Mechanisms of diseases

The course is based on a strong integration of different disciplines, thus the program of the single disciplines must be considered embedded in the program of the whole course which is reported in module General Pathology and Immunology.

The course is based on a strong integration of different disciplines, thus the program of the single disciplines must be considered embedded in the program of the whole course which is reported in module General Pathology and Immunology.

MECHANISMS OF DISEASES - 1ST SEMESTER Legend: A = asynchronous learning LEARNING OBJECTIVES BLOCK 1: CELLULAR PATHOLOGY 1. Introduction to MOD and its organization 2. Mechanisms of cellular adaptation, injury and death 3. Oxidative stress in human health and diseases 4. Intra- and extracellular accumulations leading to human diseases 5. The stem cell 6. Cellular senescence and aging (A) 7. Hydrophilic vitamins in health and disease I 8. Hydrophobic vitamins in health and disease II BLOCK 2: MEDICAL GENETICS 1. Principles of molecular diseases 2. Genetic pleyotrophy 3. Genetic heterogeneity (A) 4. The position effect 5. When genotype is not predictive of phenotype 6. The genetics of complex diseases 7. From Mendelian to complex diseases 8. Epigenetics and human diseases I 9. Epigenetics and human diseases II (A) 10. Pharmacogenetics and pharmacogenomics BLOCK 3: BASIC CONCEPTS ON PATHOGENS 1. The good and bad of microorganisms 2. Prokaryotic cell structure and function (A) 3. Microbial pathogenesis 4. Mechanisms of Antimicrobial Resistance 5. Fungal structure, function, and pathogenesis 6. Basic concepts of parasitology (A) 7. Parasites of medical relevance (A) 8. Viruses: structure, genetics and evolution 9. Viruses: classification and replication properties 10. Viruses: pathogenesis of viral infections BLOCK 4: VIROLOGY 1. RNA positive viruses I: picornaviridae 2. RNA positive viruses II: flaviviridae 3. RNA positive and negative viruses 4. RNA negative viruses I 5. RNA negative viruses II 6. Viral hepatitis I: Hepatitis A virus, Hepatitis B virus, Hepatitis D virus 7. Viral hepatitis II: Hepatitis C virus, Hepatitis E virus, Hepatitis G virus 8. DNA viruses: herpesviridae 9. DNA viruses: parvoviridae, adenoviridae, papillomaviridae 10. DNA viruses: polyomaviridae (A) 11. Retroviridae: Human immunodeficiency virus 12. Retroviridae: Human immunodeficiency virus 13. Delta retroviruses, Human endogenous retroviruses, prions (A) BLOCK 5: MICROBIOLOGY 1. Toxigenic bacteria 2. Pyogenic bacteria 3. Spore-forming bacteria 4. Intracellular bacteria (A) 5. Granulomatous infections 6. Granulomatous infections-Part II Clinical cases 7. Bacteria infecting the gut 8. Bacteria living in the gut - Focus on microbiome 9. Microorganisms infecting the central nervous system 10. Neisseria meningitidis (A) 11. Nosocomial pathogens (A) 12. Sepsis ad Septic shock 13. Invasive fungal infections 14. Biologicals and infection risk (A) BLOCK 6: INFLAMMATION AND INNATE IMMUNITY 1. Origin of innate immune cells: hematopoiesis (A) 2. The acute inflammatory response 3. Cell mediators of acute inflammation 4. Soluble mediators of acute inflammation 5. Leukocyte recruitment (A) 6. Pathogen recognition in innate immunity I 7. Pathogen recognition in innate immunity II (A) 8. The complement system 9. Pathogen killing 10. Immunometabolism (A) 11. Resolution of the inflammatory response 12. Tissue repair and fibrosis 13. Chronic inflammation 14. Acute phase reaction and systemic inflammation BLOCK 7: ADAPTIVE IMMUNITY 1. From innate to adaptive immunity: basic concepts 2. Antigen processing and presentation 3. Antigen presenting cells 4. T cells development 5. Tolerance (A) 6. T cells functions 7. B cells development 8. Antibodies 9. Immune response polarization 10. Immune circuits in chronic inflammation 11. Negative regulators of the immune response (A) 12. Immunometabolism in adaptive immunity ( A) 13. Immune response memory (A) MECHANISMS OF DISEASES - 2ND SEMESTER BLOCK 8: IMMUNOPATHOLOGY 1. Immune responses to viruses 2. Immune responses to intracellular bacteria 3. Immune responses to extracellular bacteria and fungi 4. The immune system at the epithelial barriers 5. The interaction between microbiome and the immune system (A) 6. Hypersensitivity reactions - part I 7. Hypersensitivity reactions - part II 8. Autoimmunity 9. Primary immunodeficiencies A 10. Acquired immunodeficiencies 11. Transplantation immunology 12. Systemic metabolism and immune response in complex diseases (A) 13. Immunosenescence BLOCK 9: ONCOLOGY 1. Introduction to tumors 2. Distinctive features of benign, precancerous and malignant growth 3. Metabolic derangements in cancer cells 4. The genetic basis of cancer (A) 5. Sporadic and familial cancer (A) 6. Molecular basis of cancer 7. Carcinogenesis: physical and chemical agents 8. Health impacts of air pollution (A) 9. Carcinogenesis: infectious agents (A) 10. Immune responses to tumors 11. CAR T cells in cancer immunotherapy (A) 12. Inflammation and cancer 13. Metabolic changes in patients with tumors (A) 14. Angiogenesis 15. Tumor angiogenesis BLOCK 10: VASCULAR PATHOLOGY 1. Hemostasis and coagulation 2. Atherosclerosis (A) 3. Thrombotic disease (A) 4. Shock 5. Anemias (A) BLOCK 11: BIOTECHNOLOGY APPROACHES IN TRANSLATIONAL MEDICINE 1. From somatic cells to stem cells 2. New technologies for the diagnosis and the therapies of immunologic diseases 3. From genetics to immunology: the auto-inflammatory diseases case 4. Regulation and ethics of modern technology in modern medicine 5. Flow cytometry applications in immunopathology EXPECTED LEARNING OUTCOMES BLOCK 1 Adaptation of cellular growth and differentiation Mechanisms of cellular injury and cell death (necrosis, apoptosis, autophagy, pyroptosis, necroptosis) Reactive oxygen species (ROS): types, source, effects Balance between ROS and antioxidants in human health and unbalance in human disease Intracellular accumulations of endogenous and exogenous substances Molecular and cellular aspects of protein misfolding and mechanisms of protein-folding diseases The stem cell and the concept of pluripotency Main properties of embryonic and adult stem cells The hematopoietic stem cell as a paradigm of adult stem cells Reprogrammed cells and induced pluripotency Somatic cell reprogramming by nuclear transfer ("therapeutic cloning") Hallmarks of aging Genetic and biochemical changes in aging Cellular senescence Stem cell exhaustion Altered intercellular communication Sources, biochemical functions, and health benefits of energy-releasing and energy-converting vitamins (B1, B2, B3, B5, B6, B7), and deficiency-related diseases Sources, biochemical functions, and health benefits of hematopoietic vitamins (B9, B12), vitamin C, and deficiency-related diseases Lipid-soluble vitamins (A, D, E, K), and deficiency/excess-related diseases BLOCK 2 Effect of mutations on protein function Mechanism linking mutations to disease Same gene, different phenotypes; different genes, same phenotype Mutation not affecting coding gene sequences Molecular basis of reduced penetrance in human inherited diseases Identification of genetic risk factors in complex diseases Common versus rare variant hypothesis in neurodegenerative disorders Lessons from studying monogenic disease for common disease: the genetics of Alzheimer disease and mellitus diabetes Epigenetic mechanisms Epigenetic modifications and environment Role of epigenetics in human diseases Mechanisms of action of miRNA and lncRNA Role of miRNA and lncRNA in human diseases Genetic variation and drug response Genetic variation and personalized medicine BLOCK 3 Microbiota in health and disease Basics of bacterial cell structure Properties of bacterial cell walls (Gram staining, structure of peptidoglycan, LPS structure and role in human pathogenesis, target sites for antibiotics) The genetic makeup of bacteria Mechanisms of bacterial virulence: secretory, membrane-associated, and cytosolic factors. Structure, regulation, expression and their contribution to pathogenesis and immune evasion. The eukaryotic nature of fungi and their classification The fungal relationships with humans: basic pathogenic mechanisms for opportunistic and invasive infections. Structure, morphology, genome organization and virulence factors of parasites Pathogenesis of Giardia, Trichomonas, Plasmodii, and intestinal nematodes Structure, morphology, genome organization and evolution theories of viruses Classification of the viruses infecting humans Replication's strategies Mechanisms of viral pathogenesis Determinants of communicable diseases BLOCK 4 Structures, genome organization, replication properties and pathogenesis of clinical relevant human picornaviruses. Structures, genome organization, replication properties and pathogenesis of clinical relevant human flaviviruses. Structures, genome organization, replication properties and pathogenesis of the human viruses belonging to the viral families: togaviridae, coronaviridae, rhabdoviridae Structures, genome organization, replication properties and pathogenesis of the viruses belonging to the viral families: orthomixoviridae, paramixoviridae, and pneumoviridae. Structures, genome organization, replication properties and pathogenesis of the viruses belonging to the viral families: filoviridae, arenaviridae, bunyaviridae. Structures, genome organization, replication and pathogenesis of the major viruses causing hepatitis. Structures, genome organization, replication and pathogenesis of the major viruses causing hepatitis (II). Structures, genome organization, replication properties and pathogenesis of the human herpesviruses. Structures, genome organization, replication properties and pathogenesis of the viruses belonging to the viral families: parvoviridae, adenoviridae, papillomaviridae. Structures, genome organization, replication properties and pathogenesis of the human polyomaviruses. Structures, genome organization, and replication properties of HIV. Pathogenesis of HIV. Structures, genome organization, replication properties and pathogenesis of the human delta retroviruses (HTLV-I and II). Structures and pathogenesis of the prions. BLOCK 5 Classification, pathogenetic mechanisms and diagnostic aspects of most clinically relevant bacteria. Staphylococcus, Streptococcus, Enterococcus. Corynebacterium diphtheriae. Listeria monocytogenes, Legionella pneumophila, Chlamydiae, Neisseriae. Haemophilus influenzae. Bordetella pertussis. Campylobacter, Helicobacter pylori, Vibrio cholerae, Pseudomonas aeruginosa, Acinetobacter. Clostridia and bacilli Mycobacteria Fungi (Candida, Cryptococcus, Aspergillus, dermatophytes, Blastomyces, Coccidioides, Histoplasma, Pneumocystis). The burden of nosocomial infections Anti-microbial resistance Superbugs (MRSA, VRE, KPC) BLOCK 6 The hematopoietic niche and hematopoietic stem cells Hematopoietic lineages and cytokines The normal and altered blood counts Biological and physical barriers of innate immunity Cardinal signs of acute inflammation Blood flow alterations and vascular permeability The endothelium as a reactive biological structure Mast cells, phagocytes and NK cells Molecular mediators active on vessels Molecular mediators active on leukocytes Primary inflammatory cytokines Eicosanoids Cell adhesion: adhesion molecules and cell migration, the chemokine system Pathogen-Associated Molecular Patterns (PAMPs) and Pathogen Recognition Receptors (PRRs) Danger-Associated Molecular Patterns (DAMPs) and their receptors The TLR system Intracellular PRR Opsonic receptors Genetic defects in pathogen recognition Complement system: Activation pathways, functions, regulatory mechanisms, genetic defects in the complement system Mechanisms of cell-mediated cytotoxicity: phagocytosis and degranulation Oxygen-dependent mechanisms, oxygen independent mechanisms, opsonic agents Genetic defects in pathogen killing mechanisms Energy for immunity Metabolic signatures and profiles of key immune cells Metabolic control of immune responses Neutrophils metabolism and bioenergetics of anti-microbial action Metabolism of macrophages Metabolic shifts in macrophage activation and polarization Negative regulators of the inflammatory response The hypothalamic-pituitary-adrenal axis Anti-inflammatory cytokines and eicosanoids Stem cells and growth factors in tissue renewal Multistep process of tissue repair, fibrosis, anomalies in wound healing Distinct types of chronic inflammation Cellular and molecular effectors of chronic inflammation Macrophage polarization in chronic inflammatory responses Systemic inflammation: Fever, leukocytosis, acute phase proteins BLOCK 7 Key features of acquired immunity: specificity, memory, tolerance The lymphoid system Primary and secondary lymphoid tissues, lymphatic vessels The antigen: source, structure, processing Thymus-dependent and thymus-independent antigens Structure and function of Major Histocompatibility Complex I and II MHC-I and MHC-II loci organization Superantigens Professional and non-professional antigen presenting cells Dendritic cells origin and subsets Dendritic cells maturation and migration Costimulatory molecules Intrathymic development Positive and negative selection of T lymphocytes TCR structure and repertoire generation Central and peripheral tolerance The TCR/CD3 signalling complex and transduction pathways Helper and cytotoxic T lymphocytes BCR signalling and B cell activation Antibody classes: structure and functions Isotype switch Antibody classes in primary and secondary immune responses Affinity maturation T helper subsets and polarized immune responses Differentiation and signalling in T helper cells Immune response polarization in pathology T cell / macrophage crosstalk in chronic inflammatory responses Impact on effector cells Immune granulomata: an immune perspective Regulatory T cells Myeloid regulatory cells Metabolic differences between innate and adaptive immunity Metabolism of specific T cell lineages T cell metabolism changes during immune response Vaccines and their development BLOCK 8 Recognition of viral infection by the immune system Effector mechanisms against viral infections Viral strategies for evading antiviral immune responses Recognition of intracellular infection by the immune system Microbial strategies for evading immune responses The mucosal immune system Mucosal immunity and commensal microorganisms Mucosal immunity to pathogenic microbes General issues on hypersensitivity reactions Type I hypersensitivity Type II hypersensitivity Type III hypersensitivity Type IV hypersensitivity The multifactorial pathogenesis of autoimmune diseases Failure mechanisms of the central and peripheral tolerance Effector mechanisms of autoimmune reactions Immune mechanisms of the most common autoimmune diseases Differential features of autoimmune vs autoinflammatory diseases Immune deficiency caused by defects in innate immunity Immune deficiency caused by defects in B and T maturation Iatrogenic immunodeficiencies HIV infection and immune response Acquired immune deficiency syndrome (AIDS) pathogenesis Animal models to assess HIV-1 infection and AIDS pathogenesis Immunological basis of allograft rejection Major and minor histocompatibility antigens Molecular basis of direct and indirect allorecognition Mechanisms of hyperacute, acute and chronic rejection graft-versus-host disease Age-related changes in the innate immune system Age-related changes in the adaptive immune system Impact of immunosenescence on diseases and vaccination Tissue immunometabolism: relationships in the gastrointestinal tract, liver, and adipose tissue Relationships between systemic metabolism and immunity Vitamins in the control of immunity Obesity as a multifactorial disease Immunological implications of obesity BLOCK 9 Definition of cancer and epidemiology Tumor nomenclature, TNM classification Differentiation and cell grading, rate of growth Local invasion Metastasis, pathways of spread Oncogenic signaling and tumor microenvironment as drivers of cancer metabolism Tumor sensing and metabolic adaptations to hypoxia and nutrient deprivation Signals and targets of metabolic reprogramming in cancer cells Advantages and liabilities of tumor cell metabolism Genes in which mutations cause cancer: oncogenes, tumor suppressor genes (gatekeepers and caretakers genes) Type of genetic alterations responsible for initiating cancer Activating or gain of function mutations Ectopic or heterochronic mutations Chromosome translocations Loss of function mutations Genomic instability and tumor progression Activated oncogenes in hereditary cancer syndrome: MEN2 Gatekeeper tumor suppressor genes in AD cancer syndromes The two-hit origin of cancer: the hereditary and sporadic forms of retinoblastoma The Li-Fraumeni syndrome Caretaker gene in autosomal dominant cancer syndromes BRCA1 and BRCA2 mutations in familial breast cancer Familial colon cancer Counselling and germline mutation testing The hallmarks of cancer The cancer-associated genes involved in the hallmarks of cancer Genomic instability and multistep carcinogenesis Cancer stem cells UV and ionizing radiations Chemical carcinogenesis: initiation, promotion and progression Metabolic activation of chemical compounds in vivo Factors that control chemical carcinogenesis Genotoxic and non-genotoxic effects of carcinogens Oncogenic DNA and RNA viruses Genetic mechanisms underlying the oncogenic process Host interaction with oncogenic viruses Pathogenic role of viruses into the oncogenic process Role of bacteria into the oncogenic process: the H. pylori case The immunosurveillance hypothesis Determinants of tumor antigenicity Defensive mechanisms against tumors Mechanisms of cancer immune evasion Cancer immunoediting Principles of cancer immunotherapy Epidemiologic evidence Myeloid-derived suppressor cells Tumor-associated macrophages and neutrophils Mechanisms of angiogenesis and vasculogenesis Endothelial progenitors and other pro-angiogenetic bone marrow-derived cells Angiogenetic cytokines and their receptors Common and distinctive features of blood and lymphatic vessels Role of angiogenesis to tumor survival and growth The role of the tumor microenvironment Cancer-related anorexia and cachexia Metabolic mechanisms of neoplastic cachexia Molecular mediators of neoplastic cachexia Tumor factors contributing to cancer cachexia Clinical characteristics of neoplastic cachexia Paraneoplastic syndromes BLOCK 10 Platelets Primary and secondary hemostasis and coagulation cascade Fibrinolytic system Mechanisms of atherosclerotic plaque generation: risk factors, clinical manifestations and complications Thrombus formation and evolution Thromboembolism and immunothrombosis Pathogenesis and stages of shock Disseminated intravascular coagulopathy Biology of the red blood cell and classification of anemias BLOCK 11 iPCs-technology as a tool to investigate pathogenesis and therapy of human diseases Modern translational approaches in immunologic disorders Bio-informatics approaches in the diagnosis of a new primary immune deficiencies Regulatory agencies and policies of physicians facing new challenges and technologies Flow cytometry in diagnosis and therapy of hematologic malignancies Bone marrow reconstitution

The course is based on a strong integration of different disciplines, thus the program of the single disciplines must be considered embedded in the program of the whole course which is reported in module General Pathology and Immunology.