51 research outputs found
Tumor Microenvironment and Myelomonocytic Cells
Tumor microenvironment represents an extremely dynamic niche shaped by the interplay of different cell types (e.g. tumor cells, stromal cells), their soluble products (e.g.cytokines, chemokines and growth factors) and varied physico-chemical conditions (e.g low oxygen concentration or hypoxia). Recent studies have identified myelomonocytic cells as key players in regulating the tumor microenvironment and hence, tumor progression in a variety of cancers. In view of these findings, the present book attemps to provide a comprehensive account of the diversity of tumor microenvironment across different cancers and how myelomonocytic cells have taken the center-stage in regulating this niche to direct cancer progression. A better understanding of the myelomonocytic cells and the mechanisms by which they regulate cancer progression will open new vistas in cancer therapeutics
Immunosuppressive Mechanisms of Regulatory B Cells
Funding Information: This work was financed by the National Agency for Research and Development ANID-Fondecyt Iniciación Grant Number 11170800. Doctoral training of AF was supported by ANID-PFCHA/National Doctoral Scholarship No 21181286. Publisher Copyright: © Copyright © 2021 Catalán, Mansilla, Ferrier, Soto, Oleinika, Aguillón and Aravena.Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.publishersversionPeer reviewe
Autoimmune Diseases
Autoimmune disease represents a group of more than 60 different chronic autoimmune diseases that affect approximately 6% of the population. Autoimmune diseases arise when ones immune system actively targets and destroys self tissue resulting in clinical disease with prime examples such as Lupus and Type 1 diabetes. The immune system is designed to protect us from foreign pathogens such as viruses and bacteria. However, during the process of generating immune cells for this purpose, as a negative consequence, self-reactive immune cells are also generated. This book aims to present the latest knowledge and insights regarding the different contributing factors and their interplay, discussions on several autoimmune diseases and their case studies, and therapeutic treatments, including stem cell, for autoimmune diseases
Type 3 cytokine responses during Non-Alcoholic Fatty Liver Disease (NAFLD)
Au cours des deux dernières décennies, la stéatose hépatique non alcoolique (NAFLD) a été une maladie épidémique croissante, non seulement dans les pays occidentaux mais également dans le monde entier en raison de l’augmentation continue des modes de vie sédentaires, de l’obésité, et de la résistance à l’insuline. La prévalence mondiale de la NALFD est actuellement estimée à 25% dans la population générale adulte. NALFD est composé d’un éventail d’affections hépatiques s’étendant du foie gras non-alcoolique (NAFL), stéatohépatite non-alcoolique (NASH), fibrose avancée et cirrhose qui peut progresser au carcinome hépatocellulaire (HCC). L’inflammation induite par NASH peut moduler l’activation des cellules stellaires hépatiques (CSH) et donc influencer la progression de la fibrose hépatique. Le rôle de l’inflammation de type 3, qui est caractérisée par la production des cytokines IL-17A et IL-22, dans la fibrose de type NAFLD demeure incompris.
Dans cette thèse, nous avons évalué le rôle d’IL-22 et d’IL-17A dans la fibrose liée à la NAFLD. Des biopsies cliniques de foie NAFLD humain et un modèle murin in vivo de NAFLD ont été utilisés et des expériences in vitro ont été effectuées. Nous avons démontré que l’expression hépatique d’IL-22 est plus élevée chez les femmes et chez les femelles avec NAFLD versus les hommes et les mâles. Nous avons identifié les neutrophiles et les cellules T, y compris les cellules T Th17, Th22 et γδ, en tant que principaux producteurs d’IL-22 chez les sujets féminins et les souris atteintes de NAFLD. De plus, nous avons démontré que l’absence de la signalisation endogène du récepteur IL-22 (modèle IL-22RA1 knockout) chez les souris femelles avec NAFLD, aggravait les lésions hépatiques, l’inflammation et la fibrose, comparé aux mâles. Cet effet hépatoprotecteur dépend des mécanismes anti-apoptotiques médiés par la signalisation du récepteur IL-22 qui favorisent la survie des hépatocytes et réduisent au minimum les dommages au foie. Nous avons également montré que l’expression hépatique d’IL-22BP est régulé à la hausse chez les souris femelles avec NAFLD comparé aux mâles. Dans ces femelles, le ratio d’ARN messager hépatique de l’IL-22 envers celui de l’IL-22BP est corrélé positivement avec les gènes en aval de cible d’IL-22 (gènes anti-apoptotiques et antioxydants). Par ailleurs, nous avons prouvé que les neutrophiles intrahépatiques produisent l’IL-17A in situ dans notre modèle NAFLD et ceci correspondait fortement avec la progression de la fibrose de foie et les dommages hépatiques. Nous avons fourni des preuves préliminaires que l’IL-17A peut induire des pièges extracellulaires de neutrophiles (NET) in vitro, et la signature de NETs est impliquée dans la progression de la fibrose hépatique dans notre NAFLD.
Pris ensemble, Ces résultats démontrent qu’identifié un nouveau rôle de l’inflammation de type 3 dans la fibrose liée au NAFLD, où l’action de l’IL-22 est dépendante du sexe et possède des
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fonctions hépatoprotectrices contre la fibrose du foie chez les femelles, alors que l’IL-17A agit en tant que cytokine profibrogénique et favorise la fibrose de foie.Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic, not only in western countries but
also worldwide due to the continuous rise in sedentary lifestyles, obesity, and insulin resistance
over the last two decades. The global prevalence of NALFD is currently estimated to be 25% in
the general adult population. NAFLD is comprised of a spectrum of liver disease ranging from
non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), advanced fibrosis, and
finally cirrhosis that can progress to hepatocellular carcinoma (HCC). NASH-induced
inflammation can modulate hepatic stellate cells (HSCs) activation and hence influence hepatic
fibrosis progression. The role of type 3 inflammation, which is characterized by the production of
the cytokines IL-17A and IL-22, in NAFLD-related fibrosis remain not clear.
In this thesis, we evaluated the role of IL-22 and IL-17A in NAFLD-related fibrosis using clinical
liver biopsies from a NAFLD human cohort, an in vivo NAFLD mouse model and in vitro
experiments. We report that hepatic IL-22 expression had sexually dimorphic differences in both
humans and mice with NAFLD where it was elevated in females versus males. We identified
intrahepatic neutrophils in female subjects with NAFLD as well as T cells, including Th17, Th22,
γδ T cells, in female mice with NAFLD as major producers of IL-22. In addition, we demonstrated
that lack of endogenous IL-22 receptor signaling (IL-22RA1 knockout model), exacerbated liver
injury, inflammation, and fibrosis in female but not male mice with NAFLD. This hepatoprotective
effect was dependent on IL-22 receptor signaling-induced anti-apoptotic signals that promote
hepatocyte survival and minimize liver damage. We also demonstrated that hepatic IL-22BP
expression was upregulated in female mice with NAFLD compared to males, and the hepatic IL22/IL-22BP mRNA ratio positively correlated with IL-22 downstream target genes (anti-apoptotic
and antioxidant genes) in those females. Moreover, we showed that intrahepatic neutrophils
produce IL-17A in situ in our NAFLD model and this was strongly correlated with progression of
liver fibrosis and liver injury. We provided preliminary evidence that IL-17A can induce neutrophil
extracellular traps (NETs) in vitro, and that NETs are implicated in liver fibrosis progression in our
NAFLD model.
Taken together, we identified a novel role for type 3 inflammation in NAFLD-related fibrosis, where
IL-22 act in sex-dependent manner and provided hepatoprotective functions against liver fibrosis
in females, while IL-17A act as profibrogenic cytokine and promotes liver fibrosis through
enhancing NETs
Viral infections in 47 CVID patients in allergy and immunology department of Rasool E Akram hospital in Tehran
Background: CVID is a heterogeneous primary immune deficiency with infectious,
autoimmune and autoinflamatory features. It is most common symptomatic PID in Iran, with
prevalence of 1 in 25000 to 50000 people. CVID has been divided into some phenotypes to
produce more homogenized subpopulations. CVID is not a pure Ab deficiency .and because of
both abnormalities in Tcell and innate immunity in combination with B cell dysfunction these
patients are predisposed to viral and opportunistic infections.
Method: prevalence of viral infections is reported in 47 CVID patients registered in Rasool
E Akram hospital in Tehran. Patients have been diagnosed as CVID with the PAGID-ESID
diagnostic criteria in our department or referred from other clinics for follow up and treatment.
Diagnosis of viral germs has been made by clinical signs, pathological significances and in
some cases by PCR.
Cases: 9 patients (19%) had problems with viral infections. Infections occurred befor diagnosis
of CVID in some cases or after that. Four patients (8.5 %) had problems with wart. Sever
mucocutaneus HSV infection has occurred in 3 (6 %), recurrent zona in one (2 %) and CMV
infection as colitis or pneumonitis in 3(6 %) patients. Sever progressive lethal CNS infection
with JC virus occurred in one patient.
Conclusion: evidences show that CVID is not a pure B cell defect, and we should be aware of
opportunistic and viral infections that in some cases may be fatal
Targeting STAT3 and STAT5 in Cancer
Every minute, 34 new patients are diagnosed with cancer globally. Although over the past 50 years treatments have improved and survival rates have increased dramatically for several types of cancers, many remain incurable. Several aggressive types of blood and solid cancers form when mutations occur in a critical cellular signaling pathway, the JAK-STAT pathway; (Janus Kinase-Signal Transducer and Activator of Transcription). Currently, there are no clinically available drugs that target the oncogenic STAT3/5 proteins in particular or their Gain of Function hyperactive mutant products. Here, we summarize targeting approaches on STAT3/5, as the field moves towards clinical applications as well as we illuminate on upstream or downstream JAK-STAT pathway interference with kinase inhibitors, heat shock protein blockers or changing nuclear import/export processes. We cover the design paradigms and medicinal chemistry approaches to illuminate progress and challenges in understanding the pleiotropic role of STAT3 and STAT5 in oncogenesis, the microenvironment, the immune system in particular, all culminating in a complex interplay towards cancer progression
Local microRNAs in peritoneal dialysis-related peritonitis
Infection remains a major cause of morbidity, mortality and technique failure in PD patients. Identification of peritonitis episodes and the causative organism is slow and
unreliable. The immune system has evolved to be specific for different pathogens, suggesting a pathogen specific “immune fingerprint” may be able to distinguish distinct pathogens to guide more accurate treatment decisions. microRNAs are post-transcriptional
regulators of most human genes and have roles in the majority of biological processes and pathways. They are stable, accurate and specific biomarkers in biological fluids. My work aimed to combine the immune fingerprint model with specific microRNAs in PD effluent to identify peritonitis episodes and ascertain the role of extracellular microRNAs in the acute immune response.
Approach
The microRNA profile of PD effluent was analysed in peritonitis patients with different infectious organisms to identify candidate biomarkers. The cellular source of these
microRNAs was identified, and the functional release of one microRNA (miR-223) into the extracellular space was analysed for functional stabilisation in extracellular vesicles.
Results
microRNA profiles are altered in infected compared to uninfected PD effluent, which may have diagnostic value in acute peritonitis. Four microRNAs were identified as candidate biomarkers (miR-223, miR-27a, miR-21 and miR-31), with distinct cell-specific expression patterns. Potential mRNA targets of these microRNAs were identified. miR-223 was found to be functionally stabilised in PD effluent from peritonitis patients, with a proportion likely to be incorporated into neutrophil-derived exosomes.
Conclusions
My studies prove that microRNAs are useful biomarkers of infection in PD-related peritonitis and have the potential to contribute to a pathogen-specific immune fingerprint.
Exosome-encapsulated microRNAs may have a functional role in intercellular signalling between immune cells responding to the infection and the local tissue, to help clear the
infection and resolve the inflammation
Hematology
Hematology encompasses the physiology and pathology of blood and of the blood-forming organs. In common with other areas of medicine, the pace of change in hematology has been breathtaking over recent years. There are now many treatment options available to the modern hematologist and, happily, a greatly improved outlook for the vast majority of patients with blood disorders and malignancies. Improvements in the clinic reflect, and in many respects are driven by, advances in our scientific understanding of hematological processes under both normal and disease conditions. Hematology - Science and Practice consists of a selection of essays which aim to inform both specialist and non-specialist readers about some of the latest advances in hematology, in both laboratory and clinic
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