Immune system

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Immune system
J. Ochotná
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The main functions of the immune systemImmune
system belongs to the basic homeostatic
mechanisms Defense - identification and
protection against pathogenic microorganisms and
their toxinsAutotolerance recognition of own
tissues and keeping tolerance to themImmune
surveillance - identifying and removing the old ,
damaged and otherwise changed cells
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Antigen (immunogen) substance that the immune
system recognizes and responds to it
usually proteins or polysaccharides (lipids and
nucleic acids only in the combination with
proteins or polysaccharides) Molecules lt5
kDa cant trigger an immune response, the
optimal size of the antigen molecules to initiate
immune response is about 40 kDa
autoantigen - antigen derived from his own body
exoantigen - alien substance from the external
environment allergen - exoantigen that in
susceptible individuals may
cause pathological (allergic) immune response
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Haptens small molecules, that are able to
induce specific immune response only after
the establishment to the macromolecular
carrier (separate haptens are not
immunogenic) typically drugs (eg penicillin
antibiotics, hydralazin)
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Interaction antigen antibody Binding
site of antibody (paratop) form non-covalent
complexes with the corresponding part on
antigen molecule (epitope) participation
the hydrogen bonds, electrostatic and
hydrophobic interactions, van der Waals forces
antigen-antibody complex is reversible
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Types of antigens according to antigen
presentation1) thymus dependent antigens
more frequently, mostly protein Ag for
specific humoral immune response to antigen is
necessary to cooperate with TH lymphocytes (or
response isnt enough effective) assistance
implemented in the form of cytokines produced
by TH lymphocytes
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Types of antigens according to antigen
presentation2) thymus independent antigens
in a small number of antigens can be induced
antibodies production directly without the
participation of T lymphocytes this are mainly
a bacterial polysaccharides,
lipopolysaccharides and polymer forms of proteins
(e.g. Haemophilus, Str.pneumoniae)
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Superantigens stimulate lymphocytesa
polyclonaly and massively massive activation
of T lymphocytes can cause shock e.g.
bacterial toxins (Staph.aureus, Str.pyogenes,
Pseud.aeruginosa)
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Sequestered antigens autoantigens that are
normally hidden from the immune system and
therefore unknow (e.g. the lens of the eye ,
testes,brain) if they are "uncovered" by
demage, can induce the immune response (one
of the theories of autoimmune processes)
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Components of the immune system
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Components of the immune system Lymphoid
tissues and organs Cells of the immune
system Molecules of the immune system
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Lymphoid tissues and organs are linked with
the other organs and tissues by network of
lymphatic and blood vessels Primary lymphoid
tissues and organs bone marrow, thymus
place of maturation and differentiation of
immunocompetent cells immature lymphocytes
acquire here their antigenic specificity
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Secondary lymphoid tissues and organs meeting
place of immunocompetent cells with Ag spleen -
in contrast to the lymph nodes filter the blood
and captures presented antigenslymph nodes and
their organized clusters (tonsils, appendix,
Peyer patches in the intestine) - filter lymph
and capture present antigens MALT (mucous
associated lymphoid tissue) - diffuse lymphatic
tissue, the main role is capture of antigens that
penetrate through the mucous membrane
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Cells of the immune system evolution of red
and white blood cells begin at yolk sack,
then haematopoiesis travels to fetal liver and
spleen (3 to 7 month gestation), the main
hematopoietic function has bone marrow
all blood cells arise from a pluripotent stem
cell (CD 34) stem cells self-renew and
maintain throughout life haematopoiesis is
regulated by cytokines that are secreted by
bone marrow stromal cells, activated TH cells
and macrophages
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Immune mechanisms
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Nonspecific immune mechanisms non-adaptive,
innate evolutionarily older no
immunological memory in the presence of
pathogens react quickly, in minutes (based on
molecules and cells which are in the body
prepared in advance) component cellular -
phagocytes (some are APC), NK cells
humoral - complement, interferons,
lectins
and other serum proteins
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Specific immune mechanisms adaptive,
antigen-specific evolutionarily younger
have immunological memory development of a
full-specific immune response takes several
days even weeks component cellular - T
lymphocytes (TCR) humoral
- antibodies
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Mucosal and skin immune system
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Function and structure of the mucosal and skin
immune systemMucous membranes and skin are in
constant contact with the outside environment,
there is concentrated about 80 of
immunocompetent cells.Skin - barrier against
mechanical, physical and chemical damage, and
against the penetration of microorganisms, humans
surface of about 1,5 m2 Mucosal immune system
- prevents the penetration of pathogenic
microorganisms, preventing the development of
self-harm inflammatory immune responses against
pathogens and harmless antigens from the external
environment, mucosa with an area of about 400 m2
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Natural non-immune protective mechanismsIn
protection the body against infection are
important intact mucous membranes and skin and
nonimmune protective mechanisms.mechanical
movement of cilia, air flow in the airways,
or fluid flow in the urinary
tractchemical fatty acids on skin lysozyme
in saliva, tears and sweat
antibacterial defensins, acid pH
in stomach and urinemicrobial -
non-pathogenic microflora
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Structure of mucosal immune systemMALT (mucous
associated lymphoid tissue) BALT
(bronchus associated lymphoid tissue)
GALT (gut associated lymphoid tissue)
NALT (nasal associated lymphoid tissue)o-MALT
(organized) consists from lymphoid follicles in
the mucous membrane, tonsil and adenoids,
appendix, Peyer patches d-MALT (diffuse) - is
made up of leukocytes diffusely distributed in
the lamina propria (T and B lymphocytes,
macrophages, neutrophils, eosinophils and mast
cells)
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Humoral immune mechanisms of the mucous system
sIgA (secretory immunoglobulin A) most
significant mucosal immunoglobulin, in breast
milk transcytosis - IgA is transported across
the epithelium using transport Fc receptor
(poly-Ig receptor), on luminal side is IgA
split off with the part of the receptor called
secretory component, which protects IgA against
intestinal proteases neutralize antigens
on mucosal surfaces, dont activate
complement, binds to Fc receptors on phagocytes,
in Peyers patches may be immune complexes
with IgA captured and can induce immune
response
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sIgM secretory immunoglobulin M applied in
newborns and in selective IgA deficiency more
prone to intestinal protease degradation
neutralizing antigens on mucosal surfacesIgG
get on the mucous membrane by diffusion
applies particularly in the lower airways
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Induction of mucosal immune response M cells
- specialized enterocytes that provide transport
of Ag (endocyte Ag from the
surroundings) - are in close
contact with lymphocytes and APC mucosal
immunization leads to stimulation of TH2 and TH3
lymphocytes and IgA production
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Induction of mucosal immune response
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• Immune mechanisms of inflammation (Local and
  systemic reactions)

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• Inflammation
• Is a summary of physiological responses to
  breach the integrity of the organism, leading to
  protection against infection of damaged sites,
  localization of damage and healing.
• The first signals to the development of
  inflammatory responses come from mast cells,
  phagocytes, and the substances released from
  damaged cells and extracellular components of
  matter.

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Local response to inflammation - increased
permeability of blood vessels (vasoactive
amines, complement components C3a, C5a,
leukotrienes ..., swelling at site of
inflammation) - increased expression of
adhesion molecules on endothelia - activation
of coagulation, fibrinolytic, kinin and
complement system - influence of local
nerve endings (prostaglandins, pain) - changes
in temperature (IL-1, IL-6, TNF, prostaglandins)

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• Systemic response to inflammation - depends on
  the extent of damage and duration of local
  inflammation - fever (proinflammatory cytokines
  TNF, IL-1, IFN ? stimulate hypothalamic
  center of thermoregulation) - mobilization of
  tissue metabolism - induction of expression of
  Hsp (heat-shock-proteins function as
  chaperones) - production of acute phase
  proteins(CRP, SAP, C3, C4 opsonization and
  complement activation)

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• - increased hepatic synthesis of certain
  serum transport proteins (ceruloplasmin,
  transferrin)
• - increased synthesis of protease inhibitors
  (?? macroglobulin)
• - leukocytosis Septic shock - the massive
  penetration of microorganisms
  into the bloodstream ( ? TNF)
  Anaphylactic shock - basophil degranulation and
  complement
  activation with allergen

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• Repair of damaged tissue
• - elimination of damaged cells with
  phagocytes - activation of fibroplastic
  mechanisms - activation of angiogenesis -
  regeneration and tissue remodeling

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Phagocytosis
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Phagocytosis ability to absorb particles from
the surroundingsProfessional phagocytes
cells, which provide defenses by mechanism of
phagocytosis neutrophilic and eosinophilic
granulocytes, monocytes and
macrophagesgranulocytes - defense against
extracellular pathogens -
able to perform effector functions immediately
- neutrophils dont express
MHCgpII (not APC)macrophages - removal of own
apoptotic cells,
defense against certain intracellular parasites
- fully functional after
activation by cytokines
(IFNg, TNF)
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The intersection of phagocytesin damaged and
infected tissues 7 of peripheral neutrophils
and phagocytes93 neutrophils and phagocytes in
the bone marrow this ratio changes due to
inflammatory cytokines and bacterial
products in place of damage are captured
phagocytes to endothelium (due to
inflammatory cytokine expression of adhesion
molecules is higher) the first is interactions
slows the movement of neutrophils - called
roling,
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then there is a stronger link between
endothelial cells and leukocytes and
subsequent penetration between endothelial
cells to the tissue - diapedesis ,
extravasation phagocytes are directed to the
site of inflammation by chemokines (IL-8,
MIP-1a and b, MCP-1, RANTES, C3a, C5a,
bacterial products ...), for which phagocytes
have receptors
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Receptors on phagocytesPAMPs - "pathogen
associated molecular patterns -
structures that are located on the surface of
microorganisms, but not on their own
intact cells mannose receptor galactose
receptor CD14 (binds bacterial LPS) receptors
of TLR group (binds bacterial lipoproteins,
lipopolysaccharides, bacterial DNA) scavenger
receptors (bind phospholipids on the surface
of apoptotic cells)
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Opsonization - process, which increases the
efficiency of foreign
particles phagocytosis -
the establishment of opsonins (IgG, IgA,
C3b, MBL, fibronectin,
fibrinogen, CRP, SAP)
on the surface of foreign particles Fc
receptors on phagocytes (recognize antibodies
linked to surface of micro-organism)
complement receptors (for binding C3b)
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Liquidation of absorbed organism fusion of
fagosome with lysosomes lysosomes contains -
bactericidal substances (defensins)
- hydrolytic enzymes
(cathepsin, lysozyme)
- liquid with a pH of 4-5 activation of
membrane NADPH oxidase after activation of Fc
receptors and complement receptors, which leads
to respiratory (oxidative) flash, when arise
reactive oxygen intermediates (superoxid
radical O2-, singlet oxygen, hydrogen
peroxide, hydroxyl radical), which damage the
structure of biopolymers, enzymes and DNA of
microorganisms enzyme myeloperoxidase
catalyses the reaction of H2O2 with Cl- to
form chlornan anions (ClO-) creation of nitric
oxide (NO), which produces NO synthase of
macrophages after activation with cytokines
(IFNg, TNF) that are produced by TH1
lymphocytes, NO liquidate intracellular parasites
of macrophages
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Secretory products of phagocytes IL-1, 6, TNF
(systemic response to inflammation) IL-8
(chemokine) IL-3, GM-CSF (control
haematopoiesis) TGFa, TGFb (helping healing of
tissues) metabolic products of arachidonic
acid (prostaglandins, prostacyclin,
leukotrienes and thromboxanes
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Complement
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Complement system of about 30 serum and
membrane proteins (humoral component of
nonspecific immunity) complement components in
serum are present in inactive form complement
activation has cascade character complement
proteins are synthesized in the liver, less by
tissue macrophages and fibroblasts the main
complement components C1-C9 (C3 is the central
component) other complement components
factor B, factor D, factor P regulatory
proteins C1 - inhibitor, factor I, factor H,
DAF, MCP, CR1, CD59 (protektin) inactivator of
anafylatoxin
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Function of complement Opsonization (C3b)
Chemotaxis (C3a, C5a) Osmotic lysis (MAC
C5b-C9) Anafylatoxins (C3a, C4a, C5a)
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Complement activation Alternative pathway
Clasial pathway Lektin pathway
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An alternative pathway C3 component of
complement rarely spontaneously break into C3b
and C3a C3b can covalently bind on the surface
of a particle (own cell, microorganism) or
reacts with water and inactivate to bound C3b
join a factor B, which is cleaved by factor D
to Ba and Bb, resulting complex C3bBb is
stabilized by factor P and functions as an
alternative C3 convertase C3 convertase cleaves
C3 to C3a (chemotactic for phagocytes) and
C3b, which binds to the surface of the
particles (opsonization), or gives rise to other
C3 convertases from some C3 convertases form
C3bBbC3b that act as an alternative C5
convertase, which cleaves C5 to C5a
(chemotaxis) and C5b (starts terminal lytic
phase)
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Classical pathway Can be initiated by
antibodies (IgG, not by IgG4 IgM) or so-called
pentraxins (CRP, SAP - acute phase proteins)
after binding of antibodies to the bacteria
surface, there is a change in its conformation
and C1 protein can bind C1 have to bind to the
2 molecules of antibodies, change their
conformation and get proteolytic activity - will
cleave proteins C4 and C2 fragments C4b and
C2a bind to the surface of organism and create
the classic C3 convertase (C4bC2a), which
cleaves C3 to C3a and C3b then creates a
classic C5 convertase (C4bC2aC3b) that cleaves
C5 to C5a and C5b
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Lektin pathway is initiated by serum mannose
binding lectin (MBL) MBL binds to carbohydrate
structures on the surface of some microbes,
after the bindins starts cleave C4 and C2
this way is similar to the classical way
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Terminal (lytic) phase of the complement
cascadeC5b fragments creates a complex with C6,
C7 and C8, the complex dive into the lipid
membrane of the cell and attached to it into a
circle 13-18 molecules of C9, thus create in the
membrane pores and cell can lysis (G-bacteria,
protozoans, some viruses). Most microorganisms
is to this lytic effect of complement resistant
(protection by cell wall).
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Regulation of complement and protection of own
cells Activation of complement cascade is
controlled by the plasma and membrane
inhibitors. C1 inhibitor DAF
(decay-accelerating protein)-degradation of C3
convertase factor I, MCP (membrane cofactor
protein), CR1, factor H C3b cleavage CD
59 (protectin) - prevents the polymerization of
C9 inactivator of anafylatoxin - inactivates
anafylatoxins (C3a, C4a, C5a)
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Complement receptors Bind fragments of
complement componentsCR1 - on various cells
- removing of immunecomplexesCR2 - on B
lymphocytes and FDC - activation of B
cellsCR3, CR4 - on phagocytes
- participation in opsonization, adhesion