1. Basic Immunology for internist Basic Immunology for internist 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

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 immune response 2. Discrimination self/non-self 1. Antigen specific ? ? Clonal selection

11. Specific T-cells response to Ag antigen activation & proliferation primary IR

12. secondary IR antigen Specific T-cells response to Ag

13. Specific Immune Response 2. Discrimination self/non-self 1. Antigen specific  

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

15. Discrimination Self tolerance ? ? immune cell self Ag

16. Clonal ignorance Central tolerance Peripheral tolerance Self tolerance

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

18. educated T-cell autoreactive cell Central Tolerance

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

20. 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

21. HIR CMIR Specific Immune Response

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

23. Non-specific (innate) IR

24. 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

25. Specific (adaptive) IR

26. Antigen Presenting Cell Antigen processing exogenous endogenous Antigen

27. 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

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

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

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

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

32. 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

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

34. 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

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

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

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

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

39. Abnormal Immune Response 

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

41.  Abnormal Immune Response

42. 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

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

44. 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

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

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

47.  Abnormal Immune Response

48. Autoimmunity How ?

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

50. 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

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

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

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

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. 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

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

57. 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

58. autoreactive T-cells Normal tissue Self Ag

60. 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

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

62. Ineffective intracellular killing inapparent infection overt infection

63. Mechanism

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

65. C. trachomatis persistent infection in chronic arthritis

67. M. Tuberculosis infection that caused intractable autoimmune disease

68. 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

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

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

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

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

73. Kawasaki’s Disease

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

75. VV HLA-DR TcR CD4 CD5 ICAM -1

76. 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

77. 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

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

80. 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

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 avoid Ag exposure antimicrobial

82. 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

83. Antimalarial drug change pH in phagosome

84. 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

85. 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

86. 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)

87. 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

88. 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)

89. 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

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 IL-2 DAB IL-2

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 Rituximeb anti-CD20 Rituximeb anti-CD20

92. 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)

93. 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

94. 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

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 ET-1® TGF- 

96. 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

97. 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

98. 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

99. 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

100. 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

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

105. 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

106. 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

107. 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

108. Signal Transduction

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

110. 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

111. Infection and Host defense

112. infection and immunity infection and immunity Implication exercise and immunity exercise and immunity

113. 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

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

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

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

117. Exercise and Immunity

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

119. การออกกำลังกายในผู้ติดเชื้อ HIV / AIDS เป็นไข้หวัด ออกกำลังกายได้หรือไม่ การออกกำลังกายป้องกันโรคมะเร็งได้หรือไม่

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