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26. Basophils and mast cells- types, function.

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Title: Basophils, mast cells Author: k Last modified by: fbroz Created Date: 11/1/2008 1:05:22 PM Document presentation format: P edv d n na obrazovce – PowerPoint PPT presentation

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Title: 26. Basophils and mast cells- types, function.


1
  • 26. Basophils and mast cells- types, function.
  • 27. Immune mechanisms of the inflammation (local
    and systemic reaction)
  • 28. Cytokines (overview, disposal according their
    function)
  • 29. Physiological mechanisms of regulation of the
    immune system.
  • 30. HLA system, 1st class molecules, their
    structure and function
  • 31. HLA system, 2nd class molecules, their
    structure and function
  • 32. HLA system, genetic background. HLA typing.

2
26. Basophils and mast cells - types, function.
3
Basophils
  • A type of bone marrow derived circulating
    granulocyte
  • Ability to migrate into the tissue
  • Structural and functional similarities to mast
    cells granules are containing inflammatory
    mediators express a high- afinity receptor for
    Fc fragment of IgE on the cell surface
  • Participate in immediate hypersensitivity
    reactions
  • Produce cytokines (IL-4, 13)

4
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5
Basophils surface markers
  • FceRI high-affinity receptor for Fc fragment of
    IgE
  • CD 123 receptor for IL- 3
  • CD 63 activating marker expressed after
    degranulation

6
Mast cells
  • Derived from bone marrow precursor
  • Reside in tissues adjacent to blood vessels
  • Express a high-affinity receptor for Fc fragment
    of IgE
  • Contain numerous mediator-filled granules

7
Mast cells surface markers
  • FceRI high-affinity receptor for IgE
  • CD 117- membrane gp mediates interaction
    necessary for mast cells proliferation

8
FceRI
  • complex consists
  • - a- chains with two extracellular
    immunoglobulin domains
  • - ß- chains four times cross the membrane
    both their ends are inserted to the cytoplasm
  • - ?- chain homodimer
  • - ß and ? chains contain activating motives
    ITAM (mediate transport of activating signal
    from mast cell surface after binding of IgE) in
    their cytoplasmic part

9
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10
Cytoplasmic granules
  • Histamin (dilation of small blood vessels,
    increase of vascular permeability, contraction of
    smooth muscles), proteases (cause a damage to the
    tissues)
  • Cytokines IL- 4 ( stimulates IgE production by B
    cells), 5 (activates eosinophils), 13
    (stimulates mucus secretion by airway epithelial
    cells), TNF a, IL-1
  • Growth factors TGF- ß, VEGF (vascular
    endothelial growth factor)
  • Synthetize PAF (platelet activation factor),
    LTC4- leukotrienes (stimulate prolonged smooth
    muscle contraction), PGD2- prostaglandins (cause
    vascular dilation)

11
Mast cells function
  • Participate on defence against bacterial and
    parasites infection
  • Develop immediate hypersensitivity reactions
    (production of IgE antibodies in response to an
    antigen, binding of IgE to Fc receptors of mast
    cells, cross-linking of the bound IgE by the
    antigen and release of mast cell mediators)
  • Take part in reparation of tissues -
    angiogenesis, production of intercellular
    substances

12
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13
27. Immune mechanisms of the inflammation (local
and systemic reaction)
14
Inflammation
  • a complex reaction of the innate immune system
    in vascularized tissues that involves
    accumulation and activation of leukocytes and
    plasma proteins at a site of infection, toxin
    exposure or cell injury
  • Iniciated by changes in blood vessels that
    promote leukocyte recruitment and movement of
    fluid and plasma proteins into tissue
  • Inflammation serves a protective function in
    controlling infections and promoting tissue
    repair

15
Inflammatory response
  • Local - signs redness, swelling, pain, heat
  • Systemic sings fever
  • Acute or chronic process

16
Inflammation - iniciation
  • 1. signal phagocytes and degranulated mast
    cells, substances released from damaged cells,
    parts of intercellular substance exposed by injury

17
Local inflamation
  • Increase of vessels permeability plasma fluid
    passes through the blood vessels- swelling
  • Increase of endothelial adhesivity (expression of
    cell adhesion molecules)- phagocytes and
    lymphocytes adhere to endothelial cells pass to
    the tissues
  • The coagulation, fibrinolytic, kinin and
    complement systems are activated
  • Local nerve endings are influenced (pain)
  • changes in temperature regulation

18
Local inflamation
  • phagocytes- accumulate in a site of injury,
    produce cytokines
  • Ag APC home to LN (lymph nodes) - activate T
    cells and induce their terminal differentiation,
    activation of B cells and their changes into
    plasma cells with production of antibodies
  • Mature Th 1 lymphocytes migrate from LN to the
    site of infection and stimulate macrophages

19
Systemic response (SR) to inflammation
  • Development of SR depends on
  • - range of damage
  • - duration of local inflammation
  • SR can arise also without local inflammation
  • - after massive enter of microorganisms into
    the blood septic shock
  • - after intravascular antigen impulse of
    noninfection character anaphylactic shock
  • Massive release of mediators (cytokines,
    complement, histamin)- leads to a massive
    vasodilatation- hypotensis- vascular collapse

20
Sings of systemic inflammation
  • Fever- caused by stimulation of hyppothalamic
    center of termoregulation (by proinflammatory
    cytokines TNF, IL-1, INF-gama)
  • Caused also by increase of proteosynthesis,
    increase of Hsp production (hot shock protein)

21
Mediators of inflammation
  • Cytokines produced in the site of inflammation-
    come through the blood into the liver- stimulate
    production of plasma proteins of acute
    inflammation phase (CRP, amyloid P, complement
    C3,C4), transport proteins (ceruloplasmin,
    transferin) and inhibitors of proteases (alfa
    2-macroglobulin)
  • Proteins of acute phase function -
    opsonisation, activation of complement
  • Cytokines and mediators cause bone marrow to
    release and produce leukocytes- leukocytosis

22
Reparation of damaged tissues
  • Activation of reparation process
  • - occurs during later phases of inflammation
  • - phagocytes- eliminate damaged cells
  • activation of fibroplastic mechanisms
  • activation of angiogenesis
  • start regeneration and remodelation of tissues
  • Control by cytokines, hormons, enzymes
  • Chronic inflammation accompane by fibrotic
    process

23
28. Cytokines (overview, disposal according their
function)
24
Cytokines
  • Humoral factors - provide intercellular
    communication between immune cells
    communication between immune system and other
    body systems
  • Proteins secreted by leukocytes (and by other
    cells of immune system)
  • Influence different cells of immune system
    through specific receptors
  • Forms- secreted or membrane
  • Effects - pleiotropic (1 cytokine has a several
    fysiological effects)

25
Function of cytokines
  • Activating signals for cells activate, regulate
    cell cycle, mitotic activity
  • Cause changes of the cell membranes increase of
    cytokine receptors expression
  • Participate in reparation of tissues in the
    terminal phase of inflammation
  • Regulate immune cells proliferation and
    differentiation in the immune organs
  • Influence migration of the immune cells

26
Classification of cytokines
  • Pro-inflammatory
  • Anti-inflammatory
  • With growth activity factor
  • Participating in humoral response IS
  • Participating in cell response IS
  • With antiviral effect

27
Proinflammatory cytokines
  • IL-1 produced by macrophages and T cells
    activates neutrophils, endothelial cells and T
    cells, induces synthesis of acute phase proteins
    in liver, causes fever
  • IL-6 produced by T and B cells, monocytes
    regulates B cell differentiation and
    proliferation, synthesis antibodies stimulates
    hepatocytes to produce acute phase proteins
  • IL-8 produced by monocytes, macrophages,
    endothelial cells chemotactic factor for
    neutrophils
  • IL-12, IL-18, TNF

28
TNF
  • TNF a produced by macrophages (T a B cells, NK
    cells, neutrophiles,..) after activation by
    lipopolysacharids binded to plasma protein-
    complex binds to CD14 on the macrophage surface
    causes releasing of TNF a
  • TNF a participates on early phase of
    inflammation, induces expression of adhesive
    molecules on endothelial cells and leukocytes
    stimulates proinflammatory protein production
    stimulates catabolic processes
  • TNF ß- produced by T and B cells similar effects

29
Antiinflammatory cytokines
  • IL-10 produced by Th2 cells, monocytes,
    macrophages, activated B cells inhibition of
    cytokine Th1, Tc and NK cells production
    inhibition of synthesis proinflammatory cytokines
    by macrophages
  • TGF-ß growth activator but also inhibitor of
    different cell types
  • Regulates damaged tissues reparation by
    stimulation of intercellular substances
    synthesis, modulate expression of tissue
    metaloproteases and tissue inhibitors of
    proteolytic enzymes regulates cell adhesion
    chemoatractant of fibroblasts can inhibite T and
    B cell proliferation
  • IL-4

30
CYTOKINES with activity of growth factors
  • IL-2, IL-4, IL-5, IL-6, IL-9, IL-14
  • SCF- stimulates stem cell proliferation, their
    release to the peripheral blood
  • IL-3 influences maturation of all cell lines
  • IL-7 growth factor of T cells
  • IL-11 growth factor of megakaryocytes
  • IL-15 induces proliferation of mast cells, Th
    and Tc cells

31
CYTOKINES with activity of growth factors
  • G-CSF, M-CSF, GM-CSF stimulate granulocytes
    and/or monocytes/macrophages proliferation and
    differentiation, prolongate their survival and
    increase their functional capacity during
    inflammation
  • EPO erythropoetin- stimulates red cells
    differentiation

32
CYTOKINE participating in humoral response of IS
  • IL-4 produced by Th2 cells, mast cells and
    basophils stimulates B cell proliferation,
    production of IgM,G1,E stimulates T cell
    proliferation activates macrophages growth
    factor of mast cells (antiinflammatory effect)
  • IL-13 see IL-4 chemotactic factor for
    monocytes and macrophages
  • IL-5 produced by Th2 cells, lymphocytes and
    mast cells activates and stimulates B cells and
    eosinophils proliferation, stimulates Tc cells
  • IL-9 produced by Th2 cells co-stimulating
    factor - amplifies Th cells and mast cells
    proliferation

33
CYTOKINES participating in cell mediated response
  • IL-2 produced by Th cells after stimulation by
    antigen, autocrine effect to Th cells activating
    signal for Tc cells and NK cells 2. signal for
    activation and differentiation of B cells
  • IL-12 produced by monocytes, macrophages
    stimulates maturation Th0 into Th1 cells
    activates NK cells stimulates INF- ? production
    by Th1 cells inhibites IgE secretion
  • IFN-?, GM-CSF

34
CYTOKINE with antiviral effect
  • Interferons- anti-inflammatory,
    anti-prolifferative
  • IFN-a, IFN-ß - produced by cells with nucleus
    after stimulation viruses - IFN (after binding
    to the receptor) induces in noninfected cell
    status of non-permisivity decomposition of
    viral nucleus acids and influence into
    translation of viral proteins
  • IFN- a represents 20 cytokines differ by
    glycosylation of general protein structure
    produced by leukocytes
  • - in recombinant form therapy of chronic
    active hepatitis B, hepatitis C

35
Receptors for cytokines
  • Consist of 2-3 subunits
  • 1- binds cytokine
  • Others mediate contact with intracellular
    signaling molecules
  • Results of signalisation stimulation of cell
    mitosis, differentiation, initiation of effector
    functions (degranulation, secretion of cytokines,
    activation of membrane enzymes, chemotaxis),
    inhibition of cell mitosis and induction of
    apoptosis

36
Signaling process
  • RECEPTORS of CYTOKINES are associated with
  • Protein-kinases- phosphorylate intracellular
    substances (after activation )- influence
    transcription of genes, structure of cytoskelet
  • G-proteins iniciate phosphorylation (after
    cytokine binding to the receptor) catalyze the
    replacement of GDP (guanyl diphosphate) to GTP
    and can activate a variety of cytoplasmic
    enzymes
  • Calcium ions open Ca channels (after cytokine
    binding to the receptor) increase of Ca ions
    concentration in the cytoplasma - activation of
    proteins by ca ions binding

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Regulation of local concentration of cytokines
  • Biological effects are neutralized by binding to
    nature inhibitors and soluble forms of receptors
    for cytokines
  • MMP (matrix metaloproteases) release cytokines
    from molecules of intercellular substance
  • Elastases release binded cytokines

39
29. Physiological mechanisms of regulation of the
immune system.
40
Immune mechanisms of regulation
  • Immune system is regulated by
  • Antigen
  • Antagonistic peptid
  • Antibodies
  • Cytokines and intercellular contact
  • T lymphocytes
  • Neuroendocrine regulation

41
REGULATION BY ANTIGEN
  • Antigen competition peptides from different
    antigens compete for binding-sites on the MHC gp
    antigen is able to suppress expression of other
    antigen
  • IMPORTANT IS
  • the binding strenght of peptide to MHC gp II
  • density of peptid-MHC gp II complex on the
    surface of APC
  • Immune response finishes after extinction of
    antigen due to a short life-span of effector
    lymphocytes

42
ANTAGONISTIC PEPTIDES
  • Agonists - peptide fragments of antigen with
    adequate binding to MHC gp, recognition by T
    cells with sufficient affinity induce full
    response of T cells
  • Partial agonists induce a qualitative different
    response of T cells - peptides have a similar
    structure, bind adequately to MHC gp, but make
    too weak or too strong interaction with T cells
  • Antagonists induce anergy of T cells

43
REGULATION MEDIATED BY ANTIBODIES
  • Antibodies have an effector and regulatory
    functions
  • Secreted antibodies compete with BCR for
    antigen negative regulators of B cells
    stimulation
  • Immune complexes of antibody and antigen bind
    to the surface of B cells interaction of
    signaling molecules (protein-kinases,
    protein-phosphatases) inhibit B cells
    activation ( antibody feedback)

44
REGULATION MEDIATED BY CYTOKINES AND
INTERCELLULAR CONTACT
  • Inhibition of cytokine effect by endocytosis of
    their receptors or by binding of inhibitors to
    their receptors
  • Inhibitory receptors protection against too
    easy T cells activation
  • Apoptotic receptor (Fas) mediates a negative
    regulation after binding to ligand FasL on
    activated T cells causes lysis of cell

45
NEGATIVE REGULATION mediated by T lymphocytes
  • Th2 cells produce IL-4, IL-10- suppress immune
    response of Th1 cells
  • Suppression of T cells occurs after recognition
    an antigen on cells different from APC (missing
    of co-stimulating signals)
  • CD8 T cells secrete soluble forms of TCR -
    compete with TCR on the surface of other cells-
    inhibition
  • Regulatory Tr1 cells (CD4)- secrete
    IL-10-anti-inflammatory effect, induce tolerance
    to autoantigens

46
NEUROENDOCRINE REGULATION
  • Neurotrasmiters influence leukocytes by binding
    to the specific receptors (noradrenalin)
  • CS, growth hormons, thyroxin, endorfins
    influence the leukocytes by binding to the
    specific receptors
  • Leukocytes produce endorfins, TSH, growth hormon,
    vitamin D3, ACTH
  • Cytokines influence nerve system (IL-1, IL-6)
  • Stress influences immune system-
    cortocosteroids-activity of phagocytes, NK cells

47
OTHER FACTORS
  • The same antigen can induce active immune
    response or active tolerance depends on
  • Condition of immune system
  • Character of antigen (size, structure of
    molecule)
  • Dose of antigen (too low or too high doses-induce
    tolerance)
  • Route of antigen administration (s.c.-induce
    immune response, p.o. or i.v.- induce tolerance)

48
32. HLA system, genetic background. HLA typing.
49
MHC (major histocompatibility complex)
  • human MHC HLA (human leukocyte antigens)
  • Genes of MHC complex are codominantly expressed
    alleles inherited from both parents are
    expressed equally are polymorphic many
    different alleles are present

50
Contain of MHC complex
  • MHC gp are encoded by genes localized on short
    arm of human 6. chromosome
  • The MHC locus- contains 4 single blocks of loci
  • - HLA Ags I are encoded by loci A, B, C
  • - HLA Ags II locus D
  • - HLA Ags III locus between HLA I a II
    (contains genes with nondirected participation in
    histocompatibility- genes for complement, TNF)

51
Polymorphism of MHC gp
  • A lot of different forms of alleles (of each
    isotype) exist in the population
  • Forms of alleles differ in 1 or more amino acids
    in their binding-site for peptide
  • Importance of polymorphism
  • - positive allows to bind a lot of types of
    peptides
  • - negative complicates transplantation

52
MHC gp
  • The MHC was discovered as the genetic locus that
    is the principal determinant of acceptance or
    rejection of tissue grafts exchanged between
    individuals.
  • Individuals that are identical at their MHC locus
    will accept grafts from one another
  • Individuals that differ at their MHC loci will
    reject such grafts

53
Function of MHC gp
  • Physiologic function of MHC molecules is to
    display peptides derived from protein antigens to
    antigen- specific T lymphocytes
  • bind peptides
  • transport peptides to the cell surface
  • display peptides to T lymphocytes

54
Classification of MHC gp
  • MHC gps class I
  • - display intracellular proteins to CD8 T
    lymphocytes
  • MHC gps class II
  • - display extracellular proteins to CD4 T
    lymphocytes

55
HLA typing
  • The combination of class I and class II antigens
    expressed by a person is called his/her HLA
    phenotype.
  • The combination of class I and class II alleles
    is the HLA genotype. In most cases, the genotype
    reflects the phenotype.

56
HLA typing
  • HLA typing identifies a person's HLA type and,
    therefore, helps to characterize the immune
    function of that person.
  • Different loci and different levels of resolution
    are required for different clinical applications

57
HLA typing
  • HLA typing is routinely used for
  • matching donors and recipients in solid organ or
    hematopoietic stem cell transplantation
  • helping in the diagnosis of certain autoimmune or
    anti-inflammatory diseases
  • determining eligibility of patients to tumor
    vaccination protocols when the vaccine is
    HLA-allele dependent

58
HLA typing
  • The peripheral blood lymphocytes from the
    indiviual are incubated with antibodies that are
    known to react with specific HLA molecules and
    complement.
  • If there is lysis of the cells, that individual
    carries the HLA protein recognized by that
    specific antibody.

59
HLA typing
  • Molecular techniques can now be used to type HLA
    molecules.
  • PCR using primers that amplify only certain HLA
    sequences allow accurate identification of HLA
    types.
  • This has the advantage of not requiring the
    preparation of live cells from the individual to
    be typed.

60
30. HLA system, 1st class molecules, their
structure andfunction
61
MHC gps Ist class
  • Expressed on all nucleated cells
  • Display intracellular proteins
  • isotypes of clasic HLA Ist class HLA- A,- B,- C
  • isotypes of nonclasic HLA Ist class HLA- E,- F,-
    G
  • molecules at structure similar to MHC gp Ist
    class CD1

62
Structure of MHC gp Ist class
  • 2 polypeptide chains (noncovalent association)
  • - transmembrane chain alfa subunits alfa
    -1,-2,-3
  • - ß2- microglobulin (noncovalent binding)
  • binding site for peptides N-terminal domain
    between subunits alfa 1 and 2

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64
Binding site of MHC molecules Ist class
  • Peptide-binding cleft on the surface floor-
    ß-structure, sides- a-structure
  • binding site is closed - large enough to
    accommodate peptides of 8-10 amino acids
  • a-3 subunit contains the binding site for the T
    cell co-receptor CD8

65
Processing of internalized antigens (MHC gp Ist
class)
  • MHC gps Ist class are synthesized in the ER
  • Proteins can be produced in the cytoplasm from
    viruses inside infected cells, from mutated or
    altered host genes, as in tumors- all targeted
    for destruction by proteolysis
  • Proteins are covalently tagged with small peptide
    called ubiquintin in proteasome- proteins are
    degraded
  • TAP transporters associated with antigen
    processing binds peptides, enters the ER, binds
    to MHC gps class I
  • Complex is transported to the Golgi complex- TAP
    dissociates and complex of MHC gp class I
    peptide is transported to the cell surface and
    recognized by CD8 T lymphocytes

66
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67
31. HLA system, 2nd class molecules, their
structure and function
68
MHC gps II class
  • Expressed on APC (dendritic cells, monocytes,
    macrophages, B lymphocytes)
  • Isotypes HLA-DR,-DQ,-DP
  • Display extracellular peptides to T lymphocytes

69
Structure of MHC gp IInd class
  • 2 transmembrane subunits
  • - transmembrane chain alfa consists of 2
    subunits (alfa 1 a 2)
  • - transmembrane chain beta consists of 2
    subunits (beta 1 a 2)
  • - binding-site for peptides N- terminal
    domain between subunits alfa 1 and beta 1

70
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71
Binding-site of MHC gp IInd class
  • Binding-site is opened
  • Cleft is large enough to accommodate peptides
    of 15-35- amino acids
  • ß- 2 domain contains binding-site for the T cell
    co-receptor CD4

72
Processing of internalized antigens (MHC gp IInd
class)
  • MHC gps II are synthesized in endoplasmic
    reticulum carry with invariant chain that
    contains a sequence CLIP binds to the peptide
    binding cleft- transport vesicle
  • The microbial proteins enter intracellular
    vesicles (endosomes) proteins are broken down
    by enzymes
  • Endosome fuses with transport vesicle CLIP is
    removed the cleft accepts the peptide, MHC gps
    IInd class and peptide are transported to the
    cell surface where are recognized by CD4 T cells

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74
MHC restriction
  • T lymphocytes recognize a foreign peptide antigen
    only when it is bound to MHC gp

75
Nonclasic MHC gps I class
  • expressed only on some cells
  • Specialize to binding of specific ligands
  • HLA-G is expressed on the surface of trophoblast
    cells
  • complexes HLA-E,-G with peptides are recognized
    by inhibitory receptors of NK cells induce
    tolerance of fetus in uterus
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