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Immunologia. An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing.

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Presentation on theme: "Immunologia. An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing."— Presentation transcript:

1 Immunologia

2 An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own healthy cells and tissues in order to function properly. Disorders in the immune system can result in disease, including autoimmune diseases, inflammatory diseases and cancer. Immunodeficiency diseases occur when the immune system is less active than normal, resulting in recurring and life-threatening infections. Immunodeficiency can either be the result of a genetic disease, such as severe combined immunodeficiency, or be produced by pharmaceuticals or an infection, such as the acquired immune deficiency syndrome (AIDS) that is caused by the retrovirus HIV. In contrast, autoimmune diseases result from a hyperactive immune system attacking normal tissues as if they were foreign organisms.

3 Immunologia Batteri: enzimi di restrizione Piante ed insetti: peptidi battericidi Mammiferi: proteine, cellule, organi e tessuti

4 Immunologia The earliest written mention of immunity can be traced back to the plague of Athens in 430 BCE. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time. Many other ancient societies have references to this phenomenon, but it was not until the 19th and 20th centuries before the concept developed into scientific theory. The key primary lymphoid organs of the immune system are the thymus and bone marrow, and secondary lymphatic tissues such as spleen, tonsils, lymph vessels, lymph nodes, adenoids, and skin and liver.

5 Cells of the Immune System Bone graft Multipotentia l stem cell Hematopoietic stem cell Platelets Macrophage Erythrocytes Eosinophil Neutrophil Megakaryocyte Mast cell Basophil T lymphocyte Natural killer cell Dendritic cell B lymphocyte Lymphoid progenitor cell Myeloid progenitor cell Monocyte Marrow Bone

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9 Layered defense The immune system protects organisms from infection with layered defenses of increasing specificity. In simple terms, physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals. If pathogens successfully evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.

10 Immunologia Innate Humoral and chemical barriers Inflammation Complement system Cellular barriers Adaptive Lymphocytes Killer T cells Helper T cells γδ T cells B lymphocytes and antibodies Alternative adaptive immune system

11 Immunologia The symptoms of inflammation are redness, swelling, heat, and pain which are caused by increased blood flow into a tissue. Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell. Innate Humoral and chemical barriers Inflammation Complement system Cellular barriers Adaptive Lymphocytes Killer T cells Helper T cells γδ T cells B lymphocytes and antibodies Alternative adaptive immune system Inflammation is one of the first responses of the immune system to infection.

12 Immunologia Innate Humoral and chemical barriers Inflammation Complement system Cellular barriers Adaptive Lymphocytes Killer T cells Helper T cells γδ T cells B lymphocytes and antibodies Alternative adaptive immune system The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to “complement” the killing of pathogens by antibodies. Innate Humoral and chemical barriers Inflammation Complement system Cellular barriers Adaptive Lymphocytes Killer T cells Helper T cells γδ T cells B lymphocytes and antibodies Alternative adaptive immune system Leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system.The innate leukocytes include the phagocytes (macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells.

13 Immunologia Innate Humoral and chemical barriers Inflammation Complement system Cellular barriers Adaptive Lymphocytes Killer T cells Helper T cells γδ T cells B lymphocytes and antibodies Alternative adaptive immune system The adaptive immune response is antigen-specific and requires the recognition of specific “non-self” antigens during a process called antigen presentation. Antigens are defined as anything that elicits generation of antibodies, hence they are Antibody Generators The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. Killer T cell are a sub-group of T cells that kill cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional. Each type of T cell recognises a different antigen.

14 Immunologia Innate Humoral and chemical barriers Inflammation Complement system Cellular barriers Adaptive Lymphocytes Killer T cells Helper T cells γδ T cells B lymphocytes and antibodies Alternative adaptive immune system A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen. As the activated B cell begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells.

15 Immunologia Innate Humoral and chemical barriers Inflammation Complement system Cellular barriers Adaptive Lymphocytes Killer T cells Helper T cells γδ T cells B lymphocytes and antibodies Alternative adaptive immune system A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen. As the activated B cell begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation or for uptake and destruction by phagocytes. Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells.

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18 Immunological memory When B cells and T cells are activated and begin to replicate, some of their offspring will become long-lived memory cells. Throughout the lifetime of an animal, these memory cells will remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. This is "adaptive" because it occurs during the lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future challenges. Immunological memory can be in the form of either passive short-term memory or active long- term memory. Passive memory Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by the mother. During pregnancy, a particular type of antibody, called IgG, is transported from mother to baby directly across the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother.Breast milk or colostrum also contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until the newborn can synthesize its own antibodies.This is passive immunity because the fetus does not actually make any memory cells or antibodies—it only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In medicine, protective passive immunity can also be transferred artificially from one individual to another via antibody-rich serum. Active memory and immunization Long-term active memory is acquired following infection by activation of B and T cells. Active immunity can also be generated artificially, through vaccination. The principle behind vaccination (also called immunization) is to introduce an antigen from a pathogen in order to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism. This deliberate induction of an immune response is successful because it exploits the natural specificity of the immune system, as well as its inducibility. With infectious disease remaining one of the leading causes of death in the human population, vaccination represents the most effective manipulation of the immune system mankind has developed.

19 Immunologia Effetto di una vaccinazione Effetto di un trasferimento di anticorpi (madre-feto o sieri tipo AT) L’attivazione delle cellule B e T lascia memoria immunologica Most viral vaccines are based on live attenuated viruses, while many bacterial vaccines are based on acellular components of micro-organisms, including harmless toxin components. Since many antigens derived from acellular vaccines do not strongly induce the adaptive response, most bacterial vaccines are provided with additional adjuvants that activate the antigen-presenting cells of the innate immune system and maximize immunogenicity.

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28 validazione di una struttura proteica https://prosa.services.came.sbg.ac.at/prosa.php/

29 Sintesi di peptidi e proteine con metodi biologici e chimici

30 Sintesi di peptidi e proteine con metodi biologici

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32 Sintesi di peptidi e proteine con metodi chimici

33 Robert Bruce Merrifield (1921 – 2006) was an American biochemist who won the Nobel Prize in Chemistry in 1984 for the invention of solid phase peptide synthesis (SPPS) The general principle of SPPS is one of repeated cycles of coupling-deprotection The free N-terminal amine of a solid-phase attached peptide is coupled (see below) to a single N-protected amino acid unit. This unit is then deprotected, revealing a new N-terminal amine to which a further amino acid may be attached. R. B. MERRIFIELD & JOHN MORROW STEWART Automated Peptide Synthesis, Nature 207, (1965) Sintesi di peptidi e proteine con metodi chimici

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35 Fmoc (9-fluorenylmethyl carbamate) t-Boc (Di-tert-butyl dicarbonate). Because of amino acid is an acid with a basic group at one end and an acid group at the other, polymerization of amino acids is common in reactions where each amino acid is not protected. In order to prevent this polymerization, protective groups are used. There are two major used forms of solid phase peptide synthesis – Fmoc (base labile alpha-amino protecting group) and t-Boc (acid labile protecting group). Each method involves different resins and amino acid side-chain protection and consequent cleavage/deprotection steps. Fmoc chemistry is known for generating peptides of higher quality and in greater yield than t-Boc chemistry. Impurities in t-Boc-synthesized peptides are mostly attributed to cleavage problems, dehydration and t-butylation.Fmoct-Boc Sintesi di peptidi e proteine con metodi chimici

36 The Fmoc method is considered orthogonal, since α-amino group deprotection is with base, while final cleavage from the resin is with acid. The Boc method utilizes acid for both deprotection and cleavage from the resin.

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38 semi-automatic peptide synthesizer SAP conceived for the synthesis of single peptides. The synthesis scale can be varied from 0.5 to 1 mM. conceived for the multiple synthesis of peptides: it is equipped with a U-type reaction block which carries 24 x 2ml/5ml or 10ml reactors. Depending on the reactors the resin scale can be varied from 5 to 200 µmole. developed for the requirements of combinatorial synthesis in the solid phase produced in three standard variations: 96 positions for 2ml reactor, 60 positions for 5ml reactors and 40 positions for 10ml reactors.

39 butylglycine - pyroglutamic acid - norleucine

40 β-peptides are stable against proteolytic degradation in vitro and in vivo, an important advantage over natural peptides in the preparation of peptide- based drugs. β-peptides have been used to mimic natural peptide-based antibiotics such as magainins, which are highly potent but difficult to use as drugs because they are degraded by proteolytic enzymes in the body Beta-peptides

41 MAPS Multiple Antigenic Peptide System

42 Chemical synthesis of proteins: peptide ligation

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47 Methods of protein purification Extraction Precipitation and differential solubilization Centrifugation Chromatographic methods Size exclusion chromatography Separation based on charge or hydrophobicity Hydrophobic Interaction Chromatography Ion exchange chromatography Affinity chromatography Metal binding Immunoaffinity chromatography Purification of a tagged protein High Performance Liquid Chromatography HPLC (400 atm) Ultra High Performance Liquid Chromatography UHLC (1.000 atm)

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