Download 5th seminar - lymphoid organs, lymphocyte

5th SEMINAR
THE ADAPTIVE IMMUNE RESPONSE:
LYMPHOID ORGANS
GENERATION OF MATURE NAIVE LYMPHOCYTES
LYMPHOCYTE RECIRCULATION
RECOGNITION BY CELLS OF THE
ADAPTIVE IMMUNE SYSTEM
Antigen-specific receptors:
B cell receptor (BCR) and T cell
receptor (TCR)
• The basic structure (90%) of the
receptors (BCR or TCR) is common
• Each cell expresses a receptor that is
unique in specificity (the 10% difference
means different specificity)
• These differences in antigenspecificity are achieved during
maturation in the CENTRAL
LYMPHOID ORGANS (bone
marrow and thymus)
PRIMARY (CENTRAL) LYMPHOID ORGANS
Places of the maturation (antigen-independent
development) of lymphocytes:
• bone marrow: generation of lymphoid progenitors,
maturation of B cells
• thymus: maturation of T cells (and NK cells)
GENERATION OF
LYMPHOCYTES
B cell
T cell
Maturation
Starts in the
bone marrow,
continues in the
bone marrow
Starts in the
bone marrow,
continues in
the thymus
Activation
In the peripheral lymphoid tissues
Effector cells
Plasma cell
T helper
T cytotoxic
THE BONE MARROW
• flat bones (sternum, ribs, scapulae, hip bone)
• epiphysis of long bones
Stromal cells
Stem cells
Osteoblasts
csont
BONE
Osteoclasts
Immature T cells (thymocytes) on
their way to the thymus (20x106/day)
Progenitors
Precursors
Dendritic cells
centrális
Central
sinus
sinus
Blood circulation
Mature B cells
(3x106/day)
BONE MARROW STROMAL CELLS
NURTURE DEVELOPING B CELLS
Cell-cell contact
B
Secreted factors CYTOKINES
1. Specific cell-cell
contacts between
stromal cells and
developing B cells
2. Secretion of cytokines
by stromal cells
Stromal cell
Types of cytokines and cell-cell contacts needed at each stage of
differentiation are different (see next figure)
GENERATION OF INDIVIDUAL ANTIGENSPECIFIC RECEPTOR (BCR)
STEPS OF B CELL
DEVELOPMENT IN THE
BONE MARROW
1.
rearrangement of the immunoglobulin heavy chain
(somatic gene recombination – V-D-J genes)
2.
production of heavy chains, expression of preBCR (μ
chain + surrogate light chain)
3.
allelic exclusion of heavy chain genes, IL-7-dependent
proliferation of functional heavy chain expressing pre B
cells
Limphoid progenitors
c-kit/CD44
RAG-1/RAG-2
Pro-B
H rearrangement
Pre-BCR

RAG-1/RAG-2
4.
rearrangement of the immunoglobulin light chain
(somatic recombination – V-J genes)
L rearrangement
5.
expression of functional BCRs, proliferation
6.
negative selection: clonal deletion (by apoptosis or
anergy) of self-reactive B cells
selection
clonal deletion
7.
mature, selected B cells leave the bone marrow via the
medullary sinuses
Pre-B
B
immature B
B
B
B
mature B
STRUCTURE OF THE THYMUS
Capsule
Septum
Blood
circulation
Epithelial cells
Thymocytes
Dendritic cell
Macrophage
Mature naive T- lymphocytes
Hassall’s corpuscle
STRUCTURE OF THE THYMUS
INVOLUTION OF
THYMUS
The functional amount of the thymus tissue is
decreasing by age, leading to less and less
newly produced mature T cells.
DEVELOPMENT OF T CELLS IN THE THYMUS
1.
proliferation of lymphoid progenitors after their
arrival to the thymus
2.
rearrangement of the beta chain (somatic gene
recombination – V-D-J genes)
/or gamma and delta chains  γδ T cells/
3.
production of beta chains, expression of preTCR (β
chain + preTα)
4.
allelic exclusion of beta chain genes, IL-7dependent proliferation of functional beta chain
expressing pre T cells
5.
rearrangement of the alpha chain (somatic
recombination – V-J genes)
/still some will become γδ T cells/
6.
expression of functional TCRs
7.
positive selection: clonal ignorance for those cells
which do not recognize self-MHC molecules
8.
negative selection: clonal deletion (by AICD) of selfreactive B cells
9.
mature, selected T cells leave the thymus via blood
vessels
T CELL DEVELOPMENT
limphoid progenitors
(B- CELL DEVELOPMENT)
circulation
THYMUS
c-kit/CD44
NK
RAG-1/RAG-2
Pro-T
 rearrangement
H rearrangement
Pre-T
Pre-BCR
Pre-T
Pro-B

RAG-1/RAG-2
immature T
 rearrangement
L rearrangement
positive selection
negative selection
negative selection
clonal deletion
T
T
immature B
B
B
T
mature T
Pre-B
T
B
B
mature B
AFTER LEAVING THE CENTRAL LIMPHOID ORGANS MATURE
NAIVE LYMPHOCYTES TRAVEL TO THE SITES OF ACTIVATION:
THE SECONDARY LYMPHOID ORGANS/TISSUES
SECONDARY LYMPHOID ORGANS/TISSUES
Sites of lymphocyte activation and terminal differentiation
• LYMPH NODES
• SPLEEN
• TONSILS (Waldeyer’s ring)
• Diffuse lymphoid layers under the epithelial barriers:
• SALT (skin-associated lymphoid tissue)
• MALT (mucosa-associated lymphoid tissue)
• BALT (bronchus-associated lymphoid tissue)
• GALT (gut-associated lymphoid tissue)
LYMPH NODES
STRUCTURE OF LYMPH NODES
THE SPLEEN
• No connection to lymphatic
vessels
• Filtrates blood-borne antigens
• Red pulp is the ‚cemetery’ of
RBCs
• White pulp is similar to lymph
nodes
WALDEYER’S RING
Most pathogens are acquired through the naso-oral cavity, hence there are
accumulations of mucosa-associated lymphoid tissues
(Can be referred to as NALT – nasal-associated lymphoid tissue, or organized MALT)
Tonsilitis
GALT
Kripta
Dome area Villi
GC
GALT
• the intestines are full of
symbiotic and pathogenic
microbes
• continuous antigen uptake from
the lumen by M (microfold) cells
and DCs
• low dose antigen exposure
enhances the fitness of the
immune system
• regulator mechanisms are very
important
THE LYMPHOCYTE RECIRCULATION
• Mature naive lymphocytes leave the central lymphoid
organs to travel to the sites of activation: the secondary
lymphoid organs/tissues (SLO)
• They enter the different SLOs randomly via the process
called ‚HOMING’
• They either GET ACTIVATED after recognizing an
antigen and differentiate to effector cells or they LEAVE
VIA THE EFFERENT LYMPHATIC VESSELS
• The lymph is collected by lymph nodes, the
lymphocytes pass many of them, and in every node they
may get activated
• Eventually all the lymph is flowing into the THORACIC
DUCT and get back to the circulation, so the
lymphocytes can reach another SLO
• They do their recirculation until they find an antigen or
until the end of their lifespan
HOMING
•
Similar to extravasation of neutrophil granulocytes during acute
inflammation
•
The endothelial cells of HEVs (high endothelial venules) express
mucin-like adressin type adhesion molecules
•
Mature naive lymphocytes express adhesion molecules (homing
receptors) that can interact with the ones expressed by HEVs
•
T and B cells find their areas in the SLOs by chemotaxis