Hans-Martin Jäck Abteilung für Molekulare Immunologie Medizinische Klinik III Nikolaus-Fiebiger-Zentrum FAU Erlangen-Nürnberg Adaptive Humorale Immunität

Hans-Martin JäckAbteilung für Molekulare ImmunologieMedizinische Klinik IIINikolaus-Fiebiger-ZentrumFAU Erlangen-Nürnberg

Adaptive Humorale ImmunitätEtablierung des sekundären Antikörper-Repertoires

Vertiefungsmodul ImmunbiologieRingvorlesungErlangen WS13/14

2

„Memory“Plasma cell„Memory“

Plasma cell

Naive B cellsNaive B cells

Plasma Cell Differentiation

MemoryB cell

MemoryB cell

Ag + TH

Germinal Center Reaction

&

AID

Germinal Center Reaction

&

AID

More affine &specializedantibodies

More affine &specializedantibodies

Division of Molecular Immunology, Universitätsklinikum Erlangen 3

Überblick: Adaptive humorale Immunität

Keimzentrumsreaktion, Affinitätsreifung und IgH-Klassenwechsel

AID und APOPECs

Funktion und Wirkmechanismus von AID

AID und angeborene Immunität

THEMEN


Immunsystem bildet Barrieren

BARRIERENBARRIEREN

Physikalisch• Haut• Schleim• Darmflora• Flimmerhaare

Physiologisch• pH• Temperatur

Zellulär (Leukozyten)

• Makrophagen• Granulozyten• Lymphoyzen

Entzündung• Die vier ‚ors‘

Erworben Angeboren

B- und T-Zellen

Antikörper

T-Zell-Botenstoffe• Interleukine• Zytokine• Lymphotoxine• Chemokine

Gedächtnis !!!!

Adaptive Immunität

Abwehrsystem = IMMUNSYSTEN

(Immunitas, lat.: ‚Freisein von Leistungen/Lasten‘)

• Bakterien• Pilze• Würmer• Viren• Fremde Eiweiße

Keime & fremde Substanzen

Adaptive humorale Immunität


Anatomie der Adaptiven Immunität

TH

Lymphknoten

DendritischeZelle (DZ)

NaiveCD4-T

NaiveCD8-T

MHC II MHC IDZ

TK

MHC II

T-Zellzone (extrafollikulär)

B

Infektion

TFH

Plasmazelle

Gedächtnis-B

B-Zellzone (follikulär)


L

H

Glykoproteine

Quartärstruktur • 2 identische schwere (H) (ca. 50kDa)• 2 identische leichten (L) Ketten (ca. 25kDa)• Verknüpft über Inter-Ketten-S-S-Brücken ( )

Ketten enthalten variable (V) und konstante (C) Regionen

Ketten bestehen aus Ig-Domänen• Stabilisiert über Intraketten-S-S-Brücken ( )

Diversität der V- und C-Regionen• Milliarden verschiedener V-Regionen (Idiotyp)• 2 CL: und ; 5 CH: und (Isotyp)

IgM

CHO

VL

CL

VH

CH1

CH2

CH3

Antigenbindung

Effektor-funktion

Antibodies – Structure and Function


VL

VH

CL

CH

CH

Antigen binding sites= Paratop

“Magic Part”

CH

CH

Effector sites

“Bullet Part”

Tissue distribution Serum halflife Complement Phagocytosis Recruting of cells

3 loops (fingers) from each V region form the antigen binding site (paratop)CDRs = complementary determining regions 1-3

1 2 3

3

1

2

3

Janeway

12

Antibodies – Structure and Function

Antibodies are bifunctional (Paul Ehrlich‘s Magic Bullets)

L

H

VL

VH


Antibodies – Effector Functions

Neutralisation

Agglutination

Activation of Complement

Enhancement of Phagocytosis (Opsoniation)

Recrutement of effector cells (Neutrophils, natural killer cells)

Adaptive Humoral Immunity

Generation of the Primary B Cell Repertoire

Antigen 1

B cell receptor

1

One B cell - One ReceptorOne B cell - One Receptor


LatePro-B

LatePre-B

Immature B cell

Early Pre-B

Stemcell

Central Maturation(Bone marrow)

VH→D → JH VL → JL

H

L

Pre-BCR BCR

Maturation of B Cells


µH chain

N C B cell

B cell

VH C

TranscriptionTranslation

VH Exon

V(D)J recombination generates antibody diversity

Recombination

stem cell

J segments CV segments D segments

ca. 2.5 Mb (mouse) HC locus

L chainN C

VL Exon

J V C

LC locus

Generation of Antibody DiversityS. Tonegawa

Nobel Price 1987Basel Institute of Immunology


4JH C134 VH 13 D

Recombinatorial diversity• Random assembly from V, D & J

Combinatorial diversity• Random pairing of H & L chains

ca. 107 anti-

bodies

109-1012 anti-

bodiesJunctional diversity• Unprecise V(D)J joining• Nucleotide (N) addition (TdT)• Usage of three RF in D segments

Summary: Preimmune Repertoire

B-Zellen Mensch Maus

Anzahl 1012 109

Neu/Tag 109 106

14

Division of Molecular Immunology, Universitätsklinikum Erlangen

LatePro-B

LatePre-B

Immature B cell

Early Pre-B

Stemcell


Peripheral Maturation(Spleen)

Transitional B cells

Mature B cell

Pre-BCR BCR

VH→D→ JHVL → JL

H

LPrimary

repertoire

~109-1012 specificies

HUMORAL IMMUNE RESPONSE

15

Division of Molecular Immunology, Universitätsklinikum Erlangen

LatePro-B

LatePre-B

Immature B cell

Early Pre-B

Stemcell


Peripheral Maturation(Spleen)

Transitional B cells

Mature B cell

Pre-BCR BCR

VH→D→ JHVL → JL

H

LPrimary

repertoire

~109-1012 specificies

Secondary repertoire

→ Affnity maturation→ Effector functions

Memory B cell

Plasma cell

Ag + TH

Effector Phase(lymph node, spleen, etc.)

GC

HUMORAL IMMUNE RESPONSE


Generation of Effector B Cells

IgG

Memory B

Plasma cell

Ag + TH

IgD

IgMAg + TH


Anatomie der Adaptiven Immunität

TH

Lymphknoten


NaiveCD4-T

NaiveCD8-T

MHC II MHC IDZ

TK

MHC II


B

Infektion

TFH

Plasmazelle

Gedächtnis-B



Activation of Naive CD4+ T Cells

B cell help in follicule

Activation of naive

CD4+ T cells in T cell zone

cytokines

Dendritic cell

King et al., Annu. Rev. Immunol. 2008


Ig receptors recognize• Proteins

• Lipids

• Nuclei acids

• Carbohydrates

• Organich molecules or Haptens (Half-Ag)

• Metals

• Plastic

But only proteins are good T cell-dependent antigens

The World of Antigens (Antibody generating)

Ag

IgM

IgD

NaiveB cells

Short-livedPlasma cells

IgM

+/-TH

DifferentiationClonal Expansion

+/-TH

MemoryB cell

IgG, IgA, IgE

+TH

Long-lived plasma cells

+TH

B Cell Antigens


T Cell Antigens

B-Zell-Rezeptor

(BZR)

Ag

T-Zell-Rezeptor

(TZR) MHC II MHC I

DendritischeZelle Ag-Prozessierung

& Präsentation Ag-Prozessierung

& Präsentation

T-Zellrezepror erkennt Fremd (Peptid) und Selbst (MHC)(MHC restiction - Zinkernagel & Doherty )

T-Zellrezepror erkennt Fremd (Peptid) und Selbst (MHC)(MHC restiction - Zinkernagel & Doherty )


Merkmale der adaptiven Immunität

Organimsus erinnert sich an Antigen und antwortet mit einer

besseren

spezialisierteren

schnelleren

auf das jeweilge Pathogen zurechtgeschnitte Antikörper-antwort

(über Affinitätserhöhung)

(durch IgH-Klassenwechsel)

(Signalwege ?)


Lymphnodes

PeyerPlaques

Spleen

Appendix

Tonsils

Anatomical Location

Secondary lymphatic

organs

Afferent lymphatic

vessel

Paracortex(T cell zone)

B cell zone

medulla

arteria

SecundaryB cell follicle

„Germinal center“

PrimaryB cell

follicule

Efferentlymphaticvessel

venule

From Janeway

Primaryfollicle Secondary

follicle +

Germinal center

CXCR5

IgM

Antigen

+/-TH

ExpansionIgM

Naive B cell B cell

focus

Short-livedPlasma cellShort-livedPlasma cell

Long-lived plasma cellsLong-lived

plasma cells

Memory B cell

Memory B cell

IgGIgAIgE

IgGIgAIgE

Anatomy of B Cell Response

IgD - B cellsPNA - GC B cellsCD3 - T cells

Spleen section - 7 days SRBC

BT

HEV

GC

T C

ell Z

on

eB

Ce

ll Z

on

e

+TH


T-Zell-abhängige B-Zellaktivierung

TH

Lymphknoten


NaiveCD4-T

NaiveCD8-T

MHC II MHC IDZ

TK

MHC II


B

Infektion

TFH

Plasmazelle

Gedächtnis-B


Primaryfollicle

IgM

Antigen

+TH

ExpansionIgM

Naive B cell B cell

focus





BT

HEV

GC

T C

ell Z

on

eB

Ce

ll Z

on

e


Extrafollikuläre B/T-Zell-Kooperation

CD40LBZR

Immunologische Synapse

CD40

IL2/4/5 ILR

12

MHC II +

PeptidTZRTH

B+

Gekoppelte Erkennung(Linked recognition)

B- und T-Zellepitop müssen auf dem gleichen Molekül liegen

CD40L-Defizienz• Keine Antikörper gegen

Proteine (z.B. Tetanus)• Kein Klassenwechsel• Kein Gedächtnis

→ Keine Schutzimpfung

• Aber gute Antwort gegen Kohlenhydrate !!!!→ Viel IgM im Serum

→ Hyper-IgM-Syndrom I

B-Zell-Epitop(Peptid oder

Hapten)

TrägerT-Zell-Epitop

(Peptid)NO2

OH

Träger

Primed TH

http://www.studon.uni-erlangen.de/crs816430.html

STUDON

RINGVORLESUNG

Primaryfollicle Secondary

follicle +

Germinal center

CXCR5

IgM

Antigen

+/-TH

ExpansionIgM

Naive B cell B cell

focus


Long-lived plasma cellsLong-lived

plasma cells

Memory B cell

Memory B cell

IgGIgAIgE

IgGIgAIgE




BT

HEV

GC

T C

ell Z

on

eB

Ce

ll Z

on

e

+TH


GC

1884 Fleming discovers germinal centers. The name ‘GC’ is based on Fleming’s finding that GC contain a high mitotic activity. He believed that GC are the site of germination or lymphopoiesis

1920 The idea that GC are site of lymphopoiesis fell short because it did not fit the transient appearance

1924 Latta and West proposed that GC are rather sites of death and senescence that lymphopoiesis

1940-43 Crabb and Kelsall, and Hellman found that the presence of GC correlates with chronic antigenic stimulation and that GC can be induced by immunization

As we know now, GC are the site of local proliferation and cell death, both of which contribute in antibody affinity maturation and formation of memory cells

Germinal Center (dt.: Keimzentrum)

Elise PunkenburgBachelorarbeit, Erlangen 2008

30

Light Light zonezone

Dark Dark zonezone

TFH

Germinal Center

Germinal Center

CSR

SHM

Selection

“Memory”plasma cell(long-lived)


Memory B cell

Memory B cell

IgG, IgA, IgE

IgG, IgA, IgE

Expansion

TFHT cell T cell zonezone

B cell B cell zonezone

Germinal Center ReactionModified from McHyzer-Williams2011

FDC

??

CSR?

GC exit

IgM

31GC - Molecular Changes at the Ig locus

1. Somatic hypermutation

2. IgH class switch

IgM IgG, IgA, IgE

VH

CH

VL

CL

Better and more specialized antibodiesBetter and more specialized antibodies

AID


Kinoshita & Honjo NRCB(2001)

IgH Class Switch Recombination (CSR)


IgM

IgG1

CSR

Cytokine

VH CCC3 C1 C2b C2a CC

SS3 S1 S2b S2a SS S, switch regions

DNA-Looping-out und Deletion

VH C1 C2b C2a CC Switch circle

IgH Class Switch Recombination (CSR)

AID

IL4LPS

Jäck et al.,P.N.A.S. USA 1988von Schwedler et al., Nature 1990

• Synapsis• Incision• Double-strand breaks• End-Joining/Ligation

VH C1 C2b C2a CC

C

C

C3


Einfügen von Punktmutationen willkürlich über das gesamte V-Exon des L- und H-

Ketten gens verteilt

V

SHM und Ig-Mutator

Somatic Hypermutation (SHM) of V Regions

AID

Jacob et al., Nature 1991

35Germinal Center Reaction - Selection


Dark Dark ZoneZone

Selection

Follicular dendritc cell

(FDC)FcR

CR

native antigen

C

B cellwith high-affine

Ag receptor


STEP 1: Somatic hypermutation over entire V exons

STEP 2: FDC selects B cells with higher affinity for immunizing antigen

Ag-specific antibodies

with higher affinity

Affinity Maturation

PROBLEM: Self-reactive B cells could be selected by self-antigen on FDC – ► Requirement for another checkpoint

PROBLEM: Self-reactive B cells could be selected by self-antigen on FDC – ► Requirement for another checkpoint

37


Dark Dark zonezone

TFH

GC reactionGC reaction

CSR

SHM

Selection

Expansion




FDC

CSR?

AID

IgM

SelectedB cell


B/T-Kooperation im Keimzentrum

Nutt & Tarlinton, Nat Immunol. 2011

39


Dark Dark zonezone

TFH


CSR

SHM

Selection



Memory B cell

Memory B cell

IgG, IgA, IgE

IgG, IgA, IgE

Expansion




FDC

??

CSR?

AID

GC exit

IgM

SelectedB cell

40

Staudt/

Calame/

Lassila

Model

Modified from Nutt et al., 2011

Control of PC Differentiation

Pax5

MiTF

Bcl6

Bach2

GC Program

IRF4 ↑AID

Repair

PC Program

Xbp1

Blimp1

IRF4↑↑↑↑

41


Dark Dark zonezone

TFH


CSR

SHM

Selection



Memory B cell

Memory B cell

IgG, IgA, IgE

IgG, IgA, IgE

Expansion




FDC

??

CSR?

AID

GC exit

IgM


Plasma cell

MemoryB cell

Ag

IgM

IgD

NaiveB cell

IgGIgAIgE

IgA

IgM

IgG, IgE

Effector B Cells

• Igmem → Igsec

• Ig production ↑ (100x)

• Long-lived PC in bone marrow niches

Plasma Cell (PC)

• IgGmem, IgAmem or IgEmem

• Reacts faster to Ag

• Circulates through body

• Long-lived (does not require antigen contact for survival)

• Generation requires T help

Memory B Cell


Ag

IgM

IgD

NaiveB cells

Short-livedPlasma cells

IgM

+/-TH

DifferentiationClonal Expansion

+/-TH

MemoryB cell

IgG, IgA, IgE

+TFH

Long-lived plasma cells+TFH

Summary: Effector B Cells

IgM

Germinal centerreaction

• Proliferation

• Somatic hypermutation

• Selection

• class switch

• Effector cells

IgG, IgA, IgE

Better and more

specialized abs

AID


AIDActivation-Induced Deaminase

Master regulator of secondary antibody diversification

and ?????


Entdeckt über substraktive Hybrisierung als induzierbares Gen in einer B-Lymphomlinie (CH12) mit IL4-induzierbarem IgH-Klassenwechsel (Muramatsu et al. JBC 1999)

Synthese induziert in Ag-aktivierten Keimzentren-B-Zellen

Konvertiert in ssDNA ein C zu einem U(oxidative Deaminierung)

→ Activation-Induced Deaminase = AID (Gensymbol AICD)

Notwenig für CSR und SHM

AIDCytosin Uracil

AID - Entdeckung

Deamidase

R C

O

NH2

R C

O

OH

H2O NH3

Säureamid Carbonsäure


Kurzer Ausflug in APOBEC-Familie

Enthalten alle Deaminase-Domäne mit konservierter katalytischer Stelle (rot)

Maus besitzt APOBEC1, 2, 3 (eine Form) und AID

APOBEC1 und APOBEC3 nur in Säugern

AID und APOBEC2 in allen höheren Vertebraten

Funktionen: → Editieren von RNA und DNA→ Immunität gegen Viren→ Inaktivierung von Retroelementen

Mensch

Goila-Gaul andStrebel,Retrovirology 5:51, 2008


N C

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide 1

AUG CAA UAG APOB mRNA

APOB100

Leber

AUG UAA UAG Mut APOB mRNA

N C APOB48• Navaratnam et al., LBC 1993

• Teng et al., Science, 1993

DuodenumAPOBEC1

(one !!!! mutation in RNA)

APOBEC1 – Prototyp eines RNA-editierenden Enzyms


APOBEC3G – Innate Abwehr gegen Viren und Transposon

Nur in Säugern (Lymphozyten)

Mutiert neuen ss-cDNA-Strang

Modelle antiviraler Wirkmechanis-men von APOBEG3:

(1) Reduziert Bildung viraler Transkripte

(2) Inaktivierende Mutationen in Virions

(3) Induziert Abbau mutierter Trankripte

(4) Induziert Abau nicht-mutierter Trans- kripte durch Rekrutierung zellulärer Nukleasen →Editing-unabh.Mechanismus

RNA (viral oder Retrotransposons)

RT APO3

X XX XX

mutiertecDNA

Sheehy et al. Nature 2002


Kurzer Ausflug: Retroelements

Endogene Retroelemente (bis zu 45% des menschlichen Genoms) Mutatoren, werden aber auch selber mutiert

Biologische Aktivität/Funktiono Genduplikationen

o Vergrößerung des Genoms

o Insertionsmutagenese

new protein

new RNA new cDNA

insertional mutagenesis

AIM2TLR9APOBEC3Trex1AID

TLR7RIG IMDA5

AdaptiveImmunity

From M. Wabl


AID – A Hypermutator

AIDCytosin Uracil

→ Activation-Induced Deaminase (AID)

Converts C in ssDNA to U (oxydative deamination)

Expressed in activated germinal center B cells

Discovered by Honjo et al. (1999)

Required for SHM and CSR

Defekt: Hyper-IgM syndrome type II


AID: Required for SHM & CSR

Transfection into B cell lines induces CSR

Germline-deficient AID mice have no CSR and SHM (Muramatsu et al., Cell 2000)

Patients with mutated AID (autosomal) no CSR and strongly reduced somatic mutation (Revy ; Durandy et al., Cell

2000)

AID-deficient mice and patients produce large amounts of IgM antibodies against PROTEINS (!!!!)

→ Hyper-IgM syndrome type 2

Also required for Ig gene conversion in chicken B cells (Arakawa et al., Science)


RNA Editing Model (indirect)

AID is an indirect mutator by editing (like APOBEC1) a mRNA (or miRNA) encoding (or controlling) a switch recombinase/Ig mutator

DNA Mutation Model (direct)

AID acts directly on DNA (introducing C-to-U mutations) in both processes

AID: How does it work?

• Constans, A. Class /Switch Wars 2004. The Scientist18(18):28• Honjo et al. 2004. Immunity 20:659-68


N C

AUG CAA UAG „Mutator“encodingmRNA

Aktiver „Mutator“(Endonuklease)

AID

AUG UAA UAG

Inaktiver MutatorN C

AID↑ in Keimzentrums-B-Zelle

RNA-Editing-Hypothese

„Mutator“encodingmRNA


RNA-Editing-Hypothese

Hinweise AID hat sehr starke Sequenzähnlichkeit mit APOBEC1 (RNA-

Editierung)

AID ist hauptsächlich im Zytosol lokalisiert

De-Novo Proteinbiosynthese ist für CSR notwendig (Gegenargument: CSR-spezifischer Ko-Faktor wird synthetisiert)

AID komplexiert im Zytosol mit mRNA

AID mit N51A-Mutation verliert DNA-Deaminase-Aktivität, induziert nach Transduktion in AID-defizienten B-Zellen noch CSR

• Honjo und Mitarbeiter, PNAS 2008 (Originalmanuskript)• Shivarov et al., Philos Trans R Soc Lond B Biol Sci 2009 (Review)

55

CV exon C

C C

Base excision and error prone

Base excision and error prone

Base excision and mismatch repair

Base excision and mismatch repair

A G

A G

CC C CC C

SHMSHM CSRCSR

U U UU U UU U

DNA Model


Ausflug – DNA-Reparatur

• http://www.web-books.com/MoBio/Free/Ch7G.htm• Peterson and Cote, G&D, 2004

Three major DNA repairing mechanisms: Base excision (BER), nucleotide excision (NER) and mismatch repair (MMR).


• BER repairs damaged DNA throughout the cell cycle by first removing the wrong base

• Works only if DNA's bases are modified by deamination or alkylation.

• Position of the modified (damaged) base is called the "abasic site" or "AP site".

• DNA glycosylases (e.g., Uracil-N-glycosidase = UNG) recognize AP site and remove its base.

• AP endonuclease removes the AP site and neighboring nucleotides.

• Gap is filled by DNA polymerase I and DNA ligase.

DNA-Reparatur – Base excison Repair (BER)


DNA-Reparatur – Nucleotide excison Repair (NER)

• In E. coli, proteins UvrA, UvrB, and UvrC are removedamaged nucleotides (e.g., dimer induced by UV light).

• Gap is filled by DNA polymerase I and DNA ligase.

• In yeast, the proteins similar to Uvr's are named RADxx ("RAD" stands for "radiation"), such as RAD3, RAD10. etc.


DNA-Reparatur – Mismatch Repair (MMR)

• Important for mutations unable to be repaired by BER or NER

• Mut proteins bind to mismatched bp. (Eukaroytic homologues are MSH1-5 (mismatch repair homolog), MLS1 (MutL homolog 1) und PMS (postmeiotic segregation). Mutations of MSH2, PMS1 and PMS2 are related to colon cancer.

• Activated Mut H binds to GATC and cleaves unmethylated strand at GATC. (In eukaryotes, the mechanism to distinguish the template strand from the new strand is still unclear)

• Distance between the GATC site and the mismatch can be up to 1,000 bp.

• Exonucleases remove DNA segment from cleavage site to mismatch.

• DNA polymerase III fills gap.

E.coli

Dam methylates template at GATC

GATC


BER

• AID deaminates C to U at accessible sites in S regions

• Multiple sites of deamination and UNG/APE-induced nicks

• Break processing (Mismatch repair = MMR)

• Gaps and DSBs produced

• DNA synthesis up to nick• Blunt ends at DSBs• S region ligation

From: Stavnezer et al., Annu. Rev. Immunol. 2008

MMR

nicks

nicks

DSB

Blunt DSB

DNA-Mutations-Modell (CSR)

CSR reduced by 95 % if BER is deficient!


In vitro, AID mutates ssDNA but not RNA

Class switch recombination is inhibited (95%) and somatic hypermutation is perturbed in UNG-(BER) deficient mice

DNA-Mutations-Modell - Hinweise


AID – Andere Funktionen?

LINE-1 ist in AID-defizienten B-Zellen erhöht (unpublished)

AID findet sich in großen RNA/Proteinkomplexen und ko-präzipitiert mit LINE-1 (unpublished)

AID blockiert Line1-Retrotrans-Position in HEK-Zellen (MacDuff… Harris. 2009. NAR 37:6854–1867)

AID-defiziente Patienten haben eine höhere Anfälligkeit für Autoimmunsymptome und Leukämien

→ Wie kann man das erklären?


ADAPTIVE IMMUNITY

Formation of 2 antibody repertoire

AID targets Ig locusCytosine Uracil

Protection from

Autoimmune disease

Proliferative disease

nucleus

INNATE IMMUNITY ?

cytoplasm

Activated B cell

AID – Zusammenfassung

CSR SHM

Host response to

viral infection

Inhibition of retroelement

activity

M. MetzerPromotion 2010


IgG

IgM

NaiveB-Zelle

LanglebigePlasmazelle

(IgG, IgA, IgE)


(IgG, IgA, IgE)

Gedächtnis-B-Zelle

(IgG, IgA, IgE)Keim-

zentrums-reaktion

IgGt (Tage)

Log

CA

K im

Ser

um

Primärantwort Sekundärantwort

3

2

1

0 4 8

IgM

10Ag 20Ag

Schneller und mehr !!!!

IgM

0 4 8


(IgG, IgA, IgE)

Gedächtnis-B-Zelle

(IgG, IgA, IgE)Keim-zentrums-reaktion

KurzlebigePlasmazelle

(IgM)Ag+TH

IgMKurzlebigePlasmazelle

(IgM)

NaiveB-Zelle

Ag+TH

Übersicht: Adaptive humorale Immunität

Documents

Hans-Martin Jäck Abteilung für Molekulare Immunologie Medizinische Klinik III Nikolaus-Fiebiger-Zentrum FAU Erlangen-Nürnberg Adaptive Humorale Immunität