1. Lecture 1. Innate Immunity-phagocytes/NK cells
Lecture 2. Introduction to acquired immunity-T/B cells

2. Lecture objectives
What are the components of the innate immune system?
Phagocytes and phagocytosis
Toll-like receptors (TLRs)
NK cells and their receptors
How is the innate immunity different from adaptive immunity?
Hematopoiesis (sites and cytokines)
Structure of lymphoid tissues

3. Lecture 1. Innate Immunity-phagocytes/NK cells

4. Autoimmunity or Allergy= 0
The goal of a balanced immune system
[Pathogens]= 0
[Tumor cells]= 0
Autoimmunity or Allergy= 0

5. Pathogens: the primary targets of the immune system
Parasites
Bacteria
Viruses
Fungi

6. The territory to defend by the immune system and physical barriers
Figure 1-4

7. Figure 8-6 part 2 of 2
Physical, chemical and microbiological barriers of our body

8. CORE
1-a. Antimicrobial factors on skin and mucous membranes and in the blood and tissues
Mechanical antimicrobial factors
Mechanical barrier of skin
Mucous epithelial barrier
Ciliated epithelium
Normal microflora
Mucous secretions

9. (2) Chemical antimicrobial factors
CORE
(2) Chemical antimicrobial factors
Lysozyme
Muramidase
Spermine
Peroxides
Acids
Complement
Cytokines
Antimicrobial peptides (defensins)
IgA (adaptive immunity)

10. Figure 8-5
Immune system is activated at the moment when pathogens enter the body
Neut
Mac DC
Phagocytes:
Macrophages: tissue resident
Neutrophils: recruited from blood
Dendritic cells: tissue resident; migrate to lymph nodes

11. Components of pathogens activate immune and non-immune cells
Immune cells that are activated:
Receptors:
Components of Pathogens:
Peptides
Proteins
Glycoproteins/Proteoglycans
Carbohydrates
Glycolipids
Phospholipids
Peptidoglycans
Nucleic acid
Flagella
ab-T cells
T cell receptors
B cells
B cell receptors
T cell receptors
NKT cells
gd-T cells
Phagocyte receptors
Tissue cells
Macrophages
Toll-like receptors
Neutrophils
Dendritic
cells

12. 6. Cells involved with the immune response,
CORE
6. Cells involved with the immune response,
a. Cells (description, function, important mediators they release, half-lives, relative concentrations in blood)
(1) Non-antigen specific: neutrophils, basophils, eosinophil, mast cell, macrophage, dendritic cell, natural killer cells (NK), large granular lymphocyte morphology
(2) Antigen-specific: T lymphocytes (TC, Th1, Th2), B lymphocytes
(3) Antigen presenting cells (function, location, and important cell surface markers): dendritic cells, macrophages (Kupffer, intraglomerular, alveolar, serosal, brain [microglia], spleen sinus, lymph node sinus; central role of macrophages in immunity and inflammation (cytokines secreted, vasoactive molecules, tissue damage and healing), B-cells

14. Innate (immediate and non-specific) and adaptive (late but antigen-specific) immune responses
Figure 1-7

15. Cells of Innate Immunity Neutrophils Macrophages NK cells Mast cells
Eosinophils
Basophils
Other non-blood origin tissue cells (epithelial/fibroblast cells etc)
Dendritic cells induce adaptive immunity
Phagocytic cells

16. 1-b. Phagocytic cells and the process of phagocytosis
CORE
1-b. Phagocytic cells and the process of phagocytosis
(1) Polymorphonuclear leukocytes, monocytes and macrophages (blood and tissue types; role of macrophage as antigen presenting cell and mediator of inflammation)
(2) Phagocyte cell surface receptors and markers: complement, Fc, Class II, Toll-like receptors
(3) Receptor-mediated chemotaxis (chemotactic agents: C5a, LTB4, chemokines [IL-8, MIP, MCP])

17. Phagocytic cells (continued)
CORE
Phagocytic cells (continued)
(4) Adherence to endothelium (margination and emigration: ICAMs and selectins on endothelium, integrins and selectins on phagocytes)
(5) Particle attachment, phagocytosis, formation of phagolysosomes and role of degranulation in tissue damage
(6) Metabolic burst and mechanisms of bacterial killing and digestion
(a) Oxygen-dependent antibacterial factors: Superoxide generated by NADPH oxidase; hydrogen peroxide generated by superoxide dismutase; hypochlorite and hypoiodite generated by myeloperoxidase
(b) Oxygen-independent antimicrobial proteins: acid hydrolases, muramidase, lysozyme, lactoferrin, defensins.

18. Macrophages engulf bacteria and produce inflammatory cytokines
Figure 1-14

19. Figure 1-5
Complement-mediated phagocytosis

20. Host receptors that sense the molecules of pathogens

21. Figure 8-13 TLRs on the cell surface recognize microbial products
They act as the receptors to sense the presence of pathogens.
Figure 8-13

23. Activation of TLRs induces immune cell activation and production of inflammatory cytokines
Figure 8-14

24. Figure 8-12 part 1 of 2 Recognize microbial products Bind pathogens
Surface receptors of macrophages
Figure 8-12 part 1 of 2
Recognize microbial products
Bind pathogens

25. Figure 8-12 part 2 of 2

26. Figure 8-20 Neutrophil receptors that are important for phagocytosis
Presence of neutrophils in tissue sites (not blood) is a sign of acute inflammation

27. Figure 8-21
What is happening in phagolysosomes?

28. Figure 1-13 Neutrophils: disposable phagocytes to clear pathogens
Formation of Pus

29. Leukocyte recruitment to sites of infection: rolling on selectins
Figure 8-19 part 1 of 2
Important for infiltration of tissues during inflammation

30. Leukocyte recruitment to sites of infection: a multi-step navigation
Figure 8-19 part 2 of 2
1. Selectins
2. Chemokines
3. Integrins

31. Figure 8-5
Neut
Mac DC
Phagocytes:
Macrophages: tissue resident
Neutrophils: recruited from blood
Dendritic cells: initially tissue resident but migrate to lymph nodes upon infection

32. CORE
9-f. NK cells
Distribution: 10-15% of circulating lymphocytes; lack typical T cell markers (i.e. TCR, CD3, CD4, CD8, etc.).
Markers: CD16 (IgG Fc receptor),CD28, CD56 (CD16 & 56 used to identify NK cells)
Cytokines secreted: IFNg, IL-1, GM-CSF, TNFa ; secretion induced by IL-12
Cytotoxic mechanisms: Attack cells with reduced MHC class I expression. Release perforin.
CD-28/B7-1 co-stimulating signal important
This is important mainly for T cell activation but also can be important for NK cells
Can also kill by antibody-dependent cell mediated cytotoxicity (ADCC)

33. Innate Adaptive/acquired NK cell recruitment NK. IFN-a chemokines
Virus
NK.
IFN-a
chemokines
epithelial cells
and DCs
Neutr. recruitment
Neutr.
Effector T cells
(CD4/CD8)
Antibodies
Macrophage activation
DC activation
DCs
Lymph nodes
Activate T cells and B cells
Adaptive/acquired

34. Roles of aIFNs
Figure 8-26

35. Figure 8-28 Kinetics of immune responses after viral infection
IFNa/b, TNF-a, and IL-12 activate NK cells
Figure 8-28

36. NK cell receptors allow killing of infected but not healthy cells
Figure 8-32

37. NK cells can attack tumor cells lacking MHC I expression

39. Figure 8-29
NK receptors for MHC class I, MICA, MICB, and antibody (IgG).
CD16=FcgRIII

40. Antibody-dependent cell-mediated cytotoxicity (ADCC)
Through a activating receptor CD16/Fc-gamma-RIII.
This is a collaboration of innate (NK cells) and adaptive immunity (antibody).

41. IgG Fc Receptors: serve as receptors for antibody IgGs
FcgRI (CD64): Macrophages, Monocytes FcgRII (CD32): B cells, Macrophages, Neutrophils, Monocytes. FcgRIII (CD16): NK Cells, Macrophages, Neutrophils
Most CD4 or CD8 T cells do not express Fc receptors.
FceRI on Mast cells: IgE binds this and activates mast cells

42. Functions of Fc receptors:
Effector Mechanisms (Fc g-RIII on NK cells)
Mediator release (e.g. Fc e-RI on Mast cells)
Enhancement of antigen presentation
B cell negative feedback
Complement Activation (we will revisit these later)

43. CORE
Lymphoid tissues (LT): the tissues that mainly contain lymphocytes and serve as sites of lymphocyte activation & functional differentiation
c. Primary (central) and secondary (peripheral) lymphoid tissues (functions and histologic organization as it pertains to immune function)
(1) Primary: bone marrow and fetal liver (B cells); thymus (T cells)
(2) Secondary: spleen, lymph nodes, mucosa-associated lymphoid tissue (MALT)
Examples of MALT:
Tonsils, adenoids;
Bronchial
Gastrointestinal (appendix and Peyer’s patches (M cells))
Genitourinary tract lymphoid tissues

44. Figure 1-15 The lymphatic system Peripheral lymph nodes
Mesenteric lymph nodes

45. d. Lymphocyte (lymph) traffic:
CORE
d. Lymphocyte (lymph) traffic:
High endothelial venules, efferent lymphatic vessels, thoracic duct, blood lymphocyte pool, and afferent lymphatic vessels

46. Lymphocytes traffic to and from a lymph node
Thoracic duct
Blood
Efferent
lymphatic
vessel
Most lymphocytes LN
Artery
HEV
Afferent lymphatic vessel
Some cells
Tissue sites
(e.g. skin)
Antigens/DCs
pathogens

47. T and B cells (which become memory cells) recirculate, but (disposable) myeloid cells don’t
Examples:
CD3+ T cells: Thymus Blood  LN (Ag)   Blood  inflamed tissues
CD19+ B cells: BM Blood LN (Ag)   Blood  plasma cell sites (BM, spleen, mucosal tissues) or circulation
Neutrophils: BMBlood  Sites of infection  Death
Macrophages: BM (monocytes)Blood  Sites of infection (macrophages)  Granuloma or death

49. 2o LT collects antigens, dendritic cells and lymphocytes for adaptive immune responses.
Figure 1-17
CD3+ naïve T cells become functional cells (memory /effector cells; Th1/Th2 cells) in cortex
(In cortex)
CD19+ naïve B cells undergo differentiation to Ab-producing plasma cells in GCs.

51. Figure 1-19
Immune responses
Hematopoiesis
& Filtering blood

52. Structure of spleen Lymphocytes are collected here
Lymphocytes go through central arterioles to enter the spleen.
Spleen filters blood to collect antigens and remove old red cells.
Red cells are filtered here

53. Peyer’s patches
Figure 1-20

54. 2. Introduction to acquired immunity
CORE
2. Introduction to acquired immunity
a . Specificity and heterogeneity:
Reaction to extracellular versus intracellular pathogens.
Antigen (pathogen) A versus antigen B.
c. Immunological memory
d. Discrimination between self and non-self antigens
e. Active (e.g. immunization) and passive (e.g. transfusion of anti-venom) immunity
f. Natural (infection) versus artificial immunization (vaccination)

55. Multi-step trans-endothelial cell migration
Floating
Selectin-mediated rolling on
endothelial cells
Chemokine receptor
activation
Integrin-mediated
firm adhesion
Extravasation
Chemokine gradient
Chemotaxis
Center of inflammation

56. Figure 1-18
Dendritic cell migration to lymph nodes

60. Different pathogens, different immune response
Figure 8-4

61. Typical time course of adaptive immune responses
Primary response
Slow (2 weeks)
Outcome: Weak
Secondary
Fast (several days)
Outcome: More vigorous
e.g. Hepatitis A
Hepatitis A and
Hepatitis B

62. Figure 1-21 Antigen receptors of B cells and T cells B cell Receptor
Effector molecule
T cell Receptor

63. Figure 1-22 Antigen Specificity
Antibodies neutralize pathogens in an antigen-specific manner
Antigen Specificity

64. Figure 1-24
Antibodies (B cells) bind whole proteins while TCRs (T cells) bind small peptides presented by dendritic cells

65. Peptides are presented to TCR by MHC class I or II molecules on APC (antigen presenting cells: B cells, dendritic cells and macrophages)
Figure 1-25
CD4+ T cells
CD8+ T cells
Activate
Activate

66. Figure 1-26 Activation of CD8+ T cells by antigen peptides
CD4 T cells = helper T cells: control B cells and macrophages
T cells
CD8 T cells = cytotoxic cells: kill virus-infected cells

67. Selection and expansion of antigen specific T and B cells
Marrow or thymus
Lymph nodes
Lymph nodes &
Sites of infection
Immunological memory