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