8^th Molecular Immunology & Immunogenetics Congress March 20-21, 2017 Rome, Italy

Biography:

Martina Sterclova has been working since 2004 as a Medical Doctor in the Department of Respiratory Diseases, Thomayer Hospital, Prague. In 2009, she finished her PhD studies in Immunology and Molecular Biology. Her area of interest concerns interstitial lung diseases, namely role of cytokines and chemokines in disease pathogenesis. In 2013, she gained ERS Fellowship and studied bronchoalveolar lavage cell cultures at Comprehensive Pneumology Center, Munich, Germany. She regularly publishes and actively participates in various international conferences on interstitial lung diseases.

Abstract:

Statement of the Problem: In patients with connective tissue diseases (CTDs) lung involvement may a play important prognostic role. Possible radiologic pattern of lung involvement includes usual interstitial pneumonia, typical also for idiopathic pulmonary fibrosis (IPF). We hypothesize that despite the same radiologic pattern the pathogenetic pathways in IPF and CTD may differ.

Methodology & Theoretical Orientation: Sixteen naive CTD patients with lung involvement according to high resolution tomography of the chest and 17 IPF patients were included and underwent serum Ig concentration assessment, flow cytometry of peripheral blood and bronchoscopy with bronchoalveolar lavage (BAL). BAL fluid (BALF) differential cell counts and measurement of IL-4R and BAFF in BALF supernatant were performed.

Findings: CTD patients exhibited higher BALF lymphocyte counts (p˂0.05) and lower IL-4R concentrations (p˂0.05). BAFF concentrations did not significantly differ between groups. Peripheral blood lymphocyte and CD19 counts were higher in IPF patients (p˂0.05). Autoantibodies were positive in all CTD and in 8 IPF patients. BAFF concentrations positively correlated with IgM serum concentrations (both in CTD and IPF patients, (p˂0.05)). Positive correlations among IL-4R concentrations, serum IgG, IgA and IgM concentrations and CD19 peripheral blood counts (p˂0.05) were observed in both groups. Correlations between BAFF and IL-4R BALF concentrations were positive in CTD (p˂0.01) and negative in IPF patients (p˂0.05).

Conclusion & Significance: Our data suggest that the immunologic and molecular markers in peripheral blood and BALF may differ in IPF and CTD patients. We hypothesize that anti-apoptotic effect of IL-4 on B cells may be clinically relevant in IPF patients, while different regulatory pathway may play role in CTD.

References:

1. Vasakova M, Sterclova M, Matej R, Olejar T, Kolesar L, Skibova J, Striz I (2013) IL-4 polymorphisms, HRCT score and lung tissue markers in idiopathic pulmonary fibrosis. Hum. Immunol. 74: 1346-51.

Biography:

Adnane Achour has experience in both Structural Biology and Immunology. The research group uses X-ray crystallography and small angle X-ray scattering (SAXS) to study receptor-ligand interactions between T or NK cell receptors and Major Histocompatibility Complex (MHC) molecules, as well as bacterial adhesins and virulence-associated molecules. All the studies are complemented by a wide array of immunological assays as well as an extensive amount of biochemical techniques, including surface plasmon resonance and circular dichroism. By understanding the structural details of proteins, we can probe their function and potentially design artificial ligands that could modulate their function and activity.

Abstract:

MHC-I down-regulation represents a significant challenge for T cell-based immunotherapy. T cell epitopes associated with impaired peptide processing (TEIPP) constitute a novel category of immunogenic neo-antigens that are selectively presented on TAP-deficient cells. TEIPP neo-epitopes are CD8 T cell targets, derived from non-mutated self-proteins. We recently evaluated thymus selection and peripheral behavior of TEIPP-specific T cells and demonstrated that TEIPP-specific T cells in TAP-deficient mice are deleted by central tolerance, while the same T cells in WT mice are naive and sustain. Thus the results of this study suggest that TEIPPs have potential to be successful targets for eliminating MHC-low tumors and reduce cancer immune escape. The crystal structure of H-2D^b in complex with the first identified TEIPP antigen Trh4 (MCLRMTAVM) demonstrated that, in contrast to prototypic H-2D^b peptides, Trh4 takes a non-canonical binding pattern with extensive sulfur-p interactions. Importantly, the non-canonical methionine at peptide position 5 acts as a main anchor, altering the conformation of H-2D^b residues and thereby forming a unique MHC/peptide conformer that is essential for recognition by TEIPP-specific T cells. We have previously demonstrated that modification of peptide position 3 to a proline in H-2D^b-binding peptides increases significantly the overall stability of MHC-I/peptide complexes and the immunogenicity of endogenous T cells towards cancer-associated epitopes. The results demonstrate that vaccination with Trh4-p3P induced significant CTL responses towards Trh4⁺-cancer target cells. Importantly, our results stand in strong contrast to the current dogma that stipulates that higher immunogenicity is directly linked to higher MHC/peptide complex stability. Indeed, although much more immunogenic, the H-2D^b/Trh4-p3P complex is clearly less stable than H-2D^b/Thr4. Instead, rigidification of Trh4 and the α2 helix in H-2D^b is directly responsible for enhanced TCR recognition. Our results reveal the importance of the rigidification of the MHC/peptide complex for enhanced T cell recognition. 

Left. Vaccination with Trh4-p3P induces significantly enhanced recognition of cancer target cells displaying the wild-type peptide. Right. Superposition of the crystal structures of H-2Db/Trh4 and H-2Db/Trh4-p3P demonstrates high conformational similarities.

References:

1. Van Stipdonk et al (2009) Design of agonistic altered peptides for the robust induction of CTL directed towards H-2Db in complex with the melanoma-associated epitope gp100. Cancer Research, 69, 7784-7792.

2. Uchtenhagen et al (2013) Proline substitution independently enhances H-2Db complex stabilization and TCR recognition of melanoma-associated peptides. European Journal of Immunology, 43(11):3051-3060.

3. Doorduijn et al (2016) Absence of central tolerance enables therapeutic exploitation of a CD8 T cell subset targeting hidden self-antigens. Journal of Clinical Investigation, 126(2): 784-794.

4. Hafstrand et al (2016) The MHC class I cancer-associated neo-epitope Trh4 linked with impaired peptide processing reveals a unique non-canonical TCR conformer. Journal of Immunology, 196(5):2327-34.

5. Kiessling (2016) TAP-ing into TEIPPs for cancer immunotherapy. Journal of Clinical Investigation, 126(2):480-2.

Biography:

Eugenio Luigi Iorio is a Medical Doctor, has done his Doctorate in Biochemical Sciences (PhD), Post-graduated in Clinical Chemistry and specialization in Biochemistry. He is the President of International Observatory of Oxidative Stress (Italy, Greece, Japan). According to his research, the identification and the control of oxidative stress, an emerging health risk factor related to the dysregulation of redox systems, may play a relevant role in the prevention and treatment of life-style related disorders. 

Abstract:

Most of biological processes are related to the so-called redox reactions, where one or more electrons alone or bound to a proton as hydrogen atom are transferred from a chemical species, i.e. the reducing species, to another chemical species, i.e. the oxidizing species. The transfer of a couple of electrons is related to energy metabolism being: the oxidation linked to the catabolism and to ATP production, and the reduction bound to the anabolism and to ATP expenditure. The transfer of an electron alone is related to the metabolism of the so-called reactive species that are involved in the pathophysiology of stress i.e. the global response of a living organism to internal/environmental demands or pressures (stressors). At molecular level stress response implies also the production of reactive species which main role is to mediate the cell response to endogenous and/or exogenous physical, chemical and biological stressors through a fine-tuning of cell signaling/transduction and inflammatory/immune/toxic responses (Figure 1). Therefore, any disturbance in one-electron transfer reactions can lead to the improper oxidation of target molecules (including lipids, proteins and nuclei acids) and hence to the “oxidative di-stress” or “oxidative stress” as such, an emerging health risk factor that is related to early aging and at least one hundred different diseases, including immune diseases. Oxidative stress does not show any specific clinical picture but can be diagnosed in clinical routine only by means of specific laboratory tests according to the novel approach of Redoxomics. 

Figure 1. Oxidative stress response in the innate immune system. 

References:

1. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. 2nd Edn, Clarendon Press, Oxford. 1989.

2. Rahal A, Kumar A, Singh V, Yadav B, Tiwari R, et Al. Oxidative stress, prooxidants, and antioxidants. The interplay. BioMed Res Internat. 2014. Article ID 761264, 19 pages.

3. Nishida M, Kumagai Y, Ihara H, Fujii S, Motohashi H, et Al. Redox signaling regulated by electrophiles and reactive sulfur species. J Clin Biochem Nutr. 2016. 58(2): 91–98.

4. Colucci R, Dragoni F, Moretti S. Oxidative stress and immune system in vitiligo and thyroid diseases. Oxidat Med Cell Longev. 2015. ID 631927.

5. Iorio EL, Marin MG. Redoxomics. An integrated and practical approach to genomics, metabolomics and lipidomics to manage oxidative stress. 2008. Gen-T. 2: 67.

Biography:

Alessandra Pontillo has a PhD in Experimental and Clinical Pathology (University of Trieste; 2003), and Master’s degree in Genetic Medicine (University of Trieste; 2008). Since 2013, she is an Assistant Professor at the University of Sao Paulo/USP (Sao Paulo, Brazil). She is the PI of the Laboratory of Immunogenetics in the Department of Immunology. She has expertise in innate immunity and inflammation, inflammasome, auto-inflammatory diseases, immunogenetics and population genetics. Her research projects focuses on human genetics of innate immunity and inflammation with particular interest in inflammasome complex.

Abstract:

Inflammasomes are cytoplasmic complexes capable of triggering the inflammatory cascade through the activation of caspase-1, and the consequent production of inflammatory cytokines IL-1ß and IL-18. Different inflammasome receptors (NLRP-1, NLRP-3, NLRC-4, AIM-2, IFI-16 and pyrin) are activated by distinct pathogens and/or damage molecular patterns, contributing to innate immune response in a stimulus- and cell/tissue-dependent way. Mouse genetic models have revealed the mechanistic details of inflammasome activation and its role in physiologic immune response, however little is known about the action of inflammasome in humans. Genetic studies within the human population uncover mutations and polymorphic variants in inflammasome components resulting in gain-of-function of caspase-1, and the consequent development of rare monogenic inflammatory diseases (auto-inflammatory syndromes) as well as of complex disorders which common in general population. Our group demonstrated the association of inflammasome genes in different multifactorial diseases. Candidate gene analysis have shown a significant association of inflammasome genes with a wide range of disorders, including infections (HIV-1, HPV and mycobacteria), autoimmune diseases (type-1 diabetes, SLE, celiac disease and multiple sclerosis), neurodegenerative disorders (Alzheimer and Parkinson disease), cancer (melanoma and cervical cancer) and metabolic syndromes (renal failure and obesity), revealing the contribution of one or another inflammasome in the pathogenesis of specific diseases. Deeper investigations are still going on to further depict the involvement of inflammasome dysregulation in the pathogenesis of such diseases.

Figure 1: Schematic representation of inflammasome complex with its several intracellular innate immune receptors and gene-specific SNPs.

References:

1. Da Silva W C, Oshiro T M, de Sá D C, Franco D D, Festa Neto C, Pontillo A (2016) Genotyping and differential expression analysis of inflammasome genes in sporadic malignant melanoma reveal novel contribution of CARD8, IL1B and IL18 in melanoma susceptibility and progression. Cancer Genet. 209(10): 474-480.

2. Souza de Lima D, Ogusku M M, Sadahiro A, Pontillo A (2016) Inflammasome genetics contributes to the development and control of active pulmonary tuberculosis. Infect Genet. Evol. 41: 240-4.

3. Pontillo A, Crovella S (2016) NOD-like receptors: a tail from plants to mammals through invertebrates. Curr. Protein Pept. Sci. 2016 Mar 17.

4. Santos M L, Reis E C, Bricher P N, Sousa T N, Brito C F, Lacerda M V, Fontes C J, Carvalho L H, Pontillo A (2016) Contribution of inflammasome genetics in Plasmodium vivax malaria. Infect Genet Evol. 40: 162-6.

5. Pontillo A, Bricher P, Leal V N, Lima S, Souza P R, Crovella S (2016) Role of inflammasome genetics in susceptibility to HPV infection and cervical cancer development. J. Med. Virol. 88(9): 1646-51.

Biography:

Ebtekar Masoumeh has been working as a Faculty Member at Tarbiat Modares University in Tehran. Currently, she is an Associate Professor of Immunology, and has supervised many PhD and MSc students. She has expertise in cytokines, viral immunology, HIV vaccines, aging, immunology of the nervous system and psychoneuroimmunology.

Abstract:

Statement of the Problem: During the last 15 years since the discovery of type III human interferons (IFN-λ1, IFN-λ2 and IFN-λ3), numerous biological activity of these new interferon family has been introduced by researchers. Furthermore, several studies have showed that the encapsulation of plasmid DNA with nanoparticle result to protection of plasmid DNA against DNase enzyme and increasing gene delivery to the cells. So we decided to encapsulate plasmid DNA encoding IFN-λ1 with PLGA in order to compare encapsulated and naked form of plasmid DNA encoding IFN-λ1 in the future researches.

Methodology & Theoretical Orientation: At first, the expression and bioactivity of pIFN-λ1 was investigated in vitro by sandwich ELISA and CPER assay, respectively. Then, pIFN-λ1 was encapsulated in PLGA nanoparticles using double emulsion-solvent evaporation method and characterized in terms of size, zeta potential and polydispersity index (DLS), morphology (SEM) and encapsulation efficiency and release kinetics. Uptake of nanoparticles by RAW264.7 macrophages was also studied by fluorescent microscope.

Findings: IFN-λ1 expressed in HEK293T was confirmed by sandwich ELISA and IFN-α2b was able to protect HEP2 cells against VSV infection. Developed nanoparticles were spherical in shape with a mean diameter of 381 nm (PdI: 0.279), encapsulation efficiency was 75±5% and a zeta potential of -3.35±7.75 mV was observed. Release assay in vitro showed that the plasmid DNA could be sustainably released from nanoparticles. Not only the successful expression of plasmid DNA encoding GFP revealed that nanoparticle could be engulfed by macrophages, but it also represented that the integrity of plasmid has been intact during encapsulation process.

Conclusion & Significance: Given the results in order to figure out the other new functions of this molecule or re-evaluation of previous investigations, using prepared and characterized nanoparticles instead of naked plasmids seems to be practically feasible.

References:

1. Rahimi, R, Ebtekar, M, Moazzeni, S.M, Mostafaie, A, Mahdavi, M (2015) Optimization of multi-epitopic HIV-1 recombinant protein expression in prokaryote system and conjugation to mouse DEC-205 monoclonal antibody: Implication for in-vivo targeted delivery of dendritic cells. Iranian Journal of Basic Medical Sciences, 18:145-152.

2. Hartoonian, C, Sepehrizadeh, Z, Tabatabai Yazdi, M, Jang, Y.S, Langroudi, L, Amir Kalvanagh, P, Negahdari, B, Karami, A, Ebtekar, M, Azadmanesh, K (2014) Enhancement of immune responses by co-delivery of CCL19/MIP-3beta chemokine plasmid with HCV core DNA/protein immunization. Hepatitis Monthly 14.

3. Hartoonian, C, Sepehrizadeh, Z, Mahdavi, M, Arashkia, A, Jang, Y.S, Ebtekar, M, Yazdi, M.T, Negahdari, B, Nikoo, A, Azadmanesh, K(2014) Modulation of hepatitis C virus core DNA vaccine immune responses by co-immunization with CC-chemokine ligand 20 (CCL20) gene as immunoadjuvant. Molecular Biology Reports 41: 5943-5952.

4. Nikfarjam, B.A, Ebtekar, M, Sabouni, F, Pourpak, Z, Kheirandish, M(2014) Detection of interleukin-19 mRNA in C57BL/6 mice astroglial cells and brain cortex. Basic and Clinical Neuroscience 5: 88-95.

5. Yousefi, F, Ebtekar, M, Soleimani, M, Soudi, S, Hashemi, S.M(2013)Comparison of in vivo immunomodulatory effects of intravenous and intraperitoneal administration of adipose-tissue mesenchymal stem cells in experimental autoimmune encephalomyelitis (EAE). International Immunopharmacology17: 608-616.

Biography:

Ishrat Jahan Saifi is pursuing her research under the supervision of Dr. Sheelu Shafiq Siddiqi, Associate Professor and Director at Rajiv Gandhi Centre for Diabetes and Endocrinology, J N Medical College and Hospital, Aligarh Muslim University, Aligarh, India. She has completed her Post-graduation in Biochemistry from Integral University Lucknow, India. She has presented 3 research papers, and has participated in various seminars/conferences held in India and has won second prize in poster presentation in a seminar. 

Abstract:

Existing literature and research on diabetes mellitus describe that glycation of protein is very important as well as a harmful process, which may lead to development of DM in human body. Human serum albumin (HSA) is the most abundant protein in blood and it is highly prone to glycation by the reducing sugars. 2-­deoxy d-­Ribose (dRib) is a highly reactive reducing sugar which is produced in cells as a product of the enzyme thymidine phosphorylase. It is generated during the degradation of DNA in human body. It may cause glycation in HSA rapidly and it is involved in the development of DM. In present study, HSA was glycated with different concentrations of 2-­deoxy d-­ribose at 37ºC for 4 hours. UV­ spectroscopy, fluorescence spectroscopy and circular dichroism (CD) techniques have been done to determine the structural changes in HSA upon glycation. To check the immunogenicity of modified HSA, rabbits were immunized with native and dRib modified HSA individually. Modified HSA immune sera, show higher antibody titer as compare to pre-immune sera and also with the immune sera from the native HSA immunized rabbits. Results of this study suggested that dRib is the potential glycating agent that can cause alteration in protein structure. With the results of immunological study we can conclude that dRib modified HSA is more immunogenic than native HSA. 

References:

1. Neelofar, K. M., Ahmad, J., Arif, Z., & Alam, K. (2016). Elucidating the impact of glucosylation on human serum albumin: A multi-technique approach. International Journal of Biological Macromolecules, 92, 881-891.

2. Cao, H., Chen, T., & Shi, Y. (2015). Glycation of human serum albumin in diabetes: impacts on the structure and function. Current medicinal chemistry, 22(1), 4-13.

3. Koh, G., Lee, D. H., & Woo, J. T. (2010). 2-Deoxy-D-ribose induces cellular damage by increasing oxidative stress and protein glycation in a pancreatic β-cell line. Metabolism, 5

4. Alam, S., Arif, Z., & Alam, K. (2015). Glycated-H2A histone is better bound by serum anti-DNA autoantibodies in SLE patients: Glycated-histones as likely trigger for SLE?. Autoimmunity, 48(1), 19-28.

5. Arif, B., Ashraf, J. M., Ahmad, J., Arif, Z., & Alam, K. (2012). Structural and immunological characterization of Amadori-rich human serum albumin: role in diabetes mellitus. Archives of biochemistry and biophysics, 522(1), 17-25.

Biography:

Km Neelofar is a PhD student in Rajiv Gandhi Center for Diabetes and Endocrinology, F/O Medicine, Jawaharlal Nehru Medical College and Hospital, Aligarh Muslim University, Aligarh. Her research work is on diabetic nephropathy including biochemical, molecular and immunological aspects related to this. Her review article on Diabetic Nephropathy has been published in reputed journal and 2 research articles have been communicated.

Abstract:

The integrity of protein is essential for its biological properties. However, it is very well documented that structure and functions of endogenous proteins are changed under pathophysiological conditions. Human serum albumin is the most abundant serum protein. In this study, an attempt has been made to biophysical characterization of Amadori-albumin upon early glucosylation because albumin undergoes fast glycation under hyperglycemic condition. Amadori-albumin formation was determined by NBT assay and Amadori adducts in glycated samples were confirmed by LC–MS. Structural alterations in Amadori-albumin were characterized by loss in secondary and tertiary structures, exposure of hydrophobic patches, shifting in Amide bands and increment in hydrodynamic radius. Our results clearly demonstrate that in vitro modification of HSA with high concentration of glucose induced secondary and tertiary structural alterations in the protein. Further, immunogenicity of glucose modified albumin was analyzed in experimental rabbits. The immunogenicity of glucose modified albumin was directly proportional chemical modification of protein. This structurally impaired albumin exhibits neo-epitopes which are not ordinarily present on the native molecule and these epitopes project the physiologic protein as ‘alien’ for the immune system. Hence, we can conclude that Amadori type modification occurs in diabetic patients under hyperglycemic condition.

Biography:

Abstract:

Biography:

Saadia Kerdine-Römer has experience in Immunotoxicology in the field of Skin Allergy. She has been working for many years in the activation of dendritic cells by allergenic molecules. She demonstrated that haptens can be real danger signals. She has worked on the identification of new signaling pathways in immunity cells in response to haptens. Currently, she is working on the transcription factor Nrf2 and its link in the inflammatory response of skin allergic origin.

Abstract:

Statement of the Problem: Allergic contact dermatitis (ACD) represents a severe health problem with increasing worldwide prevalence. It is a T cell-mediated inflammatory skin disease caused by chemicals present in daily or professional environment. Nickel sulfate (NiSO₄) and 2, 4-dinitrochlorobenzene (DNCB) are two chemicals involved in ACD. These contact sensitizers are known to induce an up-regulation of phenotypic markers and cytokine secretion in dendritic cells (DCs), professional antigen-presenting cells, leading to the generation of CD8⁺ Tc1/Tc17 and CD4⁺ Th1/Th17 effector T cells.

Findings: In the present study, using a peptide array approach, we identify protein kinase CK2 as a new kinase involved in the activation of human monocytes-derived DCs (MoDCs) in response to NiSO₄ and DNCB. Inhibition of CK2 activity in MoDCs leads to an altered mature phenotype with lower expression of CD54, PDL-1, CD86 and CD40 in response to NiSO4 or DNCB. We also show that CK2 activity regulates pro-inflammatory cytokine production such as TNF-a, IL-1b and IL-23 in MoDCs. Moreover, using a DC/T cell co-culture model in an allogeneic set-up, our work demonstrate that CK2 activity in MoDCs plays a major role in the Th1 polarization in response to NiSO₄ and DNCB. Interestingly, we also demonstrate that CK2 inhibition in MoDCs leads to an enhanced Th2 polarization in the absence of contact sensitizer stimulation.

Conclusion & Significance: CK2 plays: (1) a role in phenotypic maturation and cytokine production in response to NiSO₄ and DNCB; and (2) a major role in CD4+ T lymphocytes activation and in the control of Th1 polarization without affecting Th17 polarization.

Biography:

Yaffa Mizrachi Nebenzahl has her expertise in Microbiology and Immunology and has studied Microbial Pathogenesis (innate and adaptive immune to microbial infections). She has completed her PhD from the Weizmann Institute, Rehovot, Israel. She is Head of the Molecular Microbiology Laboratory, Department of Microbiology, Immunology and Genetics at the Faculty of Health Sciences in Ben Gurion University of the Negev, Israel.

Abstract:

Mortality due to pneumococcal infections remains high worldwide, augmented by widespread antibiotic resistance in many pneumococcal strains. To identify protein antigens that could be involved in the development of protective immunity to S. pneumoniae, a pneumococcal cell wall protein-enriched extract was screened using 2-D gel electrophoresis and immunoblotting with either sera obtained longitudinally from children attending day-care centers or sera obtained from mice immunized with the pneumococcal cell wall protein extract. The identified proteins that share no- or low- homology to human proteins and which are conserved among different S. pneumoniae strains were tested for their ability to elicit protection against S. pneumoniae challenge in animal models. Moreover the nature of the elicited immune response was studied in mice. S. pneumoniae proteins PtsA, GtS, Nox, PsipB, FBA, TF and FtsZ were amplified from TIGR4 strain, cloned, expressed in E. coli and purified. Mice were immunized three times intra-nasally or subcutaneously with these proteins in presence of adjuvant and challenged two weeks later. Nasopharyngeal and lung colonization levels were quantified for 48 hours following bacterial challenge and survival was monitored daily for seven days. The cytokine profile elicited by rFBA was determined by multiplex ELISA. All seven proteins elicited protective immune responses in mice as determined by reduced nasopharyngeal and lung colonization, prolonged survival, and the ability of antibodies obtained from immunized mice to ex-vivo neutralize bacterial virulence for the intra-peritoneal challenge model. Moreover, rFBA elicits Th1, Th2 and Th17-type cytokines in mice. Taken together several antigenic and immunogenic protein with no or low homology to human proteins were identified and found to elicit protective immune response in the mouse model accompanied by Th1, Th2 and Th17 type of immune responses.

References:

1. Muchnik L, Adawi A, Ohayon A, Dotan S, Malka I, Azriel S, Shagan M, Portnoi M, Kafka D, Nahmani H, Porgador A, Gershon J M, Morrison D A, Mitchell A, Tal M, Ellis R, Dagan R, Mizrachi Nebenzahl Y (2013)  NADH oxidase functions as an adhesin in Streptococcus pneumoniae and elicits a protective immune response in mice. PLoS ONE 8:e61128.

2. Elhaik Goldman S, Dotan D, Talias A,  Lilo A, Azriel S, Malka I, Portnoi M, Ohayon A, Kafka D, Ellis R, Elkabets M, Porgador A, Levin D, Azhar A, Swiatlo E, Ling E, Feldman G, Tal M, Dagan R, Mizrachi Nebenzahl Y (2016) Streptococcus pneumoniae fructose 1, 6-bisphosphate aldolase, a protein vaccine candidate, elicits Th1/Th2/Th17-type cytokines in mice. Int J Mol Med 37:1127-1138.

3. Mizrachi Nebenzahl Y, Blau K, Kushnir T, Shagan M, Portnoi M, Cohen A, Azriel S, Malka I, Adawi A, Kafka K, Dotan D, Guterman G, Troib S, Fishilevich T, Gershoni, J M, Braiman A, Mitchell A M, Mitchell T J, Porat N,  Goliand I, Chalifa Caspi V, Swiatlo E, Tal M, Ellis R, Elia N, Dagan R (2016). Streptococcus pneumoniae cell-wall-localized phosphoenolpyruvate protein phosphotransferase can function as an adhesin: Identification of its host target molecules and evaluation of its potential as a vaccine. PLoS ONE. 11:e0150320.

4. Elhaik Goldman S, Moshkovits I, Shemesh A, Filiba A, Tsirulsky Y, Voronov E, Shagan M, Benharroch D, Karo-Atar D, Dagan R, Munitz A, Mizrachi Nebenzahl Y (2016) Natural killer receptor 1 dampens the development of allergic eosinophilic airway inflammation. PLoS ONE. 11:e0160779. 

Biography:

Azar Tahghighi is an Assistant Professor at Pasteur Institute of Iran (PII). She received her PhD in Medicinal Chemistry and is experienced in synthesis of leishmanicidal compounds and evaluation of their biological activity against promastigote and amastigote forms of L. major. She is also experienced in QSAR studies and molecular docking of synthetic compounds with leishmanicidal effect. With emerging resistance to the first-line anti-malarial drugs, there is an urgent need for the development of new anti-malarial drugs to curb the disease. Currently, she is working in the Drug Discovery Lab of MVRG and her areas of interest are: design and synthesis of novel compounds with antimalarial activity, antimalarial drug design with molecular docking, synthesis of insecticides, isolation and identification of natural compounds and medicinal plants with antimalarial activity, and identification of plants with insecticide, larvicidal and repellent activity. 

Abstract:

Parasitic diseases are a major problem in tropical and subtropical regions of the world such as malaria and leishmaniasis. These diseases cause considerable mortality and morbidity annually. No vaccines are available to prevent infections. On the other hand, parasitic drug resistances have restricted the use of available drugs for the treatment of malaria and leishmaniasis. Actually, identification and development of new, cheap, efficient, and safe compounds as drug candidates for the prophylaxis and treatment of these diseases are imperative from pharmaceutical point of view. Therefore, a range of creative strategies are required to achieve new lead compounds. The first aim of our studies were to synthesize and assess antileishmanial activity of 5-(5-nitrohetero aryl-2-yl)-1,3,4-thiadiazoles with different substituents at the 2-position of thiadiazole ring. It was notable that the bioresponses and physicochemical properties of the molecules depended on the type of these substituents. In these studies, MLR and ANN models were used and predicted the antileishmanial activity of some thiadiazole derivatives. Also, molecular modeling and docking studies were conducted based on DNA topoisomerase as a target enzyme. The results suggested that hydrogen bonding and hydrophobic interactions of ligands with the active site of Leishmania major topoisomerase IB were responsible for their potent antileishmanial activity. The other aim of our study was to synthesize a series of 1,10-phenanthroline derivatives containing amino-alcohol and amino-ether substituents, and quinoline derivatives containing benzyl dialkyl amine and N-alkyl benzamidine substituents. Their anti-plasmodial activity was then evaluated intraperitoneally using the Peter's 4-day suppressive test against Plasmodium berghei-infected mice. Based on results, the synthetic compounds had about 90% suppression and also prolonged the mean survival time of treated mice in comparison with negative control groups.

References:

1. Parhizgar A R, Tahghighi A (2016) Introducing of new antimalarial analogues of chloroquine and amodiaquine: Narrative review. Iranaian Journal of Medical Science.

2. Tahghighi A, Dastmalchi S, Hamzeh-Mivehroud M, Asadpour-Zeynali K, Foroumadi A (2016) QSAR and docking studies on the (5-nitroheteroaryl-1,3,4-thiadiazole-2-yl) piperazinyl analogs with antileishmanial activity. Journal of Chemometrics 30: 284-293.

3. Tahghighi A (2014) Importance of metal complexes for development of potential leishmanicidal agents. Journal of Organometallic Chemistry 770: 51-60.

4. Tahghighi A, Emami , Razmi S, Marznaki M R, Ardestani S K, Dastmalchi S, Kobarfard F, Shafiee A, Foroumadi A (2013) New 5-(nitroheteroaryl)-1,3,4-thiadiazols containing acyclic amines at C-2: Synthesis and SAR study for their antileishmanial activity. Journal of Enzyme Inhibition and Medicinal Chemistry 28(4): 843-852.

5. Tahghighi A, Razmi S, Mahdavi M, Foroumadi P, Ardestani S K, Emami S, Kobarfard F, Dastmalchi S, Shafiee A, Foroumadi A (2012) Synthesis and anti-leishmanial activity of 5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol- 2-amines containing N-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl] moieties. European Journal of Medicinal Chemistry 50: 124-128.

Biography:

Kimihiko Okazaki has graduated from the Faculty of Medicine, Kyoto University in 1959. He has worked on various medicinal and chemical researches from 1960-1981 in both hospitals and educational institutions. He has been practicing Internal Medicine since 1981. Currently, He works at the Okazaki Medical Clinic, Japan (private clinic) since 1989.

Abstract:

Although it is well established that an equilibrium state exists among antibody molecules in the vicinity of their receptors on the surface of immune cells, namely, cytolytic T lymphocytes and mast cells, it has long been taken for granted that molecular substitutions of antibodies on their receptors never occur. Obviously, these two concepts disagree with each other because existence of equilibrium state itself indicates that every molecule of antibody keeps changing its status being attached to or detached from its receptor. In addition, a certain molecule of antibody does not necessarily attach to one certain receptor. In other words, every receptor of antibody keeps changing antibodies. The alternative concept, namely, molecular substitutions of antibodies on their receptors do occur all the time, is extremely useful. Reason is that the concept can be applied to complete cure of immune diseases; allergies and autoimmune diseases, and there is another reason that the pathogen specific antibodies can be replaced by harmless non-specific antibodies if the latter are accumulated in patients’ bodies. The necessary and sufficient condition for the accumulation is to repeat injecting the patient with non-specific antigens.

Biography:

Reyhaneh Abgoon has received her Master’s degree in Cellular and Molecular Biology from Azad University. Her research interests include immunology, molecular immunology, especially autoimmune diseases. She is working as a supervisor in Banej Elixir molecular research institute in Tehran. She has presented several research abstracts about alopecia areata which is an autoimmune disease at various international conferences.

Abstract:

Objective: In present study, effect of PTPN22 gene expression was investigated in Iranian AA patients and their respective controls.

Background: Alopecia areata (AA) is an autoimmune multifactorial disease characterized by hair loss especially from the scalp affecting approximately 5.3 million people. The gene encoding the protein tyrosine phosphatase, non-receptor type 22 (PTPN22), which is exclusively expressed in immune cells, has been considered as a risk factor associated with the pathogenesis of AA.

Methods: The study group consisted of 30 patients with AA (13 female and 17 male, mean age 26.3±12.5) and 15 (5 female and 10 male, mean age 30±5.88) healthy controls. RNA was extracted from blood sample. Thereafter, cDNA was synthesized after RNA isolation. PTPN22 expression levels were measured by real-time PCR. Furthermore, association of this PTPN22 with some baseline clinical and demographical features was assessed.

Results: PTPN22 expression levels of patients with AA were significantly higher (4.6±3.8) than those in controls (1.14±0.56) (p value=0.01). PTPN22 expression was only associated with the sex of the AA patients (Fig.1).

Conclusion: In the present study, a significant association was found between PTPN22 gene expression and susceptibility to alopecia areata.

Figure1: PTPN22 gene expression in patients with Alopecia Areata and controls.

Biography:

Sawsan Said is a PhD candidate in the Department of Molecular Biology and Genetics at the Istanbul Technical University, Istanbul, Turkey. She has been working on a subset of B cells, namely regulatory B cells in the Lab of Dr. Ayca Sayi Yazgan. 

Abstract:

The regulatory B and T cells have a pivotal role in balancing between immune pathogenicity and protection. Recently, it has been shown that the regulatory T cells could reduce H. pylori-induced gastritis in mice, at the same time allows the bacterium to colonize the mucosa at higher densities. Moreover, it was reported that IL-10⁺B cells were activated upon Helicobacter infection through TLR2-MyD88 activation, which leads to differentiation of T regulatory-1 (Tr-1) cells from naïve T cells. The interaction between Tr-1 and IL10⁺B cells may prevent the gastric precancerous lesions and serve as a good immune modulator against Helicobacter. Recently, RNA profile of B10 cells was investigated by RNA-seq, and differentially expressed genes in B10⁺ and B10^-B cells were identified. CD9 was identified as a key surface marker for most mouse IL-10⁺ B cells, and PD-1was differentially expressed in IL10+/IL10-B cells. In our study, we focus on understanding the expression profile of Helicobacter activated regulatory B cells by microarray analysis, Agilent SurePrint G3 Gene Expression Microarrays of mouse (v2) 8x60K models. Furthermore, gene expression profiling of IL-10 producing regulatory B cells would provide detailed information of B cell genes, including immune function of specific genes. Next, we aim to investigate the expression levels of the recently described genes that are expressed in B 10 cells; CD9, and PDCD1(PD1) in our samples, unstimulated B cells, H. felis stimulated B cells, stimulated IL-10+ B cells and IL-10- B cells. Based on our microarray and real-time PCR data, we wanted to investigate the immune functions of PD1+ regulatory B cells on T cell differentiation to regulatory Tr-1 cells. The PD1 functional study directed the PD1/PD-L 1 interaction blockade as tool to understand the role of PD-1 upregulated B cells in induction (Tr1) upon PD1-PD-L 1 interaction.

Biography:

Yuanyuan Cheng has worked on the molecular mechanism of macrophage polarization and function in myocardial infarction regulated by active lipid mediators and natural compounds.

Abstract:

Macrophages play important roles in resolution of inflammation and cardiac remodeling in acute myocardial infarction due to its phenotypic and functional plasticity. Arachidonic acid metabolites are known to regulate the dynamic changes between inflammatory and resolving macrophages. The aim of the present study was to explore the interactions between arachidonic acid metabolites and cellular proteins. We employed ω-alkynyl arachidonic acid as probe to profile the cellular proteins with the capability to form covalent adducts with arachidonic acid metabolites. Following the treatment of RAW264.7 cells with ω-alkynyl arachidonic acid, the cellular proteins were biotinylated via “click chemistry” alkyne-azido cycloaddition, isolated by streptavidin beads and identified by proteomic approach. As a result, glycolytic enzyme pyruvate kinase M2 (PKM2) was identified as a predominant ω-alkynyl arachidonic acid modified protein. We also identified 15-keto-PGF2α as the specific metabolite for covalent binding to PKM2 by HPLC/MS/MS. We further investigated the effects of 15-keto-PGF2α on macrophage polarization and functions. By monitoring the expression of M1 biomarkers (IL-1β, TNF-α, CXCL10, iNOS, CCL2 and IL-6) and M2 biomarkers (IL-10 and arginase 1), we discovered that 15-keto-PGF2α suppressed macrophage M1 polarization and promoted macrophage M1 polarization in RAW264.7 macrophages and bone marrow-derived macrophages. We also found that 15-keto-PGF2α markedly enhanced the phagocytosis of fluorescently-labeled beads or apoptotic H9c2 cardiac cells. By examining the cardioprotective activities of 15-keto-PGF2α in a mouse model of acute myocardial infarction, we found: 1) 15-keto-PGF2α indeed reduced infarct size on day 3 and day 7; 2) promoted the shift of macrophage M1 polarization to M2 polarization based on the immunostaining of M1 biomarker CD86 and M2 biomarker CD206 in hearts after myocardial infarction; and 3) enhanced macrophage phagocytosis of apoptotic cardiomyocytes as a result from myocardial infarction. By elucidating the underlying mechanisms, we found that 15-keto-PGF2α inhibited PKM2 expression and the formation of PKM2 dimer and suppressed nuclear translocation of PKM2. Collectively, 15-keto-PGF2α may exhibit potential cardioprotective effects by promoting macrophage M2 polarization against acute myocardial infarction in a PKM2-dependent manner.

References:

1. Cheng Y Y, Tse H F, Li X C, Han Y F, Rong J H (2016 ) Gallic acid-l-leucine (GAL) conjugate enhances macrophage phagocytosis via inducing leukotriene B4 12-hydroxydehydrogenase (LTB4DH) expression. Molecular Immunology 74: 39-46.

2. Cheng Y Y, Xia Z Y, Han Y F, Rong J H (2016) Plant natural product formononetin protects rat cardiomyocyte H9c2 cells against oxygen glucose deprivation and re-oxygenation via inhibiting ROS formation and promoting GSK-3ß phosphorylation. Oxidative Medicine and Cellular Longevity.

3. Cheng Y Y, Yang C B, Zhao J, Tse H F, Rong J H (2015) Proteomic identification of calcium-binding chaperone calreticulin as a potential mediator for the neuroprotective and neuritogenic activities of botanical drug amygdalin, Journal of Nutritional Biochemistry 26: 146-154.

4. Cheng Y Y, Li S F, Zhang Y, Tang G H, Di Y T, Hao X J, Li S L, He H P (2012) Cleidbrevoids A–C, new clerodane diterpenoids from Cleidion brevipetiolatum. Fitoterapia 83: 1100-1104.5.      Zhao J, Cheng Y Y, Yang C B, Lau S, Lao L X, Shuai B, Cai J, Rong J H (2015) Botanical drug puerarin attenuates 6-hydroxydopamine (6-OHDA)-induced neurotoxicity via upregulating mitochondrial enzyme arginase-2. Molecular Neurobiology 5: 1-12.

Biography:

Jessy S Deshane is currently an Associate Professor of Medicine at University of Alabama at Birmingham. Her work is focused on immune regulation by myeloid-derived regulatory cells (MDRCs) in chronic inflammatory lung diseases. Her team has recently identified and characterized free radical producing myeloid-lineage cells as master regulators of allergic airway inflammation. She is currently investigating the novel hypothesis that MDRCs can produce neo-antigens that trigger dysregulated immune responses in asthma. 

Abstract:

Introduction & Aim: Myeloid derived suppressor cells (MDSCs) are major contributors of immunosuppression by inducing oxidative stress and by modulating amino acid metabolism. Indoleamine 2,3-dioxygenase (IDO) is a key regulator of tryptophan (Trp) metabolism. Poor prognosis in lung cancer patients is associated with elevated IDO expression and activity. We have previously shown that a combination strategy of gemcitabine and a superoxide dismutase mimetic promoted anti-tumor immunity by enhancing metabolism of CD8⁺ memory T cells and prolonging survival in mice with lung cancer. In this study, we aim to elucidate how modulation of IDO pathway alters metabolic signaling in the tumor microenvironment (TME) and influence mitochondrial dynamics to promote long term immunity against lung cancer.

Methods: Lewis lung carcinoma cells were injected by intracardiac route into wild type (WT) and IDO^-/- mice. We assessed tumor burden, infiltration of MDSCs and CD8⁺ T cells by flow cytometry. Protein analyses of metabolic signaling pathways were performed on whole tissue and sorted cell lysates. Peripheral blood samples from Stage III–IV lung cancer patients and healthy normal relatives were used to measure serum IDO activity and percent circulating MDSCs.

Results: Circulating human MDSCs and serum IDO activity correlated with lung cancer. In a preclinical lung cancer mouse model, MDSCs were the significant contributors of IDO in the TME. Combination therapy targeted IDO signaling, specifically in MDSCs, tumor cells, and CD8⁺ T cells infiltrating the TME. Deficiency of IDO caused significant reduction in tumor burden, tumor-infiltrating MDSCs, GM-CSF, MDSC survival and infiltration of programmed death receptor-1 (PD-1)-expressing CD8⁺ T cells compared to controls. IDO^-/- MDSCs downregulated nutrient-sensing AMP-activated protein kinase (AMPK) activity, but IDO^-/- CD8⁺ T cells showed AMPK activation associated with enhanced effector function. Additionally, our studies showed that IDO pathway directly modulated mitochondrial dynamics to enhance memory T cell response.

Conclusions: Our study revealed a novel role of IDO in regulation of AMPK activation, distinct from Trp sufficiency and deficiency signaling. These data also provide mechanistic evidence that a combination treatment of gemcitabine and a SOD mimetic can metabolically reprogram the cellular components of the TME including suppressor cells, effector T cells, and tumor cells.

Biography:

Gavrilă B I did his PhD in Internal Medicine, and now he is an Assistant Professor at Dr. I Cantacuzino Clincal Hospital, Department of Internal Medicine and Rheumatology in Bucharest.

Abstract:

Background: The introduction of biologic therapy has revolutionized the treatment of rheumatoid arthritis (RA). Despite these advances, 20-40% of the patients are declared non-responders to at least one of the therapies.

Objectives: Evaluating the predictive role for the response to anti-tumor necrosis factor therapy of rheumatoid factor (RF) isotypes IgM, IgA, anti-cyclic citrullinated peptide (anti-CCP) and the evolution of serum levels of these biomarkers under biologic treatment. We have also assessed the status of this biomarkers and the response to treatment.

Methods: Prospective and observational study including 64 patients was followed for 12 months with active RA, uncontrolled by conventional synthetic DMARDs or declared non-responders to one of the biologic DMARDs.

Results: Lower baseline titres of RF type IgM (51.36±95.359 U/ml, p=0.01629), IgA (22.45±61.256 U/ml, p=0.03336) and anti-CCP (60.82±26.331 ng/ml, p=0.00011) had predictive value for achieving a good EULAR response at 6 months. Grouping patients in 2 categories (responders/non-responders), we identified significant differences between groups only for anti-CCP and response at 6 months (responders 96.04±50.355 ng/ml, non-responders 146.16±41.68 ng/ml, p=0.02834). For the EULAR response at 12 months, lower baseline titres for RF type IgM (92.93±120.22 U/ml, p=0.01032) and IgA (49.96±98.08 U/ml, p=0.00247) had predictive value for achieving a good response at 12 months. We didn’t obtain other information grouping patients in 2 categories. Monitoring the evolution of serum levels, we noticed reduction in all three biomarkers tested, statistically significant at 6 and/or 12 months from baseline. Regarding the status (positive/negative) pretreatment and the response to anti-TNF agents, we noticed significant differences regarding status for RF IgA isotype and response to treatment at 12 months (p=0.004).

Conclusion: It can be concluded that, beside their diagnostic role, these biomarkers can be used for other purposes in RA.

Biography:

Patricia Araujo has expertise in Phototherapy, area in which she has been working since 17 years. The major focuses of her study are: vitiligo, psoriasis and mycosis fungoides. She has developed theories on various responses to surgical treatments of vitiligo, which could improve NB-UVB response.

Abstract:

For stable forms of vitiligo, many are the surgical techniques proposed, in order to improve patients’ response to NB UVB. The surgical techniques for the treatment of vitiligo can be classified according to the nature of the graft. Some surgical techniques are: Minigrafts; suction blister, in which the top of the blister induced by suction is used as grafts; split thickness grafts in which a sheet of 0.2-0.3 mm thick skin, consisting almost exclusively of epidermis is used as a graft; Needling, in which, with the use of a needle it is possible to transplant pigment cells from the edge to the center in the leucoderma area. After, the patients are submitted to phototherapy NB UVB, however, patients submitted to needling have different degrees of repigmentation. We wondered why and supposed that when transplanting cells from the edge compared with when transplanting cells at least 3 cm further, better results could be achieved in the second case. Considering vitiligo as an auto immune disease, we supposed that cells far from the edge could be in better immunologic conditions, compared to those near the edge, where the number of auto antibodies could be higher. In order to put this hypothesis to test, we have done needling in both sides of the same patient. On the right side of the body, we have done needling near the edge of the lesion and, on the left side, we have done needling, at least, 3 cm far from the edge.

Biography:

Orly Avni is expert in gene regulation in the immune system. She has published many articles in reputed journals.

Abstract:

Dilated cardiomyopathy (DCM) is a life threatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab-Christian-infants, ages 4-30 months from four families were diagnosed with DCM associated with mild skin, teeth and hair abnormalities. All passed away before age 3. A homozygous sequence variation creating a premature stop codon at PPP1R13L encoding the iASPP protein, was identified in three infants, and in the mother of the other two. Patients’ fibroblasts and PPP1R13L-knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to Lipopolysaccharide, as well as ppp1r13l-knocked down murine cardiomyocytes and hearts of ppp1r13l-deficient mice. The hypersensitivity to Lipopolysaccharide was NF-kB-dependent, and its inducible binding activity to promoters of pro-inflammatory cytokine genes was elevated in patients’ fibroblasts. RNA-sequencing of ppp1r13l-knocked down murine cardiomyocytes and of hearts derived from different stages of DCM development in ppp1r13l-deficient mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Our results determined PPP1R13L as the gene underlying a novel autosomal recessive cardio cutaneous syndrome in humans, and strongly suggest that the fatal DCM during infancy is a consequence of failure to regulate transcriptional pathways necessary for tuning cardiac threshold response to common inflammatory stressors.

References:

1. T. C. Falik-Zaccai, Y. Barsheshet, H. Mandel, M. Segev, A. Lorber, S. Gelberg, L. Kalfon, S. Ben Haroush, A. Shalata, L. Gelernter-Yaniv, S. Chaim, D. Raviv Shay, M. Khayat, M. Werbner, I. Levi, Y. Shoval, G. Tal, S. Shalev, E. Reuveni, E. Avitan-Hersh, E. Vlodavsky, L. Appl-Sarid, D. Goldsher, R. Bergman, Z. Segal, O. Bitterman-Deutsch, O. Avni, Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome. EMBO molecular medicine,  (2017); (10.15252/emmm.201606523).

2. R. Hod-Dvorai, E. Jacob, Y. Boyko, O. Avni, The binding activity of Mel-18 at the Il17a promoter is regulated by the integrated signals of the TCR and polarizing cytokines. Eur J Immunol 41, 2424-2435 (2011).

3. E. Jacob, R. Hod-Dvorai, O. L. Ben-Mordechai, Y. Boyko, O. Avni, Dual function of polycomb group proteins in differentiated murine T helper (CD4+) cells. Journal of molecular signaling 6, 5 (2011).

4. E. Jacob, R. Hod-Dvorai, S. Schif-Zuck, O. Avni, Unconventional association of the polycomb group proteins with cytokine genes in differentiated T helper cells. J Biol Chem 283, 13471-13481 (2008).

5. O. Shamriz, H. Mizrahi, M. Werbner, Y. Shoenfeld, O. Avni, O. Koren, Microbiota at the crossroads of autoimmunity. Autoimmun Rev 15, 859-869 (2016); (10.1016/j.autrev.2016.07.012).

Biography:

Jongseon Choe is leading the Laboratory of Cellular Immunobiology at Kangwon National University, trying to understand how our body defends against the various pathogenic microorganisms. His team is currently focusing on the pivotal branch of the immune system, the humoral immune response.

Abstract:

Prostaglandins (PGs) are recognized as important immune regulators. Using human follicular dendritic cell (FDC)-like HK cells, we have investigated the immunoregulatory role of PGs and their production mechanisms. The present study was aimed at determining the role of TGF-β in IL-1β-induced cyclooxygenase-2 (COX-2) expression by immuno-blotting. COX-2 is the key enzyme responsible for PG production in HK cells. TGF-β, when added simultaneously with IL-1β, gave an additive effect on COX-2 expression in a dose-dependent manner. However, TGF-β inhibited IL-1β-stimulated COX-2 expression when it was added at least 12 hours before IL-1β addition. The inhibitory effect of TGF-β was specific to IL-1β-induced COX-2 expression in HK cells. The stimulating and inhibitory effects of TGF-β were reproduced in IL-1β-stimulated PG production. Based on our previous results of the essential requirement of ERK and p38 MAPKs in TGF-β-induced COX-2 expression, we examined whether the differential activation of these MAPKs would underlie the opposing activities of TGF-β. The phosphorylation of ERK and p38 MAPKs was indeed enhanced or suppressed by the simultaneous treatment or pre-treatment, respectively. These results suggest that TGF-β exerts opposing effects on IL-1β-induced COX-2 expression in HK cells by differentially regulating activation of ERK and p38 MAPKs.

Figure 1: TGF-β has an opposite effect on IL-1β-induced COX-2 expression by controlling phosphorylation levels of ERK and p38 MAPK depending on the treatment time.

References:

1. Jongseon Choe (2016) Opposing roles of TGF-β in prostaglandin production by human follicular dendritic cell-like cells. Molecular Immunology 76:41-48.

Biography:

Da Silva JB is Scientific Researcher at Instituto Butantan, São Paulo, Brazil. Dr. Da Silva is  PhD in Microbiology with expertise in clinical microbiology, studying host and pathogens interactions. Her work focus on the investigation of the mechanisms evolved in the infection by Leptospira in mammalians. Ongoing research grant 1- FAPESP -In vitro evaluation of the contribution of CCL2/MCP-1 and the importance of chemokines in the mechanisms of resistance and susceptibility to infection by Leptospira sp. and 2- CNPq-Strategies for the development of a cellular vaccine against leptospirosis.

Abstract:

Statement of the Problem: Leptospirosis is a worldwide-spread disease, affecting most mammalian species. Clinical signs can be confusing with other diseases; it is difficult in diagnosis and treatment. Chemokines are cytokines known for their role in inflammatory and immune responses to infections. Profiling chemokine expression in the course of infection may elucidate the defense mechanisms of the host. The proposal of this study is to evaluate the expression of chemokines induced by L. interrogans infection in mice strains C3H/HeJ (mutated toll4 receptor), C3H/HePas and BALB/c, respectively susceptible, intermediary and resistant to leptospirosis.

Methodology & Findings: Five mice from each strain were inoculated with virulent L. interrogans. Three and twenty four hours later animals were sacrificed and lungs and spleens were collected for chemokines profiling by qPCR. Smaller changes in chemokines expression were found in samples of lung of C3H/HeJ mice when compared to other lineages. In lung of Balb/C the expression of some chemokines were significantly elevated CXCL12 (p<0.05), CXCL16 and its receptor CXCR6 (p<0.001 and p<0.01), CXCL5 and CXCL10 (p<0.05). In C3H/HePas we detected significant increase of CXCL9 (p<0.001) and CXCL10 (p<0.01) chemokines transcripts.

Conclusion & Significance: The mice strains C3H/HePas and C3H/HeJ present the same genetic background, thus, the mutation in toll4 receptor in C3H/HeJ may be responsible for the differences in chemokine profiles and in the resulting different susceptibilities to Leptospira infection and survival. The early and most general expression of CXC chemokines especially in BALB/c that presents lower morbidity in leptospirosis, indicate an association of resistance with transcripts of CXC chemokines during infection, thus contributing to solve the disease. 

Biography:

Uriel Heresco-Levy is a Full Professor of Psychiatry at Hadassah Medical School, Hebrew University and Director of the Psychiatry Department at Herzog Memorial Hospital, Jerusalem, Israel. He is a Member of the European College of Neuropsychopharmacology (ECNP) and Fellow of Collegium International Neuro-Psychopharmacologicum (CINP). He has conducted pioneer clinical trials with N-methyl-D-aspartate receptor (NMDAR) modulators, including glycine, D-serine and D-cycloserine and has published extensively on the role of NMDAR-mediated neurotransmission and D-serine in neuropsychiatric disorders. He is the inventor of patents focusing on the use of NMDAR-neurotransmission pharmacomodulation in Parkinson's disease, major depressive disorder and autoimmune NMDAR encephalopathies. 

Abstract:

Since anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was first described a decade ago, the family of disorders associated with antibodies (AB) against neuronal surface antigens is one of the most rapidly expanding categories of neurologic disease. We hypothesized that: 1) anti-NMDAR-ABs seropositive patients can be identified among chronic treatment-resistant schizophrenia patients having atypical disease characteristics; and 2) treatment with D-serine (DSR), which acts in vivo as NMDAR co-agonist at the NR1 receptor subunit will be beneficial for the patients. Out of 17 DSM-IV-diagnosed schizophrenia patients, a 67 yr old female patient hospitalized since age 27 was seropositive for both IgG and IgM anti-NR1 AB isotypes. There was no evidence of other diseases, including malignancy. Brain MRI revealed non-specific cortical FLAIR/T2 signal hyperintensities and cEEG showed extreme delta brush (EDB) events. The patient entered a 6 wk clinical trial with DSR in doses increased gradually from 1.5 to 4 g/day. This treatment was well tolerated and resulted in increased DSR serum levels from 0.93 to 103.1 μM. No side effects were registered. Positive and Negative Syndrome Scale (PANSS) symptom clusters improved and PANSS total score decreased by 34%. The quality of life of the patient, as assessed by schizophrenia quality of life scale (SQLS) improved considerably (37% total score reduction). At 6 wks, cEEG showed significant reduction of EDB-type activity. This pilot investigation: 1) supports the hypothesis that a subgroup of treatment-resistant patients diagnosed with schizophrenia may suffer from an NMDAR-related autoimmune disorder; and 2) indicates that DSR may represent a novel type of treatment for these patients.

References:

1. Rosenthal-Simons A, Durrant A R, Heresco-Levy U (2013) Autoimmune-induced GLUR dysfunctions: conceptual and psychiatric practice implications. Eur. Neuropsychopharmacol. 23: 1659-71.

2. Durrant A R and Heresco-Levy U (2014) The role of N-methyl-D-aspartate receptor– mediated neurotransmission in attention deficit (Hyperactivity) disorder (ADHD/ADD). Current Psychopharmacology 3: 184-194.

3. Durrant A R, and Heresco-Levy (2014) D-serine in neuropsychiatric disorders Advances in Psychiatry.

4. Heresco-Levy U, Durrant A R, Ermilov M, Javitt D C, Miya K, Mori H (2015) Clinical and electrophysiological effects of D-serine in a schizophrenia patient positive for anti-N-methyl-D-aspartate receptor antibodies. Biol Psychiatry 77: e27-9.

Biography:

Mitonga M M A received his Bachelor of Science degree from the University of Limpopo, Medunsa Campus, Pretoria, in South Africa. In 2013, he joined the Department of Biology, Sefako Makgatho Health Sciences University as a Senior Technical Officer. Currently, his project focuses on the morphology and molecular characterization of metacercariae from freshwater fish of South Africa.

Abstract:

Introduction: Diplostomid metacercariae inhabit freshwater fish species as the second intermediate hosts. These parasites have been found in the eye lens, the retina, vitreous humor and the nervous system of freshwater fish. The classification of these parasitic stages to the species level using only morphology is often difficult and ambiguous. The use of molecular techniques has allowed links to be elucidated using various developmental stages of these parasites. The aim of this study was to provide a summative report on the phylogenetic tree by applying molecular biology techniques to the investigation of larval diplostomid parasites.

Materials & Methods: Diplostomid metacercariae were preserved in 70% ethanol prior to DNA extractions using Qiagen kit. Standard techniques for amplification of rRNA region were followed. The DNA amplicons were sent to Inqaba Biotech laboratory for sequencing and phylogenetic trees generated using software programs.

Results: The amplicons of these diplostomids had band sizes of 500 base pairs. The amplicons contained only partial regions (ITS-2). The parasitic species 28S rDNA genomic region was successfully amplified.

Conclusion: The application of molecular techniques on digenetic trematodes seems very promising and may yield great potential in future descriptions of morphologically similar parasitic species.

Biography:

Dr. Sandalova (PhD in Biophysics) has expertise in protein crystallography and modeling of three-dimensional structure. Her results have been published in 70 papers. Dr.Sandalova has contributed more than 100 protein structures to the Protein Data Bank. 

Abstract:

MHC-I molecules play a crucial role in immune surveillance by selectively presenting intracellular peptides at the cell surface to CD8⁺ T lymphocytes, including cytotoxic T lymphocytes, via T cell receptors (TCRs). Recognition of MHC/peptide complexes by TCRs is a critical event in initiation of immune responses. The T cell clone P14 is specific for H-2D^b in complex with the Lymphocytic choriomeningitis virus-derived epitope gp33 (KAVYNFATM). The virus escapes immune recognition by modifying peptide position 4 to phenylalanine (Y4F). Using a combination of structural biology and immunology, we have defined a novel procedure that allows for the design of super-peptides that bind with high affinity to MHC-I. This discovery provides a powerful tool for improving vaccination. The highly immunogenic super-peptides act as mimotopes of disease-associated non-immunogenic epitopes. The increased immunogenicity induces T cell responses of a magnitude never before observed and our results demonstrate that the induced CD8⁺ T cells cross-react with the original peptides, resulting in enhanced in vitro and in vivo responses. Here we present for the first time the crystal structure of P14 in complex with H-2D^b bound to five different peptides, providing a structural basis for our methodology. All five ternary structures revealed virtually the same TCR interface and contacts with an average RMSD of 0.45 Ų. Both the Vα and Vβ domains of P14 contribute equally to the interaction with H-2D^b. In contrast to many others, no contacts are formed between CDR2α and H-2D^b. Instead, several contacts are formed between the CDR3a residues Y101α and E104α and the H-2D^b residues R62, K66 and E163. Three residues of gp33, pY4, pF6 and pT8 interact with CDR3β. R97β located at the tip of CDR3β interacts with both bulky residues of peptide, pY4 and pF6, and pT8 interacts with D93β.

References:

1. Hafstrand I, Doorduijn EM, Duru AD, Buratto J, Oliveira CC, Sandalova T, van Hall T, Achour A. The MHC Class I Cancer-Associated Neoepitope Trh4 Linked with Impaired Peptide Processing Induces a Unique Noncanonical TCR Conformer. J Immunol. 2016;196:2327-34.

2. Uchtenhagen H, Abualrous ET, Stahl E, Allerbring EB, Sluijter M, Zacharias M, Sandalova T, van Hall T, Springer S, Nygren PÅ, Achour A. Proline substitution independently enhances H-2D(b) complex stabilization and TCR recognition of melanoma-associated peptides. Eur J Immunol. 2013;43:3051-60.

3. Allerbring EB, Duru AD, Uchtenhagen H, Madhurantakam C, Tomek MB, Grimm S, Mazumdar PA, Friemann R, Uhlin M, Sandalova T, Nygren PÅ, Achour A. Unexpected T-cell recognition of an altered peptide ligand is driven by reversed thermodynamics. Eur J Immunol. 2012; 42:2990-3000.

4. Madhurantakam C, Duru AD, Sandalova T, Webb JR, Achour A. Inflammation-associated nitrotyrosination affects TCR recognition through reduced stability and alteration of the molecular surface of the MHC complex. PLoS One. 2012;7:e32805.

5. Grunewald J, Kaiser Y, Ostadkarampour M, Rivera NV, Vezzi F, Lötstedt B, Olsen RA, Sylwan L, Lundin S, Käller M, Sandalova T, Ahlgren KM, Wahlström J, Achour A, Ronninger M, Eklund A. T-cell receptor-HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis. Eur Respir J. 2016;47:898-909.     

Biography:

Zana Karimi Kurdistani is a PhD student of Molecular Genetics at Fars Science and Research University in Shiraz. He is working on his thesis under the supervision of Dr. Marjan Mohammadi at the Pasteur Institute of Iran. He is working on the expression of miR-21 in serum and tissue of gastric cancer patients. He is also a Faculty Member of Genetics Department at Azad University of Sanandaj. He has been working as a Supervisor of Molecular Genetics division at Dr. Verdy's Lab. He has 5 years of clinical experience in the field of Cancer, Virology and Bacteriology.

Abstract:

Gastric cancer (GC) is the fourth most prevalent cancer and the second most frequent cause of cancer death worldwide, with the higher mortality rate in developing country particularly in East Asia. MicroRNAs (miRNAs), a recently discovered class of small, single-stranded non-coding RNA molecules, have been implicated in the regulation of cell growth, differentiation, and apoptosis. In total, serum of 70 patients with GC prior to any treatments and 70 healthy control subjects from Imam Khomeini Medical Center (Tehran, Iran) were provided in our study by the gastric cancer biobank at Pasteur Institute of Iran between 2014 and 2015. Serum miR-21 expression was significantly up-regulated in GC patients compared to healthy subjects (P=0.0023). After dividing GC patients into two early and late stages, this up-regulation maintained significant between late stage of GC patients and healthy subjects while this discrepancy was not statistically observed between early GC patients and healthy ones. Moreover, there was no significant difference between early and late stage (P>0.05). The Mann‑Whitney and Kruskal-Wallis tests showed that there were no marked correlation between the miR‑21 levels and factors such as age, gender, differentiation, lymph node metas­tasis, tumor size, venous invasion, tumor subsite, tumor type, tumor grade and tumor thickness (P>0.05). In conclusion, our analysis demonstrated that high expression of miR-21 in serum of GC samples involved in gastric cancer pathogenesis and its high level of presence has potential diagnostic value in screening for gastric cancer.  

Biography:

Nazibrola Chitadze is the Head of Serology Laboratory in the Department of Virology, Molecular Epidemiology and Genome Research at National Center for Disease Control and Public Health. She has done her graduation in Preventive Medicine, Faculty of Tbilisi State University in 2001. Her current research interests include assessment and evaluation cell mediated and humoral immunity developed in humans in response to Bacillus anthracis and Tularemia infection. In 2016, she was awarded for a special contribution to the field of public health care.

Abstract:

Francisella spp. causes zoonotic infections which are present in glandular, ulceroglandular, oculoglandular, oropharyngeal and pneumonic forms with significant morbidity. F. tularensis is considered to be a biological threat agent that poses a substantial risk to public health. Mammals can transmit the bacteria into humans directly through bites and scratches as well as through arthropod vectors and contamination of water and food sources (Ellis, Oyston et al. 2002). The disease is considered to be endemic for Georgia within a few focal areas. Small and large outbreaks are periodically reported.  A serosurvey of F. tularensis was conducted among veterinarians and farmers to determine risk for exposure and to determine risk factors for infection. A total of 300 blood samples were collected from veterinarians and farmers (150 combined samples), as well as a control group (150 samples from general population of Georgia. Samples were tested for F. tularensis specific antibodies by using a standard micro-agglutination (MAT) assay. Briefly, serial dilutions of serum were incubated overnight with safranin-stained, formalin-killed live vaccine strain (LVS) cells at room temperature, and a titer was assigned. Samples with a titer of 1:128 or greater were reported as positive. All MAT positive samples were confirmed by Western blot.  Eleven serum samples (11/110) from farmer group and 10% (4/40) from veterinary group were positive for F. tularensis Ab. None of the control group individuals were positive. This is the first study of seroprevalence of F. tularensis diseases among veterinarians and farmers. It provides a first look at the potential exposure of animal workers and the general population to zoonotic diseases. Veterinarians and farmers are at increased risk tularemia infections. Hence, this information could be a valuable contribution for the public health system of Georgia.

References:

1. Gvantsa Chanturia (2011) Phylogeography of Francisella tularensis subspecies holarctica from the country of Georgia. BMC Microbiology 2011 11:139 DOI: 10.1186/1471-2180-11-139

2. E. Elashvili (2015) Environmental Monitoring and Surveillance of Rodents and Vectors for Francisella tularensis Following Outbreaks of Human Tularemia in Georgia VECTOR-BORNE AND ZOONOTIC DISEASES 15(10): 633–636.

3. Chitadze N (2009) Water-Borne Outbreak of Oropharyngeal and Glandular Tularemia in Georgia: Investigation and Follow-up. Infection 37(6):514-21

4. Brown S L (1980) Evaluation of a safranin-O-stained antigen microagglutination test for francisella tularensis antibodies JOURNAL OF CLINICAL MICROBIOLOGY. 11(2): 146–148

5. Velidjanashvili I: Tularemia in the highlands of Meskhet- Javakheti, Stavropol Scientific Research Anti-Plague Institute of Caucasus and Southern Caucasus, Stavropol, Russia and Anti- Plague station of the Republic of Georgia, 1992, dissertation thesis in published in Russian.

6. Sakvarelidze LA, (1983) Nersesov VA, Sikharulidze MI, et al. Detection of the tularemia zoonosis in the territory of the Kartlian Plain. Zh Mikrobiol Epidemiol Immunobiol 1983; 6: 109–112.

Biography:

Dhêmerson Souza de Lima has expertise in evaluation molecular biology with the emphasis on immunology, working mainly on the following topics: tuberculosis, immunogenetics of pulmonary tuberculosis, and HLA class II and inflammasome genetics and the response immune to Mycobacterium spp. Recently he was reported that HLA-DRB1*04 gene and subtypes associated with pulmonary tuberculosis in Amazon Brazilian, and may be potential immunogenetic markers involved in disease.  Besides, he found that NLRP3-inflammasome genetics seems to be protective against the development active pulmonary tuberculosis, however, P2X7 is associated with increased susceptibility. Currently is Ph.D. student in work with innate immune response and pathway to activation inflammasome.

Abstract:

Statement of the Problem: Tuberculosis (TB) is still a major public health problem worldwide, and it is estimated that 1/3 of world population could be latently infected by Mycobacterium spp. Active TB represents a big challenge for treatment due to the natural resistance of bacteria to common antibiotics, and to the emergence of multidrug resistant strains. The development of active disease results from the host inability to effectively counteract the bacteria. In this context, both innate and acquired immunity have been taken in account as important factors for protection against TB. Nod like receptors (NLRs) and the cytoplasmic complex known as inflammasome are responsible for caspase-1 activation and the consequent production of active form of the pro-inflammatory cytokines IL-1ß and IL-18. Experimental models have showed that M. tuberculosis activates NLRP3-inflammasome and IL-1ß production. Aim of this project is to evaluate the contribution of inflammasome in human TB.

Methodology & Theoretical Orientation: The distribution of 14 single polymorphisms (SNPs) in 9 selected inflammasome genes was evaluated in a case/control cohort of Amazon TB patients (allele-specific Taqman assays and qPCR). Inflammasome activation was then analyzed in human peripheral blood monocytes-derived macrophages (MDM) stimulated with M. tuberculosis (BCG or H37Rv) by the meaning of IL-1β and IL-18 production (ELISA), gene expression modulation (gene-specific Taqman assays and qPCR). Experiments were done in the presence of common NLRP3 inflammasome activators (ATP, LPS), or inhibitors (parthenolide).

Conclusion & Significance: Polymorphisms in inflammasome genes contributes to control (NLRP3, CTSB) or development (P2X7) of active pulmonary TB. M. tuberculosis induced dramatic release of IL-1β and IL-18 from MDM, and the increase of NLRP3, IL1B and IL18 genes expression, suggesting that both indirect (through NF-kB) and direct (through caspase-1) activation of inflammasome are involved in the response. Preliminary data showed that this activation is significantly inhibited by parthenolide, confirming the involvement of inflammasome in response to M tuberculosis in human MDM. Associated SNPs positively correlated with IL-1ß and/or IL-18 production in MDM. Further experiments are going on to fully elucidate the contribution of inflammasome in TB.

Figure 1: The SNPs NLRP3 rs10754558 and CTSB rs8898 contribute to protection against the development of active pulmonary TB, however P2X7 rs2230911 is associated to increased susceptibility to active pulmonary TB. Increased activation of NLRP3-inflammasome is beneficial against the development of active pulmonary TB

References:

1. Souza de Lima D, Ogusku M M, Sadahiro A, Pontillo A (2016). Inflammasome genetics contributes to the development and control of active pulmonary tuberculosis. Infection, Genetics and Evolution Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases 41: 240-2445.

Biography:

Eman Albataineh has her expertise in Immunologic research projects about molecular immunology, allergic diseases epidemiology in Jordan as well as the Allergy-triggering factors and associated diseases. She has been working in research for 6 years in two different universities, i.e.; Jordan University of science and technology and Mutah University.

Abstract:

Alkaptonuria (AKU; MIM no. 203500) is a recessive inborn error disorder in the phenylalanine and tyrosine metabolism pathway, arising due to the deficient activity of the enzyme homogentisate 1,2-dioxygenase (HGD). Consequently, the homogentisic acid (HGA; 2,5-dihydroxyphenylacetic acid) will deposit in the connective tissue of various organs, causing a pigmentation known as ochronosis, leading to dramatic tissue degeneration, inflammation and arthritis. The disease prevalence worldwide is estimated as an ultra-rare, although higher incidence rates are recorded in Jordan. Data regarding the levels of inflammatory mediators in patients suffering of the rare disease Alkaptonuria are limited. C-reactive protein (CRP), Interleukin-1 Beta (IL-1β) and Interleukin-6 (IL-6) are acute-phase markers associated with joint inflammation. The aim of the present study is to compare the serum levels of the pro-inflammatory mediators, CRP, IL-1β and IL-6 in alkaptonuria patients (n=17) with those measured for age-matched healthy controls (n=17). Moreover, we attempt to determine the association between cytokine levels with the disease severity score and age using the Spearman correlation and multiple linear regression. The results show that the serum concentrations of the IL-1 β, IL-6 and CRP are higher in AKU patients compared with healthy controls, with a significant difference in IL-6 (p=0.02). Moreover, a positive correlation is found between the patients' serum IL-6 and patients' age and the AKU Severity Score (ro=0.73 and 0.7, respectively; p<0.05). Thus, the patients' IL-6 serum levels can predict the disease severity score in alkaptonuria patients (p<0.05). These findings suggest that the IL-6 might play a role in the pathogenesis of inflammation in AKU patients and thus targeting it may be one mode of treatment in future. However, these findings need to be supported by further studies, conducted on a larger sample of patients.

Biography:

Bojana Simovic Markovic has experience in immunopathology of liver and gastrointestinal tract research. She has a broad spectrum of publications including original article in the field of mesenchymal stem cell-dependent modulation of immune mediated diseases.

Abstract:

Statement of the Problem: The effects of mesenchymal stem cells (MSCs) on phenotype and function of natural killer T (NKT) cells, is not understood. The aim of the study is to evaluate the protective nature of MSCs against acute liver injury through attenuating hepatotoxicity of liver NKT cells in IDO dependent manner.

Methodology & Theoretical Orientation: We used concanavalin A (ConA) and α-galactosylceramide (α-GalCer) induced liver injury to evaluate effects of MSCs on NKT-dependent hepatotoxicity.

Findings: MSCs significantly reduced Con A- and α-GalCer-mediated liver damage in C57Bl/6 mice, as demonstrated by histopathological analysis and liver enzyme tests, attenuated influx of inflammatory (T-bet+ TNF-α, IFN-γ producing as well as GATA3+, IL-4-producing) liver NKT cells and down-regulated TNF-α, IFN-γ and IL-4 levels in the sera of injured mice. It was observed that the liver NKT cells cultured in vitro with MSCs produced lower amounts of inflammatory cytokines (TNF-α, IFN-γ, IL-4) and higher amounts of immunosuppressive IL-10 upon α-GalCer stimulation. MSC treatment attenuated expression of apoptosis-inducing ligands on liver NKT cells suppressed the expression of pro-apoptotic genes in the livers of α-GalCer-treated mice. MSCs reduced cytotoxicity of liver NKT cells against HepG2 hepatocyte cells in vitro. The presence of 1-methyl-DL-tryptophan, a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), in MSC-conditioned medium injected to α-GalCer-treated mice, counteracted the hepatoprotective effect of MSCs in vivo, and restored pro-inflammatory cytokine production and cytotoxicity of NKT cells in vitro. In line with these findings, human MSCs in an IDO-dependent manner, attenuated the production of inflammatory cytokines in α-GalCer-stimulated human peripheral blood mononuclear cells and reduced their cytotoxicity against HepG2 cells.

Conclusion & Significance: MSCs protects the acute liver injury by attenuating cytotoxicity and capacity of liver NKT cells to produce inflammatory cytokines in IDO dependent manner.

References:

1. Simovic Markovic B,  Nikolic A, Gazdic M, Bojic S, Vucicevic L, Kosic M, Mitrovic S, Milosavljevic M, Besra G, Trajkovic V, Arsenijevic N, Lukic ML, Volarevic V (2016) Galectin-3 Plays an Important Pro-inflammatory Role in the Induction Phase of Acute Colitis by Promoting Activation of NLRP3 Inflammasome and Production of IL-1β in Macrophages. J Crohns Colitis 10:593-606.

2. Simovic Markovic B, Nikolic A, Gazdic M, Nurkovic J, Djordjevic I, Arsenijevic N, Stojkovic M, Lukic ML, Volarevic V (2016) Pharmacological Inhibition of Gal-3 in Mesenchymal Stem Cells Enhances Their Capacity to Promote Alternative Activation of Macrophages in Dextran Sulphate Sodium-Induced Colitis. Stem Cells Int 2016: 2640746.

3. Volarevic V, Paunovic V, Markovic Z, Simovic Markovic B, Misirkic-Marjanovic M, Todorovic-Markovic B, Bojic S, Vucicevic L, Jovanovic S, Arsenijevic N, Holclajtner-Antunovic I, Milosavljevic M, Dramicanin M, Kravic-Stevovic T, Ciric D, Lukic ML, Trajkovic V (2014) Large graphene quantum dots alleviate immune-mediated liver damage. ACS Nano 8:12098-12109.

4. Volarevic V, Markovic BS, Bojic S, Stojanovic M, Nilsson U, Leffler H, Besra GS, Arsenijevic N, Paunovic V, Trajkovic V, Lukic ML (2015)  Gal-3 regulates the capacity of dendritic cells to promote NKT-cell-induced liver injury. Eur J Immunol 45:531-543.

5. Volarevic V, Misirkic M, Vucicevic L, Paunovic V, Simovic Markovic B, Stojanovic M, Milovanovic M, Jakovljevic V, Micic D, Arsenijevic N, Trajkovic V, Lukic ML (2015) Metformin aggravates immune-mediated liver injury in mice. Arch Toxicol 89:437-450.