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بسم هللا الرحمن الرحيم موارد مربوط به بحث: كليات پاسخ ايمني دربرابرانواع ميكروارگانيسم ها گريز( )Evasionميكروارگانيسم ها ازپاسخ ايمني آسيب هاي ناش ي ازپاسخ ايمني به عوامل عفوني ))Immunopathology Immune response to infections Bidirectional relationship between Immune system and infectious agents Different layers - Innate - early Induced Response - Specific Innate Immunity Innate immunity is responsible for the earliest response by the body to potential infection. Innate immunity precedes adaptive immunity. Innate Immunity The Epithelium is an Important First Line of Defense. Defensins Killing of Salmonella by human defensins secreted by Paneth cells. The small intestine is lined by finger-like absorptive villi interspersed with crypts — narrow pits containing a cluster of defensin-rich Paneth cells at the bottom. The granules of Paneth cells have high concentrations of prodefensin 5, consisting of a propiece segment (blue circles) joined to the Nterminus of mature human defensin 5 (red circles), together with Paneth cell trypsin (green triangles). After Paneth-cell degranulation, induced by the entry of bacteria into the intestinal lumen, trypsin activates defensin 5 by cleaving off its propiece. This process might function to protect the absorptive epithelium, as well as the crypt, with its intestinal stem cells that generate the absorptive enterocytes. Pathogens are Recognized and Killed by Phagocytes Phagocytes bear different receptors that recognize microbial components and induce phagocytosis. These include: CD14 (LPS Receptor) CD11b/CD18 (CR3 – C’R) Mannose Receptor Glucan Receptor. Comparison of Innate and Specific Receptors The innate immune system lacks the specificity of the adaptive (Specific) immune system. However, the innate immune system can distinguish between self and non-self. Pattern Recognition Receptors (PRR) Receptors with specificity for pathogen surfaces recognize patterns of repeating structural motifs. These receptors Receptors (PRR). are designated Pattern-Recognition The mannan-binding lectin that initiates the MB-lectin pathway of complement activation is an example of a PRR. Pathogen recognition and discrimination from self is due to the recognition of a particular of certain sugar residues, as well as the spacing of these residues, which is found only on pathogens and not on normal host cells. Pattern Recognition Receptors (PRR) Innate Receptors can Signal the Presence of Pathogens The binding of pathogens to phagocytes can trigger the innate response, acting as a signal to the body. This “Danger Signal” precedes the activation of the specific immune response. The initiation of the innate mechanisms is mediated by a family of evolutionarily conserved, transmembrane receptors that function exclusively as signaling receptors. These receptors are known as the “Toll” receptors, because they are related to the Toll receptor in the fruit fly, Drosophila. In the fruit fly, the Toll receptor triggers the synthesis of antifungal peptides in response to fungal infection. A different member of the family is involved in the production of antibacterial peptides. Innate Receptors can Signal the Presence of Pathogens . TLR Ligands Members of the TLR family Function of TLRs recognition of microbial components Generation of defensive responses to pathogens in the organism: signal transduction causes transcriptional activation, synthesis and secretion of cytokines Directs the adaptive immune responses against antigens of microbial origin Activation of signal transduction pathways by TLRs leads to induction of various genes that function in host defence: Inflammatory cytokines Chemokines Major histokompatibility complex Costimulatory molecules Additionally mammalian TLRs can induce effector molecules that can destroy directly microbial pathogens: • Inducible nitric oxide synthase • Antimicrobial peptides Toll-like Receptors (TLR) Function in Higher Organisms A Toll-like receptor, TLR-4, signals the presence of bacterial LPS in mammals. It requires the interaction with another protein, LPS binding protein (LBP). The Immune Response to Extracellular Bacteria Extracellular Bacteria Commonly Associated with Diseases Species Diseases Mechanisms of Pathogenicity Staphylococcus aureus Skin and soft tissue infections lung abscess toxic shock syndrome food poisoning Acute inflammation induced by toxins cell death from pore-forming toxins Superantigen-induced cytokine production skin necrosis, shock, diarrhea. Streptococcus pyogenes (Group A) Pharyngitis Skin infections: impetigo erysipelas, cellulitis Scarlet Fever Toxin-induced acute inflammation e.g. Streptolysin O damage of cell membranes Anti-phagocytic actions of capsule polysaccharides Streptococcus pneumoniae Pneumonia meningitis Cell wall constituent-induced acute inflammation Toxin (pneumolysin, similar to streptolysin) Escherichia coli Urinary tract infections gastroenteritis septic shock Toxins acts on intestinal epithelium Increased chloride and water secretion Endotoxin (LPS) stimulates cytokine synthesis Vibrio cholerae Diarrhea Cholera toxin – ADP ribosylates G protein subunit Leads to increased cAMP in intestinal epithelial cells Results in chloride secretion and water loss Clostridium tetani Tetanus Tetanus toxin binds to motor endplate at neuromuscular junction Causes irreversible muscle contraction Neisseria meningitis Meningitis Potent endotoxin causing acute inflammation and systemic disease Corynebacterium diphtheriae Diphtheria Diphtheria toxin ADP ribosylates elongation factor – 2 Inhibits protein synthesis Immune Responses to Extracellular Bacteria Infection by extracellular bacteria induces production of humoral antibodies. Antibodies are secreted by plasma cells in the regional lymph nodes and the submucosa of the respiratory and gastrointestinal tracts. Antibodies act in several ways: Prevention of bacterial attachment. Opsonization and removal of bacteria. Neutralization of toxins. Extracellular bacteria are pathogenic because they induce a localized inflammatory response or through toxin formation. The toxins (endotoxins and exotoxins) can be cytotoxic. Toxins may act in other ways – diphtheria toxin blocks protein synthesis through the ADP-ribosylation of the translation elongation factor EF-2. Endotoxins are components of bacterial cell walls. Exotoxins are secreted. Immune Responses to Extracellular Bacteria Antibody functions as an opsonin by binding to specific antigenic structures on the bacterial cell wall or capsule. Complement component C3b, deposited on the bacterial cell surface, is an additional opsonin. Opsonization increases phagocytosis and clearance of the bacterium. For certain Gram-negative bacteria (e.g., Neisseria species), the formation of the membrane attack complex following complement activation can lead to direct bacterial lysis. Antibody-mediated complement activation can induce the localized production of inflammatory mediators that further amplify the inflammatory response. C3a, C4a and C5a act as anaphylotoxins, inducing local mast cell degranulation, which results in vasodilation. Neutrophils, monocytes and lymphocytes are recruited to the site of inflammation by C5a, and various chemokines. Immune Responses to Extracellular Bacteria Immune Responses to Extracellular Bacteria Antibody Functions Against Extracellular Bacteria Antibody Functions Against Extracellular Bacteria Anti-Adhesin Antibodies Block Bacterial Colonization Mechanisms of Extracellular Bacterial Immune Evasion Infection Process Host Defense Evasion Mechanism Attachment to Host Cell Blockage of attachment by secretory IgA molecules Secretion of proteases that cleave secretory IgA dimers (Neisseria, Hemophilus) Antigenic variation in attachment structures (pili of N. gonorrheae) Proliferation Phagocytosis (Antibody- and Complementmediated opsonization) Production of surface structures (polysaccharide capsules, M protein, fibrin coat) Induction of apoptosis in macrophages (Shigella) Complement-mediated lysis and localized inflammation Generalized resistance of Gram-positive bacteria to complement-mediated lysis Insertion of MAC prevented by long side chain in cell wall LPS Invasion of Host Cells Antibody-mediated agglutination Secretion of elastase inactivates C3a and C5a Toxin-induced damage Neutralization of toxin by antibody Secretion of hyaluronidase (enhances invasiveness) Survival in phagocytes Generation of Reactive Oxygen Intermediates Production of catalase by Staphylococcus Evasion Through Antigenic Variability The different strains of S. pneumoniae have antigenically distinct capsular polysaccharides. The capsule prevents effective phagocytosis until the bacterium is opsonized by specific antibody and complement, allowing phagocytes to destroy it. Antibody to one type of S. pneumoniae does not cross-react with the other types, so an individual immune to one type has no protective immunity to a subsequent infection with a different type. An individual must generate a new adaptive immune response each time he or she is infected with a different type of S. pneumoniae. The Immune Response to Intracellular Bacteria Facultative Intracellular Bacteria Pathogens That Do Not Depend on Intracellular Environment For Survival Mycobacterium tuberculosis Mycobacterium leprae Salmonella enterica Brucella species Legionella pneumophila Listeria monocytogenes Francisella tularensis Obligate Intracellular Bacteria Pathogens Depend Absolutely on Intracellular Environment For Survival Bacteria prefer non-phagocytic cells as host cells, including epithelial and endothelial cells. Rickettsia prowazekii Rickettsia rickettsii Rickettsia typhi Rickettsia tsutsugamushi Coxiella burnetii Chlamydia trachomatis Chlamydia psittaci Chlamydia pneumoniae Innate immunity Against L.monocytogenes Innate immune activation by virulent Listeria monocytogenes is a multistep process. a | Bacteria in the bloodstream are bound by macrophages and internalized. In the macrophage vacuoles, bacteria secrete listeriolysin O (LLO), which lyses the vacuolar membrane and activates nuclear factor-kB (NF-kB)-mediated transcription of innate immune-response genes, such as CC-chemokine ligand 2 (CCL2). b | The CCL2 that is produced then induces the recruitment of circulating monocytes that express CC-chemokine receptor 2 (CCR2). c | Microbial products are released by infected macrophages, and these activate recruited monocytes through Toll-like receptors (TLRs) in a MyD88 (myeloid differentiation primary-response protein 88)-dependent manner. d | Monocytes differentiate into tumor-necrosis factor (TNF-a)- and inducible nitric-oxide (NO) synthase (iNOS)producing dendritic cells (TipDCs), which promote bacterial killing. Delayed-type Hypersensitivity (Type IV Hypersensitivity) Delayed-type Hypersensitivity (Type IV Hypersensitivity) Activation of Macrophages Functions of Activated Macrophages In Anti-bacterial Immunity Macrophage Response** ** Role in Cell-mediated Immunity Production of reactive oxygen intermediates, nitric oxide; increased lysosomal enzymes Killing of microbes in phagolysomes (effector function of macrophages) Secretion of Cytokines (TNF-a, IL-1, IL-12) TNF-a, IL-1: leukocyte recruitment (Inflammation) IL-12: TH-1 differentiation, IFN-g production (induction of response) Increased expression of: CD80, CD86 Class I, Class II MHC Increased T cell activation (amplification) These macrophage responses are induced by CD40 ligation to CD154 (CD40L) and T cellderived IFN-g in cell-mediated immunity; similar responses are induced by microbial products, particularly LPS, and NK cell-derived IFN-g in innate immunity. Intracellular Bacterial Evasion of Killing in Phagocytes Intracellular bacteria have evolved strategies to evade killing by the mechanisms available to the phagocyte. Macrophage effector capacity Microbial evasion mechanism Phagosome acidification Phagosome neutralization Phagosome–lysosome fusion Lysosomal enzymes Inhibition of phagosome–lysosome fusion Resistance against enzymes Intraphagolysosomal killing Evasion into cytosol Robust cell wall C3b receptor-mediated uptake, ROI ROI detoxifiers, ROI scavengers RNI Unknown (ROI detoxifiers probably interfere with RNI) Iron starvation Microbial iron scavengers (e.g., siderophores) Evasion into the Cytoplasm Three Stages of the Immune Response to Intracellular Bacteria The Central Role of T Lymphocytes Acquisition of resistance against intracellular bacteria crucially depends on T-lymphocytes, which, ideally, accomplish sterile bacterial eradication. When a “normal” immune status is provided, bacterial clearance is rapidly achieved in the case of susceptible bacteria, such as L. monocytogenes. In the case of resistant pathogens, such as M. tuberculosis, clearance frequently remains incomplete and is arrested at the stage of bacterial containment to, and growth control at, distinct foci. Bacterial containment and eradication occur in granulomatous lesions. The longer the struggle between host and microbial pathogen continues, the more essential the granuloma becomes. Granuloma formation and perpetuation are orchestrated by T-lymphocytes. The cross-talk in the granuloma between T-lymphocytes, MPs, and the other cells is promoted by cytokines. T-lymphocytes are an unavoidable element of the pathogenesis of intracellular bacterial infections. Expanding granulomas impair tissue functions by occupying space and affecting surrounding cells. Cytokines in Antibacterial Immunity Cytokine Chemokines Contribution to Major cellular source antibacterial protection in bacterial infection Major function in bacterial infection Likely Epithelial cell endothelial cell macrophage Leukocyte recruitment and activation IL-1 IL-6 Important role proven Essential role proven Macrophage Macrophage, T cell Leukocyte recruitment and stimulation Leukocyte recruitment T-cell differentiation TNF-a Essential role proven Macrophage mast cell Leukocyte recruitment NK-cell activation granuloma formation IFN-g costimulation IFN-g Essential role proven Th 1 cell NK cell Macrophage activation granuloma IL-12 Important role proven Macrophage Th 1-cell, NK-cell stimulation IL-18 IL-4 Likely, not proven Exacerbation Macrophage NK T cell, Th2 cell basophil (?) Eosinophil (?) Th 1-cell stimulation Th 1-cell inhibition IL-10 Exacerbation Macrophage Macrophage inhibition TGF-b Exacerbation likely, not proven Macrophage Macrophage inhibition Granuloma Formation Recirculating T-lymphocytes passing by the inflammatory lesion are recruited by proinflammatory cytokines and chemokines. Gradually, infiltrating cells become organized and form a granuloma predominantly consisting of MPs. TNF-a and IFN-g appear to be of crucial importance for this event. ab T cells are the dominant T-lymphocyte population throughout all stages of granuloma formation A significant proportion of gd T cells has been observed in the initial phase. These gd T cells apparently play an important role in the organization of a tight and wellstructured granulomatous lesion. Granulomas are at the forefront of protection by restricting bacterial replication at, as well as confining pathogens to, discrete foci. This is achieved by the following: Activated MPs capable of inhibiting bacterial growth Encapsulation promoted by fibrosis and calcification Necrosis leading to a reduced nutrient and oxygen supply Yet, frequently, microbial pathogens are not fully eradicated, and some organisms survive in a dormant form. A labile balance between microbial persistence and antibacterial defense develops that lasts for long periods. Granuloma Formation The Immune Response to Viral Infections Overview Immunity to viral infections is a broad subject that touches upon all aspects of cellular and humoral immune mechanisms. This reflects the strong selective pressure viruses have exerted upon the evolutionary development of the immune system. The immune system fights a ceaseless battle against infectious agents and both of these forces have been shaped by the constant conflict - microbe/immunology/survival. Viruses are by definition obligate intracellular parasites; therefore effective immunity is often directed against the infected cell rather than against the invading virus itself. The type of immune response most effective against a particular virus is heavily dependent upon the life cycle of that virus. Patterns of Viral Infection Viral infections can be divided into three general categories. 1. Acute infection followed by viral clearance due to the host immune response. (polio, influenza, rotavirus, mumps, yellow fever, RSV, etc.) 2. Acute infection followed by latent infection. (herpesviruses, etc.) 3. Acute infection followed by persistent infection in which infectious virus is continuously shed. (HIV, HBV, HCV, etc.) Cont. Patterns of Viral Infection 1. 2. 3. Cont. Patterns of Viral Infection What does this mean immunologically? Acute - Immune response completely destroys the virus and long term memory prevents reinfection. Latent - Immune response only destroys most of the infectious virus (the virus hides and periodically reactivates) and long term immunity (mostly cellmediated) must remain ever watchful. Persistent - Immune response destroys most but not all of the infected cells (no viral clearance and the remaining infected cells continuously shed virus) and long term immunity is ever vigilant but can never completely remove the virus. Host Response to Viral Infection The immune response to viral infections can be broken down into two broad categories. 1. Innate 2. Adaptive Innate Immunity Cytokines Interferons (a, b, & g) Others Cells NK cells Monocytes/Macrophages Complement Host Response to Viral Infection Cell-Mediated Effector Mechanisms Bottom line: CD8+ T cells rock. They are the predominant effector cell in the adaptive arm of the immune system in defense of viral infections. The Immune Response to Parasites Parasites and the Immune System Parasite – applies to all infectious agents. Usually understood to be protozoan and metazoan pathogens Characterized by chronicity in host and metamorphosis through multiple, usually antigenically distinct, life-cycle stages. Most express mechanisms. highly evolved immune evasion As a group, parasitic diseases remain a significant global human health problem. Leishmania Protective Type 1 Responses Protozoa Leishmania major Prototype of a protective type 1 response is resistance to L. major in resistant mice. L. major causes an early lesion of varying magnitude – in resistant mice, the lesion resolves. Resolution of the lesion is due to the activation of macrophages by IFN-g produced initially by NK cells, and subsequently by Th1 CD4 T cells. CD4 T cells play a central role – class II MHC0/0 mice are unable to control infection – b2m0/0 (class I MHC-deficient) mice heal with equivalent kinetics to wild-type mice. Protective Type 1 Responses Protozoa Leishmania major The ultimate effector molecule controlling L. major infection is the production of nitric oxide (NO) and other reactive nitrogen intermediates in response to macrophage activation by IFN-g. IFN-g is essential – neither IFN-g0/0 nor IFN-gR0/0 mice can control parasite replication. Inhibition of iNOS also results in susceptibility – the use of inhibitors after the lesion had resolved resulted in lesion reactivation and parasite overgrowth – suggests that the immune response does not result in complete removal of the parasite, but instead suggests continued control by iNOSdependent mechanisms. Trypanosoma Protective Type 1 Responses Protozoa Trypanosoma cruzi T. cruzi is able to invade many different nucleated cell types, forming a parasitophorous vacuole. Once inside the cell, the parasite leaves the vacuole and enters the cytoplasm – entry into the cytoplasm makes the T. cruzi antigens available to processing by the class I MHC pathway. CD8+ T cells play a crucial role in controlling T. cruzi – b2m0/0 and class I MHC0/0 mice are extremely susceptible to infection. IFN-g synthesis rather than classical perforin- or granzyme-mediated cytotoxicity is likely to be the major protective mechanism. Plasmodium Protective Type 1 Responses Protozoa Plasmodium Malaria, caused by Plasmodia species, is undoubtedly the most important parasitic disease of humans. Plasmodia have a complex life-cycle. Complex life-cycle involves two distinct cell types: hepatocyte (expresses class I MHC) and the erythrocyte (no MHC expression). Also involves several distinct extracellular forms of the parasite. This implies that more than one form of immune response is required to control infection. Protective Type 1 Responses Protozoa Plasmodium Antibodies are effective against the sporozoite and erythrocytic stages. Type 1 cytokines are effective against the intrahepatic stage – the injection of IL-12 into mice 2 days prior to infection with P. yoelli completely prevents infection. The effect of IL-12 in the mouse model, this was shown to be due to the production of IFN-g by NK cells and the upregulation in the liver of iNOS – NO is the assumed effector mechanism against the intracellular parasite. Hepatocytes can express iNOS – presumably IFN-g works directly on these cells to induce the parasitedirected effector response. Protective Type 1 Responses Protozoa Plasmodium The injection of IL-12 into susceptible A/J mice, prior to and following exposure to P. chabaudi-infected erythrocytes results in decreased parasitemia and increased survival – Th1 cells, IFN-g, TNF-a, and NO are implicated in this process.