Fundamental Immunology (Introduction to the Immune System) By. Faculty of Medicine, Suez canal University, Ismailia EGYPT

Transcription

1 Fogarty-IBRO School Nairobi-KENYA May 22 nd 25 th 2007 Fundamental Immunology (Introduction to the Immune System) By Ahmed El-Gohary, M.D. Faculty of Medicine, Suez canal University, Ismailia EGYPT

2 The scope of the lecture Introduction to the Immune system Innate Immunity Antigen Capture and Presentation to Lymphocytes Antigen Recognition in the adaptive Immune System

3 The Immune system Immunity is the resistance to diseases, specifically infectious diseases The physiological function of the immune system is to prevent infections and to eradicate established infections.

4 The Immune system The impact of immunology goes beyond infectious diseases. The immune system recognizes and respond to tissue grafts, Defense against tumors, Abnormal immune responses are the causes of many diseases.

5 Introduction to Immune system

6 Types of Adaptive Immunity

7 Properties of Adaptive Immunity

8 Properties of Adaptive Immunity

9 The Clonal Selection Hypothesis

10 Phases of Immune Responses

11 The two-signal requirement for lymphocyte activation

12 Principal cells of the Immune System

13 Classes of Lymphocytes

14 Maturation of Lymphocytes

15 Stages in the life History of Lymphocytes

16 Lymph Node Morphology

17 T & B Lymphocytes in peripheral L.N.

18 Recirculation of T Lymphocytes

19 Summary The physiologic function of the immune system is to protect individuals against infections. Innate immunity is the early line of defense, mediated by cells and molecules that are always present and ready to eliminate infectious microbes. Adaptive immunity is the form of immunity that is stimulated by microbes, has a fine specificity for foreign substances, and responds more effectively against each successive exposure to a microbe. Lymphocytes are the cells of adaptive immunity, and the only cells with clonally distributed receptors for antigens. Adaptive immunity consists of humoral immunity, in which antibodies neutralize and eradicate extracellular microbes and toxins, and cell-mediated immunity, in which T lymphocytes eradicate intracellular microbes. Adaptive immune responses consist of sequential phases: antigen recognition by lymphocytes, activation of the lymphocytes to proliferate and to differentiate into effector and memory cells, elimination of the microbes, decline of the immune response, and long-lived memory.

20 B lymphocytes express membrane antibodies that recognize antigens, and effector B cells antibodies that neutralize and eliminate the antigen. T lymphocytes recognize peptide fragments of protein antigens displayed on other cells. Helper T lymphocytes activate phagocytes to destroy ingested microbes and activate B lymphocytes to produce antibodies. Cytolytic (cytotoxic) T lymphocytes kill infected cells harboring microbes in the cytoplasm. Antigen-presenting cells capture antigens of microbes that enter through epithelia, concentrate these antigens in lymphoid organs, and display the antigens for recognition by T cells. Lymphocytes and antigen-presenting cells are organized in peripheral lymphoid organs, where immune responses are initiated and develop. Naive lymphocytes circulate through the peripheral lymphoid organs searching for foreign antigens. Effector T lymphocytes migrate to peripheral sites of infection, where they function to eliminate infectious microbes. Effector B lymphocytes remain in lymphoid organs and the bone marrow, from where they secrete antibodies that enter the circulation and find and eliminate microbes.

21 Microbe Recog.

22 Slide 21 MSOffice13, 5/11/2007

23 Epithelia in Innate Immunity

24 Circulating phagocytes: neutrophils and monocytes

25 Circulating phagocytes: neutrophils and monocytes

26 Migration of blood leukocytes to sites of infection

27 Receptors and responses of phagocytes MSOffice14

28 Slide 26 MSOffice14 Neutrophils and macrophages recognize microbes in the blood and extravascular tissues by surface receptors that are specific for microbial products. There are several different types of receptors, specific for different structures or patterns that are frequently found on microbial molecules. Toll-like receptors (TLRs) are homologous to a Drosophila protein called Toll, which is essential for protecting the flies against infections. TLRs are specific for different components of microbes. For instance, TLR-2 is essential for macrophage responses to several bacterial lipoglycans, TLR-4 for bacterial lipopolysaccharide (LPS, or endotoxin), TLR-5 for a component of bacterial flagella called flagellin, and TLR-9 for unmethylated CpG nucleotides also found in bacteria. Signals generated by engagement of TLRs activate a transcription factor called NF-κB (nuclear factor κb), which stimulates production of cytokines, enzymes, and other proteins involved in the anti-microbial functions of activated phagocytes., 5/23/2007

29 Neutrophils and macrophages recognize microbes in the blood and extravascular tissues by surface receptors that are specific for microbial products. There are several different types of receptors, specific for different structures or patterns that are frequently found on microbial molecules. Toll-like receptors (TLRs) are homologous to a Drosophila protein called Toll, which is essential for protecting the flies against infections. TLRs are specific for different components of microbes. For instance, TLR-2 is essential for macrophage responses to several bacterial lipoglycans, TLR-4 for bacterial lipopolysaccharide (LPS, or endotoxin), TLR-5 for a component of bacterial flagella called flagellin, and TLR-9 for unmethylated CpG nucleotides also found in bacteria. Signals generated by engagement of TLRs activate a transcription factor called NF-κB (nuclear factor κb), which stimulates production of cytokines, enzymes, and other proteins involved in the anti-microbial functions of activated phagocytes.

30 Phagocytosis and intracellular killing of microbes

31 Functions of activated macrophages.

32 Natural Killer Cells

33 The Function of Inhibitory Receptors of NK Cells

34 The Complement System

35 Cytokines of Innate Immunity

36 Cytokines of innate immunity

37 Evasion of Innate Immunity by Microbes

38 The role of innate immunity in stimulating adaptive immune responses

39 Summary All multicellular organisms contain intrinsic mechanisms of defense against infections, which constitute innate immunity. The mechanisms of innate immunity respond to microbes and not to nonmicrobial substances, are specific for structures present on various classes of microbes, are mediated by receptors encoded in i the germline, and are not enhanced by repeat exposures to microbes. The principal components of innate immunity are epithelia, phagocytes and natural killer (NK) cells, cytokines, and plasma proteins, including the proteins of the complement system. Epithelia provide physical barriers against microbes, produce antibiotics, and contain lymphocytes that may prevent infections.

40 The principal phagocytes, PMN and monocytes/macrophages, are blood cells recruited to sites of infection, where they recognize microbes by several receptors. Neutrophils and macrophages ingest microbes for intracellular destruction, secrete cytokines, and respond in other ways that contribute to elimination of microbes and repair of infected tissues. Natural killer cells kill host cells infected by intracellular microbes and produce the cytokine IFN-γ, which activates macrophages to kill phagocytosed microbes. The complement system activated sequentially on encounter with some microbes and by antibodies (in the humoral arm of adaptive immunity). Complement proteins coat (opsonize opsonize) microbes for phagocytosis, stimulate inflammation, and lyse microbes.

41 Cytokines of innate immunity (TNF, IL-1, chemokines) function to stimulate inflammation, activate NK cells (IL- 12), activate macrophages (IFN-γ), and prevent viral infections (type I IFN). Innate immune responses provide "second signals" for the activation of B and T lymphocytes. The requirement for these second signals ensures that adaptive immunity is elicited by microbes (the natural inducers of innate immune reactions) and not by nonmicrobial substance.

42 Antigen Capture and Presentation to Lymphocytes T cell receptor (TCR) recognizes a complex of a peptide antigen displayed by a major histocompatibility (MHC) molecule

43 Capture of Protein Antigens by Antigen-Presenting Cells

44 Dendritic cells

45 The capture and presentation of protein antigens by dendritic cells

46 Cross-presentation of microbial antigens from infected cells by professional APCs

47 The Structure and Function of MHC Molecules

48

49 Properties of MHC molecules and genes

50 Pathways of Intracellular processing of Protein Ags

51 MHC-associated antigen presentation in the recognition of microbes by CD4+ and CD8+ T cells

52 Summary The induction of immune responses to the protein antigens of microbes is dependent on a specialized system for capturing and displaying these antigens for recognition by the rare naive T cells specific for any antigen. Microbes and microbial antigens that enter the body through epithelia are captured by professional antigen-presenting cells (APCs), mainly dendritic cells, located in the epithelia and transported to regional lymph nodes, or are captured by APCs resident in lymph nodes and spleen. The protein antigens of the microbes are displayed by the APCs to naive T lymphocytes that recirculate through the lymphoid organs. The function of displaying peptides derived from protein antigens is performed by molecules encoded in the major histocompatibility complex (MHC).

53 Summary Proteins that are ingested by APCs from the extracellular environment are proteolytically degraded within the vesicles of the APCs, and the peptides that are generated bind to the clefts of newly synthesized class II MHC molecules. Class II MHC molecules are recognized by CD4, because of which CD4+ helper T cells are specific for class II MHC-associated peptides that are derived mainly from extracellular proteins. Proteins that are produced by microbes living in the cytoplasm of infected cells, or enter the cytoplasm from phagocytosed microbes, are degraded by cytosolic proteases and bind to the clefts of newly synthesized class I MHC molecules. Class I MHC molecules are recognized by CD8, because of which CD8+ cytolytic T lymphocytes are specific for class I MHC-associated peptides derived from cytosolic proteins.

54 Summary The role of MHC molecules in antigen display ensures that T cells only see cell-associated protein antigens, and the correct type of T cell (helper or cytolytic cell) responds to the type of microbe that T cell is best able to combat. Microbes activate APCs to express membrane proteins (costimulators) and to secrete cytokines that provide signals that function in concert with antigens to stimulate specific T cells. The requirement for these second signals ensures that T cells respond to microbial antigens and not to harmless, nonmicrobial substances.

55 Summary B lymphocytes recognize proteins as well as nonprotein antigens, even in their native conformations. It is not known if a specialized system of antigen display is essential for the induction of B cell responses. Follicular dendritic cells (FDCs) display antigens to germinal center B cells and select the high-affinity B cells during humoral immune responses.

56 Antigen Receptors of Lymphocytes

57 Antibodies

58 Antibodies

59 Features of the major isotypes (classes) of antibodies

60

61 The structure of the T cell antigen receptor (TCR)

62 Antigen recognition by antibodies and T cell antigen receptors

63 Maturation of Lymphocytes

64 maturation and selection of B lymphocytes

65 Maturation and Selection of T Lymphocytes

66 SUMMARY In the adaptive immune system, the molecules responsible for specific recognition of antigens are antibodies and T cell antigen receptors. Antibodies may be produced as membrane receptors of B lymphocytes and as proteins secreted by antigen-stimulated B cells that have differentiated into antibody-secreting cells. Secreted antibodies capable of neutralizing microbes and microbial toxins and eliminating them by activating various effector mechanisms. T cell antigen receptors (TCRs) are membrane receptors and are not n secreted.

67 SUMMARY The core structure of antibodies consists of two heavy chains and two light chains forming a disulfide-linked complex. Each chain consists of a variable (V) region, which is the portion that recognizes antigen, and a constant (C) region, which provides structural stability and, in heavy chains, performs the effector functions of antibodies. T cell receptors consist of an α chain and a β chain. Each chain contains one V region and one C region, and both chains participate in the recognition of antigens, which for most T cells are peptides displayed by MHC molecules.

68 SUMMARY The V regions of Ig and TCR molecules contain hypervariable segments, also called complementarity-determining regions, which are the regions of contact with antigens. The genes that encode antigen receptors consist of multiple segments that are separate in the germline and are brought together during the maturation of lymphocytes. In B cells, the Ig gene segments undergo recombination as the cells mature in the bone marrow, and in T cells the TCR gene segments undergo recombination during maturation in the thymus.

69 SUMMARY Receptors of different specificities are generated in part by different combinations of V, D, and J gene segments. The process of recombination introduces variability in the nucleotide sequences at the sites of recombination by adding or removing nucleotides from the junctions. The result of this introduced variability is the development of a diverse repertoire of lymphocytes, in which clones of cells with different antigen specificities express receptors that differ in sequence and recognition, and most of the differences are concentrated at the regions of gene recombination.

70 SUMMARY During their maturation, lymphocytes undergo alternating cycles of proliferation and antigen receptor expression and traverse several checkpoints at which they are selected such that only cells with complete functional antigen receptors are preserved and expanded. T lymphocytes are positively selected to recognize peptide antigens displayed by self MHC molecules. Immature lymphocytes that strongly recognize self antigens are negatively selected and prevented from completing their maturation eliminating cells with the potential of reacting in harmful ways against self tissues.

71 Thank You