Medi 4318 Introduction to host defenses Ahmad Sh. Silmi Rm 326 Admin. Building [email protected] Office hours: Every week Sun &Tues 11:00 to 12:00

Medi 4318

Introduction to host defenses

Ahmad Sh. SilmiRm 326 Admin. [email protected]

Office hours: Every week Sun &Tues 11:00 to 12:00.

What are host defenses?

What are the reasons for host defenses?

• Defense against infections.

• Defense against toxins.

• Defense against internal dangers (cancer, bad pregnancy).

• Regulating defenses: autoimmunity and pregnancy.

What are the range of mechanisms calledhost defenses?

Adaptive immunity: Selection of cells that secrete or kill. Requires DNA rearrangements and takes about a week. Have persistent memory.

Innate defenses: A broad range of mechanisms that don’trequire selection of cells to secrete or kill specific things (usuallyready instantly or within a few hours).

Why Differentiate between the Innate and Acquired Immunity ?

Innate Immunity

• Characteristics:

– Universal

– Rapid

– Lacks memory

– Non specific but ...

Acquired Immunity

• Characteristics:

– Not universal

– ‘Slow’ to develop

– Possesses memory

• Specific but….

– ‘Plays to the tune of the Innate immune system’

Both innate and immune defense cells are generated inbone marrow (or at least start there).

*

*

*

*

*

*,** Mostly

innatedefense

cells *

*

*

*

*,** Mostlyadaptiveimmune

cells.*

Kuby Fig 2.2

Adaptive immunity is all about generatingfunctional lymphocytes (B and T).

Generation of cellular diversity (bone marrow and thymus)

Selection of cells specific to a given antigen (lymph node,spleen, and mucosal tissue)

Clonal expansion of these cells (lymph node, spleen and mucosal tissue)

Function of mature cells (entire body)

A B lymphocyte has a single kind of BCR which binds onlyone type of antigen.

B lymphocyte

B cell receptor (BCR)Antigen

T lymphocyte

T cell receptor

MHC

Antigen (a bit of it)

Antigen Antigen presentingcell (APC)

A T lymphocyte has a single kind of TCR thatrecognizes only one kind of antigen.

Adaptive immunity is all about generatingfunctional lymphocytes.


Selection of cells specific to a given antigen (lymph node,spleen and mucosal tissue)

Clonal expansion of these cells (lymph node, spleen andmucosal tissue)


How and where is cellular diversity generated?

I. B lymphocytes.

Bone marrow is where B progenitor cells become mature B cellsand migrate to lymph nodes and spleen looking for antigen.

Bone marrow is the primary lymphoid organ for B cells

How and where is cellular diversity generated?

II. T lymphocytes:

Pre-T cells (no TCR) migrate from bone marrow to the thymus where they

rearrange DNA.

Within the thymus the pre-T cells

mature into T cells by rearranging

their TCR DNA and generate about

107 cells (each with one copy of unique TCR DNA) per day, then exit looking for that antigen.

This process is antigen-independent.

Thymus is the primary lymphoid organ for T cells.

A question for votes:

Where and how is B lymphocyte diversity generated?

A. In its primary lymphoid tissue, the thymus.

B. By generating new DNA sequences in every B cell.

C. In bone marrow by rearranging existing DNA.

D. In spleen by eliminating cDNA.






Naïve B cells(from bone marrow through blood)

Naïve T cells(from thymus through blood)

Antigen (either throughlymph ducts or blood)

lymph nodesor spleen

If Antigen notfound, the naïve B and T cells re-

circulate and die.

If Antigen isfound, the naïve

B and T cellssurvive and clonally

expand in the secondary lymphoid organs.

The lymph nodes and spleen are secondary lymphoid organs






A B cell has a single kind of BCR which binds onlyone type of antigen and can clonally expand and

mature into plasma cells that will secrete theBCR (Ig) which will bind that antigen.

B lymphocyte

Plasma cell

BCR

immunoglobulin

clonalexpansion

B memorycells

Clonal expansion of T Lymphocytes

T lymphocyte

T cell receptor

MHC

Antigen (a bit of it)

AntigenpreCTL

T helper cell

A single T lymphocyte Many T lymphocytes

ClonalExpansion

TCR

TCR





Functional mature cells (entire body)

Plasma cells

immunoglobulin

Functional B lymphocytes

Memory B lymphocytes

BCR

rapid clonalexpansion

Both plasma cells and memory B cellsare present in all the Ig subclasses:

IgM, many kinds of IgG, IgA, IgE.

preCTL

T helper cells.TDTH cells

TCR

TCR

Functional T lymphocytes

When mature, these cells leave thesecondary lymphoid organs, enter the

blood steam and home to where they find their antigen.

TCR

T memory cells (both types)

Clonal expansion alsoproduces memory cellsof both types. These

memory cells recirculate and

can be reactivated byexposure to

antigen in secondarylymphoid tissue.

A question for voting:

What does the term clonal expansion mean?

A. A stem cell is triggered to proliferate to forma clone of progeny cells.

B. A naïve B cell meets its antigen and proliferatesto produce lots of progeny cells.

C. A T memory cell meets its antigen on an APC ina secondary lymphoid organ and proliferates.

D. All of the above.

E. None of the above.






In the generation of diversity, why don’t lymphocytes attack our own cells?

Because of tolerance: central and peripheral.

Central tolerance involves elimination of almost all self-reactive lymphocytes at the site of production:

the primary lymphoid organs of bone marrow and thymus.

Peripheral tolerance involves suppressing immune responsesto antigens not eliminated in central tolerance.

How cells are gotten rid of in central tolerance.

By apoptosis,which is

non-inflammatory.

Before B lymphocytes can migrate out of bone marrow,all those cells bearing a BCR that reacts with a ‘self’antigen bind to bone marrow stromal cells and die.

Apoptosis

T lymphocyte central tolerance.

T cells come in two flavors: CD4 and CD8 positive.

Both are generated randomly in the thymus by recognitionof a bit of antigen presented on a particular MHC molecule

in the context of either CD4 or CD8 binding.

Major histocompatibility complex antigens(MHC)

1. MHC are cell surface molecules on APC that presentthe bit of antigen to T lymphocytes.

2. There are two kinds of MHC: class I and class II.

3. Both molecules are fairly polymorphic ( different choices in the population) and are heritable.

4. MHC class I has a one chain binding site while MHCclass II has two chains.

T cells must be activated by specific antigen presented by MHC class II (to CD4 cells) and MHC class I (to CD8 cells)

MHC class I presents internal antigen andMHC class II external antigen.

A chant for APC:

Internal proteins are processed and presented by MHC Ito CD8 positive T lymphocytes.

External proteins are processed and presented by MHC IIto CD4 positive T lymphocytes.

What do the CD4 positive T lymphocytes do?

External pathogens are complexed by Ig moleculesproduced by B lymphocytes.

Internal pathogens are killed (along with the host cell)by CD8 positive CTL.

The role of mature CD4 positive T lymphocytes

1. They provide ‘help’ in the form of cytokines in an antigen-specific manner to developing B cells that allow class-switchingand memory cell formation.

2. They provide ‘help’ in the form of cytokines in an antigen-specificmanner to developing CD8 positive T cells that greatly enhancesthe response.

3. Mature CD4 positive T cells migrate to tissues and help clearmacrophages of infections (the so-called DTH response).

So what does CD4 and CD8 have to do with the processof central tolerance in developing T cells?

This is called positive selection.

Negative selection occurs next and is similar to the B cell process.

Cortex

Medula

4. In the medula, singlepositive T cells can bind to self peptide antigenspresented on MHC class I or II on thymic dendriticcells. If they do, they die.

4

3

3. The CD4/CD8 positivethymocytes (double positive)loose CD4 or CD8 to becomeCD4 and CD8 T cells andmigrate to the medula.



Selection of cells specific to a given antigen (lymph nodespleen and mucosal tissue)



How does antigen get to lymphocytes?.

In three ways:

Through lymphatic ducts that lead to lymph nodes.

Through blood which goes to spleen.

Directly to lymphoid tissue through mucosal tissue (GALT)

MALT directly faces its antigen: an example is the gut.

The direct interface with outside is provided in the gutby specialized M cells, which take up whole antigen and feed it directly to macrophages, T and B cells inside it.

Secondary lymphoid tissues are where lymphocytes meets antigen which comes from lymph ducts (and blood) that

connect to lymph nodes (or spleen).

The spleen is very much like the lymph node only it does not have lymph node connection: only blood.

What form of antigen enters the secondarylymphoid tissue?

Free antigen whichis necessary for

survival and proliferationof B lymphocytes

Antigen inside adendritic cell,

a super APC, necessaryfor T lymphocyte survival

and proliferation.

What are dendritic cells?A kind of antigen presenting cell.

There are severalkinds of dendriticcells, but only one

that brings antigen into the lymph node.

Toregionallymphnode

Activation of

specific immune response

Dendritic cells stationed beneath skin (a sentinal cell)differentiate and migrate when encountering a

dangerous antigen.






Now we have free antigen, antigen being processed by dendritic cells and B and T lymphocytespresent in secondary lymphoid tissue, what

happens?

Free antigen binds to its BCR on B lymphocytes and stimulateslimited clonal proliferation and differentiation.

Dendritic cells present antigen to CD4 positive T lymphocytesand stimulate clonal proliferation and differentiation.

Dendritic cells present antigen to CD8 positive T lymphocytesand activate the cells for clonal expansion and differentiation.

The first and third stimulations occur much better with ‘T cellhelp’ (from antigen-specific, mature CD4 positive helper cells).

The life cycle of a B lymphocyte.

Immune memory: a much larger and faster responsethe second time around.

(mostlyIgM)

(IgM, IgG,IgA, IgE)

These secondary effects are all due to CD4 T cell help.

Plasma cell

soluble IgM

B lymphocyte

BCRclonal

expansion maturation

Antigen driven clonal expansion and maturation withoutT cell help.

APC

The B lymphocyte as anAPC

Antigen-specific BCR

Antigen processing

into peptides

MHC

peptide

T helper cell

Help comes in the form of

cytokines, soluble and cell-associated, produced by the

T helper cell.

Antigen-specific CD8 positive cells meet antigenpresented by a dendritic cell, receive help froma T helper cell, clonally expand and mature into

a cytotoxic T lymphocyte (CTL).

clonal expansionand maturation

activation of CD8positive T cell by

antigen presentedon MHC class I

activation of T-helper cells by antigen

presented by MHCclass II.

MHC II

MHC I






Output from secondary lymphoid tissue:

1. Plasma cells that produce Ig.

2. B memory cells with memory responses to specificantigens, some already Ig class switched.

3. CD4 positive T helper effector cells that may ormay not travel to the periphery.

4. CD4 memory cells for every effector population.

5. CD8 positive (CTL) that travel to the periphery.

6. CD8 memory cells for every effector population.

A question for voting:

Where are most CD4 and CD8 T cells selected fornon-recognition of self antigens?

A. In the primary lymphoid organ (bone marrow).

B.In secondary lymphoid organs (lymph nodes and spleen).

C.In the thymus at the end of their maturation process.

D.All of the above.

E.None of the above.

How do all these cells know where to go afterbeing activated?

They have receptors for or express chemokines, cell adhesionmolecules, integrins and selectins that guide them to where they should go. We shall call them collectively addressins.

The role of addressins:

naïve B or Tcell

Spleen or lymph nodeplease.

Vascular endothelial cell

Spleen or lymph node

Addressins or addresses are combinations of lectins, integrins, cell adhesion molecules (CAMs) and chemokines and chemokine receptors.

Addressins are the way immune cells find their waythrough the process of maturation and find their

targeted infection.

Naïve T lymphocyte

dendritic cell

TCR

MHC with processed antigen

Dendritic cell,please

dendritic cell

mature T helper lymphocyte

BCR

naïve B lymphocyte

naïve B cell,please

naïve B cell

The vascular endothelium expresses addresses in responseto cytokines released by macrophages and mast cells

fighting the infection (innate response).

Effector B cells (plasma cells) have addressins that allowthem to accumulate in bone marrow, secondary lymphoid

organs or just beneath the epthelium.

They then start to secrete specific Ig.

lambda secretors = yellowkappa = red.

IgA = red, IgG = green

medulary lymph nodes bone marrow

A pre-CTL leaves a secondary lymphoid organ, entersblood, extravasates into an inflamed tissue, migrates to

the site of infection then recognizes the cell to bekilled by the peptide in its MHC class I.

Death is by apoptosis, whichneatly packages everythingwithin a plasma membranewhich will be picked up by a

macrophage and disposed of.

Where antigen (vasicular stomatitis virus) specificCTLs end up.

Mature CD4 T cells also migrate into blood, cross aninflamed endothelium and are further activated by

interaction of their TCR with their antigen expressedon MHC class II.

The result is activation of the macrophage by IFNgreleased by the mature CD4 cell. This activation allowsthe macrophage to kill internalized viruses, bacteria and

parasites.






Documents

Medi 4318 Introduction to host defenses Ahmad Sh. Silmi Rm 326 Admin. Building [email protected] Office hours: Every week Sun &Tues 11:00 to 12:00