Clonal Diversification of Lymphocytes Review of last lecture Bone Marrow Thymus Whenever immature pre-T Cells recognize self-antigens, they are programmed.

Clonal Diversification

of Lymphocytes

Review of last lecture

Bone Marrow

Thymus

Whenever immature pre-T Cells recognize self-antigens, they are programmed to auto-destruct in the Thymus

Whereas

Mature T cells proliferate when they contact antigens

98% pre-T cells die in the thymus

Bone Marrow

When immature pre-B Cells recognize self-antigens then they auto-destruct in the Bone Marrow

Clones of Mature B Cells proliferate when contacting antigen

Tolerance

to self substances

Treatments for Autoimmune diseases - Wipe out the mature B cells // Reboot – some exceptions Sjögren's Syndrome

Antigen12

3

One clone of B cells (B lymphocytes)

by definition will only bind to one type of antigenic determinant

e.g., either to outside determinant

#1 or to #2 or to #3

B Cell

clone #2 B Cell

clone #1

Mature B Cells

Antigen12

3

Fc region

Fab region

B Cell clone #2 B Cell clone #1

Plasma Cell clone #1 Plasma Cell clone #2

Multi-clonal antibodies

After proliferating, many antigen stimulated B Cells differentiate into Plasma Cells

Multiclonal Stimulation Activation of specific clones of B cells

Polyclonal Activation (non-specific activation of all B cell clones in the area by i.e., endotoxic LPS)

Poly-CARBOHYDRATEANTIGEN - repeating antigenic determinants

B Cell

PROTEIN ANTIGEN NO repeating Antigenic determinants

Requires T Cell helpIgM IgG IgAHelp comes via soluble substances produced by stimulated Helper T Cells

B Cell

IgM

Cro

ss-l

inks

No Cross-links are possible

Helper T Cells Cytotoxic T CellsCD 4 positive CD 8 positive

T LYMPHOCYTES T Cells

Th Tc

Helper T Cells help B Cells and

Cytotoxic T Cells

Helper T Cell

clones

T Cells have T Cell Receptors on their surface

Not antibodies

Antigen

Even if th

ey do intera

ct, no stim

ulation of t

he Helper T

Cell--

--

The antigenic determinants are hidden within the antigen (are not yet processed), and need to be associated with a MHC 2 product

Bind in some cases via surface antibody (sometimes passively absorbed) or via complement deposited on the antigen then Phagocytize the antigen (see the lecture handout).

Followed by DIGESTION of the antigen that must occur without infecting the cell. Note Ab and complement neutralize the antigen.

Antigen Presenting Cells DO NOT Have T Cell Receptors

Antigen Presenting Cells

All types of Antigen Presenting Cells (APC) continually produce

Major Histocompatibility Complex

Class II Products(MHC Class 2 Products)

that are produced inside the cell move to the surface then

and stay on the cell surface

These MHC 2 products are only on cells which digest and then present the digested fragments of the antigens to Helper T cells

Types of Antigen Presenting Cells:

Macrophages and Macrophage-like cells

Dendritic Cells

(And Pre-dendritic Cells)

B Cells (B lymphocytes)

Types of Antigen Presenting Cells:

Macrophages and Dendritic Cells have Fc-Receptors and Complement Receptors.

Thus these types of APC also can become Armed with low levels of polyclonal Ab-Ag complexes via the Ab that may be weakly fitting (very weak affinity) at the beginning of the infection

B Cells (B lymphocytes)-- monoclonal Ab

Antigen Presenting Cell must bind and digest

the antigen

Antigen

Low levels of Ab to many substances

Toll-Like Recptors

Antigen

Complement Receptors

Major Histocompatibility Complex (MHC)Class 2 Molecule

GROOVE for an internal antigenic fragment (exposed after antigen was fragmented by host cell proteases)

PLASMA MEMBRANE

Antigen Presenting Celle.g., macrophage

Major Histocompatibility Complex MHC Class 2 Molecule

GROOVE for anantigenic fragment ( fragmented by host cell proteases )

PLASMA MEMBRANE

Antigen Presenting Cell

Digested Fragments of the Antigen then Associate with MHC Class 2 products. Antigenic Determinants are now presented to helper T cells.

HelperT CellWith a correctT Cell Receptor

CD4+

Antigen Presenting Cell (APC)

T cell receptor

CD4

APC binds to antigens and phagocytizes them. Then digests them and associates them with MHC 2 products.

HelperT CellWith a correctT Cell

Receptor

CD4+

Antigen Presenting Cell (APC)

APC binds to antigens and phagocytizes them. Then digests them and associates them with MHC 2 products.

Interleukins liberated.

Molecules that stimulate/help any type of T

cells and any B cells that have contacted their

antigenic determinants

Major Histocompatibility Complex Products MHC

Also termed HLA Human Leukocyte Antigens

Class 2 products interact with CD4 on Helper T Cells

After the T Cell Receptor binds to the antigenic fragment within the appropriate MHC product, then cells are close enough together so that

Major Histocompatibility Complex (Products)

Type 1(MHC Class 1)

Class 1 products are always being produced on virtually all host cells.

Major Histocompatibility Complex (MHC)

Class 1 ProductGROOVE

PLASMA MEMBRANE

Beta 2 Microglobulin

SYNTHESIZED VIRAL FRAGMENTS in the Infected Host Cell

Virally Infected Host Cell

series of different

small synthesized

viral fragments-- become associated

with MHC 1 products being produced by the host cell

SYNTHESIZED VIRAL FRAGMENTS

Virally Infected Host Cell

series of differentsmall synthesized viral fragments these associate with MHC 1 products

a bud or pocket of

intact virus particlesready to leave the host cell

Before it dies, the virally infected cell becomes a viral factory

Drawing of the MHC 1

Major Histocompatibility Complex (MHC) Class 1

Molecular ComplexNote the GROOVE

PLASMA MEMBRANE

outside surface

Normal Host Cell

GROOVE for small synthesizedviral fragment

One Major Histocompatibility Complex (MHC) Class 1 product associates with one of the many viral fragments synthesized within the host cell. Then the MHC-1 + viral fragment travels to the surface. Other MHC class 1 products associate with other synthesized viral fragments.

GROOVE containing one small synthesizedviral fragment

Virally Infected host cell synthesizedviral fragments

MHC-1 +

PLASMA MEMBRANE

GROOVE for small synthesizedviral fragment

PLASMA MEMBRANE

Infected host cell

synthesizedviral fragments

MHC-1 +

Other MHC class 1 products associate with other synthesized viral fragments.

SYNTHESIZED VIRAL FRAGMENTS bind the MHC 1 molecule,while inside the virally infected cell, then

move to the cell surface.

Virally Infected Host Cell

To Review:

Cytotoxic T Cell is stimulated (only) when encountering the complex of the Specific Antigenic

Fragment (recognized by its T- Cell receptor) and the MHC Class 1 product

Cytotoxic T Cell

Virally Infected Host Cell

series of differentsmall synthesized viral fragments associatedwith MHC-1 onthe infected cell’s surface

CytotoxicT Cell

With a correctT Cell

Receptor

CD8+

Virally Infected

Host Cell

T cell receptor

CD8

Virally Infected Host Cell

CytotoxicT CellWith a correctT Cell Receptor

CD8+

From Another cloneA CytotoxicT CellWith another correctT Cell Receptor CD8+

Virally infected cell is terminated via direct damage and via signals to self-destruct

Previous Pop Quiz

Question 1:

You recently saw a patient with severe inflammatory periodontal disease. Over twenty different specific B lymphocyte clones were detected in the tissues immediately surrounding the infected periodontal pockets. After several days the B cells in this area were again tested and several of the B cells clones had a higher affinity (or better fit) for the same antigens.

How do Specific B cell clones recognize antigens? And why did the fit (affinity) become higher for selected clones?

Question 2:

Pregnant ladies are advised not to receive x-rays because rapidly dividing cells are very susceptible to DNA damage.

Describe fetal T cell clonal development. What would be the possible consequences of x-rays on fetal T cell clonal development?

Previous Take-Home Open-Book Examination from Dr. Boackle  

Along with T cells, monocytes/macrophages, and high numbers of PMNs (polymorphonuclear leukocytes), a curiously elevated number of B lymphocytes and plasma cells are observed in the inflamed tissues in periodontal disease. What specific and non-specific mechanisms might be responsible for the observed numbers of stimulated B cells in these periodontal tissues? What are Toll-Like receptors and what are their possible roles in periodontal disease, especially in face of the infection with gram-negative bacteria? P Primary and secondary signals are needed for the proper stimulation and function of specific T cells (T lymphocyte clones) and of specific B cells (B lymphocyte clones) that are present in the periodontal tissues. Indeed, specific immune responses to periodontal organisms certainly occur. Describe how those lymphocytes first arrived in the inflamed periodontal tissues, then describe in detail the respective primary and secondary signals that stimulate the activation and proliferation of specific T cells (T lymphocyte clones) and of specific B cells (B lymphocyte clones)-be sure to discuss antigen presentation. Fully explain the reasons that each signal or contact is needed for proliferation of these specific lymphocytes.

TH2

TH1

TH17

Treg

Defense against Parasitic worms, allergy, asthma

Defense against intracellular pathogens

Defense against extracellular

bacteria, autoimmunity,

cancer

Immunosuppression

Undifferentiated T Helper Cell

Produce

Upon antigenic stimulation, naïve CD4+ T cells (Undifferentiated T Helper Cells) undergo proliferation and differentiate into cytokine-producing T helper (T(H)) effector cells. T(H)2 cells produce IL-4, IL-5, and IL-13 cytokines, and mediate immunity against extracellular pathogens and allergic reactions; whereas T(H)1 cells secrete effector cytokine IFN-gamma and regulate cell-mediated immunity. Directly Quoted from Pappu BP, Dong C. Curr Protoc Immunol. 2007 Nov;Chapter 6:Unit 6.25.

Quoted from

TH2

TH1

TH17

Treg

Defense against Parasitic worms, allergy, asthma

Defense against intracellular pathogens

Defense against extracellular bacteria, autoimmunity, cancer

Immunosuppression

Undifferentiated T Helper Cell

Produce

Recent studies have identified a novel T(H) subset, called T(H)17, TH(IL-17), or inflammatory T(H) (THi) cells, characterized by the production of a proinflammatory cytokine, IL-17, and regulating inflammatory responses. Thus TH17 cells may play a role in the pathogenesis of Rheumatoid Arthritis. Simvastatin (a statin) induces IFN-gamma, IL-4, and IL-27 production in monocytes, which together inhibited IL-17 transcription and secretion in CD4(+) T cells. Could statins represent a promising therapeutic approach for multiple sclerosis and other chronic inflammatory diseases? Zhang et al 2008 J. Immunol.;180:6988-96.

Quoted from

TH2

TH1

TH17

Treg

Defense against Parasitic worms, allergy, asthma

Defense against intracellular pathogens

Defense against extracellular

bacteria, autoimmunity,

cancer

Immunosuppression

Undifferentiated T Helper Cell

Produce

Treg play a critical role in the maintenance of peripheral tolerance to self-proteins. However Tregs may also facilitate early protective responses to local viral infections by somehow allowing a timely entry of immune cells (natural killer cells, dendritic cells, and T cells) to the site of infection. Concomitantly, Tregs help to prevent bystander damage to host tissues. Lund et al., Science. 2008 Apr 24

Quoted from