RECEPTORS AND CELL-SURFACE MOLECULES OF MACROPHAGES TLR4 + CD14 MHCI MHCII TLR – pattern recognition Rs CR1 (CD35) CR3 (CD11b/CD18) LFA1 (CD11a/CD18) Fc.

RECEPTORS AND CELL-SURFACE MOLECULES OF MACROPHAGES

TLR4 + CD14

MHCI

MHCII

TLR – pattern recognition Rs

CR1 (CD35)

CR3 (CD11b/CD18)

LFA1 (CD11a/CD18)

FcRIII (CD16)

FcRII (CD32)

FcRI (CD64)

Ag + IgG complex

Mannose receptor

Scavenger receptor

Mϕ

!!

Anti-viral immune response Type I INTERFERONs

vírus

IFN és IFN

!

!

Anti-viral immune response

Defense:

Innate Immunity: – type I interferons(INFα, β)

– NK cells

Adaptive immunity

B cells – antibody-mediated neutralization

T cells --- cytotoxic T cells, cytokines

!

napok

vírus-titer

2 4 6 8 101 3 5 7 9 1211 13

KINETICS OF VARIOUS ANTI-VIRAL MECHANISMS

Complement

AntibodyCytotoxic T cellsNK cells

IFNα/β, IL-12

days

lev

el/a

cti

vity

VIRUS TITER

1781: Measles epidemics in the Faroe islands

after the epidemics the island has remained measles free for 65 years

1846: Another epidemics

Those, who were elder than 65 years and were sick in 1781 were not re-infected, but some elderly got sick

1. Life long protection against some viruses exists

2. Maintenance of memory does not require the sustained or intermitting presence of the virus

IMMUNOLOGICAL MEMORY

Inhabitants: 46 000Area: 1 400 km2

THE TWO ARMS OF THE IMMUNE SYSTEM

Differentiation between harmless and harmful impactsDETECTION OF STRESS AND DANGER SIGNALSINNATE IMMUNITY

Differentiation between self and non-self structuresAntigen-specific recognitionADAPTIVE IMMUNITY

Neutralization and elimination of foreign and harmful structuresEXECUTIVE FUNCTIONSCOORDINATED AND REGULATED ACTIONS

INNATE IMMUNITY

- immediate reaction- not antigen-specific- no memory

ADAPTIVE IMMUNITY

- developes in several days- specific

- has memory

Humoral immunityCellular immunity

communication

!!

B cell memory:

Quicker responseIncrease in the number of specific B cellsThe amounts of antibody are bigerHigher affinity antibodies (‘more specific’)Isotype switch

In case of T dependent B cell activation

!!

Antigen

AActivation of ctivation of specific B cellsspecific B cells

1. 1. Clonal Clonal expansionexpansion

Antigen Antigen

2.Differentiation

Plasma cells, antibody production

MEMORY B CELLS

Antigen

!

Antigen

Antigen recognition by specific BCR induces clonal expansion and differentiation of the sepcific B cells.

Memory B cells

proliferation and differentiation to plasma cell upon re-activation or entry to the GC reaction again

and

Long-lived plasma cellsPlasma cells generated during GC reaction migrate to bone marrow andsurvive for years, producing antibody Much of circulating IgG is produced by long-lived plasma cells, provides initial protection

B cell memory is provided by:

Ig . C onc entra tion

na p o k

p rim er response

„A” a ntig né

IgM

IgGIgAIgE

Szekund er ’la syec ond a ry response

„A” és a ntig én

„B”

5 10 15 20 25 30

IgM

primary response against B antigen

!

days

Repeated immunization

!

NEUTRALIZATIONNEUTRALIZATION

IgG

IgM

IgA

A F T E R B IR T H

breas t milkIgA

0

1 0 0 %( a d u l t )

3 3y e a r

2 546 a d u l t9 1m o n t h

maternal IgG

B E F O R E B IR T H

PRODUCTION OF IMMUNOGLOBULINS

IMMUNOLOGICAL MEMORY – B CELLSIMMUNOLOGICAL MEMORY – B CELLSSUMMARYSUMMARY

Memory B cells• Perviously activated• Passed through affinity maturation• Present in the circulation• proliferation and differentiation to plasma cell upon re-activation or entry to the GC reaction again

Plasma cellsProvides serological memory by pre-existing neutralizing Abs to pathogens and/or toxins

Germinal Center reaction• B cell proliferation• Somatic hypermutation• Affinity maturation

BT

BB

BBBB

BBB

B

BB

B

FDC

FDCFDC T

B

B

plasmacell

B – T cell collaboration

T-CELL MEMORY

Central memory cells

Effector memory cells

T cell memory:

Quicker responseIncrease in the number of responding cells

!!

DEVELOPMENT OF CELLULAR MEMORYNegative regulation of the immune system

Days5 10 15 20 25 30

Naive lymphocytes

Az antigen-specific cell number

Primary effector cells

Secondary effector T

cells

Memory

DIFFERENTIATION

AICD

EXPANSION

AICD

MEMORY

Days

Activation Induced Cell Death

Effector T

Citokines/Cytotoxicity

AICD

Naive T

Central memory T

Effector T

Citokines/cytotoxicity

PERIPHERAL LYMPHOID ORGANS

PERIPHERAL TISSUESSkin dermis, gut lamina propria, alveolar space

Tissue-specific migration

Effector memory T

Effector T

Cytokines/cytotoxicity

ANTIGEN/SITE OF INFECTION

IMMUNOLOGICAL MEMORY MEDIATED BY T LYMPHOCYTES

Naive T cell Effector T cell

cytokine productioncytotoxicity

Central Memory T cell Effector T cell

• Previously activated, partially differentiated cell type• Circulating CCR7+ cells in blood, lymphoid tissues• High proliferation rate induced by activation signals• Rapid differentiation to effector cells

EffectorMemory T cell

Effector T cell

• Previously activated, partially differentiated cell type• Closest to the effector state • Circulating CCR7- cells in blood and tissues• Slow proliferation, rapid effector functions

Maintained by cytokines:IL-7, IL-15

2X107

2X105

Proliferation

cytotoxicity

Functional differences between lymphoid tcm cells and tissue-resident TEM cells

Woodland DL & Kohlmeier JR 2009 Nat Rev 9:153killing

AGE

THYMUS PERIPHERY

N

A

I

V

E

IMMUNOLOGICAL EXPERIENCEIMMUNOLOGICAL EXPERIENCE

M

E

M

O

R

Y

A TERMÉSZETES ÉS SZERZETT IMMUNITÁS EGYÜTTMŰKÖDÉSEIDŐBEN

Active and passive immunization

Active: generates memory response

Passive: ensure the protection by premade antibodies(the adaptive immune system of the person is not activated)

!!

PROTECTED SUBJECT

serum antibody

PASSZÍV IMMUNIZÁLÁS

This is a case of PASSIVE IMMUNIZATION

Immune system is not activatedprompt effect

temporary protection/effect

Immunoglobulin degradation

Human immunoglobulin transgenic mouse

immunization mouse monoclonal antibodies

ENDANGERED SUBJECT

immunization

human monoclonal antibodies

humanized mouse monoclonal antibodies

Active and passive immunization

active passive

protection slow immediate(2 weeks)

Time-span long short(years)

time

activepassive

injection

protection

!!

Anti-viral immune response

Defense:

Innate Immunity: – type I interferons(INFα, β)

– NK cells

Adaptive immunity

B cells – antibody-mediated neutralization

T cells --- cytotoxic T cells, cytokines

!

IgG

IgM

IgA

A F T E R B IR T H

breas t milkIgA

0

1 0 0 %( a d u l t )

3 3y e a r

2 546 a d u l t9 1m o n t h

maternal IgG

B E F O R E B IR T H

PRODUCTION OF IMMUNOGLOBULINS

Pathological consequences of placental Pathological consequences of placental transport of IgGtransport of IgG

(hemolytic disease of the newborn)(hemolytic disease of the newborn)

Passive anti-D IgG

anti-RhIgM

Immunization

Active PassiveHost itself produce preformed antibodies

antibodies and cells are imported to the host

biotic bioticartificial artificial

ImmunitásTermészetes

Aktív: betegség, immunizálódás

(sorozatos találkozás az adott kórokozóval)

Passzív - in utero, placentán át, maternális (anyai IgG, folyamatos, homológ)

- születés után, colostrális, anyatej útján IgG, IgA