Basic Immunology for internist Basic Immunology for internist Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of Medicine KhonKaen

Basic Immunologyfor internist

Basic Immunologyfor internist

Ratanavadee Nanagara, M.D.

Allergy-Immunology-Rheumatology UnitDepartment of MedicineKhonKaen University

Nature of Immunity

Model of Host Immune Response

Immunopathogenesis of Autoimmune Dis.

Self Tolerance

Abnormal immune response

Therapeutic implication

Cardinal features of IRCardinal features of IR

specific

memory

discrimination

The Nature of ImmunityThe Nature of Immunity

Specific (adaptive)

Non-specific (innate)

Type of Recognition & Defense

Type of Recognition & Defense

Non-specific immune responseNon-specific immune response

Cells: professional phagocytes

Physical barriers

Cytokines

Complement

Chemical property

Physical & chemical barriers: skin & mucosaPhysical & chemical barriers: skin & mucosa

lysozymein saliva

acid

mucus

cilia mucus

no

rmal

gu

t fl

ora

lysozymewashingaction

Fat

ty a

cid

sN

orm

al b

acte

rial

skin

flo

ra

washingaction ofurine

Cells : professional phagocytes Cells : professional phagocytes

• neutrophil

• macrophage• monocyte• NK cells

adhearance, chemotaxis, phagocytosis, oxidative burst, degranulation, IC killing

attack and eat kill

complement

bacteriaphagocytebacteria

2. chemotaxis

C5a

3. opsonization

C3b

1. lysis

C9C5b

Specific immune responseSpecific immune response

2. Discrimination self/non-self

1. Antigen specific ??

Clonal selection

Clonal selection

Specific Immune ResponseSpecific Immune Response

2. Discrimination self/non-self

1. Antigen specific

Nature of Immunity



Self Tolerance



Discrimination

Self tolerance

??immune cell

self Ag

Clonal ignorance

Central tolerance

Peripheral tolerance

Self tolerance

autoreactive T-cells

blood barrier

Clonal ignorance

Normal tissue Self AgSelf Ag

educated T-cellautoreactive cell

Central Tolerance

autoreactive cell

host cell

Peripheral Tolerance

program cell death … or anergy…

HLA-DRHLA-DRauto Agauto Ag

TcR

V

V

ICAM-1LFA-3

1. lack of co-stimulator molecules – “anergy”

2. stimulate fas ligand - program cell death “apoptosis”

Autoreactive T-cell

fas

HIR

CMIR

Specific Immune ResponseSpecific Immune Response

Nature of Immunity



Self Tolerance



Non-specific (innate) IR

effectiveIC killing

occult (persistent) infection

overt infection

adhearance

chemotaxis

phagocytosis

oxidative burst

degranulation

IC killing

Professional phagocytes

no disease

IC killing defect

? Clinical outcome

Specific (adaptive) IR

Antigen Presenting CellAntigen processingAntigen processing

exogenousexogenous

endogenousendogenous

Antigen

CD28LFA-1

CD2CD4

CD3

HLA-DRHLA-DRAgAg

TcR

V

V

ICAM-1LFA-3

CD80/86(B7)

auxillarymolecules

CTL-4

Tyrosine kinase

Trimolecular complex

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

chemokinesMIF

FibroblastSynoviocyte

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

Effector T-cells

CMIR

Th1

KTcNK

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6IL-5

B-lymphocyte

IgG

HIR

Th2

CD40

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

Activatedmacrophage

effectorT-cells

IF-IL-2

CD25 ®autocrineparacrine

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

Blood vessel

effectorT-cells

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1(CD106) ICAM-1 (CD54)

effectorT-cells

L. integrin (CD11/18)

VLA integrin(CD49/29)

Selectin (CD62)

Adhesion molecules

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

effectorT-cells

Stop inflammatory cells

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

effectorT-cells

VEGF

BMP

TGF-ETR

Facilitate extravasation

Nature of Immunity



Self Tolerance



Abnormal Immune ResponseAbnormal Immune Response

Immune deficiencyImmune deficiency

congenital

acquired

viral infection

splenectomy

physiologic change

immunosuppressive drugs

radiation

chronic diseases


Gel & Coombs

Classification of Immune

Response (Hypersensitivity)

Gel & Coombs

Classification of Immune

Response (Hypersensitivity)

Type I - IgE mediated

Type II - Ab mediated

Type III - Immune complex

Type IV - Delayed-type

Type I - IgE mediated

Type II - Ab mediated

Type III - Immune complex

Type IV - Delayed-type


Autoimmunity

How ?

Nature of Immunity



Self Tolerance



Triggering InfectionTriggering Infection

Abnormal Immune Response

Geneticpredisposition Geneticpredisposition

DiseaseDisease

HLA Class I - B27 Class II- DR

- DWNon HLA

Bacteria Chlamydia

Yersinia

Salmonella

Shigella

Campylobactor

H. Pyroli

Virus

How infectious agents induce

chronic inflammatory or autoimmune diseases?

How infectious agents induce

chronic inflammatory or autoimmune diseases?

T-cells are central to most model of autoimmunity

self reactiveT-cell

proliferation, cytokines, B-cell activation,

cytolysis

proliferation, cytokines, B-cell activation,

cytolysis

self reactiveT-cell

Molecular mimicry

Molecular mimicry

Presentationof cryptic cell Presentation

of cryptic cell

Hypersensitivity to

persistent organism

or their antigens

Hypersensitivity to

persistent organism

or their antigens

Immune activation by superantigen


Antigen activation

or disruption by

retroviruses

Antigen activation

or disruption by

retroviruses

self reactiveT-cell

Molecular mimicry

Molecular mimicry


of cryptic cell

Hypersensitivity to

persistent organism

or their antigens

Hypersensitivity to

persistent organism

or their antigens



Antigen activation

or disruption by

retroviruses

Antigen activation

or disruption by

retroviruses

microbe APC T-cell effector cells

cross reactivity(molecular mimicry)

self antigen

self reactiveT-cell

Molecular mimicry

Molecular mimicry


of cryptic cell

Hypersensitivity to

persistent organism

or their antigens

Hypersensitivity to

persistent organism

or their antigens



Antigen activation

or disruption by

retroviruses

Antigen activation

or disruption by

retroviruses

autoreactive T-cells

Normal tissue Self AgSelf Ag

self reactiveT-cell

Molecular mimicry

Molecular mimicry


of cryptic cell

Hypersensitivity to

persistent organism

or their antigens

Hypersensitivity to

persistent organism

or their antigens



Antigen activation

or disruption by

retroviruses

Antigen activation

or disruption by

retroviruses

Ineffective intracellular killing

inapparent infection overt infection

H. pylori

C. trachomatis

C. pneumoniae

Salmonella inf.

M. tuberculosis

Viral hepatitis B, CRetrovirus inf.Herpes zosterPrion

C. trachomatis persistent infection in chronic arthritis

M. Tuberculosis infection that caused intractable autoimmune disease

self reactiveT-cell

Molecular mimicry

Molecular mimicry


of cryptic cell

Hypersensitivity to

persistent organism

or their antigens

Hypersensitivity to

persistent organism

or their antigens



Antigen activation

or disruption by

retroviruses

Antigen activation

or disruption by

retroviruses

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

effectorT-cells

antigen

superantigen

HLA-DR

Antigen Presentation

LFA-3

ICAM -1


HLA-DRCD3

CD4

CD2

LFA-1

V

TcR

LFA-3

ICAM -1


HLA-DR

V

TcR

Normal T-cell activationNormal T-cell activation

SUPERANTIGEN

HLA-DR

V

TcRV

TcR

Activate T-cell without Ag processingActivate T-cell without Ag processing

CD4CD5

ICAM -1

Treatment of Kawasaki’s disease by giving intravenous immunoglobulin (IVIG)

V

TcR

Y

YYY

YY

Y

Y

Y

CD4CD5

HLA-DR

ICAM -1

Y

Y

self reactiveT-cell

Molecular mimicry

Molecular mimicry


of cryptic cell

Hypersensitivity to

persistent organism

or their antigens

Hypersensitivity to

persistent organism

or their antigens



Antigen activation

or disruption by

retroviruses

Antigen activation

or disruption by

retroviruses

Nature of Immunity



Self Tolerance



IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

avoid Ag exposure antimicrobial

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

Antimalarial drug

change pH in

phagosome

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

HLA-DR

TcR TcRTcR

CD3

CD4CD4CD2LFA-3

ICAM-1

Ag

TRIMOLECULAR COMPLEX

& COSTIMULATORY PATHWAY

APC TH

CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)

Cytotoxic T lymphcyte-associated antigen 4= immunoregulatory protein

? RA refractory to TNF- inhibitor? RA subset? SLE mice

CD40

CTLA4-Ig - CTLA4-Fc - LEA29Y

CTLA4-Ig - CTLA4-Fc - LEA29Y

LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)

CD40LCD40L

BCD40

HLA-DR

TcR TcRTcR

CD3

CD4CD4

CD2LFA-3

ICAM-1

Ag

APC TH


CD40 CD40LCD40L



Anti CD40L mAb( IDEC-131, hu5c8, BG9588, Biogen )

Anti CD40L mAb( IDEC-131, hu5c8, BG9588, Biogen )

RA

T

B

CD40

SLEB

CD40

B CD

40

B CD

40


HLA-DR

TcR TcRTcR

CD3

CD4CD4

CD2LFA-3

ICAM-1

Ag

APC TH


CD40



efalizumabefalizumab: humanized mAb CD11a: humanized mAb CD11a

psoriasis


CD40LCD40L

HLA-DR

TcR TcRTcR

CD3

CD4CD4

CD2LFA-3

ICAM-1

Ag

APC TH


CD40




CD40LCD40L

Anti-CD3 : HuOKT31 (Ala-Ala)

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

CAMPATH-1HCAMPATH-1H

Profound peripherallymphopenia

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

IL-2 DAB IL-2DAB IL-2

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

Rituximebanti-CD20Rituximebanti-CD20

B

CD20

immaturematurenaive

B

CD20

memory

B

CD20

P

Plasma cell

Rituximebanti-CD20Rituximebanti-CD20

B-cell depletion

Autoimmune with antibody production

refractory Wegener granulomatosis, SLE with AIHA, ITP

essential mixed cryoglobulinemia, RA (? RF+ve)

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8IVIG

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

Biologic response modifier

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

ET-1®TGF-

TNF- soluble p75-TNFR type II (etanercept)

chimeric human: mouse mAb (infliximab) humanized mAb (adalimumab) converting enzyme inhibitors (GW3333)

IL-1 recombinant IL-1R antagonist (anakinra)

soluble IL-1R type II

IL-1 Trap (recomb.IL-1R I – IgG Fc)

IL-1 converting enzyme inhibitor (caspase-1)

IFNrecombinant IFN- recombinant IFN-

IL-6 IL-6 mAb soluble IL-6R

Biologic response modifier

Signal vx-745 (inh. p38 MAPK pathway)

transduction c-Jun-N terminal kinase inhibitor

calcineurin inhibition (post R signaling)

CIS3/SOCS3 (signaling repressor)

Chemokines recombinant human IL-18 binding protein

humanized CXCL8/IL-8 Ab

oral CCR1-antagonist

ET-1 ET-1 receptor antagonist

TGF- anti-TGF-

VEGFsoluble VEGFR1-Fc

Alternative targets of cytokine modifying Rx

TNF modelTNF model

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

block adhesionmolecules

HLA DR+

CD 44LFA-1

CLA

P & E Slectin (CD62)

ICAM-1

ICAM-2VCAM-1 (CD106)

VLA-4(CD49/29)

Anti-human-ICAM-1 Ab (enlimomab)Anti-human-ICAM-1 Ab (enlimomab)

ADHESION MOLECULES

anti VCAM-1anti VCAM-1

mAb E-selectinmAb E-selectin

humanized anti–v3

(integrin mAb)

humanized anti–v3

(integrin mAb)

Humanized 4-1, 4-7 mAb (Natalizumab)2ME2 (2 methoxyextradiol) antiangiogenesis

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

Anti-inflammatory agents

NO synthetaseSuperoxide dismutase

Cytokine function: TNF model

- receptors

- down regulation

- signal transduction

TNFR-I (p55, CD120a)

TNFR-II (p75, CD120b)

2 types ofTNF receptor

Dead signal → apoptosisDown regulation

mechanism

TNF--TNFR complex

endocytosis

soluble TNFRsproduction

LPS

Location of TNFR in steady state

expressconstitutively

Inducible

TNF- overproduction

→ cytokines productionTNFR cleaved into

soluble TNFRs

Kinase cascade (MAPK, NIK, caspase)

Transcription factors (AP-1, NF-B)

TNFR II

TNFR I

TNFR associated factors (TRAF 1-6)

caspase

NIK

MAPK

RIP: R. interacting protein

TRADD- TNFR I asso death domain FADD: factor asso death domain

NF-BNF-B

AP-1AP-1

IL-1, IL-6, IL-8, IL-10, GM-CSFAdhesion molecules PGE2, collagenase

Signal Transduction

Protein transcription

TNF-, IL-1, IL-6, IL-8, COX2, INOS

• Transcription associated protein

• Protein kinase cascade

• Transcription factors

Rx targetRx target

TNF family proteins

fas

TRAIL dead R 4

TRAIL = TNF related apoptosis-inducing ligand

TRAIL dead R 5

BAFF-RBLyS

APRIL TACI

BCMA

LymphocyteLymphocyte


Humanized mAbHumanized mAb

anti fas mAbanti fas mAb

IgIg

BAFF-R = B-cell activating factor receptorTACI = transmembrane activator and calcium modulator and cyclophilin ligand-interactorBCMA = B-cell maturation

BLyS = B-lymphocyte stimulator (increase serum level in SLE) differentiation, activation, survivalAPRIL = a proliferation inducing ligand

BelimumabLymphostat RA, SLE

Signal Transduction

HLA-DR

stimulusspecificreceptor

signal transduction transcriptiontranslation

proteins

Receptor associating

proteins

Protein kineasepathways

Translocation oftranscription factors

mRNAmRNA

post-transcription

cell surface cytoplasm nucleus

HLA-DR

stimulusspecificreceptor

signal transduction transcriptiontranslation

proteins

Receptor associating

proteins

Protein kineasepathways

Translocation oftranscription factors

mRNAmRNA

post-transcription

MAPK inhibitor Scio-469 (oral )

phase IIb

MAPK inhibitor Scio-469 (oral )

phase IIb

RANKL

AMG162 Humanized Ab

AMG162 Humanized Ab

Antiresorptive during bone remodeling

siRNATNF blockademouse model

siRNATNF blockademouse model

Calcineurin

inhibitor

Calcineurin

inhibitor

JNK inhibitorJNK inhibitor

TRAF inhibitorTRAF inhibitor

Infection

and

Host defense

infection

and

immunity

infection

and

immunity

ImplicationImplication

exercise

and

immunity

exercise

and

immunity

physicalbarriers

dendritic cell (APC)

neutropenianeutropeniadisruptiondisruption

IC killing defectIC killing defectPMN

T-cell

ด่�านป้�องกั�นกัารติ�ด่เชื้��อด่�านป้�องกั�นกัารติ�ด่เชื้��อnon-specific cells specific IR

abn lymphocyte function

abn lymphocyte function

HIRYYYY

CMIR

NK cells

bacteria

TB

virus

fungus

IC bacteria

ชื้น�ด่ของกัารติ�ด่เชื้��อ

ชื้น�ด่ของกัารติ�ด่เชื้��อ

กัารติอบสนองหลั�กั

กัารติอบสนองหลั�กั

Efficiency of Immune ResponseEfficiency of Immune Response

change of flora

physilogic change

pH cilia

disruptedbarriers

extreme agegenes socioeconomic

statushormone(steroid)

Exercise

and

Immunity

Exercise & IRExercise & IR

(NK cells)chronic exercise

(at least 16 wk)

acute boat of exercise

กัารออกักั�าลั�งกัายในผู้��ติ�ด่เชื้��อ HIV / AIDSกัารออกักั�าลั�งกัายในผู้��ติ�ด่เชื้��อ HIV / AIDS

เป้�นไข�หวั�ด่ ออกักั�าลั�งกัายได่�หร�อไม่�

กัารออกักั�าลั�งกัายป้�องกั�นโรคม่ะเร%งได่�หร�อไม่�

Immune Response

immune ↔ infection

acute vs chronic

relaxation exercise

Documents

Basic Immunology for internist Basic Immunology for internist Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of Medicine KhonKaen