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1 Lecture #12 – Animal Immune Systems. 2 Key Concepts: Innate immunity provides broad-spectrum defense against many pathogens Acquired immunity is very.

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Presentation on theme: "1 Lecture #12 – Animal Immune Systems. 2 Key Concepts: Innate immunity provides broad-spectrum defense against many pathogens Acquired immunity is very."— Presentation transcript:

1 1 Lecture #12 – Animal Immune Systems

2 2 Key Concepts: Innate immunity provides broad-spectrum defense against many pathogens Acquired immunity is very specific, develops over time, and relies on B and T cells Antigen recognition properties of B and T cells B and T cell binding sites develop randomly! Integrated B and T cell function When the immune system goes wrong…

3 3 Some definitions…. Pathogen = anything that causes disease  Microbes (bacteria, protozoans), viruses, fungal spores, pollen, dust mites, etc  Secretions (venoms, animal saliva)  Non-self tissue cells (transplant rejections)  Some cancer cells Antigens = cell surface proteins and other molecules that the body recognizes as non- self Generates Pathology Generates Antibodies Pathogens have Antigens

4 4 Schematic of the human immune system The immune system is spread diffusely throughout the body – a system of organs, nodes and lymph vessels

5 5 Diagram of the blood cells Remember, the white blood cells are the defenders

6 6 Some WBC’s circulate though the lymph, the blood and the interstitial fluid Some are permanently housed in lymph nodes, thymus gland, spleen, appendix and a few other glands

7 7 Table showing the stages of defense Defense is step-wise 90% of pathogens are neutralized by innate immunity  Multiple strategies to destroy pathogens Any remaining pathogens are normally attacked by the acquired immune system

8 8 Innate Immunity – you are born with it Pathogens are ubiquitous Innate immunity includes both external and internal systems to eliminate pathogens Any and all pathogens are targeted This system does not recognize specific pathogens – it goes after any non-self cell or molecule

9 9 Innate Immunity – external defenses Skin – vital barrier Mucous membranes – trap, cilia evacuate Secretions – skin and mucous membranes secrete anti-microbial proteins; stomach secretes acids Sweeping cilia in trachea

10 10 Innate Immunity – internal defenses Sometimes pathogens get past the barriers and into the tissues Non-specific WBC’s attack  Neutrophils  Monocytes  macrophages  Dendritic cells  Eosinophils  Basophils

11 11 Innate Immunity – internal defenses Phagocytic WBC’s cells ingest and destroy microbes in the tissues  Neutrophils – the most abundant, but short-lived  Macrophages develop from monocytes – large and long- lived, also stimulate acquired  Dendritic cells – mostly function to stimulate the acquired immune system

12 12 Model of a macrophage ingesting a fungal spore

13 13 Micrograph of macrophage ingesting bacteria

14 14 Innate Immunity – internal defenses Eosinophils destroy multi- cellular parasites by releasing toxic enzymes  Also contribute to allergic responses Basophils contribute to inflammatory and allergic responses Schistosoma mansoni

15 15 Additional Internal Defenses Antimicrobial proteins  Lysosymes work in macrophages; also found in saliva, tears and mucous  Complement proteins result in lysis; also help trigger inflammation and activate acquired immunity  Interferons limit intra-cellular spread of viruses  Defensins are secreted by macrophages, attack pathogens Natural killer cells attack virus-infected cells and cancer cells The inflammatory response

16 16 Diagram showing complement protein function Complement Protein Function: these proteins complement other immune system processes

17 17 Additional Internal Defenses Antimicrobial proteins  Lysosymes work in macrophages; also found in saliva, tears and mucous  Complement proteins result in lysis; also help trigger inflammation and activate acquired immunity  Interferons limit intra-cellular spread of viruses  Defensins are secreted by macrophages, attack pathogens Natural killer cells attack virus-infected cells and cancer cells The inflammatory response

18 18 Diagram of interferon activity Interferons initiate production of proteins that inhibit viral reproduction

19 19 Additional Internal Defenses Antimicrobial proteins  Lysosymes work in macrophages; also found in saliva, tears and mucous  Complement proteins result in lysis; also help trigger inflammation and activate acquired immunity  Interferons limit intra-cellular spread of viruses  Defensins are secreted by macrophages, attack pathogens Natural killer cells attack virus-infected cells and cancer cells The inflammatory response

20 20 Additional Internal Defenses Antimicrobial proteins  Lysosymes work in macrophages; also found in saliva, tears and mucous  Complement proteins result in lysis; also help trigger inflammation and activate acquired immunity  Interferons limit intra-cellular spread of viruses  Defensins are secreted by macrophages, attack pathogens Natural killer cells attack virus-infected cells and cancer cells The inflammatory response

21 21 A natural killer cell (yellow) attacking a cancer cell (red).

22 22 Additional Internal Defenses Antimicrobial proteins  Lysosymes work in macrophages; also found in saliva, tears and mucous  Complement proteins result in lysis; also help trigger inflammation and activate acquired immunity  Interferons limit intra-cellular spread of viruses  Defensins are secreted by macrophages, attack pathogens Natural killer cells attack virus-infected cells and cancer cells The inflammatory response

23 23 Diagram of the inflammatory response The Inflammatory Response Usually localized, in response to tissue injury Cascade of events May also be systemic – increased WBC release from bone marrow; fever

24 24 Critical Thinking Why do tissues swell near a cut???

25 25 Critical Thinking Why do tissues swell near a cut???

26 26 Invertebrates Also Have Innate Defense Systems Amoeboid cells ingest by phagocytosis in echinoderms Insect exoskeleton acts as a barrier similar to skin Hemocytes in insect hemolymph function similarly to vertebrate innate internal defenses Research indicates little immune system memory  Little capacity for acquired immunity as seen in vertebrates

27 27 Defense is step-wise 90% of pathogens are neutralized by innate immunity – both external and internal Any remaining pathogens are normally attacked by the acquired immune system Same diagram of step-wise immune system function

28 28 Acquired Immunity Develops over time, in response to exposure to pathogens Highly specific – lymphocytes develop that match each incoming pathogen  B cells and T cells  Some circulate in tissues; some are permanently located in lymph nodes, the spleen and other lymph system structures Pathogen contact with lymphocytes, phagocytes, and other triggers initiates rapid immune responses

29 29 Remember – the lymph system is closely tied to the circulatory system Lymph vessels absorb excess fluids in capillary beds Pathogens in the blood are rapidly exposed to the phagocytes and lymphocytes in the lymph system  Every heart beat pushes blood, and any pathogens it carries, past the immune system structures

30 30 The next 3 slides show the relationship between the capillary beds and the lymph vessels

31 31

32 32 Lymph fluid is returned to blood at shoulder ducts Diagram of lymphatic system

33 33 Remember – the lymph system is closely tied to the circulatory system Lymph vessels absorb excess fluids in capillary beds Pathogens in the blood are rapidly exposed to the phagocytes and lymphocytes in the lymph system  Every heart beat pushes blood, and any pathogens it carries, past the immune system structures

34 34 Antigen Recognition by B and T Cells Remember, antigens are the non-self molecules that initiate the immune response Mostly cell surface proteins, other cell surface molecules, or toxins dissolved in fluid (venoms and other secretions) Most pathogens have several different kinds of antigens  Because of this, there are usually several different lymphocytes that recognize and respond to the pathogen Antigens have specific binding sites

35 35 Diagram showing structure of the cell membrane Membranes are complex, with many surface molecules

36 36 Antigen Recognition by B and T Cells Remember, antigens are the non-self molecules that initiate the immune response Mostly cell surface proteins, other cell surface molecules, or toxins dissolved in fluid (venoms and other secretions) Most pathogens have several different kinds of antigens  Because of this, there are usually several different lymphocytes that recognize and respond to the pathogen Antigens have specific binding sites

37 37 Diagram showing epitope structure Epitopes are the specific binding sites found on all antigens

38 38 Lymphocytes – B and T Cells Remember, lymphocytes are one of the categories of white blood cells Each B or T cell has ~100,000 antigen receptors – all of the exact same type  Each B or T cell recognizes a single antigen The receptor molecules and recognition process are different for B cells vs. T cells  Both types of receptors are protein-based  Both have both constant and variable regions

39 39 Diagram showing development of all the blood cells and how lymphocytes have a separate origin from other white blood cells.

40 40 Lymphocytes – B and T Cells Remember, lymphocytes are one of the categories of white blood cells Each B or T cell has ~100,000 antigen receptors – all of the exact same type  Each B or T cell recognizes a single antigen The receptor molecules and recognition process are different for B cells vs. T cells  Both types of receptors are protein-based  Both have both constant and variable regions

41 41 Diagram showing the receptor molecules in B cells and T cells. This diagram is used several times in the next sequence of slides. Constant regions have stable amino acid sequences from cell to cell; Variable regions have different amino acid sequences from cell to cell

42 42 Antigen Recognition – B Cells B cell receptors are Y-shaped Each branch of the “Y” has 2 parts, called chains  Inner, heavy chain makes the full “Y”  Outer, light chain is located on the branches of the “Y”  Both chains are proteins  Chains are linked by chemical bonds The bottom of the “Y” is anchored in the B cell membrane

43 43 B Cell Receptor Structure

44 44 The protein structure of a B cell receptor

45 45 Antigen Recognition – B Cells The bottom regions of both chains have constant amino acid sequences The outer branches of both chains have variable amino acid sequences  These variable ends are the antigen binding sites  They bind directly to the epitopes  B cells recognize unaltered antigens!

46 46 B Cell Receptor Structure

47 47 Antigen Recognition – T Cells T cell receptors are unbranched α chain and β chain are chemically linked Both are anchored in the membrane Both have basal constant regions and terminal variable regions A single antigen binding site is at the terminus

48 48 T cell receptor structure

49 49 T Cells DO NOT recognize intact antigens on intact pathogens T cells recognize antigen fragments that have been bound to a self-cell protein called a major histocompatibility molecule  MHC  major histocompatibility complex of genes codes for these molecules MHC molecules bind to antigen fragments inside a self-cell, and present the fragments at the surface of the cell T cells detect the presented antigen+MHC complex

50 50 Diagram showing the production of MHC molecules, how they become attached to antigen fragments, and how the complex is presented at the cell surface. This diagram is used repeatedly in the next sequence of slides. MHC – self-cell proteins

51 51 T Cells DO NOT recognize intact antigens on intact pathogens T cells recognize antigen fragments that have been bound to a self-cell protein called a major histocompatibility molecule  MHC  major histocompatibility complex of genes codes for these molecules MHC molecules bind to antigen fragments inside a self-cell, and present the fragments at the surface of the cell T cells detect the presented antigen+MHC complex

52 52 Development of MHC Variation MHC alleles are numerous  Many more than just the 2 alleles common for most genes (ie: not just dominant vs. recessive)  As a result, MHC molecules are the most polymorphic proteins known Because of the high degree of variation, it is very rare for any two individuals to have the exact same set of MHC molecules  MHC molecules are unique to the “self”  Help to distinguish “self” from “non-self” cells

53 53 Development of MHC Variation MHC alleles are numerous  Many more than just the 2 alleles common for most genes (ie: not just dominant vs. recessive)  As a result, MHC molecules are the most polymorphic proteins known Because of the high degree of variation, it is very rare for any two individuals to have the exact same set of MHC molecules  MHC molecules are unique to the “self”  Help to distinguish “self” from “non-self” cells

54 54 T Cells DO NOT recognize intact antigens on intact pathogens T cells recognize antigen fragments that have been bound to a self-cell protein called a major histocompatibility molecule  MHC  major histocompatibility complex of genes codes for these molecules MHC molecules bind to antigen fragments inside a self-cell, and present the fragments at the surface of the cell T cells detect the presented antigen+MHC complex

55 55 Two classes of MHC molecules: each found in a different type of antigen presenting cell

56 56 Class I MHC Found in most nucleated cells They bind antigen fragments if the cell has been infected, or is cancerous Class I MHC+antigen complexes are recognized by cytotoxic T cells Cytotoxic T cells then destroy the infected or cancerous cell

57 57 Antigen Presentation – Class I MHC molecules are presented on infected or cancerous cells

58 58 Class II MHC Found in dendritic cells, macrophages and B cells Present antigens from pathogens that have been engulfed by phagocytosis Class II MHC+antigen complexes are recognized by helper T cells Activated helper T cells begin a cascade of events that control the infection

59 59 Antigen Presentation – Class II MHC molecules are presented on phagocytic cells

60 60 In both cases, the T cell recognizes ONLY THE COMBINATION of antigen + self-protein

61 61 Review: B and T Cell Receptors B cell receptors bind directly to antigen on intact pathogen T cell receptors bind to MHC+antigen complex on self-cells

62 62 Review: B and T Cell Receptors Remember – both B and T cells have multiple receptors per cell (as many as 100,000), all identical

63 63 Lymphocyte (B & T cell) Development Lymphocytes are all produced from stem cells in the bone marrow Some mature in the bone marrow (B cells) The rest mature in the thymus gland (T cells)

64 64 Lymphocyte (B & T cell) Development Maturation = development of the B and T cell receptors Once the cells are fully differentiated, they migrate into the rest of the body  Some stay permanently in the organs of the lymph system  Some circulate constantly through blood, lymph and interstitial fluids

65 65 Lymphocyte (B & T cell) Development Step 1 – generation of diversity Step 2 – testing and removal Step 3 – clonal selection Steps 1 and 2 occur during the development of the B and T cells Step 3 occurs after exposure of the fully developed B and T cells to antigens

66 66 Lymphocyte (B & T cell) Development Step 1 – generation of diversity The genes that code for the antigen receptors are randomly rearranged by enzymes during lymphocyte maturation  These are the genes that code for the variable regions of the light and heavy chains of B cells Ditto for the variable regions of the α and β chains of T cells  These chains are then linked together to form the T cell receptor molecule

67 67 Diagram showing the development of diversity in the receptors of a B cell. This diagram is used repeatedly in the next sequence of slides. Example: gene re-alignment for the light chain of a B cell receptor.

68 68

69 69 The coding gene has 40 variable (V) segments and 5 joining (J) segments

70 70 During differentiation of each B cell, one V segment is snipped out and attached to one J segment. Recombinase enzymes randomly snip and join!

71 71 40 V regions x 5 J regions = 200 possible combinations of V and J in the functional gene. Each cell ends up with only one of these possible combinations for the light chain.

72 72 The V+J segment is attached via an intron to the C segment that codes for the constant region of the light chain.

73 73 This “new” gene is processed and translated into the protein that makes up the light chain

74 74 The DNA coding for the heavy chain goes through the same kind of random rearrangement process, but there are more V regions

75 75 The light and heavy chains form independently and are then linked Additional variation occurs during the linkage Thus the enormous number of possible receptors Many millions of different receptors are produced in B cells!!!

76 76

77 77 Lymphocyte (B & T cell) Development Step 1 – generation of diversity The genes that code for the antigen receptors are randomly rearranged by enzymes during lymphocyte maturation  These are the genes that code for the variable regions of the light and heavy chains of B cells Ditto for the variable regions of the α and β chains of T cells  These chains are then linked together to form the T cell receptor molecule

78 78 Lymphocyte (B & T cell) Development Step 2 – testing and removal The rearrangement process is entirely random Each new receptor is “tested” against self- cells – both during development and during migration into lymph system organs Receptors that bind to self-cells or self-MHC molecules are eliminated or deactivated

79 79 Critical Thinking Why would testing be so important???

80 80 Critical Thinking Why would testing be so important???

81 81 Differentiation and testing result in an enormous variety of B and T cells – each capable of recognizing a single antigen ~ different B cells!!!! Similar numbers of different T cells Usually no duplication – you start out with a single cell of each type Clonal selection (the next step) builds a population of duplicate lymphocytes

82 82 Lymphocyte (B & T cell) Development Step 3 – clonal selection Each B and T cell has receptors that are specific to a single antigen Incoming pathogens typically display several antigens Virtually always, there is a B or T cell receptor to match at least one of the pathogen’s antigens

83 83 Critical Thinking How are incoming pathogens exposed to these myriad B and T cells???

84 84 Critical Thinking How are incoming pathogens exposed to these myriad B and T cells???

85 85 Diagram showing clonal expansion of selected B cell Lymphocyte (B & T cell) Development Step 3 – clonal selection When a lymphocyte receptor encounters a matching antigen, the lymphocyte is activated Activation = stimulation of the lymphocyte to begin mitotic cloning

86 86 Lymphocyte (B & T cell) Development Step 3 – clonal selection Duplicate lymphocytes are rapidly produced Two clonal populations form Effector cells are short-lived and carry out the immune system response (varies based on type of lymphocyte – more later) Memory cells are long-lived and “remember” the epitope  Memory cells allow for rapid response to that same pathogen the next time it enters the body  Memory cells confer active immunity

87 87 Diagram showing clonal expansion of selected B cell Clones divide into two populations: effector and memory

88 88 Lymphocyte (B & T cell) Development Step 3 – clonal selection Duplicate lymphocytes are rapidly produced Two clonal populations form Effector cells are short-lived and carry out the immune system response (varies based on type of lymphocyte – more later) Memory cells are long-lived and “remember” the epitope  Memory cells allow for rapid response to that same pathogen the next time it enters the body  Memory cells confer active immunity

89 89 Graph showing accumulation of memory cells after repeated exposures. Step 3 – clonal selection Memory cells accumulate over repeated exposure to the same pathogen EX is for B cells; T cells also accumulate

90 90 Critical thinking If the immune system response is so rapidly initiated, why do we ever get sick???

91 91 Critical thinking If the immune system response is so rapidly initiated, why do we ever get sick???

92 92 Diagram showing how B cell and T cell functions are integrated Integrated B and T Cell Function

93 93 Simultaneous

94 94 Diagram of helper T cell binding to antigen presenting cell. Helper T Cell Function Nearly all pathogens activate helper T cells Dendritic phagocytes 1 o activate naïve helper T cells  Important in primary immune response Macrophages 1 o activate memory helper T cells  Important in secondary immune response

95 95 Helper T Cell Function Clones of active and memory T cells develop after exposure Active helper T cells secrete proteins that stimulate cytotoxic T cells and B cells

96 96 Diagram showing activated helper T cell functions. Active helper T cells stimulate the rest of the immune system: both cytotoxic T cells and B cells

97 97 Diagram showing cytotoxic T cell function Cytotoxic T Cell Function Activated cytotoxic T cells release proteins that perforate target cells & initiate apoptosis The activated T cell releases, and moves on to target additional infected or cancer cells Class I MHC molecule

98 98 B Cell Function Remember, B cells recognize and bind to specific intact pathogens B cells also engulf some pathogens by phagocytosis  Antigens are presented on the B cell surface  These antigens are recognized by helper T cells  Helper T cells activate the B cell Only its one specific antigen can be presented by each type of B cell

99 99 Some B cells are activated directly by exposure to the antigen

100 100 B Cell Function Remember, B cells recognize and bind to specific intact pathogens B cells also engulf some pathogens by phagocytosis  Antigens are presented on the B cell surface  These antigens are recognized by helper T cells  Helper T cells activate the B cell Only its one specific antigen can be presented by each type of B cell

101 101 Diagram showing an activated helper T activating a B cell Most B cells are activated by proteins secreted from active helper T cells

102 102 B Cell Function Remember, B cells recognize and bind to specific intact pathogens B cells also engulf some pathogens by phagocytosis  Antigens are presented on the B cell surface  These antigens are recognized by helper T cells  Helper T cells activate the B cell Only its one specific antigen can be presented by each type of B cell

103 103 Diagram showing secretion of antibodies from activated B cell B Cell Function Activated B cells form 2 clones – plasma cells and memory cells Plasma cells release antibodies

104 104 Table of antibodies and their functions Antibodies Each activated B cells produces thousands of clones Each clonal B cell releases nearly a billion antibodies  2000 antibodies per second  Each B cell has a 4 – 5 day life span

105 105 Antibodies Five classes of antibodies are secreted Each recognizes and attacks specific pathogens Read through this table for understanding; don’t memorize

106 106 Antibodies Only one antibody per type of B cell  But remember, most pathogens have multiple antigens with multiple epitopes  Many B cells are activated

107 107 Diagram showing how antibodies work Antibody Mediated Pathogen Disposal

108 108 Integrated B and T Cell Function Responses to pathogens are coordinated and simultaneous, NOT mutually exclusive All components of the immune system are activated Positive feedback increases function

109 109 Active vs. Passive Immunity Active immunity is generated when the acquired immune system is activated  Memory cells are generated  Exposure to pathogen OR vaccination with inactivated pathogen that still retains antigens  Confers long-term protection (often, lifetime) Passive immunity is generated when antibodies alone are transferred  Does not generate memory cells  Antibodies cross placenta; are injected  Short-term protection

110 110 Critical Thinking What would be the advantage of passive immunity???

111 111 Critical Thinking What would be the advantage of passive immunity???

112 112 Immune System Failure Allergic responses  Hypersensitive response to allergenic antigens  Antibody tails bind to mast cells  Exposure causes massive histamine release Autoimmune diseases  Immune system fails to distinguish self-cells Immunodeficiency diseases  Immune system fails  Can be genetic, developmental, or acquired  AIDS; also some cancers, chemotherapy, stress

113 113 Allergic Responses Most generated by IgE antibodies Antibody tail binds to mast cells IgE accumulates on mast cell surface Eventually, allergen binds between 2 IgE This triggers massive release of histamine Histamine dilates blood vessels…..

114 114 Immune System Failure Allergic responses  Hypersensitive response to allergenic antigens  Antibody tails bind to mast cells  Exposure causes massive histamine release Autoimmune diseases  Immune system fails to distinguish self-cells Immunodeficiency diseases  Immune system fails  Can be genetic, developmental, or acquired  AIDS; also some cancers, chemotherapy, stress

115 115 Rheumatoid Arthritis

116 116 Diabetes

117 117 Multiple Sclerosis

118 118 Lupus

119 119 Immune System Failure Allergic responses  Hypersensitive response to allergenic antigens  Antibody tails bind to mast cells  Exposure causes massive histamine release Autoimmune diseases  Immune system fails to distinguish self-cells Immunodeficiency diseases  Immune system fails  Can be genetic, developmental, or acquired  AIDS; also some cancers, chemotherapy, stress

120 120 T CellHIV

121 121 Graph showing relationship between HIV concentration, antibody concentration and T cell concentration over time – 40 million people are infected by HIV; 15 million children have been orphaned by AIDS

122 122 REVIEW – Key Concepts: Innate immunity provides broad-spectrum defense against many pathogens Acquired immunity is very specific, develops over time, and relies on B and T cells Antigen recognition properties of B and T cells B and T cell binding sites develop randomly! Integrated B and T cell function When the immune system goes wrong…


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