The Role Of Macrophages and Dendritic Cells in Viral Immunity

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

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.

·         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.

MФ & DC Roles in Innate Immunity against viruses

1.   Phagocytosis- MФ

In order to perform phagocytosis Macrophages should be activated

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.

·         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

·         Phagocytosis occur with or without opsonisation(the process of attaching opsonins such as IgG  or complement fragment, to microbial surfaces to target the microbes for phagocytosis).

2.   Inflammatory Response

o   Recognition

o   Cytokines

Recognition

o   A key property of the innate immune system is the ability to recognize viruses as ‘foreign’.

o   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 :

1.    Macrophages;

2.    Dendritic cells.

o   These receptors present either in cell membranes or cytoplasm where they detect and activated by that viral components.

o   NB: Macrophages (PRRs) is a family of transmembrane PRRs, called toll-like receptors (TLRs)

o   TLRs, the membrane-bound toll-like receptors detects:

1.    Viral glycoproteins,

2.    dsRNA, ssRNA, and the sequence CpG in viral DNA.

o   RIG-I, the cytoplasmic protein receptors detects :

1.    Double-stranded RNA (dsRNA) or

2.    Single-stranded RNA (ssRNA) with a 5′-triphosphate.

Cytokines

o   When PRRs binds these PAMPs, a series of reactions occur which lead to the synthesis of cytokines, the primary output of the innate defense system.

o   The presence of cytokines in the blood is typically one of the earliest indications that the host has been infected with a virus.

o   Over 80 known cytokines are secreted by infected cells including :IFN-α, IFN-β, TNF-α,IL-6, IL-12, and IFN-γ.

o   Cytokines bind receptors on other cells.

o   For example, IFN produced by infected cells engages receptors on neighboring cells.

o   Those cells then produce hundreds of cellular proteins which have antiviral activities.

o   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.

o   TNF-α : one of the earliest cytokines produced changes nearby capillaries so that circulating white blood cells can be easily brought to the site of infection.

o   TNF-α can also bind to receptors on infected cells and induce an antiviral response.

o   Within seconds, a series of signals is initiated that leads to cell death, apoptosis an attempt to prevent the spread of infection.

3.   Direct cytotoxicity

MФ & DC Roles in Acquired Immunity against viruses

1.   Antigen Presentation: MФ & DC

·         When virus infect other cells, e.g.  Dendritic cell type-1(DC-1) that can express both arms MHC II and MHC1 on its surface

·         TLRs present in sentinel cells e.g DC-1 bind to specific epitope will define both the releasing cytokines together with the use of MHC-1 or MHCII or both

·         a-MHC II arm

·         The viral protein constitute inside the infected -DC1

·         DC-1 act as APC process viral protein and display it through its surface via MHC-II

·         MHC II stimulate Th1 that connected to DC-1 through TCR & CD4 (2signals)

·         Moreover DC-1 stimulates Th1 through secretion of cytokine IL-12 (3^rd signal)

·         Th1 undergoes proliferation and differentiation

·         Effector Th1                                    Memory Th1

·         Secrete cytokines

·         IL2-IFN Ɣ

·         Stimulate CD8 T cytotoxic in the lymph node

·         CD8 T cytotoxic migrates and attacks the infected cells through binding its TCR and CD8 to MHC1 with viral peptide on surface of infected hepatocyte

·         Destruction of the infected cell through

·         Perofrin make pores in the target cell membrane then Ganzym enter the pores hydrolyses the nucleic acid of infected cell

·         b- MHC 1 arm

·         On the other hand CD8 cytotoxic bind to DC1 MHC1 arm through TCR and CD8(2 signals)

·         And activated by cytokines from Th1 IL2-IFN Ɣ ( other 2 signals)

·         T cytotoxic undergoes proliferation and differentiation into:

·         Effector T cytotoxic                             Memory T cytotoxic

·         Effector CD8T cytotoxic leave lymph node to circulation and migrate to the infected hepatocyte,

·         And most prominently that epitope presented by DC-1 will define the type of effector CD8 cytotoxic cell

·         2 different pathway of killing infected hepatocyte:

·         1- CD8 T cytotoxic migrates and attacks the infected cells through binding its TCR and CD8 to MHC1 on surface of infected hepatocyte

·         Destruction of the infected cell through

·         Perofrin make pores in the target cell membrane then Ganzym enter the pores hydrolyses the nucleic acid of infected cell

2.   Antibody Dependent Cell Mediated Cytotoxicity (ADCC) - MФ

·         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

ŽMF, NK, Neutrophils, eosinophils

·         Killing Of Target Is Accomplished

ŽTNF (M, NK)