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