1. The Immune System
Chapter 21

2. Immune System functional system rather than organ system Hematopoetic
Vasculature
Lymphatic
Fig 21.1

3. Innate vs. Adaptive Immune System – Introduction
Innate: structural defenses; responds to nonspecific foreign substances
First line: external surface epithelium & membranes
Second line: inflammatory processes – antimicrobial proteins, phagocytes, etc.
Fig 21.1

4. Innate vs. Adaptive Immune System – Introduction
Adaptive: responds to specific foreign substances
Innate & adaptive mechanisms work together
Fig 21.1

5. Innate, Surface Defenses
Skin
physical barrier to microbes
Keratin resistant to most bacterial enzymes & toxins
secretions are acidic pH 3-5
Mucosa
physical barrier & produces a variety of protective chemicals
Gastric mucosa
very acidic & produces proteolytic enzymes
Saliva & lacrimal fluid contain lysozyme
Mucous
traps bacteria & moves them away from epithelial surface

6. Innate, Internal Defenses
Based on recognition of surface carbohydrates (glycocalyx)
Glycocalyx is recognized as “self” or “non-self”
Figure 3.3

7. Innate, Internal Defenses
Phagocytes
Macrophages: derived from monocytes
Free Macrophages: roam through tissues
Fixed Macrophages: Kupffer cells (liver) & microglia (brain)
Ingest cellular debris, foreign material, bacteria, fungi
Neutrophils: ingest pathogens
Eosinophils: weakly phagocytic of pathogens. Attack parasites (degranulation)
Mast Cells: phagocytic of various bacteria

8. Innate, Internal Defenses
Phagocytic mechanisms:
Adherence: cell binds to invader
Aided by opsonization (a chemical process that enhances binding via complement & antibodies)
Ingestion: formation of phagolysosomes
Respiratory Bursts: merge phagosome with lysosome & flood phagolysosome with free radicals (macrophage)
Defensins: proteins that crystallize out of solution & pierce pathogen membranes (neutrophils)

9. Mechanism of Phagocytosis
Figure 21.2

10. Innate, Internal Defenses
Natural Killer Cells:
Small population of large granular lymphocytes
Non specific for “non-self”
Not phagocytic: attack is by release of perforins that perforate the target cell plasma membrane.
Shortly after perforation the target nucleus disintegrates.
Release chemicals that enhance the inflammatory response

11. Innate, Internal Defenses: Inflammation
tissue response to injury
Triggered by injury – trauma, heat, chemical irritation, infection, etc.
Beneficial effects
Prevents spread of injury
Disposes of cellular debris & pathogens
Promotes repair

12. Innate, Internal Defenses: Inflammation
cardinal signs of inflammation
Redness
Heat
Swelling
Pain
(functional impairment Rigor)
Weapons of the Spanish Inquisition

13. Innate, Internal Defenses: Inflammation
Inflammatory response: signs are associated with vasodilation & increased vascular permeability
Dilation: redness, heat
Permeability: edema, (increased pressure) pain
Pain also associated with bacterial toxins & some mediators (kinins, PGs)

14. Innate, Internal Defenses: Inflammatory Response
Mechanisms causing vasodilation & vascular permeability
Injured cells release inflammatory mediators
Histamines
Kinins
Prostaglandins
Complement
Cytokines (also activated by receptors on macrophages in response to microbial glycocalyx)

15. Innate, Internal Defenses: Inflammatory Response
Edema
Dilutes harmful substances
Provides nutrients (& O2) for repair
Enhances entry of clotting protein
Epithelial breaches also stimulate b-defensin release from epithelial cells

16. Events in Inflammation
Figure 21.3

17. Innate, Internal Defenses: Inflammatory Response
Phagocyte mobilization: infiltration of damaged area by neutrophils & macrophages

18. Innate, Internal Defenses: Inflammatory Response
Leukocytosis: leukocytosis inducing factors released by injured cells promote rapid release of WBCs from marrow
Margination: increased vascular permeability causes decreased fluid in vessels; blood flow slows & neutrophils are able to move to vessel margins. Here endothelial markers (CAMs) allow neutrophils to cling to vessel walls (pavementing).

19. Innate, Internal Defenses: Inflammatory Response
Diapedesis: neutrophils migrate through capillary walls
Chemotaxis – inflammatory chemicals attract neutrophils to move up the chemical concentration gradient (neutrophils respond first)
As the process continues, monocytes diapedes into the area & become macrophages. With chronic inflammation, macrophages predominate

20. Inflammatory Response: Phagocytic Mobilization
Figure 21.4

21. Innate, Internal Defenses: Inflammatory Response
Macrophages clean up cellular debris & pathogens
If pathogens were associated with the injury, activation of the complement cascade occurs & elements of adaptive immunity join the process

22. Innate, Internal Defenses
Viral replication – (viruses lack metabolic processes) Viruses release nucleic acid (RNA or DNA) into cytoplasm. The information on the nucleic acid is incorporated into the cell’s DNA. Normal cellular mechanisms then produce viral structural components. Multiple new viral particles are produced & released from the cell (sometimes killing the cell)

23. Innate, Internal Defenses
Antiviral proteins: interferon & complement
Interferon: some cells produce & release interferons (IFNs) when invaded by virus
Released interferons stimulate nearby cells to produce proteins (PKR) that interfere with viral replication by disrupting protein synthesis & the ribosome
Not virus specific.

24. Interferon (IFN)
Figure 21.5

25. Innate, Internal Defenses
Complement – a group of plasma proteins (20) that are activated in the presence of foreign substances
Complement activation enhances & amplifies inflammation
Bacteria & some other cell types are lysed by complement activation
Complement activation enhances both innate & adaptive defenses

26. Innate, Internal Defenses
Complement activation pathways
Classical pathway: requires antibodies
Antibodies bind to target (antigen)
Complement protein C1 binds to the antibody-antigen complex (complement fixation)
Alternative pathway: complement factors interact with microorganism glycocalyx
Both pathways lead to a cascade of protein activation, leading to activation of C3

27. Innate, Internal Defenses
C3 is the start of the; Final Common Pathway
C3 cleaves to form C3a & C3b
C3a (& C5a) enhance inflammation by increasing histamine release, increasing vascular permeability & stimulating chemotaxis
C3b coats bacterial membrane supplying adhesion points (opsonization)
C3b initiates the cascade forming the membrane attack complex (MAC)
The MAC forms a hole in the cell membrane & enhances Ca2+ influx  cell lysis

28. Innate, Internal Defenses; Complement
Figure 21.6

29. Innate, Internal Defenses
C-reactive proteins (CRP) produced by the liver in response to inflammatory molecules can activate the classical pathway by binding to membrane & activating C1. Also participates in opsonization.
Fever – a systemic response to infection. Leukocytes & macrophages release pyrogens that raise the hypothalamic “set point” for temperature

30. ADAPTIVE DEFENSES ADAPTIVE DEFENSES
Innate & adaptive mechanisms work together in a cohesive fashion

31. Adaptive Defenses: Characteristics
Specificity: directed at specific targets
Systemic: not restricted to initial site of infection / invasion
Memory: after initial exposure & activation, a more rapid & more vigorous response is made to subsequent exposures to pathogens
(secondary response)

32. Adaptive Defenses: Components
Humoral Immunity: (antibody mediated immunity) provided by antibodies floating free in body fluids
Cell mediated immunity:
lymphocytes directly attack specific invaders by lysis or indirect attack by initiating inflammation and/or activating other lymphocytes & macrophages

33. Adaptive, Humoral Immunity
Antigen = any substance that can mobilize the immune system & provoke an immune response*
*Humoral and/or cell mediated

34. Adaptive, Humoral Immunity
Complete antigens (proteins, nucleic acids, lipids, polysaccharides):
Immunogenicity: the ability to stimulate specific lymphocytes & specific antibodies
Reactivity: the ability to react with activated lymphocytes & antibodies
Hapten (an incomplete antigen): a smaller molecule that is not immunogenic until attached to proteins

35. Adaptive, Humoral Immunity
Antigenic determinants: sites on an antigenic molecule that are immunogenic
Epitope
Major Histocompatibility Complex (MHC): cell surface glycoproteins associated with self recognition
Figure 21.7

36. Adaptive Immune System: Cells
Lymphocytes
T-cells
B-cells
Antigen Presenting Cells (APCs)

37. Adaptive Immune System: Cells
Lymphocytes: initially uncommitted
T-cells: are sorted in the Thymus
Positive selection: recognize MHC survive
Negative selection: react against to self-antigens on MHC killed
2% of initial T-cell precursors
T-cells manage the immune response
B-cells: are sorted in the marrow by an incompletely understood process
Figure 21.9

38. Adaptive Immune System: Cells
Immunocompetence: as T- or B-cells mature they become immunocompetent, they display receptors on their cell membrane for a specific antigen.
All of the receptors on one cell are identical; immunity depends upon genetic coding for appropriate receptors.

39. Adaptive Immune System: Cells
Antigen Presenting Cells (APCs)
APCs ingest foreign material, then present antigenic fragments on their cell surface where they are recognized by T-cells
T-cells: respond to antigen only if it is displayed on plasma membrane.
APCs: Macrophages & B lymphocytes
Interactions between APCs & lymphocytes & lymphocyte-lymphocyte interactions are critical to immune response

40. Adaptive, Humoral response
Humoral response (clonal selection)
B-cells: Antigen challenge to naïve immunocompetent B-cell
Antigen binds to B-cell receptors & form cross-links between receptors
Cross linked antigen-receptor complex undergoes endocytosis; B-cell presents to T-cell

43. Humoral Immunity Active humoral immunity: Passive humoral immunity:
B-cells encounter & respond to antigen to produce an antibody
Passive humoral immunity:
Introduced “non-native” antibody

44. Active Humoral Immunity
Naturally acquired: natural exposure to antigen (i.e. infection)
Artificially acquired: vaccines; dead/attenuated or fragmented pathogen injected to elicit an immune response
Bestow immunity without disease; primary response
Booster shots (secondary response); intensify response
Shortcomings – adverse reactions & the immunity is less durable (poor memory) & has less cell mediated component

45. Passive Humoral Immunity
Natural: maternal antibody crosses the placental barrier conferring temporary immunity to the baby (degrades after a few months)
Artificial: antibodies harvested from an outside source given by injection protect from immediate threat but no memory is formed (antitoxins, antivenins , gamma globulin, etc.)

46. Antibodies A.K.A Immunoglobulins & gamma globulins Structure variable
hypervariable
constant
Figure 21.13a

47. Antibodies Constant (C) region defines antibody class
determines chemical & cellular interactions
determines how class functions to eliminate antigens

48. Antibody Classes
Antibody Classes: IgM, IgG, IgA, IgD, IgE (Ig = immunoglobulin)

49. Antibody Classes
IgG: the most abundant circulating Ig. The dominant circulating Ig of the primary & the secondary response. Crosses the placenta. Complement binding (Monomer).
IgA: the Ig of secretions. Helps prevent antigen penetration of membranes (Dimer).
IgD: the Ig of B-cell activation. Found on B-cell surface (Monomer).

50. Antibody Classes IgM: occurs as a monomer & a pentamer
Occurs on the B-cell surface (Monomer).
The Ig of early primary plasma cell response, circulating antibody; a potent agglutinator. Complement binding (Pentamer).

51. Antibody Classes IgE: the Ig associated with allergies.
Stem binds to mast cells & basophils.
Receptor binding results in histamine release & inflammation.
Found mostly in mucosa of respiratory & GI tract (Monomer).

52. Antibody Targets & Functions
Immune complex formation = antigen-antibody binding.
All the following events are initiated by antigen-antibody binding.
Complement fixation:
Neutralization:
Agglutination:
Precipitation:
Inflammation & phagocytosis prompted by debris

53. Antibody Targets & Functions
Complement fixation: cells & bacteria.
Immune complex formation exposes a complement binding site on the C region of the Ig.
Complement fixation results in cell lysis.
Neutralization: immune complex formation blocks specific sites on virus or toxin & prohibit binding to tissues
Agglutination: cells are crosslinked by immune complexes & clump together
Precipitation: soluble molecules (such as toxins) are crosslinked, become insoluble, & precipitate out of the solution
Inflammation & phagocytosis prompted by debris
Figure 21.14

54. Antibody Targets & Functions
Monoclonal antibodies: antibodies produced by descendants of a single cell
Pure antibody preparations that are specific for a single antigenic determinant
Research / diagnostic / therapeutic use

55. Cell Mediated Immune Response
T-cell activation: involves recognition of PM surface antigens only
Antigen is combined with MHC & displayed on PM
T-cell receptors: bind to the MHC & are stimulated by the associated antigen
The addition of a co-stimulator (cytokines, interleukins, etc) prompts the T-cell to form a clone
In the absence of a co-stimulator the T-cell becomes tolerant to antigen (anergy)

56. Cell Mediated: MHC MHC occurs as two classes
MHC I on virtually all tissue cells
MHC II only on PM some immune system cells

57. Cell Mediated: MHC display properties
Figure 21.16a
MHC I on virtually all tissue cells
Display only proteins produced inside the cell
Endogenous antigens = foreign proteins produced by the cell (viral / cancer)
Stimulate the CD8* cell population
form cytotoxic T-cells (Killer T, TC)
*formerly T8 cells

58. Cell Mediated: MHC display properties
Figure 21.16b
MHC II found only on PM of B-cells, some T-cells & APCs
Display proteins derived from a phagocytized target
Exogenous antigen: foreign protein from outside the cell – presented to PM surface
Stimulates the CD4* cell population
form Helper T-cells (TH)
*formerly T4 cells

59. Cell Mediated: T-cell roles
Helper T-cells (TH) stimulate B-cells & other T-cells to proliferate
Figure 21.18

60. Cell Mediated: T-cell roles
Activated TH cells interact with B-cells displaying antigen & produce cytokines that prompt the B-cell to mature & form antibody
Figure 21.18

61. Cell Mediated: T-cell roles
TH cells also produce cytokines that promote TC cells
TH cells recruit other WBCs & amplify innate defenses (inflammatory)
Subpopulations of TH cells specialize in specific sets of activations
Figure 21.18

62. Cell Mediated: T-cell roles
Cytotoxic T-cells (TC, Killer T): directly attack & kill cells with specific antigen
Activated TC cells are co-stimulated by TH cells

63. Cell Mediated: T-cell roles
Figure 21.19a
TC mechanism (Cytotoxic T-cells, Killer T)
TC binds to cell & releases perforin & granzymes
In the presence of Ca2+ perforin forms pores in target cell PM
Granzymes enter through pores & degrade cellular contents
TC then detaches & moves on
Macrophages clean up

64. Cell Mediated: T-cell roles
Other T-cells
*Regulatory T-cells (TReg): release inhibitory cytokines that suppress B-cell & T-cell activity
Help to prevent autoimmune events
*formerly Suppressor T (TS)
Gamma Delta T-cells (Tgd): live in the intestine. Function in surveillance & are triggered much like NK cells

65. Organ Transplants/Rejections
Types of Organ Transplants
Autograft: tissue graft from one body site to another (same person)
Isograft: graft received from a genetically identical donor (identical twin)
Allograft: graft received from genetically non-identical donor (same species)
Xenograft: graft received from another species of animal

66. Organ Transplants/Rejections
Transplant rejection: mediated by the immune system (especially TC, NK, antibodies)
Auto/Isograft: MHC compatible
Xenograft: most MHC incompatible
Allograft: attempt to obtain the best MHC match

67. Organ Transplants/Rejections
Immunosuppressive therapy: used to delay/prevent rejection
Corticosteroids: suppress inflammation
Antiproliferative: prevent/kill rapidly dividing cells
Immunosuppressant: prevent/kill rapidly dividing cells
Side effects tend to be harsh
Increased risk of infection

68. Immunologic Dysfunction
Immunodeficiency
Congenital/Genetic: varied inborn errors
Acquired:
Drugs: immunosuppressive / cancer drugs Radiation therapy – marrow
Cancer: can be viewed as a failure of immune surveillance
Hodgkin’s disease: lymph node cancer
AIDS/HIV: kills TH cells

69. Immunologic Dysfunction
Autoimmune disease: production of antibody & TH against self tissues
Examples & tissue effected
Multiple sclerosis: white matter of nervous system
Graves disease: thyroid
Type I diabetes mellitus: beta cells of pancreas
Systemic Lupus Erythrematosis: (anti DNA) kidneys, heart, lungs & skin
Rheumatoid Arthritis: destroys joints (cartilage)
Glomerulonephritis: impaired renal function (may be secondary to other autoimmune disease)

70. Immunologic Dysfunction
Mechanisms of immunologic dysfunction
Failure of lymphocyte programming
New self antigens
Gene mutation
Structural change – haptens, infection
Foreign antigens that closely resemble self antigen resulting in cross reactivity.

71. Immunologic Dysfunction
Hypersensitivities (Allergies): the immune system responds to a harmless substance as if it were a threat.
Allergen = antigens of an allergic response
Figure 21.21

72. Hypersensitivities: Types
Immediate hypersensitivity (Type I): symptoms within seconds of exposure to an allergen
(requires sensitization = previous exposure)
Figure 21.21

73. Hypersensitivities: Type I
Anaphylaxis (IgE mediated; mast / basophils)
Local: histamine induced vasodilation & increased permeability. Watery eyes, runny nose, itching & redness. Respiratory  allergy induced asthma
Systemic: anaphylactic shock: associated with allergens that have systemic distribution. Widespread vasodilation, airway swelling
Atopy: the tendency to display Type I symptoms to certain environmental antigens without prior sensitization

74. Hypersensitivities: Types II & III
Subacute hypersensitivity (IgG & IgM mediated)
Cytotoxic reactions (Type II): antibodies bind to cellular antigens promoting complement fixation / inflammation / phagocytosis (transfusion reaction)
Immune complex h. (Type III): widely distributed antigen reacts with antibody.
Antigen-antibody complexes cannot be cleared; persistent inflammation / tissue damage (farmer’s lung; associated with autoimmune disorders)

75. Hypersensitivities: Type IV
Delayed hypersensitivity (cell mediated) takes one to three days to react.
Involves TC, TH1 & macrophages.
Allergic contact dermatitis (poison ivy, heavy metals, TB tine tests).
Agents act as haptens & elicit response after binding to tissue

76. Developmental Aspects of the Immune System
Stem cells arise from embryologic liver & spleen
Self tolerance develops in Thymus (T-cells) & bone marrow (B-cells)
Immunocompetence: the “library” of receptors is genetically determined
Immune system degrades with aging

78. Immunocompetent B or T cells
Key:
= Site of lymphocyte origin
Red bone marrow
= Site of development of immunocompetence as B or T cells; primary lymphoid organs
= Site of antigen challenge & final differentiation to activated B & T cells
Immature lymphocytes
Circulation in blood 1 1 1
Lymphocytes destined to become T cells migrate to the thymus & develop immunocompetence there. B cells develop immunocompetence in red bone marrow.
Thymus
Bone marrow 2
After leaving the thymus or bone marrow as naive immunocompetent cells, lymphocytes “seed” the lymph nodes, spleen, & other lymphoid tissues where the antigen challenge occurs.
Immunocompetent, but still naive, lymphocyte migrates via blood 2 2
Lymph nodes, spleen, & other lymphoid tissues 3
Mature (antigen-activated) immunocompetent lymphocytes circulate continuously in the bloodstream & lymph & throughout the lymphoid organs of the body. 3 3
Activated immunocompetent B & T cells recirculate in blood & lymph
Figure 21.8

79. Primary & Secondary Humoral Responses
Figure 21.10

80. Types of Acquired Immunity
Figure 21.11

81. Major Types of T Cells
Figure 21.14

82. T Cell Activation: Step One – Antigen Binding
Figure 21.16

83. Helper T Cells (TH)
Figure 21.17a

84. Helper T Cells
Figure 21.17b

85. Summary of the Primary Immune Response
Figure 21.19