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

Nature of Immunity Model of Host Immune Response Immunopathogenesis of Autoimmune Dis. Self Tolerance Abnormal immune response Therapeutic implication

Cardinal features of IR specific memory discrimination The Nature of Immunity

Specific (adaptive) Non-specific (innate) Type of Recognition & Defense

Non-specific immune response Cells: professional phagocytes Physical barriers Cytokines Complement Chemical property The cell can talk Immune assistant

Physical & chemical barriers: skin & mucosa lysozyme in saliva acid mucus cilia mucus normal gut flora lysozyme washing action Fatty acids Normal bacterial skin flora washing action of urine

Cells : professional phagocytes neutrophil macrophage monocyte NK cells adhearance, chemotaxis, phagocytosis, oxidative burst, degranulation, IC killing attack and eat kill

complement bacteria phagocyte bacteria 2. chemotaxis C5a 3. opsonization C3b 1. lysis C9 C5b

phagocyteopsoninbinding _ + C3b ++ Ab + Ab + C3b ++++ Y Y

Specific (adaptive) Non-specific (innate) Type of Recognition & Defense  specific  memory  discrimination  specific  memory  discrimination Cardinal features 1 o vs. 2 o IR clonal selection self/non-self

Specific antigen activation primary IR Clonal selection & proliferation

secondary IR antigen Memory

Nature of Immunity Model of Host Immune Response Immunopathogenesis of Autoimmune Dis. Self Tolerance Abnormal immune response Therapeutic implication

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 Ag

educated T-cell autoreactive cell Central Tolerance

autoreactive cell host cell Peripheral Tolerance program cell death … or anergy…

HLA-DR auto Ag TcR VV VV ICAM-1 LFA-3 1. lack of co-stimulator molecules – “anergy” 2. stimulate fas ligand - program cell death “apoptosis” Autoreactive T-cell fas

Specific (adaptive) Non-specific (innate) Type of Recognition & Defense  specific  memory  discrimination  specific  memory  discrimination Cardinal features 1 o vs. 2 o IR clonal selection self-nonself CMIR 2 types  & The cells can talk via CYTOKINES HIR

Nature of Immunity Model of Host Immune Response Immunopathogenesis of Autoimmune Dis. Self Tolerance Abnormal immune response Therapeutic implication

Non-specific (innate) IR

effective IC killing occult (persistent) infection overt infection adhearance chemotaxis phagocytosis oxidative burst degranulation IC killing Professional phagocytes no disease IC killing defect ? Clinical outcome PMN, monocytes/ macrophage

Specific (adaptive) IR

Antigen Presenting Cell Antigen processing exogenous endogenous Antigen

CD28 LFA-1 CD2 CD4 CD3 HLA-DR Ag TcR VV VV ICAM-1 LFA-3 CD80/86(B7) auxillary molecules CTL-4 Tyrosine kinase Trimolecular complex

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 chemokines MIF Fibroblast Synoviocyte

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 Effector T-cells CMI R Th1 K Tc N K

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IL-5 B-lymphocyte IgG HIR Th2 CD40

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG Activated macrophage effector T-cells IF-  IL-2 CD25 ® autocrine paracrine

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG Blood vessel effector T-cells

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1 (CD106 ) ICAM-1 (CD54) effector T-cells L. integrin (CD11/18) VLA integrin (CD49/29) Selectin (CD62) Adhesion molecules

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG effector T-cells Stop inflammatory cells

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG effector T-cells VEGF BMP TGF-  ETR Facilitate extravasation

Antibody  Neutralized Ag  Complement fixed  (chemotaxis, permeability & lysis)  Opsonization

Nature of Immunity Model of Host Immune Response Immunopathogenesis of Autoimmune Dis. Self Tolerance Abnormal immune response Therapeutic implication

Abnormal Immune Response 

Immune deficiency congenital acquired viral infection splenectomy physiologic change immunosuppressive drugs radiation chronic diseases

 Abnormal Immune Response

Gel & Coombs Classification of Immune Response (Hypersensitivity)

SRSA Ag Y Y Y IgE Mast cell Type I Anaphylaxis

IFN-  IL-2 IL-4 IL-6 IL-5 B-lymphocyte Type II Ab-mediated IgG Y Y Y Y Y Y Y Y Y Y Y Y Y Target organ

LE cell IFN-  IL-2 IL-4 IL-6 IL-5 B-lymphocyte IgG Type III Immune complex Y Y Y Y Y Y

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG effector T-cells Type IV Cell mediated

 Abnormal Immune Response

Autoimmunity How ?

Nature of Immunity Model of Host Immune Response Immunopathogenesis of Autoimmune Dis. Self Tolerance Abnormal immune response Therapeutic implication

Triggering Infection Triggering Infection Abnormal Immune Response Genetic predisposition Genetic predisposition Disease HLA Class I - B27 Class II- DR - DW Non 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 reactive T-cell proliferation, cytokines, B-cell activation, cytolysis proliferation, cytokines, B-cell activation, cytolysis

self reactive T-cell Molecular mimicry Molecular mimicry Presentation of cryptic cell Presentation of cryptic cell Hypersensitivity to persistent organism or their antigens Hypersensitivity to persistent organism or their antigens Immune activation by superantigen Immune activation by superantigen Antigen activation or disruption by retroviruses Antigen activation or disruption by retroviruses

self reactive T-cell Molecular mimicry Molecular mimicry Presentation of cryptic cell Presentation of cryptic cell Hypersensitivity to persistent organism or their antigens Hypersensitivity to persistent organism or their antigens Immune activation by superantigen Immune activation by superantigen Antigen activation or disruption by retroviruses Antigen activation or disruption by retroviruses

microbeAPC T-cell effector cells cross reactivity (molecular mimicry) self antigen

self reactive T-cell Molecular mimicry Molecular mimicry Presentation of cryptic cell Presentation of cryptic cell Hypersensitivity to persistent organism or their antigens Hypersensitivity to persistent organism or their antigens Immune activation by superantigen Immune activation by superantigen Antigen activation or disruption by retroviruses Antigen activation or disruption by retroviruses

autoreactive T-cells Normal tissue Self Ag

self reactive T-cell Molecular mimicry Molecular mimicry Presentation of cryptic cell Presentation of cryptic cell Hypersensitivity to persistent organism or their antigens Hypersensitivity to persistent organism or their antigens Immune activation by superantigen Immune activation by superantigen Antigen activation or disruption by retroviruses Antigen activation or disruption by retroviruses

Ineffective intracellular killing inapparent infection overt infection

Mechanism

H. pylori C. trachomatis C. pneumoniae Salmonella inf. M. tuberculosis Viral hepatitis B, C Retrovirus inf. Herpes zoster Prion

C. trachomatis persistent infection in chronic arthritis

M. Tuberculosis infection that caused intractable autoimmune disease

self reactive T-cell Molecular mimicry Molecular mimicry Presentation of cryptic cell Presentation of cryptic cell Hypersensitivity to persistent organism or their antigens Hypersensitivity to persistent organism or their antigens Immune activation by superantigen Immune activation by superantigen Antigen activation or disruption by retroviruses Antigen activation or disruption by retroviruses

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG effector T-cells antigen superantigen

HLA-DR Antigen Presentation LFA-3 ICAM -1

Trimolecular complex HLA-DR CD3 CD4 CD2 LFA-1 VV TcR LFA-3 ICAM -1

Trimolecular complex HLA-DR VV TcR Normal T-cell activation

SUPERANTIGEN HLA-DR VV TcR VV Activate T-cell without Ag processing CD4 CD5 ICAM -1

VV HLA-DR TcR CD4 CD5 ICAM -1

Treatment of Kawasaki’s disease by giving intravenous immunoglobulin (IVIG) VV TcR Y Y Y Y Y Y Y Y Y CD4 CD5 HLA-DR ICAM -1 Y Y

self reactive T-cell Molecular mimicry Molecular mimicry Presentation of cryptic cell Presentation of cryptic cell Hypersensitivity to persistent organism or their antigens Hypersensitivity to persistent organism or their antigens Immune activation by superantigen Immune activation by superantigen Antigen activation or disruption by retroviruses Antigen activation or disruption by retroviruses

Nature of Immunity Model of Host Immune Response Immunopathogenesis of Autoimmune Dis. Self Tolerance Abnormal immune response Therapeutic implication

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs avoid Ag exposure antimicrobial

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs

Antimalarial drug change pH in phagosome

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs

HLA-DR TcR  TcR CD3 CD4 CD2 LFA-3 ICAM-1 Ag TRIMOLECULAR COMPLEX & COSTIMULATORY PATHWAY APC THTH CD80/86 (B7) CD28 CTLA4 (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) CD40L

B CD40 HLA-DR TcR  TcR CD3 CD4 CD2 LFA-3 ICAM-1 Ag APC THTH CD80/86 (B7) CD28 CTLA4 (CD154) CTLA4 (CD154) CD40 CD40L CD40L TRIMOLECULAR COMPLEX & COSTIMULATORY PATHWAY Anti CD40L mAb ( IDEC-131, hu5c8, BG9588, Biogen ) Anti CD40L mAb ( IDEC-131, hu5c8, BG9588, Biogen ) RA T B CD40 SLE B CD40 B B LFA-1 (CD11a/CD18) JJ316 anti rat CD28 mAb

HLA-DR TcR  TcR CD3 CD4 CD2 LFA-3 ICAM-1 Ag APC THTH CD80/86 (B7) CD28 CTLA4 (CD154) CTLA4 (CD154) CD40 TRIMOLECULAR COMPLEX & COSTIMULATORY PATHWAY efalizumab : humanized mAb CD11a psoriasis LFA-1 (CD11a/CD18) LFA-1 (CD11a/CD18) CD40L CD40L JJ316

HLA-DR TcR  TcR CD3 CD4 CD2 LFA-3 ICAM-1 Ag APC THTH CD80/86 (B7) CD28 CTLA4 (CD154) CTLA4 (CD154) CD40 TRIMOLECULAR COMPLEX & COSTIMULATORY PATHWAY LFA-1 (CD11a/CD18) CD40L Anti-CD3 : HuOKT3  1 (Ala-Ala) JJ316

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs CAMPATH-1H Profound peripheral lymphopenia

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs IL-2 DAB IL-2

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs Rituximeb anti-CD20 Rituximeb anti-CD20

B CD20 immature mature naive B CD20 memory B CD20 P Plasma cell Rituximeb anti-CD20 Rituximeb anti-CD20 B-cell depletion Autoimmune with antibody production refractory Wegener granulomatosis, SLE with AIHA, ITP essential mixed cryoglobulinemia, RA (? RF+ve)

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs IVIG

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs Biologic response modifier (Targeting therapy)

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs 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) IFN  recombinant 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-  VEGF  soluble VEGFR1-Fc Alternative targets of cytokine modifying Rx TNF model

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs block adhesion molecules

HLA DR+ CD 44 LFA-1 CLA P & E Slectin (CD62) ICAM-1 ICAM-2 VCAM-1 ( CD106) VLA-4 (CD49/29) Anti-human-ICAM-1 Ab (enlimomab) ADHESION MOLECULES anti VCAM-1 mAb E-selectin humanized anti–  v  3 (integrin mAb) humanized anti–  v  3 (integrin mAb) Humanized 4-1, 4-7 mAb (Natalizumab) 2ME2 (2 methoxyextradiol) antiangiogenesis

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs Anti-inflammatory agents NO synthetase Superoxide dismutase

OR

Searching for the secretinside basic immunology And finally….

Cytokine function: TNF model - receptors - down regulation - signal transduction

TNFR-I (p55, CD120a) TNFR-II (p75, CD120b) 2 types of TNF receptor Dead signal → apoptosis Down regulation mechanism TNF-  -TNFR complex endocytosis  soluble TNFRs production LPS Location of TNFR in steady state express constitutively Inducible TNF-  overproduction → cytokines production TNFR 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-  B AP-1 IL-1, IL-6, IL-8, IL-10, GM-CSF Adhesion 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 target

TNF family proteins fas TRAIL dead R 4 TRAIL = TNF related apoptosis-inducing ligand TRAIL dead R 5 BAFF-R BLyS APRIL TACI BCMA Lymphocyte Therapeutic implication Humanized mAb anti fas mAb Ig BAFF-R = B-cell activating factor receptor TACI = transmembrane activator and calcium modulator and cyclophilin ligand-interactor BCMA = B-cell maturation BLyS = B-lymphocyte stimulator (increase serum level in SLE) differentiation, activation, survival APRIL = a proliferation inducing ligand Belimumab Lymphostat RA, SLE

Signal Transduction

HLA-DR stimulus specific receptor signal transductiontranscription translation proteins Receptor associating proteins Protein kinease pathways Translocation of transcription factors mRNA post- transcription cell surfacecytoplasmnucleus

HLA-DR stimulus specific receptor signal transductiontranscription translation proteins Receptor associating proteins Protein kinease pathways Translocation of transcription factors mRNA 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 siRNA TNF blockade mouse model siRNA TNF blockade mouse model Calcineurin inhibitor Calcineurin inhibitor JNK inhibitor TRAF inhibitor

Infection and Host defense

infection and immunity infection and immunity Implication exercise and immunity exercise and immunity

physical barriers dendritic cell (APC) neutropenia disruption IC killing defect PMN  T-cell ด่านป้องกันการติดเชื้อ non-specific cells specific IR abn lymphocyte function abn lymphocyte function

effective IC killing inapparent (persistent) infection overt infection adhearance, chemotaxis, phagocytosis, oxidative burst, degranulation, IC killing

HIR Y Y Y Y CMIR NK cells bacteria TB virus fungus IC bacteria ชนิดของการติด เชื้อ การตอบสนอง หลัก

Efficiency of Immune Response 6. physiology change of flora physilogic change pHcilia disrupted barriers extreme age genes socioeconomic status hormone (steroid)

Exercise and Immunity

Exercise & IR (NK cells) chronic exercise (at least 16 wk) acute boat of exercise

การออกกำลังกายในผู้ติดเชื้อ HIV / AIDS เป็นไข้หวัด ออกกำลังกายได้หรือไม่ การออกกำลังกายป้องกันโรคมะเร็งได้หรือไม่

Immune Response immune ↔ infection acute vs chronic relaxation exercise