shock protein, and plasminogen-binding protein. This paper discusses the findings of these investigations and their relevance to the diagnosis, management, and pathogenesis of autoimmune pancreatitis.

Autoimmune pancreatitis (AIP) accounts for approximately 5% of chronic pancreatitis cases and is an important consideration in the differential diagnosis of pancreatic pathologies. The underlying pathophysiology of AIP is thought to involve lymphocyte infiltration and associated sclerosis. Although AIP is a benign condition that is treatable with corticosteroids, it can have imaging and clinical findings indistinguishable from pancreatic cancer. As such, the radiologist plays an important management role in distinguishing AIP from more sinister conditions. In addition, there are several extrapancreatic imaging findings in the context of AIP that have been recently described. This pictorial review outlines both the pancreatic and extrapancreatic imaging features in AIP and the response to steroid therapy. Important imaging features that allow AIP to be differentiated from other pancreatic pathology, including adenocarcinoma, lymphoma, and acute pancreatitis will be discussed.

Background—The pathology of non-alcoholic chronic pancreatitis has not yet been sufficiently studied.Aims—To identify the major changes of pancreatic tissue in patients surgically treated for non-alcoholic chronic pancreatitis.Patients—Pancreatectomy specimens from 12 patients with non-alcoholic chronic pancreatitis, including four patients with autoimmune or related diseases (Sjögren’s syndrome, primary sclerosing cholangitis, ulcerative colitis, and Crohn’s disease), were reviewed.Methods—Morphological changes were studied histologically and immunohistochemically (to type inflammatory cells) and compared with the pancreatic alterations found in 12 patients with alcoholic chronic pancreatitis.Results—In patients with non-alcoholic chronic pancreatitis, with or without associated autoimmune or related diseases, pancreatic inflammation particularly involved the ducts, commonly resulting in duct obstruction and occasionally duct destruction. None of these features was seen in alcoholic chronic pancreatitis which, however, showed pseudocysts and calcifications.Conclusion—The pancreatic changes in patients with non-alcoholic chronic pancreatitis clearly differ from those with alcoholic chronic pancreatitis. The term chronic duct destructive pancreatitis is suggested for this type of pancreatic disease.

Type 1 diabetes is a disease that results from a disturbed glucose metabolism due to a deficiency in insulin production. This deficiency is the consequence of immune-mediated damage to the insulin-producing p-cells. The cause of type 1 diabetes is presently unknown and probably multifactorial. The initiation and progression of the inflammatory process that destroys the p-cells involves the interplay of environmental factors with an autoimmune-prone genetic background. Abnormal immune regulation explains the autoimmune phenomena observed in diabetic patients and in spontaneous animal models for the disease to a limited extent only. The precise reason for the immune system to target the pancreatic islets of Langerhans is still unclear. The pathogenic process in the pancreas is characterized by the pathology-related intra-islet infiltration of T and B-lymphocytes that mediate islet destruction. This T and B-celUnfiltration is preceded by an accumulation of macrophages and dendritic cells at the islet periphery. The early peri-islet accumulation of these antigen presenting cells probably reflects the first response of the immune system that is progressively heading for islet destruction. Macrophages are involved in every step of the diabetogenic process. In the non-obese diabetic (NOD) mouse that spontaneously develops diabetes, various macrophage-abnormalities like defective maturation, reduced phagocytosis and increased production of IL-12, have been described previously. Moreover, macrophages are present in higher numbers in the pancreas of the NOD mouse from birth onwards, randomly distributed in the connective tissue and exocrine parenchyma. In this thesis we present the results of our studies on the murine pancreatic macrophage compartment. We have questioned in particular the possible underlying causes for the abnormal early peri-islet accumulation of macrophages. Therefore, the studies were performed with an emphasis on the interactions of macrophages with the extracellular matrix of the pancreatic connective tissue. In our first study we show that the depletion of macrophages and dendritic cells from the endocrine pancreas was accompanied by a total disappearance of lymphocytes from the pancreas. Hence, pancreatic macrophages and dendritic cells are critically involved in the local progression of islet inflammation in NOD mice by mediating the retention and possibly the recruitment of lymphocytes to the pancreas. Importantly, this depletion significantly postponed the onset of diabetes, leading to a strongly decreased incidence by 35 weeks of age. In the second study described, we have phenotypically characterized the pancreatic macrophages. The majority of macrophages were characterized by the expression of MMGL and sialoadhesin. Only a minority of these pancreatic macrophages expressed the macrophage marker F4/80 under non-inflammatory conditions. By contrast, macrophages expressing F4/80 were observed massively before the onset of destructive insulitis in the NOD pancreas, and their presence is particularly associated with islet destruction. This suggests that F4/80 identifies a particular subset of inflammatory macrophages in the pancreas that are virtually absent under non- inflammatory conditions. Interestingly, in the fetal pancreas mature macrophages were exclusively identified by their expression of F4/80 and these macrophages lacked the expression of MMGL and sialoadhesin. In addition, we present data that support the conclusion that macrophages develop from pre-existing precursors that are present in the fetal pancreas at E12. 5. Using an in vitro approach, we demonstrated that their numbers significantly increased in fetal pancreas explants cultured with M-CSF. This increase of F4/80-positive cells was paralleled by an increase in the number of insulin-producing cells, suggesting that macrophages support insulin-cell growth in vitro. These results are in line with the results of the third study that is presented in this thesis. Early postnatal pancreases from NOD mice are characterized by an increase in the percentage of endocrine tissue and by enlarged and irregularly-shaped islets, concomitantly with the presence of increased numbers of macrophages. Importantly, the levels of the extracellular matrix protein fibronectin are significantly increased during this pre-weaning period as well. Fibronectin labeling was mostly localized at the islet-ductal pole, islet periphery and in intralobular septa. Interestingly, pancreatic macrophages mainly reside at sites with intense fibronectin-labeling. In a fourth study we demonstrate that, paradoxically, NOD macrophages exhibit impaired fibronectin-mediated adhesion and migration due to the defective expression of the integrin-type fibronectin receptor a-chain, CD49d. In addition, we show that extracellular-regulated kinase-1/2 (ERK-1/2) is a negative regulator of CD49d expression in macrophages. NOD macrophages were characterized by increased levels of the activated form of this kinase when stimulated with the toll-like receptor-4 (TLR-4) ligand, lipopolysaccharide (LPS). LPS-stimulation resulted in the impaired upregulation of CD49d levels in NOD macrophages as compared to macrophages of other mouse strains. We believe that this specific defect in the macrophage compartment of NOD mice might play a role in the observed peri-islet accumulation. At the end of this thesis, we have postulated the working hypothesis that the observed presence of higher levels of the endogenous TLR-4 ligand fibronectin in the NOD pancreas in combination with the inappropriate TLR-4-responsiveness of NOD macrophages contributes to their local retention and activation. This unfortunate activation may damage the neighboring islets, unintentionally provoking an immune response eventually leading to the development of autoimmunity. We have uncovered several abnormalities that may trigger a mechanism that possibly contributes to the development of spontaneous autoimmune diabetes in the NOD mouse. Whether similar abnormalities are present in type 1 diabetic patients remains to be established
De pancreas, ook wel alvleesklier genoemd, is een in de buikholte gelegen orgaan met verschillende functies. Het grootste gedeelte van de pancreas bestaat uit exocrien weefsel dat verteringsenzymen uitscheidt in de dunne darm. Slechts iets meer dan één procent van de pancreas wordt gevormd door de eilandjes van Langerhans. Deze endocriene eilandjes produceren verschillende hormonen die worden uitgescheiden in het bloed. Het belangrijkste hormoon is insuline, gemaakt door de p-cellen die zijn gelegen in het midden van de eilandjes. Insuline verlaagt de glucose-spiegel en reguleert zo de opslag van energie uit ons voedsel. Patiënten met type 1 diabetes hebben een gevaarlijk hoge concentratie van glucose in het bloed door een tekort aan insuline. Dit tekort wordt veroorzaakt door de vernietiging van de p-cellen door het eigen afweersysteem en resulteert in een ernstige verstoring van het metabolisme. Deze immuunreactie tegen deze eiland-cellen ontstaat vaak al op heel jonge leeftijd en is onomkeerbaar. Patiënten met type 1 diabetes zijn daarom genoodzaakt hun verdere leven insuline te gebruiken. Er zijn verschillende afwijkingen gevonden in het immuunsysteem van type 1 diabetes patiënten, die gerelateerd zijn aan het onstaan van autoimmuniteit. Deze autoimmuniteit lijkt echter voornamelijk gericht te zijn tegen de endocriene eilandjes en daarom noemen we type 1 diabetes een orgaan-specifieke autoimmuunziekte. Waarom het immuunsysteem van type 1 diabetes-patiënten zich juist tegen de eigen p-cellen keert is niet duidelijk. Het kan zijn dat de oorzaak van de immuunrespons tegen de eilandjes in de pancreas zelf ligt. Om te bestuderen wat er in de pancreas plaatsvindt voordat de specifieke afweerreactie ontstaat, zijn we genoodzaakt onderzoek te doen in proefdieren. Niet-obese diabetische (NOD)-muizen ontwikkelen spontaan diabetes. Voorafgaand aan de specifieke immuunreactie tegen de p-cellen zien we in de pancreas van deze muizen veel niet-specifieke afweercellen rondom de eilandjes. Deze niet-specifieke immuuncellen worden macrofagen genoemd. Macrofagen zijn in alle organen aanwezig en vormen daar de eerste verdediging tegen pathogene indringers. Macrofagen ruimen bacteriën op en alarmeren andere cellen van het immuunsysteem om een afweerreactie tot stand te brengen. Deze afweerreactie moet specifiek gericht zijn tegen de pathogene indringers en niet tegen ons eigen weefsel. Dit laatste gebeurt helaas wel bij patiënten met type 1 diabetes. Er is echter onvoldoende bewijs dat de afweerreactie tegen de eilandjes samenhangt met een eerdere infectie. Omdat macrofagen mede onze afweerreactie aansturen, kunnen ze een heel belangrijke rol spelen in het ontstaan van autoimmuunziekte. In het onderzoek dat is beschreven in dit proefschrift, hebben we de macrofagen in de pancreas nader bestudeerd en onderzocht wat de oorzaak kan zijn van de vroege accumulatie van macrofagen rondom de eilandjes. We laten zien dat er verschillende typen macrofagen aanwezig zijn in de pancreas. In de volwassen muis bleek een bepaald type macrofaag specifiek geassocieerd met ontsteking en deze is in hoge mate aanwezig in de pancreas van de NOD muis. De pancreas macrofagen bevinden zich in het bindweefsel van de pancreas, tussen het exocriene weefsel maar ook rondom de eilandjes waar veel fibronectine aanwezig is. Fibronectine is een matrix eiwit wat enerzijds een rol speelt bij pancreas¬ontwikkeling en anderzijds bij de ontwikkeling en mobiliteit van macrofagen. In de pancreas van NOD muizen werden allereerst verhoogde concentraties fibronectine gevonden in de periode voorafgaand aan het ontstaan van de afweerreactie tegen de eilandjes. Verder laten wij zien dat de eilandjes in de pancreas van de NOD muis groter en grilliger van vorm zijn dan die in gezonde muizen. Deze afwijkingen kunnen samenhangen met het verhoogde aantal macrofagen dat in de NOD pancreas aanwezig is. In tegenstelling tot wat wij hadden verwacht, vertonen macrofagen van de NOD muis een verzwakte interactie met fibronectine. Ze hebben een verstoorde expressie van een van de eiwitten waarmee macrofagen aan fibronectine binden, het CD49d integrine. Dit leidt tot een defect in de beweeglijkheid van de NOD macrofagen over fibronectine en kan daardoor bijdragen aan de vroege accumulatie van de macrofagen rondom de eilandjes. De oorzaak van de defecte expressie van dit integrine ligt in een verstoorde aansturing van de expressie binnenin de cel. Deze verkeerde aansturing is ook betrokken bij de activatie van macrofagen door moleculen uit de bacteriewand. Stimulatie van de NOD macrofagen door deze moleculen of eiwitten die daar op lijken, leidt tot een verstoorde expressie van CD49d maar ook tot een verstoorde activatie van de macrofaag. Eén van de eiwitten die tot deze verstoorde activatie kan leiden is fibronectine, wat in verhoogde mate aanwezig is in de NOD pancreas. Deze factoren tezamen kunnen bepalend zijn voor de ongewenste beschadiging van de eilandjes door de macrofagen in de NOD muis. De orgaan-specifieke afwijkingen in combinatie met de door ons gevonden defecten in de NOD macrofaag kunnen het lokale evenwicht in de pancreas verstoren, mogelijk gevolgd door schade aan de eilandjes en de initiatie van een specifieke immuunrespons. De beschreven resultaten bieden mogelijk de basis voor een nieuwe hypothese voor het onstaan van lokale activatie van pancreas macrofagen. Ook macrofagen van patiënten met type 1 diabetes vertonen een verstoorde respons op hetzelfde ligand als door ons is getest in de NOD muis. Wij hopen dat met onze bevindingen in de NOD muis een nieuwe weg kan worden geopend in het onderzoek naar het ontstaan van type 1 diabetes in de mens

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the immune-mediated destruction of insulin-producing beta-cells of pancreatic islets, culminating in critical insulin deficiency. Both genetic and environmental factors likely orchestrate an immune-mediated functional loss of beta cell mass, leading to the clinical manifestation of disease and lifelong dependence on insulin therapy. Additional evidence suggests the role of innate and adaptive immune mechanisms leading to inflammation in beta cells mediated by proinflammatory cytokines and chemokines, activation of beta-cell-reactive T cells,and failure of immune tolerance. Viral infections have been proposed as causal determinants or initiating triggers for T1D but remain unproven. Understanding the relationship between viral infections and the development of T1D is essential for T1D prevention. Importantly, virus-induced innate immune responses, particularly type I interferon (IFN-I, IFN-a/b), have been implicated in the initiation of islet autoimmunity and development of T1D. The goal of my thesis project is to investigate how the IFN-I signaling pathway affects the development of T1D using the LEW.1WR1 rat model of autoimmune diabetes. My hypothesis is that disrupting IFN-Isignaling via functional deficiency of the IFN-I interferon receptor (IFNAR) prevents or delays the development of virus-induced diabetes.For this purpose, I generated IFNAR subunit 1(IFNAR1)-deficient LEW.1WR1 rats using CRISPR-Cas9 genome editing and confirmed the functional disruption of IFNAR1. The absence of IFNAR1 results in a significant delay in onset and frequency of diabetes following poly I:C challenge and reduces the incidence of insulitis after poly I:C treatment. The frequency of diabetes induced by Kilham rat virus (KRV) is also reduced in IFNAR1-deficient LEW.1WR1 rats. Furthermore, I observe a decrease in CD8+T cells in spleens from KRV-infected IFNAR1-deficient rats relative to that in KRV-infected wild-type rats. While splenic regulatory T cells are depleted in WT rats during KRV-infection, no such decrease is observed in KRV-infected IFNAR1-deficient rats. A comprehensive bulk RNA-seq analysis reveals a decrease of interferon-stimulated genes and inflammatory gene expression in IFNAR1-deficient rats relative to wild-type rats following KRV challenge. Collectively, the results from these studies provided mechanistic insights into the essential role of virus-induced, IFN-I-initiated innate immune responses in the early phase of autoimmune diabetes pathogenesis.

Cyclin D3 and CDK11 are downregulated in pancreatic islet endocrine cells during the autoimmune attack progression in autoimmune-prone NOD (Non-obese diabetic) mouse strain. D-type cyclins are crucial in order to connect mitogenic signals with the Rb/E2F pathway, which regulates transcription of factors involved in further cell cycle progression. CDK11, protein-kinase PITSLRE, exhibits two gene products: p58 and p110 (p130 in mouse) in humans. CDK11p110 regulates transcription and RNA splicing. CDK11p110 is expressed in all cell cycle phases, while CDK11p58 is only expressed during mitosis (G2/M) and is essential in apoptosis. The interaction between CDK11p58 and cyclin D3 has been reported and it represses certain nuclear receptors action. This observation may suggest that in pancreatic beta cells simultaneous downregulation of cyclin D3 and CDK11 may obey to a coordinated regulation of both molecules. In this thesis we have studied whether there is a causal relationship between coordinated cyclin D3 and CDK11 downregulation and type 1 diabetes in vivo and in vitro.The outcome of our research will allow us to establish whether cyclin D3 and CDK11 are molecular targets in type1 diabetes
La ciclina D3 i CDK11 estan regulades a la baixa en les cèl•lules endocrines de l'illot pancreàtic durant la progressió atac autoimmune en la soca de ratolins NOD propensos a la diabetis autoimmune. Les ciclines de tipus D són crucials per connectar senyals mitogèniques amb la via Rb/E2F , que regula la transcripció de factors implicats en la progressió del cicle cel • lular . El gen que codifica per a la CDK11 , proteïna-quinasa PITSLRE, té dos productes gènics en humans: p58 i p110 ( p130 al ratolí ). LaCDK11p110 regula la transcripció i processament del 'ARN. La CDK11p110 s'expressa en totes les fases del cicle cel•lular , mentre que la CDK11p58 només s'expressa durant la mitosi (G2 / M) i participa en processos apoptòtics . La interacció entre CDK11p58 i ciclina D3 reprimeix certa acció d'alguns receptors nuclears, per exemple afecta negativament l'activitat transcripcional del receptor d'andrògens . Aquesta observació pot suggerir que en les cèl•lules beta del pàncrees la regulació a la baixa simultània de ciclina D3 i CDK11 pot obeir a una regulació coordinada de les dues molècules . En aquesta tesi s'ha estudiat si hi ha una relació causal entre la regulació a la baixa coordinada de ciclina D3 i CDK11 i l'aparició de la diabetis tipus 1 , in vivo i in vitro .El resultat de la nostra recerca ens permetrà establir si la ciclina D3 i la CDK11 podran ser blancs moleculars en la diabetis tipus 1.
Ciclina D3 y CDK11 están regulados a la baja en las células endocrinas del islote pancreático durante la progresión ataque autoinmune en la cepa de ratones NOD predispuesta genéticamente a la autoinmunidad. Los ciclinas de tipo D son cruciales para conectar las señales mitogénicas con la vía Rb/E2F, la cual regula la transcripción de factores implicados en la progresión del ciclo celular. El gen que codifica para la CDK11, la proteína-quinasa PITSLRE, tiene dos productos génicos en humanos: p58 y p110 ( p130 en el ratón). CDK11p110 regula la transcripción y procesameinto del ARN. CDK11p110 se expresa en todas las fases del ciclo celular, mientras que CDK11p58 sólo se expresa durante la mitosis (G2 / M) y está implicada en procesos apoptóticos. La interacción entre CDK11p58 y ciclina D3 reprime cierta acción de algunos receptores nucleare, por ejemplo, afecta negativamente a la actividad transcripcional del receptor de andrógenos. Esta observación puede sugerir que en las células beta del páncreas la regulación a la baja simultánea de ciclina D3 y CDK11 puede obedecer a una regulación coordinada de ambas moléculas. En esta tesis se ha estudiado in vivo e in vitro si existe una relación causal entre la regulación a la baja coordinada de ciclina D3 y CDK11 y la aparición de la diabetes tipo 1.El resultado de nuestra investigación nos permitirá establecer ciclina D3 y CDK11 como blancos moleculares en la diabetes tipo 1.

Background: Intestinal inflammation elicited by environmental determinants including dietary proteins and microbes is implicated in type 1 diabetes (T1D) pathogenesis. Also, intrinsic pancreatic abnormalities could precede classic insulitis, contributing to T1D. Materials and Methods: Spontaneous rat T1D models were used for in situ analyses of gut and pancreas to explore novel disease pathways using immunohistochemistry and detailed morphometry, gene expression studies, and molecular screening analyses. Results: In BBdp rats, feeding a cereal diet stimulated T1D under germ-free or specific pathogen-free (SPF) conditions compared with a protective hydrolyzed casein (HC) diet. Cereal-induced T1D was paralleled by increased gut T cell infiltration and TH1-associated pro-inflammatory transcription. HC-fed rats displayed an increased number of anti-inflammatory CD163+ M2 macrophages compared with cereal-fed rats. Cereal-associated promotion of T1D in Lewis diabetes-prone (LEW-DP) rats, a different rat model, similarly featured gut T cell infiltration in conjunction with decreased immunoregulation. The Camp gene was induced in diet-protected HC-fed BBdp rats. Camp encodes the cathelicidin antimicrobial peptide (CAMP), a pleiotropic immunomodulatory host defence factor. Intestinal CAMP was enriched in CD163+ M2 macrophages and could represent a novel marker of these tolerogenic innate immune cells. CAMP expression was also discovered in pancreatic lymph nodes (PLN) and islets, indicating a novel role for this factor in target tissue homeostasis. There was a positive correlation between pancreatic CAMP and total islet number. Also, islet-associated CAMP+ cells were increased in rats with islet inflammation, suggesting upregulation in parallel with insulitis. Exogenous CAMP/LL-37 injections increased the abundance of T1D-protective probiotic bacteria and promoted islet neogenesis in BBdp rats. A prospective partial pancreatectomy (PPx) study was performed to obtain pre-diabetic pancreas biopsies from iii pre-insulitic BBdp rats. The number of endothelium-associated CD68+ macrophages was increased in pre-diabetic pancreata, indicating that perivascular inflammation was an early lesion in the animals. In addition, pre-diabetic pancreata featured enhanced regenerative Reg3a and Reg3b gene expression, indicating abnormal islet expansion preceding insulitis. Conclusions: Small intestinal inflammation paired with deficits in local immunoregulation parallels T1D development. CAMP represents a novel factor in T1D that could have several pleiotropic functions including regulation of commensal microbes, intestinal homeostasis, and pancreatic homeostasis. In addition, target tissue abnormalities precede insulitis and T1D. This research focused on the integrative biology of T1D pathogenesis in spontaneous rat models. This work provides a novel working model that incorporates key roles for gut lumen antigens, intestinal immunity, and the role of islets and altered regenerative capacity in T1D. This research could lead to new therapeutic opportunities for T1D treatment.

La diabetis tipus 1 (DM1) és una malaltia autoimmune causada per la destrucció de cèl·lules productores d'insulina β en els illots pancreàtics, aquesta destrucció és mediada per limfòcits. En aquesta tesi es pretén donar a conèixer les dianes moleculars de les cèl·lules β responsables de la mort de les cèl·lules β causada per l'atac limfocític. Es van realitzar assajos de microarrays per tal d’identificar els gens expressats diferencialment en les cèl·lules endocrines d’illots, com a conseqüència de la infiltració insulítica, mitjançant la comparació de cèl·lules endocrines d’ illots provinents de ratolins NOD (Non Obese Diabetic)- model de ratolí predisposat genèticament a la diabetis autoimmune-, amb les provinents del seu homòleg lliure de limfòcits, NOD / SCID. Curiosament, vam descobrir que la ciclina D3 (CcnD3) es regula a la baixa a conseqüència de la inflamació d'una manera dosi-dependent, mentre que l'activitat proliferativa de les cèl·lules β no es veu alterada per aquesta disminució en l’expressió de ciclina D3. A més, les cèl·lules NIT-1 que sobreexpressen Ciclina D3 resten protegides de l'apoptosi espontània i de l'apoptosi induïda per un entorn proinflamatori proporcionat per IL-β. Per demostrar la relació de causalitat entre la repressió de CcnD3 repressió i la mort de les cèl·lules β in vivo, hem estudiat l’aparició de diabetis espontània en ratolins NOD deficients en CcnD3 (NODCcnD3KO). Els ratolins NODCcnD3KO desenvolupen diabetis exacerbada en comparació amb companys de llodrigada de tipus salvatge (WT) (88% enfront de 61% respectivament), i aquest fet deu únicament a la deficiència de CcnD3 a les cèl·lules β i no a un augment de diabetogenicitat del repertori limfocític dels ratolins NODCcnD3KO. No obstant això, l'exacerbació de la diabetis requereix de la complicitat de tots dos, la deficiència CcnD3 i la inflamació, ja que els ratolins NOD/SCIDCcnD3KO, els quals no tenen limfòcits, no desenvolupen diabetis espontània. CcnD3 té també un paper essencial en la fisiologia les de cèl·lules β del pàncrees, ja que illots pancreàtics deficients en CcnD3 no experimenten canvis adients en les concentracions intracel·lulars de Ca2+ en resposta a concentracions canviants de glucosa en el medi, el qual denota una sensibilitat deficient a la glucosa en aquests illots. Aquest deteriorament d'acoblament concentració de glucosa en el medi extracel·lular i l’augment a la concentració intracel·lular de Ca2+ no és a causa dels canvis en els nivells d’expressió del transportador de glucosa GLUT-2 entre illots NODCcnD3 KO i NODWT. D'altra banda, hem desenvolupat ratolins transgènics que sobreexpressen ciclina D3 en cèl·lules β pancreàtiques (NOD/RIPCcnD3). Aquests ratolins mostren protecció contra la diabetis autoimmune i rescaten ratolins NOD CcnD3KO de desenvolupar diabetis exacerbada.
Type 1 Diabetes (T1D) is an autoimmune condition caused by the lymphocytemediated destruction of insulin-producing β cells in pancreatic islets. This thesis aims to unveil the final targets in the β cells responsible for the β cell loss caused by the lymphocytic attack. Microarray studies were performed to assess differentially expressed genes in islet endocrine cells as a consequence of insulitic infiltration by comparing the autoimmune-prone Non-Obese Diabetic (NOD) mouse model with its congenic, lymphocyte-free, NOD/SCID strain. Interestingly, we discovered that cyclin D3 (CcnD3) underwent downregulation in beta cells upon inflammatory insult in a dose-dependent manner, while the proliferative activity of beta cells downregulating CcnD3 was not altered. Moreover, NIT-1 cells stably overexpressing CcnD3 were protected from spontaneous apoptosis and from apoptosis induced by a proinflammatory environment provided by IL-1β. To demonstrate the causal link between CcnD3 repression and β cell death in vivo, we studied spontaneous diabetes onset in CcnD3 deficient NOD mice (NODCcnD3KO). NODCcnD3KO mice developed exacerbated diabetes compared to the wild type (WT) littermates (88% versus 61% respectively), and this fact was solely due to the CcnD3 deficiency in the β cells and not to an increased diabetogenicity of the NODCcnD3KO lymphocytic repertoire. However, diabetes exacerbation required the complicity of both CcnD3 deficiency and inflammation, since plain NOD/SCID CcnD3KO mice did not develop spontaneous diabetes. CcnD3 also plays an essential role in pancreatic β-cell fitness, since pancreatic islets deficient in CcnD3 do not experience proper intracellular Ca2+ influx changes in response to different concentrations of glucose. This impairment, coupling glucose concentration in the extracellular milieu and intracellular increase in Ca2+ concentration, is not due to changes in Glut-2 expression levels between the CcnD3 KO and WT islets. Moreover, we developed transgenic mice overexpressing cyclin D3 in pancreatic β cells (NOD/RIPCcnD3). These mice exhibit protection from autoimmune diabetes and NOD CcnD3KO mice are prevented from developing exacerbated diabetes.
La diabetes tipo 1 (T1D) es una enfermedad autoinmune causada por la destrucción de las células β productoras de insulina en los islotes pancreáticos por parte de los linfocitos. En esta tesis pretendemos dar a conocer dianas moleculares de las células β responsables de pérdida de la célula β causadas por el ataque linfocitico. Desarrollamos un estudio de microarreglos en el cual encontramos genes expresados diferencialmente en células endócrinas del islote como consecuencia de la infiltración insulítica mediante la comparación de un modelo de ratón autoinmune susceptible No Obeso Diabético (NOD) con una cepa congénica libre de linfocitos NOD/SCID. Interesantemente, descubrimos que, la ciclina D3 (CcnD3) experimentó una disminución como consecuencia de un asalto inflamatorio de forma dosis dependiente, mientras que la actividad de proliferación de las células β no fue alterada. Además, células NIT-1 que sobreexpresan CcnD3 fueron protegidas de apoptosis espontánea y apoptosis inducida por un entorno proinflamatorio proporcionado por la IL-1β. Para demostrar la relación causal entre la represión de la CcnD3 y la muerte de las células β in vivo, hemos estudiado la aparición de la diabetes espontánea en ratones NOD deficientes en CcnD3 (NODCcnD3KO). Los ratones NODCcnD3KO desarrollan una diabetes exacerbada en comparación con sus compañeros de camada de tipo salvaje (WT) (88% contra el 61% respectivamente) y este hecho debido únicamente a la deficiencia de CcnD3 de las células β y no a un aumento de diabetogenicidad del repertorio linfocítico de los ratones NODCcnD3KO. Sin embargo, la exacerbación de la diabetes requiere la complicidad de ambos, la deficiencia de CcnD3 e inflamación, ya que los ratones NOD/SCIDCcnD3KO, los cuales carecen de linfocitos, no desarrollan diabetes espontánea. CcnD3 tiene también un papel escencial en la fisiología de las células β del páncreas, ya que los islotes deficientes de CcnD3 no experimentan cambios apropiados en las concentraciones intracelulares de Ca2+ en respuesta a diferentes concentraciones de glucosa en el medio. Este deterioro en el acoplamiento de la concentración de glucosa en el medio extracelular y aumento de la concentración intracelular de Ca2 + no es debido al cambio del nivel de expresión del transportador de GLUT-2 entre islotes NODCcnD3 KO y NODWT. Por otro lado, hemos desarrollado ratones transgénicos que sobreexpresan la ciclina D3 en células β pancreáticas (NOD/RIPCcnD3). Estos ratones muestran protección contra la diabetes autoinmune y rescatan a ratones NOD CcnD3KO de desarrollar diabetes exacerbada.

The chapter on the pancreas includes some basic facts in regards to anatomy and physiology, but then goes on to focus on the diagnosis and management of pancreatitis, hereditary pancreatitis, and autoimmune pancreatitis. It covers the recent advances in genetics, nutritional management, interventional diagnostic or therapeutic procedures, and recommended treatment regimens.