Immunology Concept, Functions and Types of Immunity

1. Immunology Concept, Functions and Types of Immunity

2. Introduction Concept and functions of Immunity Types of Immunity

3. Part I Concept and functions of Immunity

4. I Concept of Immunity 1)Tranditional concept----Immunity refers to protection against infectious diseases. 2)Modern concept---- Immunity is a function of which an individual recognizes and excludes antigenic foreign substances. It is normally beneficial,but sometimes,it is injurious.

5. II Concept of Immunology 1) Tranditional concept----anti-infection immunity to different types of pathogenic microorganisms. 2) Modern concept----Immunology is an independent subject about composition,functions of immune system; mechanism of immune response and the disease associated with immunity.         

6. III Functions of Immunity Immune defense Immune homeostasis Immune surveillance

7. Functions and Manifestation of Immunity Functions Normal Manifestation Abnormal Manifestation Immune Anti-infection Hypersensitivity Defense Immunodeficiency Immune Eliminate injured and senile cells immune dismodulation Homeostasis Tolerate to self components Autoimmune disease Immune destroy transformed cells Tumor or Surveillance (anti-tumor ) Persistent virus infection Prevent from persistent infection

8. Part II Types of Immunity         I. Innate Immunity (or native immunity/ non-specific immunity /congenital immunity)         II. Adaptive Immunity (or acquired immunity/specific immunity)

10. I. Innate immunity  ( natural immunity/ non-specific immunity ) Innate immunity: Protection against infection that relies on mechanisms that exist before infection,are capable of a rapid response to microbes,and react in essentially the same way to repeated infections. Exists at birth Be the first line of defense against infection

11. 1. Characteristics Exists naturally Non–specific No immune memory (innate immunity can’t be enhanced by the second stimulation of the same antigen) Immune memory: Exposure of the immune system to a foreign antigen enhances its ability to respond again to that antigen. Hereditable No racial difference

12. 2. Composition (1) Barriers Physical barrier : skin and mucosa Chemical barrier: antimicrobial substances in secretion of skin and mucosa Biotic barrier: normal flora existing on the surface of skin and mucosa Anatomic barrier . blood- brain barrier . blood- placental barrier . blood- tymus barrier

13. (2)  Humoral factors Complement Lysozyme Interferons(IFN) C-reactive protein

14. (3)Cells participating in innate immunity Phagocyte: endocytosis and phagocytosis mononuclear phagocytes ----Monocytes,Macrophages (M F)----PRR Neutrophils Nature killer cells (NK)—KAR/KIR,IgG Fc receptor Dentritic cells(DC) ?d T cells B1 cells Other cells participating in innate immunity

16. Macrophages

17. Macrophages excluding the pathogen

18. Over view What are the main types of white blood cells? Name the two main types of immunity? What are the main distinctions between these two categories? What cells are involved in which aspects of the immune system?

19. Lymphocytes Many types; important in both humoral and cell-mediated immunity B-cells produce antibodies (APC cell) T- cells Cytotoxic T cells Helper T cells Memory cells

20. Lymphocytes Natural Killer cells Large granular lymphocytes (not B or T) Kills tumor cells Kills cells infected with certain viruses (intracellular pathogens)

21. Monocytes/Macrophage Phagocytosis and killing of microorganisms Activation of T cells and initiation of immune response Monocyte is a young macrophage in blood There are tissue-specific macrophages APC cells

22. Dendritic Cells Phagocytosis and killing of microorganisms Function as antigen presenting cells (APC) In the blood and tissues – mature and migrate to the lymph nodes

23. Neutrophil Granulocyte Cytoplasmic granules Polymorphonuclear Phagocytosis Short life span (hours) Very important at “clearing” bacterial infections Innate Immunity

24. Eosinophils Kills Ab-coated parasites through degranulation Involved in allergic inflammation A granulocyte Double Lobed nucleus Orange granules contain toxic compounds

25. Basophils Might be “blood Mast cells’ A cell-killing cells Blue granules contain toxic and inflammatory compounds Important in allergic reactions

26. Antigen-presenting cells (APC) Highly specialized Process antigen and display peptide fragments on cell surface Involved in T-cell activation Macrophages, dendritic cells and B-cells

27. Immune system divisions Innate immunity First line of defense Adaptive (acquired) immunity Takes time to develop Humoral immunity (antibody–mediated specific immunity) Cell-mediated immunity (The aspect of the adaptive immune response where antigen-specific T cell have a main role) Active immunity Passive or maternal immunity Injection of Immunoglobulin Absorption of maternal antibodies

28. Innate vs. adaptive immunity Innate immunity First line of defense (present in all individuals at all times) Immediate (0 – 4 hours) Non-specific Does not generate lasting protective immunity Adaptive immune response (late: > 96 hours) Is initiated if innate immune response is not adequate (> 4 days) Antigen-specific immunity Generates lasting protective immunity (e.g. Antibodies, memory T-cells)

29. Immune system cells Innate immunity Granulocytes (i.e. neutrophils) Macrophages Dendritic cells Natural killer (NK) cells Adaptive immunity Lymphocyte B cells T cells Cytotoxic T cells (CTLs) Helper T cells (Th) Memory cells

30. Innate immune system The first line of defense: Penetration of the epithelial surface of the body by microorganism (e.g. bacteria) Engulfment of microorganism by macrophages, neutrophils, and dendritic cells Release of cytokines and chemokines Inflammation

31. Killing by granulocytes Macrophages and neutrophils recognize pathogen by means of cell-surface receptors Example: mannose receptor, CD14 receptor, scavenger receptors, glucan receptor etc. Binding of MØ/neutrophils with pathogen leads to phagocytosis Bound pathogen is surrounded by phagocyte membrane Internalized (phagosome) Killing of pathogen (Phagolysosome*) Oxidative burst (synthesis of hydrogen peroxide (H2O2)or free oxygen radicals) Acidification Antimicrobial peptides (e.g. defensins) * Phagolysosome = lysosome +phagosome

32. Phagocytosis

33. Phagocytosis (Immunology animation: Janeway) http://www.blink.biz/immunoanimations/# Immune response (IV) 9.1 - Phagocytosis

34. Humoral immune response Cell-surface immunoglobulin receptors (BCR) detect extracellular pathogens Once activated, secrete immunoglobulins as soluble antibodies Antibodies Variable region (2 identical antigen-binding sites) Constant region (determines how antibody disposes of the pathogen once it is bound)

35. Cell killing – NK cells NK cells do not require prior immunization or activation They attach to ‘target’ cells (ADCC) Cytotoxic granules are released onto surface of cell Effector proteins penetrate cell membrane and induce programmed cell death

36. Inflammation

37. Cytokines Low molecular weight, soluble proteins that are produced in response to an antigen and function as chemical messengers for regulating the innate and adaptive immune system Innate immune system Macrophages and Dendritic cells Tumor necrosis factor-alpha (TNF-?) Interleukin-1 (IL-1) Interleukin-12 (IL-12) Adaptive immune system T-lymphocytes Interleukin-2 (IL-2) Interleukin-4 (IL-4)

38. II.Adaptive immunity( acquired immunity/specific immunity)  Adaptive immunity: The form of immunity that is mediated by T or B lymphocytes and stimulated by exposure to infectious agents. Take effects after innate immune response Be the second line of defense against infection

39. 1.Characteristics  Specificity Acquired (set up after birth ) Immune memory (Adaptive immunity can be enhanced by the second stimulation of the same antigen) Transferable Self-limitation

41. 2.Composition T cell : Cell-mediated immunity (CMI) B cell : Humoral immunity(HI) or antibody-mediated immunity

44. 3.The process of immune response in adaptive immunity Recognition of antigens Activation,proliferation and differenciation of T or B lymphocytes Effector phase of immune response ----Elimination of antigens

46. Comparison of Adaptive and Innate Immunity Innate immunity Adaptive immunity Characteristics Exists naturally Acquired by antigen stimulation after birth Responds rapidly in the early develops slowly stage of infection No antigen specificity Has antigen specificity No immune memory Has immune memory Participates in natural defence Participates in specific immune response Cells Neutrophil,Phagocytes,NK cell et al. T cell, B cell, APC Molecules Complement.lysozyme,cytokines et al Antibody,cytokines

47. Immunology Terms Antigen Any molecule that binds to immunoglobulin or T cell receptor Pathogen Microorganism that can cause disease Antibody (Ab) Secreted immunoglobulin Immunoglobulin (Ig) Antigen binding molecules of B cells Vaccination Deliberate induction of protective immunity to a pathogen Immunization The ability to resist infection

48. Types of Immunity Humoral immunity Immunity that is mediated by antibodies Can be transferred by to a non-immune recipient by serum Cell Mediated Immunity Immune response in which antigen specific T cells dominate

49. Cells of the Immune system Many cells of the immune system derived from the bone marrow Hematopoetic stem cell differentiation

50. The Pathway of Specific Immune Response

52. Cellular Immunity .vs. Antibody Immunity Carried out by T-Cells Infected cells are killed by Cytotoxic T –Cells. Carried out by B-cells Antibodies are produced and dumped into blood stream. Antibodies bind to antigens and deactivate them.

53. Immune Response Explained Antigen infects cells. Macrophage ingests antigen and displays portion on its surface. Helper T- Cell recognizes antigen on the surface of the macrophage and becomes active. Active Helper T-Cell activates Cytotoxic T-Cells and B-Cells. Cytotoxic T-Cells divide into Active Cytotoxic T-cells and Memory T – Cells. Active Cytotoxic T-Cells kill infected cells. At the same time, B-Cells divide into Plasma Cells and Memory B- Cells. Plasma cells produce antibodies that deactivate pathogen. Memory T and Memory B cells remain in the body to speed up the response if the same antigen reappears. Supressor T-Cells stop the immune response when all antigens have been destroyed.

54. Immune Response Summary

55. Primary .vs. Secondary Immune Response Primary Immune Response This is a response to an invader the First time the invader infects the body. No measurable immune response for first few days. Next 10 – 15 days antibody production grows steadily Secondary Immune Response A more rapid response to an invader the 2nd time it invades the body. Antibody production increases dramatically and in a much shorter time period..

56. Primary .vs. Secondary Immune Response

57. Passive .vs. Active Immunity Active Immunity This is immunity where the body is “actively” producing antibodies to fight infection. Ex: You have a throat infection and you are actively creating antibodies to fight it. Vaccination: An injection of a weakened strain of an infectious microbe (pathogen) that causes the body to undergo active immunity (produce antibodies). Passive Immunity This is immunity where antibodies are given to a person from the blood of another person or animal. This immunity only lasts for a short period of time. ex: Breastfeeding mothers pass antibodies to their children through the milk.

72. Immunoglobulin Element of adaptive immune mechanism Better known as antibody It recognize the foreign objects How they work (examples) Animation1 Animation2 There are 5 classes of human antibodies: IgG, IgM, IgA, IgD, and IgE. The simplest antibodies, such as IgG, IgD, and IgE, are "Y"-shaped macromolecules called monomers An antibody or immunoglobulin is a large Y-shaped glycoprotein belonging to the immunoglobulin superfamily; used by the immune system to identify and neutralize foreign objects like bacteria and viruses. An antibody contains two sites called paratopes that recognize a specific target, which is called an antigen. Paratopes can be thought of as similar to locks and are specific for just one particular part of the antigen called an epitope, which can be considered similar to a key. This specific lock and key interaction allows an antibody to tag a microbe or an infected cell for attack by other parts of the immune system. The binding of an antibody can also neutralize its antigen target directly by, for example, blocking a part of a microbe that is essential for its survival and growth in the body. 1890 - Demonstration of antibody activity against diphtheria and tetanus toxins. Beginning of humoral theory of immunity. The HV regions of a Fab, representing both light and heavy chains, are highlighted in purple. The antigen is green. The part of the antigen in direct contact with the antibody is called the antigenic determinant, or epitope. This ribbon structure shows the antibody's HV (purple) and FR (yellow) regions of the Fab, and their interaction with an epitope of the antigen.There are 5 classes of human antibodies: IgG, IgM, IgA, IgD, and IgE. The simplest antibodies, such as IgG, IgD, and IgE, are "Y"-shaped macromolecules called monomers An antibody or immunoglobulin is a large Y-shaped glycoprotein belonging to the immunoglobulin superfamily; used by the immune system to identify and neutralize foreign objects like bacteria and viruses. An antibody contains two sites called paratopes that recognize a specific target, which is called an antigen. Paratopes can be thought of as similar to locks and are specific for just one particular part of the antigen called an epitope, which can be considered similar to a key. This specific lock and key interaction allows an antibody to tag a microbe or an infected cell for attack by other parts of the immune system. The binding of an antibody can also neutralize its antigen target directly by, for example, blocking a part of a microbe that is essential for its survival and growth in the body. 1890 - Demonstration of antibody activity against diphtheria and tetanus toxins. Beginning of humoral theory of immunity. The HV regions of a Fab, representing both light and heavy chains, are highlighted in purple. The antigen is green. The part of the antigen in direct contact with the antibody is called the antigenic determinant, or epitope. This ribbon structure shows the antibody's HV (purple) and FR (yellow) regions of the Fab, and their interaction with an epitope of the antigen.

73. Structure of immunoglobulin Two identical heavy (H) chains and two identical light (L) chains combine to form this Y-shaped antibody molecule Heavy chains a and ? have approximately 450 amino acids. (50kDa) Heavy chains µ and e have approximately 550 amino acids. Light chain 250 amino acid (25kDa) a variable region that differs between different B cells, but is the same for all immunoglobulins produced by the same B cell or B cell clone. The variable domain of any heavy chain is composed of a single immunoglobulin domain. These domains are about 110 amino acids long Heavy chains a and ? have approximately 450 amino acids. (50kDa) Heavy chains µ and e have approximately 550 amino acids. Light chain 250 amino acid (25kDa) a variable region that differs between different B cells, but is the same for all immunoglobulins produced by the same B cell or B cell clone. The variable domain of any heavy chain is composed of a single immunoglobulin domain. These domains are about 110 amino acids long

74. Disulfide bonds Bonds between two amino acids result of the SH (sulfhydral) group of one amino acid covalently bonding to the SH group of another amino acid Stronger than hydrogen bonds Eg. Hair proteins are held together by disulfide bonds Disulfide bonds play an important role in the folding and stability of some proteins, usually proteins secreted to the extracellular medium. Used to stabilize many proteins that play structural roles, such as hair.  In fact, getting a "permanent" is all about breaking and reforming disulfide bonds in hair to make straight hair curly. Disulfide bonds play an important role in the folding and stability of some proteins, usually proteins secreted to the extracellular medium. Used to stabilize many proteins that play structural roles, such as hair.  In fact, getting a "permanent" is all about breaking and reforming disulfide bonds in hair to make straight hair curly.

75. Heavy chains The heavy chains each have four domains Variable domains (VH) Constant domains (CH1,2,3) The heavy chains each have four domains. The amino terminal variable domains (VH) are at the tips of the Y. These are followed by three constant domains: CH1, CH2, and the carboxy terminal CH3, at the base of the Y's stem. A short stretch, the switch, connects the heavy chain variable and constant regions. The hinge connects CH2 and CH3 (the Fc fragment) to the remainder of the antibody (the Fab fragments). The two identical protein chains in an antibody molecule that contain the most amino acids and, therefore, have the greater molecular weight. An immunoglobulin fold is a common all-ß protein fold that consists of a 2-layer sandwich of ~7 antiparallel ß-strands arranged in two ß-sheets. The backbone switches repeatedly between the two ß-sheets. Typically, the pattern is (N-terminal ß-hairpin in sheet 1)-(ß-hairpin in sheet 2)-(ß-strand in sheet 1)-(C-terminal ß-hairpin in sheet 2). The cross-overs between sheets form an "X", so that the N- and C-terminal hairpins are facing each other.The heavy chains each have four domains. The amino terminal variable domains (VH) are at the tips of the Y. These are followed by three constant domains: CH1, CH2, and the carboxy terminal CH3, at the base of the Y's stem. A short stretch, the switch, connects the heavy chain variable and constant regions. The hinge connects CH2 and CH3 (the Fc fragment) to the remainder of the antibody (the Fab fragments). The two identical protein chains in an antibody molecule that contain the most amino acids and, therefore, have the greater molecular weight. An immunoglobulin fold is a common all-ß protein fold that consists of a 2-layer sandwich of ~7 antiparallel ß-strands arranged in two ß-sheets. The backbone switches repeatedly between the two ß-sheets. Typically, the pattern is (N-terminal ß-hairpin in sheet 1)-(ß-hairpin in sheet 2)-(ß-strand in sheet 1)-(C-terminal ß-hairpin in sheet 2). The cross-overs between sheets form an "X", so that the N- and C-terminal hairpins are facing each other.

76. Light chain The light chains are constructed of two domains Variable (VL) Constant (CL)

77. Structure of immunoglobulin The fragment antigen binding (Fab fragment) The fragment crystallizable region (Fc region) Antibodies bind to antigens by reversible, noncovalent interactions, including hydrogen bonds and charge interactions The fragment antigen binding (Fab fragment) is a region on an antibody which binds to antigens. It is composed of one constant and one variable domain of each of the heavy and the light chain. These domains shape the paratope—the antigen binding site—at the amino terminal end of the monomer. The two variable domains bind the epitope on their specific antigens. The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system. In IgG, IgA and IgD antibody isotypes, the Fc region is composed of two identical protein fragments, derived from the second and third constant domains of the antibody's two heavy chains; IgM and IgE Fc regions contain three heavy chain constant domains (CH domains 2-4) in each polypeptide chain Antibodies are capable of binding a wide variety of antigens, including macromolecules and small chemicals. The reason for this is that the antigen - binding region of antibody molecules forms a flat surface capable of accommodating many different shapes. Antibodies bind to antigens by reversible, noncovalent interactions, including hydrogen bonds and charge interactions. The parts of antigens that are recognized by antibodies are called epitopes, or determinants. Different antigenic determinants may be recognized based on sequence (linear determinants) or shape (conformational deter- determinants). Some of these epitopes are hidden within antigen molecules and are exposed as a result of a physicochemical change (neodeterminants). The fragment antigen binding (Fab fragment) is a region on an antibody which binds to antigens. It is composed of one constant and one variable domain of each of the heavy and the light chain. These domains shape the paratope—the antigen binding site—at the amino terminal end of the monomer. The two variable domains bind the epitope on their specific antigens. The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system. In IgG, IgA and IgD antibody isotypes, the Fc region is composed of two identical protein fragments, derived from the second and third constant domains of the antibody's two heavy chains; IgM and IgE Fc regions contain three heavy chain constant domains (CH domains 2-4) in each polypeptide chain Antibodies are capable of binding a wide variety of antigens, including macromolecules and small chemicals. The reason for this is that the antigen - binding region of antibody molecules forms a flat surface capable of accommodating many different shapes. Antibodies bind to antigens by reversible, noncovalent interactions, including hydrogen bonds and charge interactions. The parts of antigens that are recognized by antibodies are called epitopes, or determinants. Different antigenic determinants may be recognized based on sequence (linear determinants) or shape (conformational deter- determinants). Some of these epitopes are hidden within antigen molecules and are exposed as a result of a physicochemical change (neodeterminants).

78. Antigen binding some pictures

79. Antigen binding some pictures

80. Structure of immunoglobulin Functional consequences: (VH) and (VL) are positioned to stereochemically react with antigen The stem is good for mediate effector functions The structural features discussed so far have important functional consequences. The variable regions of both the heavy and light chains, (VH) and (VL), lie at the tips of the Y, where they are positioned to stereochemically react with antigen. The stem of the Y projects in a way to efficiently mediate effector functions such as the activation of complement. Its CH2 and CH3 domains bulge to facilitate interaction with effector proteins. Geometric fit and a chemical (electrostatic charge) fit, often called complementarity -- the antibody has + charge where the antigen is -, and the antibody has knobs where the antigen has indentations Constant fragment. The portion of an antibody molecule that carries out the biological activities of that class of antibody. Biological activity includes binding to receptors on phagocytes and activating the classical complement pathway. The amino acid sequence of the Fc portion of an antibody is the same for every antibody in that class. The structural features discussed so far have important functional consequences. The variable regions of both the heavy and light chains, (VH) and (VL), lie at the tips of the Y, where they are positioned to stereochemically react with antigen. The stem of the Y projects in a way to efficiently mediate effector functions such as the activation of complement. Its CH2 and CH3 domains bulge to facilitate interaction with effector proteins. Geometric fit and a chemical (electrostatic charge) fit, often called complementarity -- the antibody has + charge where the antigen is -, and the antibody has knobs where the antigen has indentations Constant fragment. The portion of an antibody molecule that carries out the biological activities of that class of antibody. Biological activity includes binding to receptors on phagocytes and activating the classical complement pathway. The amino acid sequence of the Fc portion of an antibody is the same for every antibody in that class.

81. Hinge Two disulfide bonds in the hinge region unite the two heavy chains The hinge allows the two antigen-binding Fab regions of each antibody molecule to move Two disulfide bonds in the hinge region, between cys235 and cys238 pairs, unite the two heavy chains. The hinge allows the two antigen-binding Fab regions of each antibody molecule to move, enabling them to simultaneously bind antigen epitopes that are separated from one another by varying distances Two disulfide bonds in the hinge region, between cys235 and cys238 pairs, unite the two heavy chains. The hinge allows the two antigen-binding Fab regions of each antibody molecule to move, enabling them to simultaneously bind antigen epitopes that are separated from one another by varying distances

82. Conclusion Changes in the antigen binding site conformation are vital for antigen recognition Herewith the variety of antibody conformation is vital for our health

83. Humoral Immune Response

84. Cellular Events Antigen is “processed” by T lymphocytes and macrophages. Possess special receptors on surface. Termed “antigen presenter cell” APC. Antigen presented to B cell

85. Cellular Immune Response Important in defending against: fungi, parasites, bacteria. Responsible for hypersensitivity, transplant rejection, tumor surveillance. Thymus derived (T) lymphocytes

86. Cell Mediated Reaction Helper T cells – turn on immune response Suppressor T cells – turn off immune response Cytotoxic T cells directly attack antigen

87. Cell Mediated Immunity

88. Basic Antibody Structure

89. Antibodies responding to different antigens have different V regions but the C region is the same for all antibodies in a given class C regions form the stem of the Y-shaped antibody and: Determine the class of the antibody Serve common functions in all antibodies Dictate the cells and chemicals that the antibody can bind to Determine how the antibody class will function in elimination of antigens Antibody Structure

90. Plasma cells make over a billion different types of antibodies Each cell, however, only contains 100,000 genes that code for these polypeptides To code for this many antibodies, somatic recombination takes place Gene segments are shuffled and combined in different ways by each B cell as it becomes immunocompetent Information of the newly assembled genes is expressed as B cell receptors and as antibodies Mechanisms of Antibody Diversity

91. Random mixing of gene segments makes unique antibody genes that: Code for H and L chains Account for part of the variability in antibodies V gene segments, called hypervariable regions, mutate and increase antibody variation Plasma cells can switch H chains, making two or more classes with the same V region Antibody Diversity

92. Antibodies themselves do not destroy antigen; they inactivate and tag it for destruction All antibodies form an antigen-antibody (immune) complex Defensive mechanisms used by antibodies are neutralization, agglutination, precipitation, and complement fixation Antibody Targets

93. Complement fixation is the main mechanism used against cellular antigens Antibodies bound to cells change shape and expose complement binding sites This triggers complement fixation and cell lysis Complement activation: Enhances the inflammatory response Uses a positive feedback cycle to promote phagocytosis Enlists more and more defensive elements Complement Fixation and Activation

94. Neutralization – antibodies bind to and block specific sites on viruses or exotoxins, thus preventing these antigens from binding to receptors on tissue cells Other Mechanisms of Antibody Action

95. Agglutination – antibodies bind the same determinant on more than one antigen Makes antigen-antibody complexes that are cross-linked into large lattices Cell-bound antigens are cross-linked, causing clumping (agglutination) Precipitation – soluble molecules are cross-linked into large insoluble complexes Other Mechanisms of Antibody Action

96. Mechanisms of Antibody Action

97. Since antibodies are useless against intracellular antigens, cell-mediated immunity is needed Two major populations of T cells mediate cellular immunity CD4 cells (T4 cells) are primarily helper T cells (TH) CD8 cells (T8 cells) are cytotoxic T cells (TC) that destroy cells harboring foreign antigens Other types of T cells are: Suppressor T cells (TS) Memory T cells Cell-Mediated Immune Response

98. Major Types of T Cells

99. Soluble antibodies The simplest ammunition of the immune response Interact in extracellular environments such as body secretions, tissue fluid, blood, and lymph Importance of Humoral Response

101. T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells T cells are best suited for cell-to-cell interactions, and target: Cells infected with viruses, bacteria, or intracellular parasites Abnormal or cancerous cells Cells of infused or transplanted foreign tissue Importance of Cellular Response

102. Immunocompetent T cells are activated when the V regions of their surface receptors bind to a recognized antigen T cells must simultaneously recognize: Nonself (the antigen) Self (a MHC protein of a body cell) Antigen Recognition and MHC Restriction

104. Both types of MHC proteins are important to T cell activation Class I MHC proteins Always recognized by CD8 T cells Display peptides from endogenous antigens MHC Proteins

105. Endogenous antigens are: Degraded by proteases and enter the endoplasmic reticulum Transported via TAP (transporter associated with antigen processing) Loaded onto class I MHC molecules Displayed on the cell surface in association with a class I MHC molecule Class I MHC Proteins

106. Class I MHC Proteins

107. Class II MHC proteins are found only on mature B cells, some T cells, and antigen-presenting cells A phagosome containing pathogens (with exogenous antigens) merges with a lysosome Invariant protein prevents class II MHC proteins from binding to peptides in the endoplasmic reticulum Class II MHC Proteins

108. Class II MHC proteins migrate into the phagosomes where the antigen is degraded and the invariant chain is removed for peptide loading Loaded Class II MHC molecules then migrate to the cell membrane and display antigenic peptide for recognition by CD4 cells Class II MHC Proteins

109. Class II MHC Proteins

110. Provides the key for the immune system to recognize the presence of intracellular microorganisms MHC proteins are ignored by T cells if they are complexed with self protein fragments Antigen Recognition

111. If MHC proteins are complexed with endogenous or exogenous antigenic peptides, they: Indicate the presence of intracellular infectious microorganisms Act as antigen holders Form the self part of the self-antiself complexes recognized by T cells Antigen Recognition

112. T cell antigen receptors (TCRs): Bind to an antigen-MHC protein complex Have variable and constant regions consisting of two chains (alpha and beta) T Cell Activation: Step One – Antigen Binding

113. MHC restriction – TH and TC bind to different classes of MHC proteins TH cells bind to antigen linked to class II MHC proteins Mobile APCs (Langerhans’ cells) quickly alert the body to the presence of antigen by migrating to the lymph nodes and presenting antigen T Cell Activation: Step One – Antigen Binding

114. TC cells are activated by antigen fragments complexed with class I MHC proteins APCs produce co-stimulatory molecules that are required for TC activation TCR that acts to recognize the self-antiself complex is linked to multiple intracellular signaling pathways Other T cell surface proteins are involved in antigen binding (e.g., CD4 and CD8 help maintain coupling during antigen recognition) T Cell Activation: Step One – Antigen Binding

115. T Cell Activation: Step One – Antigen Binding

116. Before a T cell can undergo clonal expansion, it must recognize one or more co-stimulatory signals This recognition may require binding to other surface receptors on an APC Macrophages produce surface B7 proteins when nonspecific defenses are mobilized B7 binding with the CD28 receptor on the surface of T cells is a crucial co-stimulatory signal Other co-stimulatory signals include cytokines and interleukin 1 and 2 T Cell Activation: Step Two – Co-stimulation

117. Depending on receptor type, co-stimulators can cause T cells to complete their activation or abort activation Without co-stimulation, T cells: Become tolerant to that antigen Are unable to divide Do not secrete cytokines T Cell Activation: Step Two – Co-stimulation

118. T cells that are activated: Enlarge, proliferate, and form clones Differentiate and perform functions according to their T cell class T Cell Activation: Step Two – Co-stimulation

119. Primary T cell response peaks within a week after signal exposure T cells then undergo apoptosis between days 7 and 30 Effector activity wanes as the amount of antigen declines The disposal of activated effector cells is a protective mechanism for the body Memory T cells remain and mediate secondary responses to the same antigen T Cell Activation: Step Two – Co-stimulation

120. Mediators involved in cellular immunity, including hormonelike glycoproteins released by activated T cells and macrophages Some are co-stimulators of T cells and T cell proliferation Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to: Release interleukin 2 (IL-2) Synthesize more IL-2 receptors Cytokines

121. IL-2 is a key growth factor, which sets up a positive feedback cycle that encourages activated T cells to divide It is used therapeutically to enhance the body’s defenses against cancer Other cytokines amplify and regulate immune and nonspecific responses Cytokines

122. Examples include: Perforin and lymphotoxin – cell toxins Gamma interferon – enhances the killing power of macrophages Inflammatory factors Cytokines

123. Regulatory cells that play a central role in the immune response Once primed by APC presentation of antigen, they: Chemically or directly stimulate proliferation of other T cells Stimulate B cells that have already become bound to antigen Without TH, there is no immune response Helper T Cells (TH)

124. Helper T Cells (TH)

125. TH cells interact directly with B cells that have antigen fragments on their surfaces bound to MHC II receptors TH cells stimulate B cells to divide more rapidly and begin antibody formation B cells may be activated without TH cells by binding to T cell–independent antigens Most antigens, however, require TH co-stimulation to activate B cells Cytokines released by TH amplify nonspecific defenses Helper T Cell

126. Helper T Cells

127. TC cells, or killer T cells, are the only T cells that can directly attack and kill other cells They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized Their targets include: Virus-infected cells Cells with intracellular bacteria or parasites Cancer cells Foreign cells from blood transfusions or transplants Cytotoxic T Cell (Tc)

128. Bind to self-antiself complexes on all body cells Infected or abnormal cells can be destroyed as long as appropriate antigen and co-stimulatory stimuli (e.g., IL-2) are present Natural killer cells activate their killing machinery when they bind to MICA receptor MICA receptor – MHC-related cell surface protein in cancer cells, virus-infected cells, and cells of transplanted organs Cytotoxic T Cells

129. In some cases, TC cells: Bind to the target cell and release perforin into its membrane In the presence of Ca2+ perforin causes cell lysis by creating transmembrane pores Other TC cells induce cell death by: Secreting lymphotoxin, which fragments the target cell’s DNA Secreting gamma interferon, which stimulates phagocytosis by macrophages Mechanisms of Tc Action

130. Mechanisms of Tc Action

131. Suppressor T cells (TS) – regulatory cells that release cytokines, which suppress the activity of both T cells and B cells Gamma delta T cells (Tgd) – 10% of all T cells found in the intestines that are triggered by binding to MICA receptors Other T Cells