Macrophages & dendritic cells in viral infection


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The Roles of Macrophages and Dendritc Cells Against Viral Infection.
1-Roles in Innate Immunity
2-Roles in acquired Immunity

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  • Figure 43.2 Overview of animal immunity
  • these types of RNAs are usually not found in the cytoplasm of unifected cells; rather they are typically products of viral replication.
    These ligands are indispensable components of the microorganisms and, for that reason, they are not readily altered by mutation or selection (Beutler, 2004)
    RIG 1retinoic acid-inducible gene .
  • Macrophages & dendritic cells in viral infection

    1. 1. Presented by Dr. Faris Salama
    2. 2. Agenda • • • • • • • • Introduction about immunity. What’s a virus ? Cells of The Immune System. Macrophages (MФ)& Dendritic Cells ( DC) MФ & DC Roles in Innate Immunity against viruses. Fate of Macrophages Interaction With Viruses MФ & DC Roles in Acquired Immunity against viruses. Conclusion
    3. 3. Fig. 43-2 Pathogens (microorganisms and viruses) INNATE IMMUNITY • Recognition of traits shared by broad ranges of pathogens, using a small set of receptors • Rapid response ACQUIRED IMMUNITY • Recognition of traits specific to particular pathogens, using a vast array of receptors • Slower response Barrier defenses: Skin Mucous membranes Secretions Internal defenses: Phagocytic cells Antimicrobial proteins Inflammatory response Natural killer cells Humoral response: Antibodies defend against infection in body fluids. Cell-mediated response: Cytotoxic lymphocytes defend against infection in body cells.
    4. 4. What’s a virus ? • Viruses are intracellular parasites that can only replicate inside cells. • Made of very simple structures, consisting of proteins and nucleic acid. • They fall into two distinct groups, depending on their nucleic acid: DNA and RNA viruses.
    6. 6. Agranulocytes
    7. 7. Sub-categories of Leucocytes Agranulocytes Monocytes Macrophages Alveolar - Lung Mesangial - Kidney Microglial - Brain Kupffer - Liver Dendritic Cells Langerhans - Epidermis interstitial interdigitating Plasmacytoid
    8. 8. Macrophages • Macrophage are the chief phagocytic cell – Derived from monocytes • Free macrophages wander throughout a region in search of cellular debris • Kupffer cells (liver) and microglia (brain) are fixed macrophages
    9. 9. Dendritic Cells • DC are derived from bone marrow progenitor myeloid cells In the presence of cytokines, such as 1- Granulocyte-macrophage colony-stimulating factor (GM-CSF), 2- Interleukin 4 (IL-4) 3- Tumor necrosis factor alpha (TNF-a), 4- Stem cell factor.
    10. 10. Dendritic Cells • DC are the most potent antigen-presenting cells (APC) of the immune system, They are critical in the initial activation and recruitment of T cells during immune responses • Although most APC can present antigen to and activate memory T cells, DC almost exclusively initiate primary immune reactions involving naive T cells,Cell mediated immunity.
    11. 11. MФ & DC Roles in Innate Immunity against viruses
    12. 12. Macrophages Activation • Macrophages are activated by a variety of stimuli in the course of an immune response. - One of the earliest activating signals comes from chemokines. - Macrophages are further activated by cytokines secreted by T helper cells [IFN-gamma] - and by mediators of the inflammatory response - and by various microbial products.
    13. 13. Macrophages Changes which occur during this transition: •Cells enlarge [5-10x] •Intracellular organelles increase in number and complexity •Cells acquire increased phagocytic ability •Increased secretion of many soluble factors
    14. 14. MФ & DC Roles in Innate Immunity against viruses 1) Phagocytosis : MФ 2) Inflammatory Response: MФ & DC Secretion of an amazing variety of powerful soluble chemical signals cytokines , known as monokines which are vital to the immune responses.( e.g. IFN)
    15. 15. 1-Phagocytosis - MФ • Macrophages can perform viral nucleic acid phagocytosis with or without opsonisaion( the process of using intermediary (Opsonizing) proteins such as antibodies IgG or complement that coat the pathogen to target the microbes for phagocytosis. • Phagocytosis itself is an important activating stimulus.
    16. 16. Mechanism of Phagocytosis • • Chemotaxis Adherence – recognition of carbohydrate “signature” – • • Aided by opsonization Ingestion Digestion 01/09/14 immune response - M.A. Shalaby 21
    17. 17. 2-Inflammatory Response - MФ & DC • Recognition • Cytokines
    18. 18. Recognition • A key property of the innate immune system is the ability to recognize viruses as ‘foreign’. • Viral proteins and nucleic acids are called Pathogen-Associated Molecular Patterns (PAMPs) distinguished from cellular counterparts by cellular proteins called Pattern Recognition Receptors (PRR )that present on cells of the innate immune system : • Macrophages; • Dendritic cells. • These receptors present either in cell membranes or cytoplasm where they detect and activated by that viral components. • NB: Macrophages (PRRs) is a family of transmembrane PRRs, called tolllike receptors (TLRs)
    19. 19. Recognition • TLRs, the membrane-bound toll-like receptors detects: 1. Viral glycoproteins, 2. dsRNA, ssRNA, and the sequence CpG in viral DNA. DNA • RIG-I, the cytoplasmic protein receptors detects : 1. Double-stranded RNA (dsRNA) or 2. Single-stranded RNA (ssRNA) with a 5′-triphosphate.
    20. 20. Pattern Associated Molecular Patterns- PAMPs
    21. 21. Pattern Associated Molecular Patterns- PAMPs
    22. 22. Cytokines • When PRRs binds these PAMPs, a series of reactions PAMPs occur which lead to the synthesis of cytokines, the primary output of the innate defense system. • The presence of cytokines in the blood is typically one of the earliest indications that the host has been infected with a virus. • Over 80 known cytokines are secreted by infected cells including :IFN-α, IFN-β, TNF-α,IL-6, IL-12, and IFN-γ.
    23. 23. Cytokines • Cytokines bind receptors on other cells. • For example, IFN produced by infected cells engages receptors on neighboring cells. • Those cells then produce hundreds of cellular proteins which have antiviral activities. • NB.: When cytokines enter the circulation, they elicit symptoms typical of many viral infections, including fever, sleepiness, lethargy, muscle pain, loss of appetite, and nausea.
    24. 24. Cytokines • TNF-α : one of the earliest cytokines produced. • TNF-α changes nearby capillaries so that circulating white blood cells can be easily brought to the site of infection. • TNF-α can also bind to receptors on infected cells and induce an antiviral response. • Within seconds, a series of signals is initiated that leads to cell death, an attempt to prevent the spread of infection.
    25. 25. Fate of Macrophages Interaction With Viruses Kupffer cell as an example 1- MФ may fail to phagocytose virions e.g., in Venezuelan equine encephalitis virus infection, this is an important factor favoring prolonged high viremia. viremia 2- Virions may be phagocytosed and destroyed because the macrophage system is so efficient.. efficient 3- Virions may be phagocytosed and then transferred passively to the adjacent cell (hepatocytes in liver) e.g., as in Rift valley fever virus infection, the virus replicates in liver cells causing sever hepatitis, the hepatitis virus produced in the liver sustains high viremia. 4- Virions may be phagocytosed by macrophages and replicates in them, more commonly as in infectious canine hepatitis, the virus replicates in both macrophages and hepatocytes, producing severe hepatitis.
    26. 26. MФ & DC Roles in Acqiured Immunity against viruses
    27. 27. MФ & DC Roles in Acquired Immunity against viruses 1) Antigen presentation to T cells to initiate specific immune responses ( Humoral – Cell Mediated ) MФ & DC 2) Antibody dependent cell cytotoxicity (ADCC)- MФ
    28. 28. 1-Antigen presentation to T cells • Role of Dendritic Cells • Major Histocomptability Complex
    29. 29. 1-Antigen presentation to T cells • DC are the most potent antigen-presenting cells (APC) of the immune system, They are critical in the initial activation and recruitment of T cells during immune responses • Although most APC can present antigen to and activate memory T cells, DC almost exclusively initiate primary immune reactions involving naive T cells,Cell mediated immunity.
    30. 30. Dendritic Cells .Multiple, populations of DC have been identified, including •1- Interdigitating DC; •Are critical APC that are located at portals of virus entry such as skin and within/beneath mucosal epithelial surfaces lining the gastrointestinal, respiratory, and urogenital tract, they are also present within the interstitial of virtually all tissue •Its function; 1- Secretion of an amazing variety of powerful soluble chemical signals cytokines 2- These cells migrate to the draining lymph nodes where they can present Ag to T cells 3- Potent inducers of T cell activation
    31. 31. Dendritic Cells • 2- Follicular DC; • Occur within germinal centers of lymphoid tissues such as lymph nodes and spleen. • Its function; • These cells efficiently captured (phagocytose) circulating Ag, which they then present to B lymphocytes, that express the relevant surface receptor specificity, leading to B cell activation and development of humoral (antibody- mediated) immunity
    32. 32. Major Histocompatibility complex (MHC) antigens; MHC antigens are polymorphic proteins the major function of which is to display the portions of immunogenic proteins to Ag specific T lymphocytes. Antigen processing and displayed by MHC complex molecules Class I MHC antigens are expressed on the surface of all nucleated cells except neural cells, and RBCs Class I MHC antigens on the surface of all viral infected cells are typically display the immunogenic protein from the infected virus that are recognized by antigen specific cytotoxic T lymphocytes 1- In class I MHC pathway, peptides are produced from proteins in the cytosol and transported to endoplasmic reticulum (ER) where they bind to class I MHC molecules. The peptide MHC complex are transported to cell surface and displayed for recognition by CD8 T cell
    33. 33. Class II MHC antigen is expressed principally on antigen presenting cells which are Dendritic cells, Macrophages, and B lymphocytes 1.Class II MHC molecule display viral protein at the cell surface that are recognize by antigen specific CD4 T lymphocytes, 2.In class II MHC pathway, proteins are ingested pathway into vesicles and degraded into peptides, which bind to class II MHC molecules being transported in the same vesicles.
    34. 34. 2-Antibody Dependent Cell Mediated Cytotoxicity (ADCC) - •  is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyse a target cell, whose membrane-surface antigens have been bound by specific antibodies. • Cells Capable of Cytotoxicity Express Fc Receptors • Antibody Binds Target Cell, Cytotoxic Cells Bind Fc Portion Of Ab • Antibody Provides The Specificity • Examples Of Cells Capable Of ADCC – MΦ , NK, Neutrophils, eosinophils • Killing Of Target Is Accomplished – TNF (MΦ , NK) – Lytic enzymes (MΦ , Neutrophils, Eosinophils, NK)
    35. 35. ADCC
    36. 36. Conclusion Innate Immunity • Phagocytosis : MФ • Inflammatory Responses: MФ & DC Acquired Immunity • Antigen Presentation: MФ & DC • Antibody Dependent Cell Mediated Cytotoxicity (ADCC) - MФ
    37. 37. Thank you