Clonal Diversification of Lymphocytes Review of last lecture Bone Marrow Thymus Whenever immature...
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Transcript of Clonal Diversification of Lymphocytes Review of last lecture Bone Marrow Thymus Whenever immature...
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
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.
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
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