1. ACQUIRED IMMUNITY
RECOGNITION

2. 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
Macferlene Burnet
Ehrlich Paul

3. 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

4. DIVERSITY OF LYMPHOCYTES
1012 lymphocytes in our body ( B and T lymphocytes)
How many SPECIFICITIES ?
Assumption 1 (Lamarcian)
The receptor can be
activated by many
different antigens
Assumption 2 (Darwinian)
All lymphocytes have
a different receptor
Cc. (minimum) 10 million various (107) B lymphocyte clones with different antigen-recognizing receptors
Cc. (minimum) 10 – 1000 million various ( ) T lymphocyte clones with different antigen-recognizing receptors

5. BINDING OF ANTIGEN TO THE SELECTED
B-LYMPHOCYTES RESULTS IN CLONAL EXPANSION
B cell
B Cell Receptor (BCR) Ag
Differentiation
Plasma cell
ACTIVATION
Clonal expansion
Antibody
(immunoglobulin Ig) secretion
MEMORY B CELLS

6. Clonal selection induces proliferation
and increases effector cell frequency
No. of cell divisions
No. of
cells with
useful
specificity
Threshold of
protective effector
function

7. POSSIBLE FATES OF B-LIMPHOCYTE CLONES
Transient, not final differentiation state
Activation
Clonal expansion/proliferation
Differentiation
Plasma cell
Antibody production
Circulation
Restricted life span Homeostasis
Apoptosis
Memory cell

8. Antigen recognizing receptor
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

9. TWO FORMS OF IMMUNOGLOBULINSa a
TWO FORMS OF IMMUNOGLOBULINS
Membrane-bound Ig
Antigen-specific
receptor
Antigen binding H L H L
Secreted Ig
Antigen-specific
soluble protein
EFFECTOR MOLECULE b a
signalling
B CELL
PLASMA CELL

10. IMMUNOGLOBULIN IgG VH
FV= VH+ VL VL
Antigen binding site

11. Bacteria are not well informed
how to display Ag determinants
for proper binding by host-antibodies
host-antibodies need to be flexible

12. TIME COURSE OF THE ADAPTIVE IMMUNE RESPONSE
Days
Antibody
g/ml serum
Antigen A
Recognition
Activation
AFFERENT
Lag
Response to antigen A
Antigen B
Primary Response to antigen B
A antigén

13. Rapid, prompt response (hours) No variable receptors
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
CHARACTERISTICS OF INNATE AND ACQUIRED IMMUNITY
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

14. ORGANIZATION AND STRUCTURE OF THE IMMUNE SYSTEM

15. 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

16. ORGANIZATION OF THE IMMUNE SYSTEM
T-lymphocytes
Cellular
immune response
Helper Th
Cytotoxic Tc
Pathogens
Allergens
WALDEYER RING
Tonsils, adenoids
Palatinal, pharyngeal
lingual and tubar tonsils
Thymus
Spleen
Lymph nodes
CENTRAL
PRIMARY
LYMPHOID ORGANS
PERIPHERAL
SECONDARY
LYMPHOID ORGANS
Blood circulation
Lymph circulation
Bone marrow
Stem cells
Lymphatic vessels
Nyirokerek
B-lymphocytes
Antibodies
Antigens

17. 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

18. CENTRAL (PRIMARY)
LYMPHOID ORGANS

19. GENERATION OF BLOOD CELLS BONE MARROW TRANSPLANTATION
BEFORE BIRTH
AFTER BIRTH
Yolk sac
Flat bones
Liver
Cell number (%)
Spleen
Tubular bones
years
months
BIRTH
BONE MARROW TRANSPLANTATION

20. Őssejtek felfedezése Till és McCullogh 1960
Spleen of irradiated mouse
Injected with bone marrow cells
Colony forming units (CFU)

21. T cell precursors migrating to the thymus
THE BONE MARROW
HSC cell: assymetric division
7-8000/day
self renewal
B-precursor
2-3x108
Dendritic cell
B-cell precursors
Stem cell
Stromal cell
Bone
Pre-B
2-3x107
T cell precursors migrating to the thymus
2x107
B-cell
1-3x106
Central
sinus
Mature naive
B-lymphocytes

22. „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 HSC maintenance fenntartása (50% HSC ha KO)
CAR sejtek (CXCL12
abundant reticular cells)
Makrofágok Reg. of Osteogenesis, maintenance of HSC
Adipocytes negative regulators
Trabecular bone
osteoblast provide growth factors and adhesion molecules

23. Haematopoietic stem cell niches
Figure 1 | Haematopoietic stem cell niches. In the bone marrow, haematopoietic stem cells (HSCs) can be found near the endosteal surface (a); in association with CXCL12‑abundant reticular (CAR) cells (b); and in the periphery of sinusoids and perivascular nestin-expressing cells (c). Each niche is thought to provide signals that support HSC behaviour, although the relationship between HSCs that are present in different niches is still unclear (dotted arrows). Likewise, blood vessels in the bone marrow are often in close association with bone, although their interaction is still poorly understood (d). At the endosteal surface, osteoblastic cells express factors that participate in HSC retention; osteoclasts regulate osteoblastic cell function by inducing bone remodelling; and macrophages regulate osteoblastic cell activity and the retention of HSCs. In the bone marrow stroma, HSCs are associated with CAR cells, which express factors that promote HSC retention. Adipocytes negatively regulate HSCs in the steady state. In the perivascular area, HSCs are associated with nestin-expressing cells, which promote HSC retention and are regulated by macrophages and the sympathetic nervous system (SNS).
FE. Mercier Nat Rev Immunol 2012

24. | Immune cell niches. During B cell differentiation
Figure 2 | Immune cell niches. During B cell differentiation, haematopoietic stem cells (HSCs) and pre-pro‑B cells are found in close association with CXCL12‑abundant reticular (CAR) cells (a), whereas pro‑B cells are more often in contact with interleukin‑7 (IL‑7)-secreting stromal cells (b). Later in B cell development, a population of immature B cells can be found in close association with endothelial cells (c). Naive B and T cells, which can respond to blood-borne pathogens, are found within a perivascular niche that is constituted by a network of dendritic cells (DCs) (d). Bone marrow-resident memory CD4+ T cells reside next to IL‑7-secreting stromal cells and are mostly found in a quiescent state (e). Plasma cells also reside in the bone marrow. CAR cells, eosinophils and megakaryocytes express factors that promote plasma cell engraftment and survival (f).

25. Adamo et al., Nature 2009, North TE, et al. Cell 2009
Biomechanical stress
HSC recruitment
Adamo et al., Nature 2009, North TE, et al. Cell 2009

26. Scheme of B Cell Development in the Bone Marrow
Immature & mature B
Central Sinus
E n d o os t e u m
Progenitors
Pre-B X
Stromal cells X X
Macrophage

27. HEMATOPOIETIC STEM CELL
BONE MARROW
HSC
HEMATOPOIETIC STEM CELL
MYELOID
PRECURSOR
THYMUS
B-cell
LYMPHOID
PRECURSOR
NK-cell
T-cell DC
neutrophil
monocyte
mast
BLOOD
BLOOD
TISSUES
LYMPHOID TISSUES
neutrophil
B-cell
T-cell
mast
mackrophage DC

28. STRUCTURE OF THE THYMUS Mature naive T- lymphocytes
Capsule
Septum
Blood circulation
Epithelial cells
Thymocytes
Dendritic cell
Macrophage
Hassal’s corpuscle
Mature naive T- lymphocytes

29. STRUCTURE OF THE THYMUS

30. THYMUS INVOLUTION 3 day-old infant 70 years old
Starting at birth, the T-cellproducing tissue of the thymus is gradually replaced by fatty tissue. This process is called the involution of the thymus. The graph shows the percentage of thymic tissue that is still producing T cells at different ages. The micrograph in panel a shows a section through the thymus of a 3-day-old infant; the micrograph in panel b shows a section through the thymus from a 70-year-old person for comparison. Tissue is stained with hematoxylin and eosin (red and blue). Magnification x 20.
70 years old

31. REDUCED RESISTANCE TO INFECTION AND TUMORIGENESIS
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