5th SEMINAR THE ADAPTIVE IMMUNE RESPONSE: LYMPHOID ORGANS
GENERATION OF MATURE NAIVE LYMPHOCYTES LYMPHOCYTE RECIRCULATION
Slide 2 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 antigen- specificity are achieved during maturation
in the CENTRAL LYMPHOID ORGANS (bone marrow and thymus) Slide 3
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) Slide 4 GENERATION OF
LYMPHOCYTES B cellT cell Maturation Starts in the bone marrow,
continues in the bone marrow Starts in the bone marrow, continues
in the thymus ActivationIn the peripheral lymphoid tissues Effector
cellsPlasma cell T helper T cytotoxic Slide 5 THE BONE MARROW
Dendritic cells Stem cells Stromal cells BONE Central sinus
Osteoblasts Osteoclasts ProgenitorsPrecursors Blood circulation
Immature T cells (thymocytes) on their way to the thymus (20x10 6
/day) Mature B cells (3x10 6 /day) flat bones (sternum, ribs,
scapulae, hip bone) epiphysis of long bones Slide 6 BONE MARROW
STROMAL CELLS NURTURE DEVELOPING B CELLS Types of cytokines and
cell-cell contacts needed at each stage of differentiation are
different (see next figure) 1.Specific cell-cell contacts between
stromal cells and developing B cells 2.Secretion of cytokines by
stromal cells Secreted factors - CYTOKINES B Stromal cell Cell-cell
contact Slide 7 Slide 8 GENERATION OF INDIVIDUAL ANTIGEN- SPECIFIC
RECEPTOR (BCR) Slide 9 Limphoid progenitors mature B H
rearrangement Pre-BCR L rearrangement selection clonal deletion B B
B B Pro-B Pre-B c-kit/CD44 RAG-1/RAG-2 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 ( chain + surrogate light chain)
3.allelic exclusion of heavy chain genes, IL-7-dependent
proliferation of functional heavy chain expressing pre B cells
4.rearrangement of the immunoglobulin light chain (somatic
recombination V-J genes) 5.expression of functional BCRs,
proliferation 6.negative selection: clonal deletion (by apoptosis
or anergy) of self-reactive B cells 7.mature, selected B cells
leave the bone marrow via the medullary sinuses immature B Slide 10
Blood circulation Macrophage Hassalls corpuscle Dendritic cell
Thymocytes Epithelial cells Capsule Septum Mature naive T-
lymphocytes STRUCTURE OF THE THYMUS Slide 11 Slide 12 INVOLUTION OF
THYMUS The functional amount of the thymus tissue is decreasing by
age, leading to less and less newly produced mature T cells. Slide
13 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 T cells/ 3.production of beta chains, expression
of preTCR ( chain + preT) 4.allelic exclusion of beta chain genes,
IL-7- dependent proliferation of functional beta chain expressing
pre T cells 5.rearrangement of the alpha chain (somatic
recombination V-J genes) /still some will become 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 self- reactive B
cells 9.mature, selected T cells leave the thymus via blood vessels
Slide 14 T CELL DEVELOPMENT NK rearrangement Pre-T Pre-T positive
selection negative selection T T T mature T limphoid progenitors
THYMUS rearrangement c-kit/CD44 RAG-1/RAG-2 (B- CELL DEVELOPMENT)
circulation Pro-T T mature B H rearrangement Pre-BCR L
rearrangement negative selection clonal deletion B B B B Pro-B
Pre-B immature B immature T Slide 15 AFTER LEAVING THE CENTRAL
LIMPHOID ORGANS MATURE NAIVE LYMPHOCYTES TRAVEL TO THE SITES OF
ACTIVATION: THE SECONDARY LYMPHOID ORGANS/TISSUES Slide 16
SECONDARY LYMPHOID ORGANS/TISSUES LYMPH NODES SPLEEN TONSILS
(Waldeyers 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) Sites of
lymphocyte activation and terminal differentiation Slide 17 LYMPH
NODES Slide 18 STRUCTURE OF LYMPH NODES Slide 19 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
Slide 20 Tonsilitis WALDEYERS 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) Slide 21 GALT
Dome area Villi GC Kripta Slide 22 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 Slide 23 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 Slide 24 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
