Download B CELL

ACQUIRED IMMUNITY
RECOGNITION
ADAPTIV IMMUNITY IS TRANSFERABLE
Antibodies, antibody specificity, diversity
Antibodies were discovered in the late 1800s (Emil Behting, Shibasaburo
Kitasato) SERUM THERAPY antibodies specific to toxins
Discovery of blood group antigens (Landsteiner)
QUESTION: How can so many different pathogens and other structures be
recognized by antibodies? What drives and How the production of antibodies?
Niels Jerne
Ehrlich Paul
Macferlene Burnet
Macfarlane Burnet (1956 - 1960)
CLONAL SELECTION THEORY
What is a clone in fact?
Antibodies are natural products that appear on
the cell surface as receptors and selectively react
with the antigen
Lymphocyte receptors are variable and carry
various antigen-recognizing receptors
‘Non-self’ antigens/pathogens encounter the
existing lymphocyte pool (repertoire)
Antigens select their matching receptors from
the available lymphocyte pool, induce clonal
proliferation of specific clones and these clones
differentiate to antibody secreting plasma cells
The clonally distributed antigen-recognizing
receptors represent about ~107 – 109 distinct
antigenic specificities
DIVERSITY OF LYMPHOCYTES
1012 lymphocytes in our body ( B and T lymphocytes)
Assumption 1 (Lamarcian) How many
Assumption 2 (Darwinian)
The receptor can be
SPECIFICITIES
All lymphocytes have
activated by many
?
a different receptor
different antigens
Cc. (minimum) 10 million various (107) B lymphocyte clones with
different antigen-recognizing receptors
Cc. (minimum) 10 – 1000 million various (107 - 9) T lymphocyte
clones with different antigen-recognizing receptors
BINDING OF ANTIGEN TO THE SELECTED
B-LYMPHOCYTES RESULTS IN CLONAL EXPANSION
B cell
B Cell Receptor
(BCR)
A nti g e n
Ag
Plasma cell
ACTIVATION
Clonal expansion
Differentiation
Antibody
(immunoglobulin Ig)
secretion
MEMORY B CELLS
A nti g e n
A nti g e n
Clonal selection induces proliferation
and increases effector cell frequency
No. of
cells with
useful
specificity
Threshold of
protective effector
function
No. of cell divisions
POSSIBLE FATES OF B-LIMPHOCYTE CLONES
Transient, not final
differentiation state
Activation
Clonal expansion/proliferation
Differentiation
Memory cell
Circulation
Restricted life span
Homeostasis
Apoptosis
Plasma cell
Antibody production
THE B-CELL ANTIGEN RECOGNIZING RECEPTOR AND
ANTIBODIES PRODUCED BY PLASMA CELLS HAVE THE
SAME PROTEIN STRUCTURE = IMMUNOGLOBULIN
B CELL
Antigen recognizing
receptor
BCR
Immunoglobulin (Ig)
Antibody
TWO FORMS OF IMMUNOGLOBULINS
Membrane-bound Ig
Antigen-specific
receptor
Antigen binding
L
L
L
H
H
Secreted Ig
Antigen-specific
soluble protein
EFFECTOR MOLECULE
L
H
H
ab
signalling
PLASMA CELL
B CELL
IMMUNOGLOBULIN IgG
VH
FV= VH+ VL
VL
Antigen binding
site
Bacteria are not well informed
how to display Ag determinants
for proper binding by host-antibodies
host-antibodies need to be flexible
TIME COURSE OF THE ADAPTIVE IMMUNE
RESPONSE
Antibody
g/ml serum
Lag
Recognition
Activation
AFFERENT
Response to
antigen A
Primary
Response to
antigen B
Antigen A
Days
AAntigen
antigénB
CHARACTERISTICS OF INNATE AND ACQUIRED IMMUNITY
•
•
•
•
•
•
•
NATURAL/INNATE
Rapid, prompt
response (hours)
No variable receptors
Limited number of
specificities
No improvement
during the response
No memory
Not transferable
Can be exhausted,
saturated
•
•
•
•
•
•
•
•
ADAPTIVE/ACQUIRED
Time consuming
Variable antigen receptors
Many very selective
specificities
Efficacy is improving
during the response
Memory
Can be transferred
Regulated, limited
Protects self tissues
COMMON EFFECTOR MECHANISMS FOR THE
ELIMINATION OF PATHOGENS
ORGANIZATION AND STRUCTURE OF THE
IMMUNE SYSTEM
ORGANIZATION AND STRUCTURE OF THE
IMMUNE SYSTEM
ORGANS OF THE IMMUNE SYSTEM
LYMPHOID ORGANS
GENERATION AND MIGRATION OF CELLS OF THE
IMMUNE SYSTEM
LYMPHOCYTE HOEMOSTASIS, RECIRCULATION
THE ROLE OF LYMPHATICS IN THE TRANSPORTATION
OF ANTIGENS
INITIATION OF IMMUNE RESPONSE IN PERIPHERAL
LYMPHOID ORGANS
ORGANIZATION OF THE IMMUNE SYSTEM
T-lymphocytes
Pathogens
Allergens
Lymph nodes
Blood circulation
Lymph circulation
Cellular
immune response
Thymus Helper Th
Cytotoxic Tc
Spleen
PERIPHERAL
SECONDARY
LYMPHOID
ORGANS
WALDEYER RING
Tonsils, adenoids
Palatinal, pharyngeal
lingual and tubar tonsils
Antigens
Nyirokerek
Lymphatic
vessels
Bone
marrow
CENTRAL
PRIMARY
LYMPHOID
ORGANS
Stem cells
B-lymphocytes
Antibodies
ORGANIZATION OF THE IMMUNE SYSTEM
LYMPHOCYTES CONGREGATE IN SPECIALIZED TISSUES
•
CENTRAL (PRIMARY) LYMPHOID ORGANS
– Bone marrow
– Thymus
DEVELOPMENT TO THE STAGE OF ANTIGEN RECOGNITION
•
PERIPHERAL (SECONDARY) LYMPHOID ORGANS
– Spleen
– Lymph nodes
– Skin-associated lymphoid tissue (SALT)
– Mucosa-associated lymphoid tissue (MALT)
– Gut-associated lymphoid tissue (GALT)
– Bronchial tract-associated lymphoid tissue (BALT)
ACTIVATION AND DIFFERENTIATION TO EFFECTOR CELLS
•
BLOOD AND LYMPH CIRCULATION
– Lymphatics
– collect leaking plasma (interstitial fluid) in
connective tissues
– Lymph
– cells and fluid
– No pump
– one way valves ensure direction – edema
– Several liters (3 – 5) of lymph gets back to the blood daily – vena cava
superior
CENTRAL (PRIMARY)
LYMPHOID ORGANS
GENERATION OF BLOOD CELLS
BEFORE BIRTH
AFTER BIRTH
Cell number (%)
Yolk sac
80
Flat bones
Liver
60
40
Spleen
20
Tubular bones
0
0 1 2 3 4 5 6 7 8 9
10
20
30
40
50
60
70
years
months
BIRTH
BONE MARROW
TRANSPLANTATION
Őssejtek felfedezése
Till és McCullogh 1960
Spleen of irradiated mouse
Injected with bone marrow
cells
Colony forming units (CFU)
THE BONE MARROW
HSC cell: assymetric division
7-8000/day
self renewal
Stromal cell
Stem cell
Bone
csont
B-cell precursors
B-precursor
2-3x108
Pre-B
2-3x107
B-cell
1-3x106
Dendritic cell
2x107
T cell precursors
migrating to the thymus
Central
centrális
sinus
sinus
Mature naive
B-lymphocytes
„Niche”-s provide the appropriate microenvironment for
hematopoiesis
HSC
hematopoietic stem cells
Entothel
soluble factors(SCF, GM-CSF etc)
adhesion mol. (VCAM, ICAM, E-selectin.), CXCL12
Mesenchimal cells
MSC (stroma)
CXCL12, nestin + cells
CAR sejtek (CXCL12
abundant reticular cells)
HSC maintenance fenntartása (50% HSC ha KO)
Makrofágok
Reg. of Osteogenesis, maintenance of HSC
Adipocytes
negative regulators
Trabecular bone
osteoblast
provide growth factors and adhesion molecules
Haematopoietic stem cell niches
FE. Mercier Nat Rev Immunol 2012
| Immune cell niches. During B cell differentiation
Biomechanical stress
HSC recruitment
Adamo et al., Nature 2009, North TE, et al. Cell 2009
Scheme of B Cell Development in the Bone Marrow
Progenitors
E
n
d
o
o
s
t
e
u
m
Stromal cells
Pre-B
X
X
X
Macrophage
Immature &
mature B
Central
Sinus
BONE MARROW
HSC
MYELOID
PRECURSOR
HEMATOPOIETIC STEM CELL
LYMPHOID
PRECURSOR
BLOOD
BLOOD
DC
monocyte mast neutrophil
TISSUES
DC
THYMUS
mackrophage mast neutrophil
B-cell
NK-cell
T-cell
LYMPHOID TISSUES
B-cell
T-cell
STRUCTURE OF THE THYMUS
Capsule
Septum
Blood
circulation
Epithelial cells
Thymocytes
Dendritic cell
Macrophage
Mature naive T- lymphocytes
Hassal’s corpuscle
STRUCTURE OF THE THYMUS
THYMUS INVOLUTION
3 day-old
infant
70 years old
THYMUS INVOLUTION
•Up to puberty/adolescence the size of the thymus is increasing and naive T
lymphocytes are produced in waves to ensure protective immune responses
•A sustained loss of tissue mass, cellularity and functionality of the thymus starts
after puberty and lasts to middle age followed by a slower rate of involution
extending to old age
•DN cells do not proliferate and differentiate
•Diversity of the TCR repertoire progressively becomes more limited
•The thymic tissue is replaced by fat deposits
•In old people naive peripheral T cells proliferate more extensively than those in
younger individuals to compensate low cell numbers and reach their replicative limits
earlier than in young people
REDUCED RESISTANCE TO INFECTION AND TUMORIGENESIS
Similar number of T cell progenitors to young individuals
Limited IL-7 production, Bcl-2 expression and TCRβ rearrangement
Replicative potential of thymic stromal cells is decreased
The levels of nerve growth factor (NGF) secreted by medullary thymic epitelial cells
(TEC) and IGF-1 produced by thymic macrophages decline