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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?
Ehrlich Paul
Niels Jerne Macferlene Burnet
Macfarlane BurnetMacfarlane Burnet (1956 - 1960) (1956 - 1960)
CLONAL SELECTION THEORY 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
What is a clone in fact?
Cc. (minimum) 10 mCc. (minimum) 10 milliillion various (10on various (1077) B lymphocyte clones with ) B lymphocyte clones with different different aantigntigeen-recognizing receptorsn-recognizing receptors
CCc. (minimum) 10 – 1000 mc. (minimum) 10 – 1000 milliillion various (10on various (1077 - - 99) ) TT lymphocyte lymphocyte clones with different clones with different aantigntigeen-recognizing receptorsn-recognizing receptors
DIVERSITY OF LYMPHOCYTES
AAssumptionssumption 2 2 (Darwinian) (Darwinian)AAll lymphocytes have ll lymphocytes have a different receptor a different receptor
AAssumption ssumption 11 (Lamarcian)(Lamarcian)TThe receptor can behe receptor can beactivated by many activated by many different different antigensantigens
10101212 l lyymphocytes in our body ( B and T lymphocytes)mphocytes in our body ( B and T lymphocytes)
How many SPECIFICITIES
?
Antigen
ACTIVATIONACTIVATIONClonal expansionClonal expansion
Antigen Antigen
Differentiation
Plasma cell
Antibody(immunoglobulin Ig)
secretion
MEMORY B CELLS
BINDING OF ANTIGEN TO THE SELECTED B-LYMPHOCYTES RESULTS IN CLONAL EXPANSION
B cell
B Cell Receptor (BCR)
Ag
Clonal selection induces proliferationand increases effector cell frequency
No. of cell divisions
No. ofcells with
usefulspecificity
Threshold ofprotective effectorfunction
POSSIBLE FATES OF B-LIMPHOCYTE CLONES
ActivationClonal expansion/proliferation
Differentiation
Plasma cellAntibody production
Memory cell
CirculationRestricted life span
HomeostasisApoptosis
Transient, not final differentiation state
Antibody
THE B-CELL ANTIGEN RECOGNIZING RECEPTOR AND ANTIBODIES PRODUCED BY PLASMA CELLS HAVE THE
SAME PROTEIN STRUCTURE = IMMUNOGLOBULIN
Antigen recognizing receptor
BCRImmunoglobulin (Ig)
B CELL
HH HHLL LL
HH HH
LL LL
Secreted IgSecreted IgAntigen-specificAntigen-specificssoluble proteinoluble protein
EFFECTOR MOLECULEEFFECTOR MOLECULE
TWO FORMS OF IMMUNOGLOBULINS
Membrane-bound IgMembrane-bound IgAntigen-specificAntigen-specific
receptorreceptor
signalsignalllinging
B CELLPLASMA CELL
Antigen binding
FVFV= = VHVH+ + VLVLVVHH
VVLL
IMMUNOGLOBULIN IgG
Antigen binding site
Bacteria are not well informedhow to display Ag determinantsfor proper binding by host-antibodies
host-antibodies need to be flexible
Days
Antibody
g/ml serum
Antigen A A antigén
Response to antigen A
RecognitionActivationAFFERENT
Lag
TIME COURSE OF THE ADAPTIVE IMMUNE RESPONSE
Antigen B
Primary Response to
antigen B
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
ORGANIZATION AND STRUCTURE OF THE IMMUNE SYSTEM
ORGANS OF THE IMMUNE SYSTEM
LYMPHOID ORGANS
ORGANIZATION AND STRUCTURE OF THE IMMUNE SYSTEM
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
Pathogens
Allergens
Antigens
Stem cells
B-lymphocytes
Antibodies
T-lymphocytes
Cellular immune response
Helper ThCytotoxic Tc
Blood circulationLymph circulation
Bone marrow
Thymus
Nyirokerek
CENTRALPRIMARY
LYMPHOID ORGANS
Lymphatic vessels
Spleen
Lymph nodes
PERIPHERALSECONDARYLYMPHOID ORGANS
ORGANIZATION OF THE IMMUNE SYSTEM
WALDEYER RINGWALDEYER RINGTonsils, adenoidsTonsils, adenoidsPalatinal, pharyngeal Palatinal, pharyngeal lingual and tubar tonsilslingual and tubar tonsils
ORGANIZATION OF THE IMMUNE SYSTEM
• CENTRAL (PRIMARY) LYMPHOID ORGANS– Bone marrow– ThymusDEVELOPMENT 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
LYMPHOCYTES CONGREGATE IN SPECIALIZED TISSUES
CENTRAL (PRIMARY)
LYMPHOID ORGANS
00
20
40
60
80
1 2 3 4 5 6 7 8 9 10 20 30 40 50 60 70
GENERATION OF BLOOD CELLS
BEFORE BIRTH AFTER BIRTH
Spleen
Liver
Yolk sac
Cel
l num
ber
(%)
BIRTH
months years
Flat bones
Tubular bones
BONE MARROW TRANSPLANTATION
Spleen of irradiated mouseInjected with bone marrow
cellsColony forming units (CFU)
Őssejtek felfedezéseŐssejtek felfedezéseTill és McCullogh 1960Till és McCullogh 1960
centrálissinus
csont
THE BONE MARROW
T cell precursors migrating to the thymus
2x107
HSC cell: assymetric division 7-8000/day self renewal
B-precursor 2-3x108
Pre-B2-3x107
B-cell1-3x106
Mature naiveB-lymphocytes
Dendritic cell
B-cell precursors
Stem cellStromal cell
Bone
Centralsinus
„Niche”-s provide the appropriate microenvironment forhematopoiesis
HSC hematopoietic stem cells
Entothel soluble factors(SCF, GM-CSF etc)adhesion mol. (VCAM, ICAM, E-selectin.), CXCL12
Mesenchimal cellsMSC (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
Haematopoietic stem cell niches
FE. Mercier Nat Rev Immunol 2012
| Immune cell niches. During B cell differentiation
Biomechanical stressBiomechanical stress
HSC recruitmentHSC recruitment
Adamo et al., Nature 2009, North TE, et al. Cell 2009Adamo et al., Nature 2009, North TE, et al. Cell 2009
Immature &mature B
CentralSinus
Progenitors Pre-B
Stromal cells
X
X
X
Endoosteum
Macrophage
Scheme of B Cell Development in the Bone Marrow
DC mackrophage
MYELOID PRECURSOR
BONE MARROW
HSC HEMATOPOIETIC STEM CELL
mast
DC monocyte neutrophilmast
neutrophil
TISSUES
BLOOD
B-cell T-cell
T-cellNK-cell
THYMUS
B-cell
LYMPHOIDPRECURSOR
LYMPHOID TISSUES
BLOOD
Blood circulation
Macrophage
Hassal’s corpuscle
Dendritic cell
Thymocytes
Epithelial cells
CapsuleSeptum
Mature naive T- lymphocytes
STRUCTURE OF THE THYMUS
STRUCTURE OF THE THYMUS
3 day-old infant
70 years old
THYMUS INVOLUTION
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 TUMORIGENESISREDUCED RESISTANCE TO INFECTION AND TUMORIGENESISSimilar number of T cell progenitors to young individuals
Limited IL-7 production, Bcl-2 expression and TCRβ rearrangementReplicative 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
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