Immunity in Defense and Disease PDF

Immunity in Defense and Disease Apply what you have learnt to understand - Immunological defenses against Microbes - Immunological defenses against Tumors - Reaction against Transplant - Diseases caused by abnormal immune response Animation on what we have learnt: 1. General IS: Human...

Immunity in Defense and Disease Apply what you have learnt to understand - Immunological defenses against Microbes - Immunological defenses against Tumors - Reaction against Transplant - Diseases caused by abnormal immune response Animation on what we have learnt: 1. General IS: Human Immune System - How it works! (Animation) (youtube.com) 2. Adaptive IS: The Adaptive Immune System (youtube.com) NTTH-HCMIU-IM  IMMUNOLOGICAL DEFENSES AGAINST MICROBES Table of Content 1. Pathogenic microbes and their interaction with human host 2. Anti- bacterial immune response 3. Anti-viral immune response 4. Anti-fungal immune response 5. Anti-parasite immune response 6. Immune Evasion NTTH-HCMIU-IM 1. Pathogenic microbes and their interaction with human host 1.1. Pathogenic Microbes Microbiologists deal with four fundamental kinds of microbial infectious agents – bacteria – fungi – viruses – parasites » helminthes (worms) » protozoa (single-celled) Why are we afraid of pathogenic Microbes? NTTH-HCMIU-IM Because... They cause diseases, so called infectious diseases, and epidemics The phenotype of acute infectious disease is characterised by? – type of the infectious agent – the target organ – localization (extra- or intracellular) – the immune response evoked NTTH-HCMIU-IM Do our IS react to different pathogens in a same way? Do we react to same pathogen in a same way? NTTH-HCMIU-IM 1. Pathogenic microbes and their interaction with human host 1.2 Interaction between host and pathogens Host-parasite interactions differ amongst different individuals The outcome depends on characteristics of the host as well as of the microbe. There is a trade-off between over- and under- reactivity – too much and too little is equally bad Both hosts and parasites are engaged in a fitness-enhancing adaptive race Bonus What do affect the reaction of immune system towards pathogens? NTTH-HCMIU-IM One of the reasons… Location of infectious agents in host tissue Microbial type Extracellular Intracellular Bacterium E. coli, Salmonella Mycobacteria, Listeria Fungus Candida Histoplasma Parasite Helminths (worms) Plasmodium Virus None All is of the essence for development and differentiation of IRs NTTH-HCMIU-IM  2. Antibacterial Immunity 1- The innate immunity: a- Complement activation b- Phagocytosis c- The inflammatory response 2- The acquired immune responses: a-The humoral mechanisms (Abs)- Th2 Response: “principal role” b-Cell mediated immune response- Th1 Response: “minor role” NTTH-HCMIU-IM  IR to infection with Extracellular bacteria H CMI NTTH-HCMIU-IM  Immunity To Intracellular Bacteria 1) Innate immunity It is mainly by natural killer (NK) cells - They kill infected cells and secrete IFN-γ - IFN-γ activate phagocytosis to kill intracellular microbe E.g. tuberculosis, leprosy, listeriosis 2) Acquired immunity is mainly by CMI/ Th1 Response - Activation of macrophages to kill intracellular microbes - Lysis of infected cells by cytotoxic cells (CTLs) - Most of these organisms are resistant to phagocytosis, cause chronic infection and granuloma formation NTTH-HCMIU-IM Elimination of Intracellular bacteria CD4 CD8 NTTH-HCMIU-IM Feedback of adaptive on Innate Immunity Cooperation of T4, T8 in defending Intracellular bacteria NTTH-HCMIU-IM  Th1/2 choice made by the immune system has profound effect on the outcome of some diseases (e.g. Leprosy) Tuberculoid Leprosy Lepromatous Leprosy Infection by Mycobacterium Infection by Mycobacterium leprae. leprae. Th1 cells produce IFN-g. Th2 cells cannot activate Activation of Macrophages Macrophages. Destruction of intracellular Unchecked proliferation of bacteria. intracellular bacteria. Milder damage. Gross destruction of tissues. Patients survive. Fatal. Balance of two subset determines response to disease NTTH-HCMIU-IM Figure 6-21 NTTH-HCMIU-IM  Classification Symptoms Disease response Can heal on its A few flat lesions, some Tuberculoid own, persist, or large and numb; some leprosy may progress to a nerve involvement more severe form Lesions similar to May persist, revert Borderline tuberculoid but more to tuberculoid, or tuberculoid numerous; more nerve advance to another leprosy involvement form Reddish plaques; Mid- May regress, moderate numbness; borderline persist, or progress swollen lymph nodes; leprosy to other forms more nerve involvement Many lesions, including Borderline flat lesions, raised May persist, lepromatous bumps, plaques, and regress, or progress leprosy nodules; more numbness Many lesions with bacteria; hair loss; more severe nerve Lepromatous involvement with Doesn’t regress leprosy peripheral nerve thickening; limb Tuberculoid vs Lepromatous Leprosy weakness; disfigurement NTTH-HCMIU-IM  3. Anti-Viral Immunity 1) Humoral immunity: a- Virus neutralization * In viraemic infections: Abs neutralize virus, preventing its attachment to receptor sites on susceptible cells e.g. Poliovirus, mumps, measles, rubella * In superficial non-viraemic infections (influenza) Secretory IgA neutralizes virus infectivity at the mucous surfaces b- Antibodies destroy free virus particles directly by: * Aggregation of virus and opsonization * Complement mediated lysis Both mechanisms act on virus- infected cells NTTH-HCMIU-IM  3. Anti-Viral Immunity 2) Cell-mediated immunity (CMI): mediated by Cytotoxic T-cells (CTLs); NK cells; Activated macrophages CMI acts on virus- infected cells through: - CTLs kill virus infected cells directly after recognition of viral Ags on cell surface in association with MHC-I - Th-cells stimulated by viral antigens release cytokines; Cytokines attract and activate macrophages to kill virus infected cells - NK destroy virus infected cells early in infection before Ab appearance - Antibody-Dependent Cell mediated Cyto-toxicity (ADCC): Ab binds to virus infected cells; Such cells are lysed by NK cells, macrophages and polymorphs NTTH-HCMIU-IM  3. Anti-Viral Immunity 3) Anti-viral activity of interferons (IFNs) Virus infected cells produce INF-α; INF-α inhibit intracellular replication of viruses IFN-α activate NK-cells to kill virus infected cells IFNs have no direct effect on extracellular virus IFNs act early in viral diseases before Abs INFs activity is not specific Three anti-viral systems induced via IFNs are being studied and partly understood at this point: ✓Mx proteins: hydrolyze GTP; Block viral RNA polymerase; Block transport of viral nucleoproteins (influenza virus) into nucleus. ✓2',5' oligo(A) synthetase and ribonuclease L: activated by dsRNA ✓PKR, double stranded RNA- dependent protein kinase: Story of IFN and IFN-type I https://www.youtube.com/watch?v=R1h-LPwD1Y8 NTTH-HCMIU-IM Immunity to viruses NTTH-HCMIU-IM  E.g: Hepatitis B virus (HBV) infection the liver is composed of hepatocytes (60%), endothelium, macrophages and lymphocytes. infections of the liver are protracted, suggesting that liver has a tolerogenic effect on the immune response (for HBV 45 – 120 days). 90% of infections are cleared by the immune response Principal cells involved: NK cells, T cells, B cells, Kupffer cells HBV is not by itself cytopathogenic Liver pathology is caused by the immune system: acute hepatitis; chronic hepatitis; glomerulonephritis; hepatocellular carcinoma. How does IS cause liver pathology? NTTH-HCMIU-IM Immunopathology due to viral infection Jung & Pape, Lancet Infect Dis 2002;2:43-50 NTTH-HCMIU-IM  4. Anti-Fungal Immunity 1) Innate immunity is mediated by: - Neutrophils and macrophages - Fungi are readily eliminated by phagocytes → Fundamental for clearing fungal infection 2) Acquired immunity (cell mediated immunity) - CMI acts in a manner similar to its action against intracellular bacteria - in many situations Th1 reactions are protective whereas Th2 reactions are detrimental to the host intracellular fungi are cleared by the same mechanisms that clear intracellular bacteria. Disseminated fungal infection are seen in immunodeficients NTTH-HCMIU-IM  5. Immunity to parasites immunity against intracellular protozoa is principally mediated by Th1- triggered Macrophages immunity against helminthic infections is mediated by Th2 cells, IgE and mastcells/ basophils chronic parasite-infections are common owing to weak innate immunity and parasite capacity to evade the immune response NTTH-HCMIU-IM Pathogens and effective response NTTH-HCMIU-IM  Important issues not yet addressed Type of immune deficiency as related to kind of microbes Mechanisms for immune evasion by microbes Vaccine engineering Effects of microbes on » allergic disposition » development of autoimmune disease » chronic fatigue syndrome NTTH-HCMIU-IM 6. Microbial evasion of immune responses NTTH-HCMIU-IM Evasion of Innate Immunity by Microbes NTTH-HCMIU-IM Immune Evasion targeting on cytokine production It is believed that components of microorganisms have the capacity to induce cytokine synthesis in host cells. Pro-inflammatory cytokines such as IL-1, IL-6, IL-8 and TNF are believed to be the major pathological mediators of inflammatory diseases ranging from arthritis to periodontal diseases. Epstein-Barr virus foster the generation of T helper cells that do not produce IL- 2. Epstein-Barr virus produces an analog of IL-10 that favors TH2 cells, rather than TH1. Parasites such as tape worms induce high levels of IgE, an immunoglobulin induced by TH2 cells→ this may be a protective ploy to avoid destructive inflammatory processes. NTTH-HCMIU-IM  Example with one intracellular pathogen: TB TB mechanism for cell entry – The tubercle bacillus can bind directly to mannose receptors on macrophages via the cell wall-associated mannosylated glycolipid (Lipoarabinomannan/ LAM). TB can grow intracellularly – Effective means of evading the immune system – Once TB is phagocytosed, it can inhibit phagosome-lysosome fusion – TB can remain in the phagosome or escape from the phagosome (Either case is a protected environment for growth in macrophages) Slow generation time ‒ Immune system cannot recognize TB, or cannot be triggered to eliminate TB. High lipid concentration in cell wall ‒ accounts for impermeability and resistance to antimicrobial agents; Accounts for resistance to killing by acidic and alkaline compounds in both the inracellular and extracelluar environment.; Also accounts for resistance to osmotic lysis via complement depostion and attack by lysozyme. Antigen 85 complex (mylcolyl transferase, FbpA/B/C): ‒ It is composed of proteins secreted by TB that can bind to fibronectin. These proteins can aid in walling off the bacteria from the immune system NTTH-HCMIU-IM IR IN TB Tuberculosis Epidemics https://www.youtube.com/watch?v=hTscEEWD5Ho Tuberculosis invasion https://www.youtube.com/watch?v=hNLID8F99Qo All about TB https://www.youtube.com/watch?v=yR51KVF4OX0 NTTH-HCMIU-IM Immune evasion via multiple antigenic variants of microbes (serotypes) NTTH-HCMIU-IM Immune Evasion via antigenic drift// antigenic shift in Influenza A Mutation Recombination completely different to genetic or allelic drift NTTH-HCMIU-IM  Immune Evasion in Trypanosoma Immune evasion via sequential DNA rearrangements of microbial antigens. silent Variant Surface Glycoprotein (VSG) genes NTTH-HCMIU-IM Immune evasion via sequential DNA rearrangements of microbial antigens. (continued) NTTH-HCMIU-IM Immune evasion mechanisms of different viruses- I NTTH-HCMIU-IM Immune evasion mechanisms of different viruses- II NTTH-HCMIU-IM Immune evasion mechanisms of different viruses- III NTTH-HCMIU-IM  Viral evasion of IFN: PKR inhibition protein kinase R (PKR) eukaryotic translation initiation factor 2-alpha (eIF2a) © New Science Press Ltd. 2004 NTTH-HCMIU-IM  Viruses Evade Interferon Response Viruses adapt to the interferon response by making proteins that neutralize PKR (dsRNA dependent protein kinase). Adenoviruses Evasion Mechanisms: – They produce VA (Virus- Associated) RNA (160 nt long) that binds PKR – This RNA takes double stranded form, however PKR does not get activated, no eIF2 phosphorylation; Translation proceeds as expected – Adenoviruses also produce E1A which sequesters p300/CPB which are co-factors, needed for interferon expression Epstein Barr Virus encodes for RNA that acts in similar manner At-class ASSIGNMENT: IMMUNOEVASION OF VIRUSES NTTH-HCMIU-IM  Summary- Immune response to pathogens Immunity to infection depends on a combination of innate mechanisms (phagocytosis, complement, etc.) and antigen specific adaptive responses (antibody, effector T lymphocytes). The immune system regulates which specific responses predominate (humoral vs. cell-mediated) based on the body compartment infected (intracellular vs. extracellular) and on cytokine signals present at initial antigen contact (Th1 vs. Th2 responses). Recovery from natural infection or artificial immunization promote specific longterm immunity to re-infection (immunological memory). Disease-causing microbes/ Pathogens have virulence mechanisms that resist or evade innate and/or specific immune effector functions. Immune System - Fighting Infection by Clonal Selection (2009) Etsuko Uno wehi.tv (youtube.com) NTTH-HCMIU-IM What you have learnt… IMMUNOLOGICAL DEFENSES AGAINST MICROBES Table of Content 1. Pathogenic microbes and their interaction with human host 2. Anti- bacterial immune response 3. Anti-viral immune response 4. Anti-fungal immune response 5. Anti-parasite immune response 6. Immune Evasion NTTH-HCMIU-IM  FYI IR against other pathogens…. IMMUNOLOGY OF PARASITIC HELMINTH INFECTIONS ANDREW S. MACDONALD†, MARIA ILMA ARAUJO‡ AND EDWARD J. PEARCE* Host IR to worm infection are remarkably similar for different types of helminthes: Th2-like with the production of significant quantities of IL-4, IL-5, IL- 9, IL-10, and IL-13 and consequently the development of strong immunoglobulin E (IgE), eosinophil, and mast cell responses. → HOW COME? It is the focus of many studies…. Infection and Immunology 2002 NTTH-HCMIU-IM  HIV and infection Recent studies have highlighted how abortive infection of resting and thus nonpermissive CD4 T cells in lymphoid tissues triggers a lethal innate immune response against the incomplete DNA products generated by inefficient viral reverse transcription in these cells. Sensing of these DNA fragments results in pyroptosis, a highly inflammatory form of programmed cell death, that potentially further perpetuates chronic inflammation and immune activation. (Doitsh et al. 2016) NTTH-HCMIU-IM  Tasks of the immune response differentiate self from non-self differentiate dangerous from safe Self Tolerate Damage (autologus molecules) (cancer) Safe Dangerous Ignore Eliminate (food, innocuous molecules) (infectious agents) Non-self NTTH-HCMIU-IM NTTH-HCMIU-IM  Immunosuppressive effects of oral bacteria on immune function Impairment of B and T cell function (P. intermedia, P. asaccharolytica, P. endodontalis, P. melaninogenica) Production of specific toxins that kill monocytes (A. actinomycetemcomitans) Provoke the release of peroxide, prostaglandins and other mediators capable of inhibiting lymphocyte function (T. denticola) Modulate expression of cytokines NTTH-HCMIU-IM Cytokines produced by host cells in response to components/products from periodontopathogens NTTH-HCMIU-IM  Cytokine-induction by LPS from periodontopathogens other than P. gingivalis NTTH-HCMIU-IM  Cytokine-inducing components of Gram- positive bacteria Gram- negative bacteria NTTH-HCMIU-IM