mechanism of immune systems

8/7/2019 Mechanism of Immune Systems

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HOST DEFENSE AGAINST VIRAL INFECTIONHOST DEFENSE AGAINST VIRAL INFECTION--

ANIMALSANIMALS

Primary defenses- physical and chemical barriers

-skin

-mucous secretions

-tears

-acid pH

-surface cleansing mechanisms (swallowing,

blinking)


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IMMUNE DEFENSESIMMUNE DEFENSES

Three critical processes in the immune defense:

-recognition

-amplification

-control

The immune response to viral infection consists of:Innate (nonspecific) defense: first line of immune

defense, responds to any infection, recognizes

characteristics common to microbial invaders,consists

of interferons, complement, natural killer cells, dictatesthe adaptive response

Adaptive (specific) defense: antibody response and the

lymphocyte-mediated response also called the humoral

and cell-mediated responses


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Innate and adaptive

immune responses:


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The innate immune response:The innate immune response:

Can be activated rapidly and functions within hours

of a viral infection.

Continued activity is damaging to the host.

Considerable interplay occurs between the adaptive

and innate immune defenses.

Important components are:

-cytokines

-complement

-collectins

-natural killer (NK) cells


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Differentiates self from nonself, tailored to the

particular invader

Has memory; subsequent infection by the same

agent are met with a robust and highly specific

response that stops the infection

Consists of the:

antibody response - humoral response

lymphocyte mediated response- cell-mediated

response

The adaptive immune response:The adaptive immune response:


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ONeill, Scientific American, Jan 2005 pp. 38-45


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The inflammatory response:The inflammatory response:

Essential in initiating immune defenses

Cell and tissue damage caused by infection

induces the inflammatory response

Provides communication with the components of

the immune system

Characterized by redness, heat, swelling and pain


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The inflammatory assault is initiated by TollThe inflammatory assault is initiated by Toll--like receptorslike receptors


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Inflammation can be initiated in

several ways:

By interferon released by

immature dendritic cells

Locally produced cytokines,

such as interleukin-1, tumor

necrosis factor- Eand

interferon-K control the

reactions that occur during

inflammation

Inflammatory cytokines also

activate B and T cells that are

needed for the adaptive

response


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Cytokines:Cytokines:

Regulatory proteins that mediate intercellular

communication during an antiviral defense.

Their presence is one of the first indicators that the

host has been infected.

They act locally, near the cells that make them.

They control inflammation, induce and antiviral state

in cells and regulate the adaptive immune response.

They exert their activities by binding to specific

receptors and activating gene expression. Three types of interferons are the most important

cytokines in the innate response to viral infection.


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Ifn-Kis induced only when certain lymphocytes are

stimulated to replicate and divide after binding a foreign

antigen

Ifn-E and Ifn-F are induced by viral infection of any cell

type

InterferonsInterferons


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Ifn is induced by accumulation of double stranded

RNA (dsRNA).

Ifn induces gene expression at the transcriptional

level after binding to specific cell surface receptors.

A cell that is bound to interferon and responds to it

is in an antiviral state. Ifn induces expression of more that 100 genes,

products of many of these genes possess broad

spectrum antiviral activity.

They lead to cell death by apoptosis or programmedcells death, limiting cell to cell spread of virus.

Production of large amounts if Ifn causes common

symptoms such as fever, chills, nausea, etc.

InterferonsInterferons


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Interferon induced antiviral responses:Interferon induced antiviral responses:

Both viral and cellular protein synthesis stops in Ifn

treated cells.

This is dues to two cellular proteins, ds-RNA activated

protein kinase (Pkr) and ribonuclease L (RNase L).

Pkr is a serine/threonine kinase that has antiviralproperties, as well as antiproliferative and antitumor

functions.

Activated Pkr phosphorylates the alpha subunit of the

translation initiation factor eIF2, inhibiting translation. RNase L is a nuclease that can degrade cellular and viral

RNA; its concentration increases after Ifn treatment.


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RNase L concentration increases 10-1,000 fold after

Ifn treatment, but is inactive unless 2-5-oligo(A)synthetase is produced.

2-5-oligo(A) synthetase produces 2, 5 oligomers of

adenylic acid, only when activated by dsRNA.

These poly(A) oligomers then activate RNase L,

which degrades all host and viral mRNA in the cell.

RNase L participates not only in Ifn-mediated

antiviral defense, but also in apoptosis.

Ifn is a broad spectrum, highly effective antiviral

agent. However, viruses have developed numerous

mechanisms for inhibiting interferon action.

Interferon induced antiviral responses:Interferon induced antiviral responses:


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Humoral response

Consists of lymphocytes of the B-cell lineage

Interaction of a specific receptor on precursor B

lymphocytes with antigens promotes differentiation

into antibody secreting cells (plasma cells). Cell-mediated response

Consists of lymphocytes of the T-cell lineage

Cytotoxic T cells (Tc cells) and T-helper cells (Thcells) are the key effectors of this response.

The adaptive immune response:The adaptive immune response:


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T lymphocytes recognize antigens on the surface of

self cells.

The antigens on self cells can be recognized only by a

receptor on the surface of T cells when they are bound

to the MHC family of membrane proteins.

The Th cells recognize antigens bound to MHC class II

molecules and produce powerful cytokines that affect

other lymphocytes (B and T cells) by promoting or

inhibiting cell division and gene expression.

Once activated by Th cells, Tc cells differentiate into

CTLs that can kill virus infected cells.

Cell-mediated response cont.


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The antigen receptors on the surface of B and T cellsThe antigen receptors on the surface of B and T cells

B cells have about 100,000 molecules

of a single antibody receptor per cell,which has specificity for one antigen

epitope.

T cells bearing the surface membraneprotein CD4 always recognize

peptides bound to MHC class II

proteins and function as Th cells.

T cells bearing the surface membraneprotein CD8 always recognize peptide

antigens bound to MHC class I

proteins and function as cytotoxic T

cells.


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Endogenous antigen processing: MHC class I peptideEndogenous antigen processing: MHC class I peptide

presentationpresentation

Intracellular proteins of host and virus are marked for

degradation by ubiquitination and are degraded by theProteasome.

The resulting viral peptides are transported into the ER

lumen by the Tap1-Tap2 heterodimeric transporter.

In the ER lumen, viral peptides associate with newly

synthesized MHC class I molecules.

MHC class I-peptide complex is transported to the cellsurface via the golgi compartments.

On the cell surface, the MHC class I-peptide complex

interacts with the T- cell receptor of a Tc cell carrying the

CD8 coreceptor.


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Endogenous antigen processing: MHC class I peptide presentationEndogenous antigen processing: MHC class I peptide presentation


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Exogenous antigen processing: MHC class II peptideExogenous antigen processing: MHC class II peptide


MHC class II complex is prevented form binding to viral

peptides in the ER by association with the invariant chain.

The complex is transported through golgi where the

invariant chain is removed, activating the MHC class II

complex.

The peptides are derived from extracellular proteins

that enter the cell by endocytosis.

Viral proteins are degraded in the lysosomes by

proteases that are activated by low pH.

Endosomes fuse with vesicles containing MHC class II.

On the surface of the cell the MHC class II complex

interacts with the T cell receptor of a Th cell carrying the

CD4 coreceptor.


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Exogenous antigen processing: MHC class II peptideExogenous antigen processing: MHC class II peptide


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