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

3. Presented by
Dr. Faris Salama

4. Agenda
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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

6. 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.

7. 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.

8. Viruses Families
VIRUS
FAMILY
NUCLEIC A.
ADENOVIRUS
ADENOVIRIDAE
DNA (ds)
PORCINE CIRCOVIRUS
CIRCOVIRIDAE
DNA (ss)
REOVIRIDAE
RNA (ds)
PARAMYXOVIDAE
RNA (ss)
PORCINE ROTAVIRUS
BLUE EYE DISEASE

9. Agranulocytes

10. Sub-categories of Leucocytes
Agranulocytes
Monocytes
Macrophages
Alveolar - Lung
Mesangial - Kidney
Microglial - Brain
Kupffer - Liver
Dendritic Cells
Langerhans - Epidermis
interstitial
interdigitating
Plasmacytoid

12. 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

13. 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.

14. 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.

15. MФ & DC Roles in Innate
Immunity against viruses

17. 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.

18. 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

19. 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)

20. 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.

21. Mechanism of Phagocytosis
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Chemotaxis
Adherence –
recognition of
carbohydrate
“signature”
–
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Aided by opsonization
Ingestion
Digestion
01/09/14
immune response - M.A. Shalaby
21

22. 2-Inflammatory Response - MФ & DC
• Recognition
• Cytokines

23. 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)

24. 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.

25. Pattern Associated Molecular Patterns- PAMPs

26. Pattern Associated Molecular Patterns- PAMPs

27. 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.

28. 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.

29. 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.

30. 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.

31. MФ & DC Roles in Acqiured
Immunity against viruses

32. 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

33. 1-Antigen presentation to T cells
• Role of Dendritic Cells
• Major Histocomptability Complex

34. 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.

36. 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

37. 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

40. 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

41. 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.

42. 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)

43. ADCC

44. Conclusion
Innate Immunity
• Phagocytosis : MФ
• Inflammatory Responses:
MФ & DC
Acquired Immunity
• Antigen Presentation: MФ
& DC
• Antibody Dependent Cell
Mediated Cytotoxicity
(ADCC) - MФ

45. Thank you