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

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

3. Cardinal features of IR specific memory discrimination The Nature of Immunity

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

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

6. 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

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

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

9. phagocyteopsoninbinding _ + C3b ++ Ab + Ab + C3b ++++ Y Y

10. 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

11. Specific antigen activation primary IR Clonal selection & proliferation

12. secondary IR antigen Memory

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

14. Discrimination Self tolerance ? ? immune cell self Ag

15. Clonal ignorance Central tolerance Peripheral tolerance Self tolerance

16. autoreactive T-cells blood barrier Clonal ignorance Normal tissue Self Ag

17. educated T-cell autoreactive cell Central Tolerance

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

19. 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

20. 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

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

22. Non-specific (innate) IR

23. 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

24. Specific (adaptive) IR

25. Antigen Presenting Cell Antigen processing exogenous endogenous Antigen

26. 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

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

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

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

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

31. 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

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

33. 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

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

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

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

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

38. Abnormal Immune Response 

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

40.  Abnormal Immune Response

41. Gel & Coombs Classification of Immune Response (Hypersensitivity)

42. SRSA Ag Y Y Y IgE Mast cell Type I Anaphylaxis

43. 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

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

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

46.  Abnormal Immune Response

47. Autoimmunity How ?

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

49. 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

50. How infectious agents induce chronic inflammatory or autoimmune diseases?

51. How infectious agents induce chronic inflammatory or autoimmune diseases? T-cells are central to most model of autoimmunity

52. self reactive T-cell proliferation, cytokines, B-cell activation, cytolysis proliferation, cytokines, B-cell activation, cytolysis

53. 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

54. 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

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

56. 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

57. autoreactive T-cells Normal tissue Self Ag

59. 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

60. Ineffective intracellular killing inapparent infection overt infection

61. Mechanism

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

63. C. trachomatis persistent infection in chronic arthritis

65. M. Tuberculosis infection that caused intractable autoimmune disease

66. 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

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

68. HLA-DR Antigen Presentation LFA-3 ICAM -1

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

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

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

72. VV HLA-DR TcR CD4 CD5 ICAM -1

73. 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

74. 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

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

77. IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells 1 2 3 4 Collagenase MMP PGs 5 6 7 8

78. IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells 1 2 3 4 Collagenase MMP PGs 5 6 7 8 avoid Ag exposure antimicrobial

79. IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells 1 2 3 4 Collagenase MMP PGs 5 6 7 8

80. Antimalarial drug change pH in phagosome

81. IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells 1 2 3 4 Collagenase MMP PGs 5 6 7 8

82. 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

83. 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

84. 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

85. 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

86. IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells 1 2 3 4 Collagenase MMP PGs 5 6 7 8 CAMPATH-1H Profound peripheral lymphopenia

87. IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells 1 2 3 4 Collagenase MMP PGs 5 6 7 8 IL-2 DAB IL-2

88. IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells 1 2 3 4 Collagenase MMP PGs 5 6 7 8 Rituximeb anti-CD20 Rituximeb anti-CD20

89. 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)

90. IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells 1 2 3 4 Collagenase MMP PGs 5 6 7 8 IVIG

91. IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells 1 2 3 4 Collagenase MMP PGs 5 6 7 8 Biologic response modifier (Targeting therapy)

92. IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells 1 2 3 4 Collagenase MMP PGs 5 6 7 8 ET-1® TGF- 

93. 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

94. 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

95. IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells 1 2 3 4 Collagenase MMP PGs 5 6 7 8 block adhesion molecules

96. 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

97. IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells 1 2 3 4 Collagenase MMP PGs 5 6 7 8 Anti-inflammatory agents NO synthetase Superoxide dismutase

98. OR

100. Searching for the secretinside basic immunology And finally….

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

102. 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

103. 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

104. 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

105. Signal Transduction

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

107. 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

108. Infection and Host defense

109. infection and immunity infection and immunity Implication exercise and immunity exercise and immunity

110. 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

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

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

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

114. Exercise and Immunity

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

116. การออกกำลังกายในผู้ติดเชื้อ HIV / AIDS เป็นไข้หวัด ออกกำลังกายได้หรือไม่ การออกกำลังกายป้องกันโรคมะเร็งได้หรือไม่

117. Immune Response immune ↔ infection acute vs chronic relaxation exercise