IMMUNOLOGY

1. IMMUNOLOGY Usep Abdullah Husin

2. Topic • Introduction • Element of Immunity • Immunogenetic • Immune Response • Antigen & Immunogen & Vaccine • Immunoglobulin • Complement System • Cytokines

3. IX. Antigen-Antibody Reaction X. Immunology in Infection diseases XI. Immunoprophylaxis XII. Hypersensitivity Reaction XIII. Autoimmune Diseases XIV. Immunodeficiency

4. I. Introduction Immunology “Imunis” All of physiology mechanism => foreign agent => - neutralize with or - eliminate => without - metabolism tissue damage

5. History X1st century => China XV1st => variolasi 1798 : E. Jenner : Cowpox => Smallpox 1880 : Vaccine (L. Pasteur) 1908 : => cellular (Metchnikof) => humeral (Ehrlich) >>> 1970 : molecular biology

6. Imunity changing factor • Genetic • Age • Metabolism • Environment & nutrition • Anatomy • Microbe • Physiology

7. Function of Immunity • Defense • Homeostasis • Surveillance

8. Innate (natural) Immunity Acquired (adaptive) Natural : all of creature (+) Such as : 1. Physical hindered 2. Cellular hindered 3. Chemical hindered

9. Adaptive With functional characteristic : 1. Specificity Heterogeneity 2. Differentiate : “SELF” & “NOT SELF” 3. Memory

10. II. Elements of Immunity Operator of Immunity : Limphoreticular system • Phagocyte cells : MPS, Neutrophyl, Eosinophyl • Lymphoid cells : B cell & T cell • Mediator cells : Basophile, Mastocyt Which come from : “Hematopoetic Stem Cell” (0,001 % Bone marrow)

11. NK cell

12. Lymphoid Tissues Consists of : Lymphoid cells Lymphoid tissues Lymphoid Cells Lymphoid cell Immunocyt Specific cellular product (Ig & CMI) BMPrimary Lymph glands Secondary Lymph gland Immunogen (Prolif. & Dif)

13. Primary Lymphoid Organ Thymus gland Function : Maturity T cells BM Thymus gland Circulation Cortex Medulla CD4+ CD4- CD8- CD4+CD8+ Circulation CD 8+

14. Bursa Fabricius Only can be found in bird family B cell BM Secondary lymphoid organ Stem cell B cell Secondary lymphoid organ Consists of : lien, lymph node, Payer Patch, Tonsil as antigen filter Bursa Fabricius Bone Marrow

15. Bone Marrow Myeloerythroid cells IL-2 SCF IL-7 SCF SCF Hematopoietic sterm cell Lymphoid stem cell ? Virgin B lymphocyte B cell precursor Secondary lymphoid organs IL-3 SCF Thymus IL-2 IL-7 SCF Thymic factors T cell precursor Virgin T lymphocyte

16. Lymphocyt Circulation Blood Circulation Tissues Afferent lymph duct Spleen Lymph node Efferent Lymph duct Ductus Thoracicus

17. Screening of Antigen ANTIGEN PULMO SKIN GIT Resp. Tract. Circulation Peribronchial Lymphoid Tissues Tonsil PP Spleen Lymph node Regional

18. Structure Immunology of Spleen Periarterioler sheet Trabecular artery Red pulp Central arteriole Center germinal

19. Immunologist Structure of Lymph node Germinal Center Paracortex Cortex Medulla Efferent Lymph canal Artery Vena

20. III. Immunogenetic All of immune response processes with genetic basic. “All factors which regulate Immune Response to foreign agents => hereditary” Very widely of scope : HLA & Blood Group Clinical aspects : • Blood grouping, tissue/organ transplantation. • Autoimmune disease, producing of vaccine, etc.

21. MHC = HLA (man) Genetic: position: short arm of Chromosome 6 length: 3,5 x 106 bps 5’ C C A T T T A A C C - - - 3’ 3’ C C T A A A T T C C - - - 5’

22. HLA Complex Class II Class III Class I C4B 21A Endo 21B BF DP DQ DR TNF BC centromere    C4A C2 TNF kilobases 0 500 1000 1500 2000 2500 3000 3500 Figure 5-1. Organization of the HLA complex on the short arm of human chromosome 6. Regions encoding the 3 classes of MHC proteins are indicated by braces. Endo denotes a cluster of genes within the class II region that encode protease components and peptide transport proteins required for processing endogenous antigens (see text). Class III proteins are unrelated to class I and II and are not involved in antigen presentation. Among proteins encoded in the class III region are tumor necrosis factors  and , and complement factors C2, C4, B and F.

23.  chain Extracellular region CHO CLASS I HLA 101 86 S 1 2 S In all nucleus’s cells 164 NH2 2-microglobulin NH2 Such: A, B, C => L M A S S 203 S 3 Extracellular region S 259 • Functions: • Immune aware • Tissue rejected COOH 282 membrane 306 PO4 cytoplasm 338 COOH Figure 5-2. Schematic representation of a class I HLA protein. The molecule consists of an MW 44,000 polymorph transmembrane polypeptide ( chain) non covalently associated with an MW 12,000 non polymorph polypeptide (2-microglobulin). The 3 extracellular domains of the  chain are designated 1, 2, and 3. The binding site for immunogenic peptides (T cell determinants, is formed by the cleft between the 1 and 2 domains.

24. -helix 2 Peptide binding groove 8-strand -pleated sheet 1 N N C C 2m 3 Figure 5.3. Diagrammatic structure of a class I HLA molecule (side view). In this ribbon diagram of the polypeptide backbone, the polypeptides are oriented as in Fig 3-2, but only the extracellular region is depicted. The peptide binding site as a cleft (or groove) formed by 8 strands of –pleated sheet and a pair of -helices from the 1 and 2 domains. The –sheet structure forms the floor and the type helices the walls of the cleft. –strands are depicted is broad arrows and –helices as narrow coils.

25. -helix -pleated sheet forming floor of antigen-binding groove -helix N N Figure 5-4. Peptide-binding site of a class I HLA molecule, viewed along an axis perpendicular to the cell surface. Eight strands of -pleated sheet contributed by the 1 and 2 domains forms the floor of the site, and 2 -helices, one from each of the 2 domains, form the walls. The groove accommodates peptides 8-9 amino acid residues long, leaving them partially accessible for interaction with the T cell antigen receptors.

26.  chain  chain Class II HLA NH2 NH2 CHO 15 19 S 1 1 S 78 79 CHO Extracellular region 117 At B cell => macrophage 107 118 CHO S S 2 2 S S Extracellular region 163 173 • Functions: • T cell aware • Tissue rejected 193 200 membrane 214 221 cytoplasm 237 229 COOH COOH Figure 5-5. Schematic representation of a class II HLA molecule. The molecule consists of an MW 34.000 polypeptide ( chain) noncovalently associated with an MW 29.000 polypeptide ( chain).

27. 1 NH2 -helix COOH -pleated sheet forming floor of antigen-binding groove COOH NH2 1 -helix Figure 5-6. Structure of the peptide binding site of a class II HLA molecule. The binding site is similar to that of class I molecules, except that it is formed by the 1 and  1 domains of the class II molecule and is relatively open at both ends to accommodate longer peptides.

28. Cell surface Surface Ag- Class I MHC complex Peptide transporter To cell surfaces 2m Class I MHC Endogenous peptides Exogenous antigen Processing Peptides nucleus RER To cell surfaces Class II MHC Surface Ag- Class II MHC complex Figure 5.7. The pathway of assembly and transport for antigen-MHC complexes containing class I (top) and class II (bottom) HLA molecules. MHC polypeptide of initially expressed in the rough endoplasmic reticculum (RER). Class I proteins sequentially bind endogenous peptides and 2-microglobulin (2m) in the RER lumen and are than transported to the cell surface. Class II proteins associate with invariant chain (li) in the RER and so are prevented from binding endogenous peptides, they are translocated instead to an endosomal compartment, where li dissociates and is replaced by exogenous peptides.

30. Blood Grouping Erythrocyte antigen: A B O Rh ABO Group Before 20th : transfusion ? 1900 Landsteiner

32. ABO Genetic ABO single gene ABO with 3 allele A,B,O A,B codominant KH binding + H substrate Genotype Phenotype Er-Ag Allo ab A anti B anti - O/O O O - A,B anti AO,AA A A + - B anti - BO,BB B B - A anti - AB AB AB + +

33. Rhesus Factor Levine & Stetson (1939) => Ag + Asera from post partum mother Ag + S.I rabbit by Rhesus of erythrocyte => “Rh factor” => Rh. Ag. Natural antibody (-), except by “immunization”

34. Genetic of Rhesus • > 30 Ag. Rhesus type Fisher & Race 3 gene with allele partner’s => 5 determinant antigen D, C, E, E, C. Wiener 1 gene locus => “multiple complex allele” DA Rho, rh’, rh”, hr’, hr”.

35. IV. Immune Response Definition: • “Self” & “not self” • “Virgin” lymphocyte (109/day), with IG & TCR => 108 antigen type • “Clonal restriction” • “Clonal selection” • Each others cells communication.

36. 6 6 Imunogen 2 2 1 1 1 1 3 1 5 3 5 4 4

38. TCR endosome MHC II IMMUNOGEEN TH cell lissome MACROPHAGE Antigen-presenting cell (AFC) CD 4 Figure 3-3. Capture, processing, and presentation of antigen by an APC. The immunogen is captured by phagocytosis, receptor-mediated endocytosis, or pinocytosis and is broken down into fragments. Some fragments (antigens) become associated with class II MHC proteins and are transported to the cell surface, where they can be recognized by CD4 T cells. TCR, T cell receptor.

39. T cell IL-2 Autoactivation MHC II molecules IL-1 CD4 T cell IL-2R proliferation APC TH cell Activation TH cell Release of cytokines and other growth and differentia- tion factors Costimulation Processed antigens Figure 3-4. The cell activation. The APC presents an antigen in the context of class II MHC to the TH cell and also provides a costimulatory signal. The 2 signals lead to activation of the TH cell. The APC also releases IL-1, which acts on both the APC and the TH cell to promote activation. Activation leads to IL-2 receptor expression and IL-2 secretion by the TH cell, resulting in autocrine growth stimulation.

40. Helper factors Memory B cell B cell CD4 TCR Ag Proliferation B cell Progeny MHC II Plasma cell differentiation IL-2R B cell Ig Ag receptors Antibody Figure 3-5. B cell activation. Antigen binding to the surface immunoglobulins, coupled with soluble or contact-mediated helper factors from an activated TH cell, lead to proliferation and differentiation. Cytokines involved in TH cell help include IL-2, IL-4 and IL-6.

41. TCR (already triggered) IL-2R TCR target cell (cell death) Ag IL-2 TH cell Tc cell Auto- activation MHC I IL-2R CD4 MHC I CD8 Toxins Figure 3-6. To cell activation requires contact with specific antigen in the context of a class I MHC molecule on the surface of a target cell. It also requires IL-2 from a nearby activated TH cell. The activated Tc cell kills the target cell either by secreting cytotoxins (as shown) or by inducing it to commit suicide.

42. V. ANTIGEN and IMMUNOGENICITY Definition : 1. Immunogen 2. Antigen 3. Immunogenicity 4. Antigenicity Classification : 1. Exogen antigen 2. Endogen antigen : - Xenogeny Ag. (Heterolog) - Autolog Ag. - Alogenic Ag.

43. Immunogenicity Commonly is a macromolecule protein. 1. Molecule antigenisity 2. Molecule size 3. Complexity of Chemistry structure 4. Genetic constitution 5. Method of entry 6. Dosage 7. Digestibility

44. Determinant Antigenic

45. Hapten I K Hapten carrier Immunogen I.K agent Hapten

46. B B Receptor Imunogenik Thymus dependent Ag and Thymus independent Ag T Macrophage cell B HLA DR Thymus dependent antigen Plasma cell

47. Cross Reaction

48. Adjuvant of Immunogen >>> Immunogenicity antigen pathway >>> Retention >>> Molecule size Local stimulation

49. VI. IMMUNOGLOBULIN Definition : Protein as humoral immunity effectors molecule The function of Ig : Binding Ag  Biological activity Thus as complex molecule

50. Example Antibody to Viral It has particular part which could : • Binding virus • Be able to enter respiratory tract • Not be broken by enzyme • Be able to joint with leukocyte