Clonal Diversification
of Lymphocytes
Review of last lecture
Whenever immature pre-T Cells recognize
self-antigens, they are programmed to autodestruct in the Thymus
Thymus
Bone Marrow
98% pre-T cells
die in the thymus
Whereas
Mature T cells
proliferate when
they contact
antigens
Treatments for Autoimmune diseases - Wipe out the mature B
cells // Reboot – some exceptions Sjögren's Syndrome
When immature pre-B Cells recognize self-antigens
then they auto-destruct in the Bone Marrow
Bone Marrow
Tolerance
to self substances
Clones of Mature B Cells proliferate
when contacting antigen
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
1 Antigen
2
3
Mature B Cells
B Cell
B Cell
clone #2
clone #1
Fc
region
1 Antigen
2
3
Fab
region
B Cell clone #2
B Cell clone #1
After proliferating, many antigen stimulated B
Cells differentiate into Plasma Cells
Plasma Cell clone #1
Plasma Cell clone #2
Multi-clonal antibodies
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-CARBOHYDRATE
ANTIGEN - repeating
antigenic determinants
PROTEIN ANTIGEN
NO repeating
Antigenic determinants
B Cell
B Cell
IgM
Requires T Cell help
IgM
IgG
IgA
Help comes via soluble
substances produced by
stimulated Helper T Cells
Th
Tc
Helper T Cells
CD 4 positive
Helper T Cells help
B Cells and
Cytotoxic T Cells
Cytotoxic T Cells
CD 8 positive
T LYMPHOCYTES
T Cells
T Cells have T Cell
Receptors on their surface
Not antibodies
Helper T Cell
clones
Antigen
The antigenic determinants are hidden within
the antigen (are not yet processed), and need to
be associated with a MHC 2 product
Antigen Presenting Cells
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
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
Low levels of
Ab to many
substances
Antigen
Toll-Like
Recptors
Complement
Receptors
Antigen Presenting Cell
must bind and digest
the antigen
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 Cell
e.g., macrophage
Major Histocompatibility Complex
MHC Class 2 Molecule
GROOVE for an
antigenic 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.
APC binds to antigens and phagocytizes them.
Then digests them and associates them with
MHC 2 products.
T cell receptor
Helper
T Cell
With a
correct
T Cell
Receptor
CD4
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
Helper
T Cell
With a
correct
T Cell
Receptor
CD4+
Antigen
Presenting
Cell (APC)
Major Histocompatibility
Complex Products MHC
Also termed HLA
Human Leukocyte Antigens
After the T Cell Receptor binds to the antigenic fragment within
the appropriate MHC product, then cells are close enough together
so that
Class 2 products interact with
CD4 on Helper T Cells
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 Product
GROOVE
Beta 2 Microglobulin
PLASMA MEMBRANE
SYNTHESIZED VIRAL
FRAGMENTS in the Infected Host Cell
series of different
small synthesized
viral fragments-Virally
become associated
Infected
with MHC 1 products
Host
being produced by
Cell
the host cell
SYNTHESIZED
VIRAL
FRAGMENTS
series of different
small synthesized
viral fragments
these associate with MHC 1 products
Virally
Infected
Host
Cell
a bud or pocket of
intact virus particles
ready to leave the host cell
Before it dies, the virally infected cell becomes a viral factory
Major Histocompatibility
Complex (MHC) Class 1
Drawing of the MHC 1
Molecular Complex
Note the GROOVE
outside surface
PLASMA MEMBRANE
Normal Host Cell
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.
synthesized
GROOVE for small
viral fragment
GROOVE containing one small synthesized
viral fragment
PLASMA MEMBRANE
Virally Infected host cell MHC-1 +
synthesized
viral fragments
Other MHC class 1 products associate
with other synthesized viral fragments.
synthesized
GROOVE for small
viral fragment
PLASMA MEMBRANE
MHC-1 +
Infected host cell
synthesized
viral fragments
To Review:
SYNTHESIZED VIRAL
FRAGMENTS bind the MHC 1 molecule,
while inside the virally infected cell, then
move to the cell surface.
Virally
Infected
Host
Cell
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
series of different
small synthesized
viral fragments associated
with MHC-1 on
the infected cell’s surface
Cytotoxic
T Cell
Virally
Infected
Host
Cell
T cell receptor
Cytotoxic
T Cell
With a
correct
T Cell
Receptor
CD8+
CD8
Virally
Infected
Host
Cell
Cytotoxic
T Cell
With a
correct
T Cell
Receptor
CD8+
Virally
Infected
Host
Cell
From Another
A Cytotoxic
T Cell
With another
correct
T Cell
Receptor
clone
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.
Quoted from
TH2
Produce
Defense against
Parasitic worms,
allergy, asthma
TH1
Undifferentiated
T Helper Cell
TH17
Treg
Defense against
intracellular
pathogens
Defense against
extracellular
bacteria,
autoimmunity,
cancer
Immunosuppression
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 IFNgamma 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
Produce
Defense against
Parasitic worms,
allergy, asthma
TH1
Undifferentiated
T Helper Cell
TH17
Defense against
intracellular
pathogens
Defense against
extracellular bacteria,
autoimmunity, cancer
Treg
Immunosuppression
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
Produce
Defense against
Parasitic worms,
allergy, asthma
TH1
Undifferentiated
T Helper Cell
TH17
Treg
Defense against
intracellular
pathogens
Defense against
extracellular
bacteria,
autoimmunity,
cancer
Immunosuppression
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