macrophages & dendritic cells in viral infection
DESCRIPTION
The Roles of Macrophages and Dendritc Cells Against Viral Infection. 1-Roles in Innate Immunity 2-Roles in acquired ImmunityTRANSCRIPT
Presented byPresented by
Dr. Faris SalamaDr. Faris Salama
AgendaAgenda• Introduction about immunity.Introduction about immunity.• What’s a virus ?What’s a virus ?• Cells of The Immune System.Cells of The Immune System.• Macrophages (MMacrophages (MФФ)& Dendritic Cells ( DC))& Dendritic Cells ( DC)• MMФФ & DC Roles in Innate Immunity against viruses. & DC Roles in Innate Immunity against viruses.• Fate of Macrophages Interaction With VirusesFate of Macrophages Interaction With Viruses• MMФФ & DC Roles in Acquired Immunity against & DC Roles in Acquired Immunity against
viruses.viruses.• ConclusionConclusion
Fig. 43-2
INNATE IMMUNITY
Recognition of traitsshared by broad rangesof pathogens, using asmall set of receptors
•
• Rapid response
• Recognition of traitsspecific to particularpathogens, using a vastarray of receptors
• Slower response
ACQUIRED IMMUNITY
Pathogens(microorganisms
and viruses)
Barrier defenses:SkinMucous membranesSecretions
Internal defenses:Phagocytic cellsAntimicrobial proteinsInflammatory responseNatural killer cells
Humoral response:Antibodies defend againstinfection in body fluids.
Cell-mediated response:Cytotoxic lymphocytes defendagainst infection in body cells.
What’s a virus ?What’s a virus ?
• Viruses 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.
Viruses FamiliesViruses Families
VIRUS FAMILY NUCLEIC A.
ADENOVIRUS ADENOVIRIDAE DNA (ds)
PORCINE CIRCOVIRUS CIRCOVIRIDAE DNA (ss)
PORCINE ROTAVIRUS REOVIRIDAE RNA (ds)
BLUE EYE DISEASE PARAMYXOVIDAE RNA (ss)
Agranulocytes
Sub-categories of Sub-categories of LeucocytesLeucocytes
AgranulocytesMonocytes
Macrophages Dendritic Cells
Alveolar - LungMesangial - KidneyMicroglial - BrainKupffer - Liver
Langerhans - Epidermisinterstitial interdigitating Plasmacytoid
MacrophagesMacrophages• Macrophage are the chief phagocytic cellMacrophage are the chief phagocytic cell
– Derived from monocytesDerived from monocytes
• Free macrophages wander throughout a region in Free macrophages wander throughout a region in search of cellular debrissearch of cellular debris
• Kupffer cells (liver) and microglia (brain) are Kupffer cells (liver) and microglia (brain) are fixed macrophagesfixed macrophages
• 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.
Dendritic CellsDendritic 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.
Dendritic CellsDendritic Cells
MMФФ & DC Roles in Innate & DC Roles in Innate Immunity against virusesImmunity against viruses
Macrophages ActivationMacrophages Activation
• Macrophages are activated by a variety of stimuli Macrophages are activated by a variety of stimuli
in the course of an immune response.in the course of an immune response.
- One of the earliest activating signals comes - One of the earliest activating signals comes
from chemokines. from chemokines.
- Macrophages are further activated by - Macrophages are further activated by
cytokines secreted by cytokines secreted by T helper T helper cells [ cells [IFN-IFN-
gammagamma] ]
- and by - and by mediators of the inflammatory response mediators of the inflammatory response
- and by - and by various microbial productsvarious microbial products..
MacrophagesMacrophages
Changes which occur during this transition:Changes which occur during this transition:
•Cells Cells enlargeenlarge [5-10x] [5-10x]
•Intracellular Intracellular organelles increaseorganelles increase in number in number
and complexityand complexity
•Cells acquire increased Cells acquire increased phagocytic abiphagocytic ability lity
•Increased Increased secretion of many soluble factors secretion of many soluble factors
MMФФ & DC Roles in Innate & DC Roles in Innate Immunity against virusesImmunity against viruses
1)1) Phagocytosis : Phagocytosis : MMФФ
2)2) Inflammatory Response: Inflammatory Response: MMФФ & DC & DC
Secretion of an amazing variety of powerful soluble Secretion of an amazing variety of powerful soluble
chemical signals chemical signals cytokines cytokines , known as , known as monokinesmonokines
which are vital to the immune responses.( e.g. which are vital to the immune responses.( e.g.
IFN)IFN)
1-Phagocytosis - 1-Phagocytosis - MMФФ
• Macrophages can perform viral nucleic acid Macrophages can perform viral nucleic acid
phagocytosis phagocytosis with or without opsonisaion( the
process of using intermediary (using intermediary (OpsonizingOpsonizing) proteins ) proteins
such as such as antibodiesantibodies IgG or or complementcomplement that coat the that coat the
pathogen pathogen to target the microbes for phagocytosis..
• Phagocytosis itself is an important activating Phagocytosis itself is an important activating
stimulus. stimulus.
Mechanism of PhagocytosisMechanism of Phagocytosis• ChemotaxisChemotaxis• Adherence – Adherence –
recognition of recognition of carbohydrate carbohydrate “signature”“signature”– Aided by opsonizationAided by opsonization
• IngestionIngestion• DigestionDigestion
04/11/23 21immune response - M.A. Shalaby
2-Inflammatory Response - M2-Inflammatory Response - MФФ & DC & DC
• RecognitionRecognition• CytokinesCytokines
RecognitionRecognition• 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 Pathogen-Associated
Molecular Patterns Molecular Patterns ((PAMPsPAMPs) ) distinguished from cellular
counterparts by cellular proteins called Pattern Recognition Pattern Recognition
ReceptorsReceptors ((PRRPRR )that present on cells of the innate immune system :)that present on cells of the innate immune system :
• Macrophages;Macrophages;
• Dendritic cells.Dendritic cells.
• These receptors present either in cell membranes or cytoplasm
where they detect and and activated by activated by that that viral components.
• NB: Macrophages (PRRs) is a family of transmembrane PRRs, Macrophages (PRRs) is a family of transmembrane PRRs,
called toll-like receptors (TLRs)called toll-like receptors (TLRs)
RecognitionRecognition• TLRs, the membrane-bound toll-like receptors
detects:
1.1.Viral glycoproteins,Viral glycoproteins,
2.2.dsRNA, ssRNA, and the sequence CpG in viral dsRNA, ssRNA, and the sequence CpG in viral DNADNA.
• RIG-I, the cytoplasmic protein receptors detects :
1.1.Double-stranded RNA (dsRNA) or Double-stranded RNA (dsRNA) or
2.2.Single-stranded RNA (ssRNA)Single-stranded RNA (ssRNA) with a 5′-triphosphate.
Pattern Associated Molecular Patterns- PAMPs
Pattern Associated Molecular Patterns- PAMPs
Cytokines
• When PRRsPRRs binds these PAMPsPAMPs, a series of reactions
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 presence of cytokines in the blood is typically one of
the earliest indications that the host has been infected the earliest indications that the host has been infected
with a virus.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.
Cytokines
• Cytokines bind receptors on other cells.
• For example, IFN produced IFN produced by infected cells
engages receptors on neighboring cells.
• Those cells then produce hundreds of cellular cellular
proteins which have antiviral activities.proteins which have antiviral activities.
• NB.: When cytokines enter the circulation, they elicit symptoms typical NB.: When cytokines enter the circulation, they elicit symptoms typical
of many viral infections, including fever, sleepiness, lethargy, muscle of many viral infections, including fever, sleepiness, lethargy, muscle
pain, loss of appetite, and nauseapain, loss of appetite, and nausea.
Cytokines
• TNF-αTNF-α : one of the earliest cytokines produced.
• TNF-αTNF-α changes nearby capillaries so that circulating
white blood cells can be easily brought to the site of
infection.
• TNF-αTNF-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.
Fate of Macrophages Interaction With VirusesFate of Macrophages Interaction With VirusesKupffer cell as an example
1- MMФФ may fail to phagocytose virions e.g., in Venezuelan equine encephalitis virus infection, this is an important factor favoring prolonged high viremiahigh viremia.
2- Virions may be phagocytosed and destroyed because the macrophage system is so efficientmacrophage system is so 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 hepatitissever hepatitis, the 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.
MMФФ & DC Roles in & DC Roles in Acqiured Immunity Acqiured Immunity
against virusesagainst viruses
MMФФ & DC Roles in Acquired & DC Roles in Acquired Immunity against virusesImmunity against viruses
1)1) Antigen presentation to T cells Antigen presentation to T cells
to initiate specific immune responses to initiate specific immune responses
( Humoral – Cell Mediated ) ( Humoral – Cell Mediated ) MMФФ & DC & DC
2) 2) Antibody dependent cell cytotoxicity Antibody dependent cell cytotoxicity
(ADCC)-(ADCC)- M MФФ
• Role of Dendritic Cells
• Major Histocomptability Complex
1-Antigen presentation to T 1-Antigen presentation to T
cells 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.
1-Antigen presentation to T 1-Antigen presentation to T
cells 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 Secretion of an amazing variety of powerful soluble chemical signals chemical signals cytokines cytokines 2- These cells migrate to the draining lymph nodes where they can present Ag to T cells3- Potent inducers of T cell activation
Dendritic CellsDendritic 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
Dendritic CellsDendritic Cells
Major Histocompatibility complex (MHC) antigensMajor Histocompatibility complex (MHC) antigens;
MHC antigens are polymorphic proteins the major function of which is to display the portions of immunogenic proteins display the portions of immunogenic proteins to Ag specific T lymphocytes.to Ag specific T lymphocytes.
Antigen processing and displayed by MHC complex moleculesClass 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 lymphocytescytotoxic T lymphocytes
1- In class I MHC pathway, peptides are produced from proteins in the cytosol and transported to endoplasmic endoplasmic reticulum (ER) 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
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 TCD4 T lymphocytes,
2.2.In class II MHC pathwayIn class II MHC pathway, proteins are ingestedingested into vesiclesvesicles and degraded into peptides, which bind to class II MHC molecules being transported in the same vesicles.
• 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 ReceptorsCells Capable of Cytotoxicity Express Fc Receptors
• Antibody Binds Target Cell, Cytotoxic Cells Bind Fc Portion Of AbAntibody Binds Target Cell, Cytotoxic Cells Bind Fc Portion Of Ab
• Antibody Provides The SpecificityAntibody Provides The Specificity
• Examples Of Cells Capable Of ADCCExamples Of Cells Capable Of ADCC
– MM, NK, Neutrophils, eosinophils, NK, Neutrophils, eosinophils
• Killing Of Target Is Accomplished Killing Of Target Is Accomplished
– TNF (MTNF (M, NK) , NK)
– Lytic enzymes (MLytic enzymes (M, Neutrophils, Eosinophils, NK), Neutrophils, Eosinophils, NK)
2-2-Antibody Dependent Cell Antibody Dependent Cell Mediated Cytotoxicity (ADCC) - Mediated Cytotoxicity (ADCC) -
ADCC
ConclusionConclusion
Innate ImmunityInnate Immunity• Phagocytosis : Phagocytosis : MMФФ• Inflammatory Responses: Inflammatory Responses:
MMФФ & DC & DC
Acquired ImmunityAcquired Immunity• Antigen Presentation: Antigen Presentation: MMФФ
& DC & DC • Antibody Dependent Cell
Mediated Cytotoxicity (ADCC) - MMФФ
Thank youThank you