Introduction to the immune system Innate humoral immunity

Transcription

1 Introduction to the immune system Innate humoral immunity Bartosz Wojciuk Immunology course for the 2nd year Medical Faculty students Pomeranian Medical University Academic year 2017/2018, winter semester

2 Seminar frameprogramme Introduction to the immune system functions and components- general remarks Humoral innate immunity- complement system activity

3 Important definitions The immune system- the system of different cells subsets that circulate in the lymphatic system and blood to protect us host against foreign agents Antigen- anything that activates an immune response, usually foreign substances but it may also come from native tissues Pathogen- a microorganism which is a causative agent of an infection Tolerance- non-reactivity of the immune system, usually refers to self but may include foreign tissues present in organ transplants Autoimmunity- a failure of tolerance, the reaction of immune system directed towards native tissues

4 Antigen recognition Immune response Effectory mechanisms

5 Effects of the Immune System Beneficial: Protection from pathogens Detrimental: Tissue damage (inflammation) Damage to self (hypersensitivity or autoimmunity)

6 Antigen recognition Immune response Effectory mechanisms

7 Does it work like this? Source: Brodin et al. Systems level immune response and personalized medicine Expert Rev. Clin. Immunol. 9(4), (2013)

8 On no!!!!!!!!!

9 Or maybe hopefully Source: Brodin et al. Systems level immune response and personalized medicine Expert Rev. Clin. Immunol. 9(4), (2013)

10 Overview of the Immune System Interactions between the two systems

11 Comparison of Innate and Adaptive Immunity Innate (nonspecific) Immunity (present at birth) No time lag Exposure leads to immediate maximal response Adaptive (specific) Immunity A lag time between exposure and maximal response Not antigen specific Non-specific response - effective against a wide range of pathogens and foreign substances, does not detect difference between pathogens treating all foreign substances in the same way and always giving the same response No memory Antigen specific Highly-specific response Development of memory (after exposure to antigen)

12 Cells of the Immune System basic scheme

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19 Lymphoid organs The primary (or central) lymphoid organs: - the bone marrow - the thymus - fetal liver The secondary (or peripheral) lymphoid organs: - the spleen - the lymph nodes - the mucosa-associated lymphoid tissue (MALT) Selection of lymphocytes which are tolerant to self components B- cells from bone marrow T-from thymus Activation and differentiation of lymphocytes into effector cells which then migrate to peripheral tissues via chemokines

20 Lymphoid organs

21 Lymph nodes are set at all crossroads where lymph is drained, after arriving from peripheral areas. The principal node groups drain: - lymphatics of the lower extremities - lymph nodes of the pelvis - lymph nodes of the abdomen - lymph nodes of the thorax - lymph nodes of the upper limbs - lymph nodes of the head and the neck The LYMPH NODE: - the cortex (called zone B or the,, thymus-independent zone )- the majority of B lymphocytes develop. lymphocytes do not pass through the thymus. - the T or,, thymus-dependent zone is located under zone B and contains majority of T lymphocytes.

22 MALT The mucosa -associated lymphoid tissue (MALT) the diffuse system of small concentrations of lymphoid tissue in various sites of the body such as thyroid, breast, lung, salivary glands, eye and skin. The components of MALT are sometimes subdivided into the following: GALT (gut-associated lymphoid tissue). - Tonsils (Waldeyer's ring), - Adenoids (Pharyngeal tonsils) - Peyer's patches Lymphoid aggregates in the appendix and large intestine Lymphoid tissue accumulating with age in the stomach Small lymphoid aggregates in the oesophagus BALT (bronchus-associated lymphoid tissue) NALT (nose-associated lymphoid tissue) LALT (larynx-associated lymphoid tissue) SALT (skin-associated lymphoid tissue)

23 Does it work like this?

24 Or maybe hopefully

25 Overall Antigen recognition Laboraory outcomes Immune response Clinical symptoms Effectory mechanisma

26 Seminar frameprogramme Introduction to the immune system functions and components- general remarks Humoral innate immunity- complement system activity

27 Innate (nonspecific) immuno response Anatomical barriers to prevent microbes from entering the body Mechanical factors Chemical factors Biological factors Humoral components Cytokines (interferon) Chemokines Complement - Lysozyme - Fibronectin Acute phase reactants Cellular components Neutrophils Monocytes and macrophages NK cells Eosinophils

28 Innate (nonspecific) immuno response Anatomical barriers mechanical factors COMPONENTS Intact skin Mucous membranes Mucus Hair Cilia Tear ducts Saliva Epiglottis Urine FUNCTIONS physical barrier to the entrance of microbes Inhibit the entrance of many microbes, but not as effective as intact skin Viscous fluid, traps microbes Filter microbes and dust in the nose vestible Together with mucus, trap and remove microbes and dust from upper respiratory tract Tears dilute and wash away irritating substances and microbes Washes microbes from surfaces of teeth and mucous membranes of mouth Prevents microbes and dust from entering trachea Washes microbes from urethra

29 Innate (nonspecific) immuno response Anatomical barriers chemical factors COMPONENTS Gastric juice FUNCTIONS Destroys bacteria and most toxins in stomach Acid ph of skin Unsaturated fatty acids Sebaceous (oil) and sweat glands reduce skin s ph to 3-5 Discourages growth of many microbes (microbicidal effect) Antibacterial substance secreted by sebaceous glands

30 Innate (nonspecific) immuno response Anatomical barriers biological factors COMPONENTS Normal flora of skin and mucosa (mainly upper respiratory tract, gut and lower genital tract) FUNCTIONS Colonization resistance, continuous stimulation of the immune system, immune system modulation

31 Innate (nonspecific) immuno response humoral components COMPONENTS Interferon (IFN) Complement Lysozyme fibronectin Acute phase reactants FUNCTIONS Protects uninfected host cells from viral infection Causes lysis of microbes. Promotes phagocytosis, contributes to, inflammation attracts white blood cells to site of infection Antimicrobial substance in perspiration, tears, saliva, nasal secretions, and tissue fluids; splitting of bacterial murein Nonspecific opsonin Serum proteins: i.e. C-reactive protein, fibrinogen, transferrin.

32 Seminar frameprogramme Introduction to the immune system functions and components- general remarks Humoral innate immunity- complement system activity

33 Seminar frameprogramme Introduction to the immune system functions and components- general remarks Humoral innate immunity- complement system activity

34 CYTOKINES Cytokines are the soluble messengers of the immune system, are released by one cell to cause a response in another, These are not antibodies, but rather substances (glycoproteins) released during the activation of inflammatory cells by various stimuli, White blood cells and certain other cells of the immune system produce cytokines when an antigen is detected, There are many different cytokines, which affect different parts of the immune system, Some stimulate activity (WBC more effective killers, attract WBC to a trouble spot), other cytokines inhibit activity (helps to end an immuno response), Cytokines also participate in specific immunity.

35 Cytokines Produced locally Very short half-lives (of seconds to minutes) Effective at picomolar concentrations The effect of cytokines- paracrine (on near cells), autocrine (the same cell both produces and reacts to the cytokines) Functions of cytokines- pleiotropic Promotion/inhibition of inflamation Promotion of hematopoiesis Activating B-cells Activating T-cells Summary of cytokine functions

36 CYTOKINES Interleukin 1(Il-1) - Interleukin 28 (Il-28) Tumor necrosis factor alpha (TNF- secreted by macrophages, mast cells, has cytotoxic effect (tumor cells, inflammatory cells) Tumor necrosis factor beta (TNF- secreted by Th1and Tc cells, has cytotoxic effect (tumor cells)

37 Chemokines Chemokines (chemoattractant cytokines) small peptides (molecules) produced by many cell types, released by pathogens and infected tissues to attract and activate phagocytes (nonspecific immuno response) Activities similar to cytokines

38 The complement system The complement system, the major effector/compound of humoral nonspecific immunity, consists of nearly 30 serum and membrane proteins, which act in sequence. One protein activates another and so on. This sequence is called the complement cascade. There are three basic pathways activating complement system: - the classical pathway - the alternative pathway - the lectin pathway The three pathways share a common terminal reaction sequence that generates a macromolecular membrane-attack complex (MAC), which lyses a variety of cells, bacteria, and viruses

39 The complement components The proteins and glycoproteins of complement system are synthesized largely by: - liver hepatocytes (significant amounts of complement) - monocytes, - tissue macrophages, - epithelial cells of the gastrointestinal tract. Each complement is designated by numerals (C1- C9), or by letter symbols (e.g., factor D, P)

40 Pathways of complement activation CLASSICAL PATHWAY LECTIN PATHWAY ALTERNATIVE PATHWAY antibody dependent antibody independent Activation of C3 and generation of C5 convertase activation of C5 LYTIC ATTACK PATHWAY

41 Components of the Classical Pathway C1q C3 C4 C1 complex

42 Classical Pathway Generation of C3-convertase C1q

43 Classical Pathway Generation of C3-convertase C1q C4b2a is C3 convertase C4b

44 Classical Pathway Generation of C5-convertase C1q C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway C4b C3b

45 Lytic pathway Generation of C5 convertase leads to the activation of the Lytic pathway

46 Components of the lytic pathway C5 C6 C7 C 9

47 Lytic pathway C5-activation C5a b C4b C3b

48 Lytic pathway assembly of the lytic complex C6 C7 b

49 The Membrane Attack Complex (MAC) C5a C Å C6 C5b C7 C8 C9 C9 C9 C9 C9 C9 C9 C9 C9 C9 C9 Hole is formed in bacterial cell leading to lysis

50 Biological effects of C5a

51 Complement Recognition: Ig recognizes an antigenic determinant and fixes to it with its Fab part. The first component of complement, C1 fixes on the Fc part of the Ig and becomes an active enzyme. Activation: C1q component is attached to the Fc part of Ig. C1 fixes C4 on the cell membrane.

52 Complement Activation: C4 fixes C2 and forms a C4-C2 complex called C3 convertase C3 is the major component of complement. C3 splits into C3a and C3b. C3a is an anaphylatoxin capable of degranulating mast cells, provoking vasodilation, and acting as a chemotactic factor for neutrophils C3b fixes on the cell membrane Membrane-attack complex (MAC): C5b-C9

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54 Components of mannose-binding lectin pathway C4 MBL C2 MASP1 It is initiated by binding of mannose binding lectin MBL- to bacterial surfaces with mannose containing polysacharides.next to the MBL connect two serine proteases: MASP1 and MASP 2. The complex MBL+MASP1+MASP2 are similar to the cmplex C1q+C1r+C1s from classical complement pathway. Next steps of these way are also identical with classical pathway

55 Mannose-binding lectin pathway C4b2a is C3 convertase; it will lead to the generation of C5 convertase MASP1 MBL C4b C2 C4b

56 Components of the alternative pathway C3 P

57 Spontaneous C3 activation Generation of soluble C3 converters C3 i b C3 i The soluble of C3iBb complex has a very short half life

58 C3-activation the amplification loop If spontaneously-generated C3b is not degraded C3b b C3bb

59 C3b stabilization and C5 activation C3b finds an activator (protector) membrane P This is stable C5 convertase of the alternative pathway C3b b C3 b

60 C5-convertase of the three pathways C5-convertase of the Classical and Lectin Pathways C5-convertase of the Alternative Pathway C4b C3b C3b C3b

61 The complement functions: Opsonization destroy bacteria by attaching to them, thus making the bacteria easier for neutrophils and macrophages to identify and ingest -C3b Lysis - killing bacteria and viruses directly -C5b-C9 (MAC) Chemotaxis attracting macrophages and neutrophils to a trouble spot, causing bacteria to clump together, and neutralizing viruses. - C5a and C3a The complement system also participates in specific immunity.