Physiological mechanisms of regulation of the immune system

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Physiological mechanisms of regulation of the
immune system
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Regulation by antigen

• Induce immune responses and extinction
• Affinity maturation of B lymphocytes
• Maintaining immunological memory
• Antigenic competition
• Threshold density of the complex MHC II-gp Ag on
  APC

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Regulation by antibodies

• Antibodies competes with the BCR for antigen
  (negative regulator of B lymphocyte stimulating)
  
• IgG immune complexes bind to the BCR and FcgR on
  B cells, resulting in blocking activation of B
  lymphocytes
• Regulation via idiotypic network

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Regulation by cytokines and cellular contact

• Interaction APC - T lymphocyte
• Interaction TH1 macrophages
• Interaction TH2 - B lymphocytes
• Mutual regulation of activity TH1 versus TH2
• Development of leukocyte subpopulations

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Regulation by cytokines and cellular
contactInteraction between APC and T cell

• T cellTCR - antigen-specific receptor
• CD4 or CD8 - coreceptor (MHCgp binding)
• CD 28 - costimulatory receptor (binds CD 80, CD
  86)
• CTLA-4 - inhibitory receptor (binds CD 80, CD 86)

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Regulation by cytokines and cellular
contactInteraction between TH1 and TH2 cells
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Negative regulation of effector cells

• CTLA-4 - T cell inhibitory receptor, binds
  ligands CD80 and CD86
• Self-destruction interaction of the apoptotic
  receptor Fas with ligand FasL on the surface of
  activated T lymphocytes
• Inhibitory receptors of NK cells

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Suppression mediated by T lymphocytes

• Mutual negative interaction TH1 and TH2
  cytokine-mediated
• Clonal elimination or anergy of T lymphocytes
  after contact with antigen on the surface of
  other cells than APC
• Regulatory T cells (Treg, Tr1, Th3 - CD 4) help
  to maintain tolerance to autoantigens produce
  TGFb, IL-10

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Factors influencing the outcome of the immune
response

• The same antigen can induce an active immune
  response or an active state of tolerance, the
  result of response depends on many factors
• State of the immune system
• Properties of antigen
• Dose of antigen
• Route of antigen administration

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Cytokines (Tissue hormones)
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Cytokines

• Regulatory proteins and glycoproteins produced by
  leukocytes and other cells
• Essential regulators of the immune system
• Apply also outside the immune system
  (angiogenesis, tissue regeneration,
  carcinogenesis, treatment of many brain
  functions, embryonic development ...)
• Cytokines - secreted      - membrane
  (CD 80, CD86, CD40L, FasL ..)

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Cytokines

• Pleiotropic effect
• Operates in a cascade
• Cytokine network
• Cytokine system is redundant
• Effects of cytokines - autocrine
  - paracrine - endocrine
• Are known as interleukins (IL-1IL-38)(except
  TNF, lymphotoxin, TGF, interferons, CSF and
  growth factors)

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B cells communicate via cytokines with other
cells, such as T cells and macrophages
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Overview of the most important cytokines
Cytokine Produced Function
IL-1 MF, N T cell costimulation, induction of TNF and IL-8, pyrogen
IL-2 Th1 Growth factor for T cells
IL-4 Th2, basophils Th2 differentiation, B cell stimulation, isotype switching to IgE and IgG4, Th1 inhibition
IL-5 Th2, eosinophils B cell stimulation, growth factor for eosinophils
IL-6 Th2, MF, N T and B cell stimulation, stimulation of Ig production, induction of acute phase proteins synthesis, pyrogen
IL-8 MF, other cells Granulocyte activation and chemotaxis (primarily neutrophils)
IL-10 Th2,M, Treg Th1 and MF inhibition, B cell differentiation to plasma cell
IL-12 MF, DC, B Th1 differentiation, NK stimulation
TNF M, MF, NK Induction of local inflammation, endothelium activation, induction of apoptosis
TGFb T, MF, platelets The anti-inflammatory effect (control of lymphocyte proliferation, control of Ig production, control MF activity), stimulation of fibroblasts and osteoblasts, gain production of extracellular matrix
IFNa L, M, MF Inhibition of viral replication
IFNb Fibroblasts, epithelial cells Inhibition of viral replication
IFNg Th1, NK MF activation, stimulation of MHC gp. expression, Th2 inhibition
MF macrophages M monocytes N neutrophils
DC dendritic cells NK natural killers L
lymphocytes B B cell T T cell
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Clasification of cytokines by functions

• Proinflammatory cytokines (IL-1, IL-6,IL- 8,IL-
  12,IL- 18, TNF)
• Antiinflammatory cytokines (IL-4, IL-10, TGF?)
• Cytokines with the activity of hematopoietic
  cells growth factor (IL-2, 3, 4, 5, 6, 7, 9,
  11, 14, 15, CSF, SCF, LIF, EPO)
• Cytokines applying in TH2 humoral immunity (IL-4,
  5, 9, 13)
• Cytokines applying in the cell-mediated immunity
  TH1 (IL-2, 12, IFN?, GM-CSF, lymphotoxin)
• Cytokines with anti-viral effect (IFN-?, IFN-??,
  IFN- ?)

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Cytokine receptors

• Consisting of 2 or 3 subunits
• One subunit binds cytokine, other are associated
  with cytoplasmic signaling molecules (protein
  kinases)
• Signaling subunit is shared by several different
  cytokine receptors - called receptor family
• Signaling through these receptors may lead to
  proliferation, differentiation, activation of
  effector mechanisms or blocking the cell cycle
  and induction of apoptosis

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Possibilities of therapeutic affecting of the
immune system
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Causal treatment

• a) Stem cell transplantation    
• treatment of severe congenital disorders of the
  immune system and some lymphoproliferative and
  myeloproliferative disorders
• complications infectious complications
                      Graft-versus-host disease
• obtaining stem cells - from bone marrow
                               - from umbilical
  cord blood                              - from
  peripheral blood

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Causal treatment

• b) Gene therapy
• transduction of the missing gene to hematopoietic
  stem cells using viral vectors
• used as a treatment for 2 forms of SCID

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Substitution treatment

• autologous stem cell transplantation (following
  chemotherapy and radiotherapy)
• treatment with intravenous immunoglobulin
  (derived from plasma of blood donors)
• substitution of C1 inhibitor for hereditary
  angioedema
• substitution of erythropoietin in patients with
  chronic renal failure
• substitution of G-CSF in agranulocytosis

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Immunomodulation

• medical procedure to adjust the disrupted
  immune function
• Non-specific immunosuppression
• nonspecific affects not only autoreactive and
  aloreactive                        lymphocytes,
  but also other components of
  immunity (risk of reduction antiinfectious and
  antitumor immunity)
• used for treatment of autoimmune diseases, for
  organ transplantation and severe allergic
  conditions

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Non-specific immunosuppression

• Corticosteroids
• anti-inflammatory, immunosuppressive effects
• suppress the expression of some genes (IL-2,
  IL-1, phospholipase A, MHC gp II, adhesion
  molecules)
• inhibition of histamine release from basophils
• higher concentrations induce apoptosis of
  lymfocytes

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Non-specific immunosuppression

• Immunosuppressants affecting the metabolism
  of DNA (cytostatics)
• cyclophosphamide (alkylating agent)
• methotrexate (antimetabolite)
• azathioprine (purine analogue)
  

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Non-specific immunosuppression

• Immunosuppressant selectively inhibiting
  T cells
• immunosuppressive ATB cyclosporine A,
  tacrolimus, rapamycin (suppressing the
  expression of IL-2 and IL-2R in activated T
  lymphocytes)
• anti-CD3 monoclonal antibody (imunosuppression
  after transplantation, treatment of
  rejection crises)

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Non-specific immunosuppression

• Immunoglobulins in the immunosuppressive
  indication
• polyspecific intravenous immunoglobulins
• inhibition of B lymphocytes
• antiidiotype activity
• inhibition of cytokines
• neutralization of toxins
• inhibition of complement activation

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Anti-inflammatory and antiallergic treatment

• nonsteroidal anti-inflammatory drugs
• antihistamines - blocking H1 receptor
                            - reduce the
  expression of adhesion molekules
                            - reduce the
  secretion of histamine ...
• inhibitors of inflammatory cytokine -
  monoclonal antibodies against TNF
                            - thalidomide
  (TNF inhibitor)
• Anti IgE antibodies (omalizumab)
• - severe allergic
  astma

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Non-specific immunostimulant therapy

• synthetic immunomodulators
• Methisoprinol (Isoprinosine) - used in viral
  infections with more
  severe or relapsing course
• bacterial extracts and lysates
• Broncho-Vaxom - prevention of recurrent
  respiratory tract infections
• Ribomunyl
• products of the immune system
• IL-2 - renal adenocarcinoma
• IFNa, IFNb - viral hepatitis, some leukemia
• Erythropoietin renal failure
• G-CSF, GM-CSF neutropenia
• Transfer factor (blood donors leukocytes
  undergoing dialysis)
• Thymus hormones              

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Antigen-specific immunomodulation

• specific immunomodulation induce of an immune
  response or tolerance to a specific antigen
• active immunization
• passive immunization
• specific immunosuppression

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Antigen-specific immunomodulation

• Active immunization (vaccination) the induction
  of immunity after exposure to an antigen
• activates specific cellular and humoral immunity
• creates long-term immunity (memory cells)
• protect against a pathogen bearing this
  antigen or similar antigen (prophylaxis)

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Antigen-specific immunomodulation

• active immunization (vaccination)
• vaccines are made from inactivated or attenuated
  microorganisms or their antigens (polysaccharide
  capsule, toxins)
• attenuated vaccines cannot be used by
  immunocompromised individuals
• risk of infection or anaphylactic reactions

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Antigen-specific immunomodulation

• Passive immunization
• natural - transfer of maternal antibodies in
  fetal blood
• therapeutically - the use of animal antibodies
  against various toxins
  (snake toxins, tetanus toxin, botulinum toxin)
• prophylaxis - the human immunoglobulin from
  immunized individuals
  (hepatitis A, rabies, tetanus)
•                     - Anti-RhD antibodies
  prevent immunization of mother
  with RhD
  fetus erythrocytes
• provides a temporary (3 weeks) specific humoral
  immunity
• the risk anaphylactic reactions

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Antigen-specific immunomodulation

• Specific immunosuppression induction of
  tolerance to a specific antigen
• induction of tolerance by oral administration of
  antigen (treatment of certain autoimmune
  diseases)
• allergen immunotherapy (pollen, insect poisons)
• Vaccination against cancer
• immunization by dendritic cells

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Antiinfection immunity
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Defence against extracellular pathogens

• bacteria (gram-negative, gram-positive cocci,
  bacilli), unicellular parasites
• pathogens induce inflammation
• removed by phagocytosis - neutrophil granulocytes
  
• opsonization (IgG and IgA antibodies, C3b,
  lectins, CRP...)

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Defence against extracellular pathogensOpsonisati
on and phagocytosis
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Defence against extracellular pathogens

• Phagocytes are attracted to the site of infection
  by chemotactic substances (C5a, C3a and
  chemotactic products of bacteria)
• ingested bacteria are destroyed by the
  microbicidal systems (products of NADP-H
  oxidase, hydrolytic enzymes and bactericidal
  substances in lysosomes)
• phagocytes produce proinflammatory cytokines
  (IL-1, IL-6, TNF)

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Defence against extracellular pathogens

• IgM - complement activation
• IgG - complement activation, opsonization
• IgA - opsonizationsIgA prevents against
  infection by intestinal and respiratory bacteria
• in the defense against bacterial toxins apply
  neutralizing antibodies (Clostridium tetani and
  botulinum )

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Defence against extracellular pathogens

• "indirect toxins - bacterial Lipopolysaccharide
  (LPS) stimulates big number of monocytes to
  release TNF, which can cause septic shock
• individuals with immunodeficiency of phagocytes,
  complement and antibodies production are
  especially at risk of infections with
  extracellular bacterial

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Defense against intracellular pathogens
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Defense against intracellular pathogens

• bacteria, fungi and unicellular parasites
• intracellular parasites are resistant to the
  microbicidal mechanisms of phagocytes
• macrophages, which absorbed them, produce IL-12 ?
  TH1 differentiation, production of IFNg and
  membrane TNF ? activation of macrophages and
  production of NO

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Defense against intracellular pathogens
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Defense against intracellular pathogens

• TC lymphocytes apply in the defense against
  intracelular parasites, which escape from
  phagolysosomes
• individuals with certain disorders of phagocytes
  and defects of T lymphocytes are at risk of
  infections with intracellular microorganisms

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Defense against intracellular pathogens
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Anti-viral defense
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Anti-viral defence

• interferons - production of IFNa and IFNb is
  induced in infected cells IFNg activates
  macrophages (iNOS)
• IFNa and IFNb - prevents viral replication
• - induce proliferation of NK cells
• - increase the expression of HLA-I

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Anti-viral defence - interferons
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Anti-viral defence

• NK cells - ADCC (Antibody-dependent cell-mediated
  cytotoxicity) NK cell bind with CD16 (Fcg
  receptor) to IgG which has bound to the surface
  of infected cell and then NK cell release
  perforins and granzymes (degranulation)
• infected macrophages produce IL-12 (a strong
  activator of NK cells)

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Anti-viral defence - NK cell activation
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Anti-viral defence

• in the defense against cytopathic viruses applied
  antibodies
• sIgA inhibit mucosal adhesion of viruses (defense
  against respiratory viruses and enteroviruses)
• neutralizing IgG and IgM antibodies activate the
  classical pathway of complement, that is able to
  lyse certain viruses
• opsonized viral particles are phagocytosed
• IgA and IgG have preventive effect in secondary
  viral infection

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Anti-viral defence - antibodies
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Anti-viral defence

• effector TC lymphocytes destroy infected cells in
  direct contact (granzym/perforin FasL) and by
  produced cytokines (lymfotoxin)
• some viruses after infection integrate into the
  host genome, where persist for years (varicella
  zoster, EBV, papillomavirus)
• individuals with T lymphocyte immunodeficiency
  and with combined immune disorders are at risk by
  viral infections
• increased susceptibility to herpes infections in
  individuals with dysfunction of NK cells

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Anti-viral defence NK cells and Tc lymphocytes
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Defense against protozoa parasites
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Defense against protozoa parasites

• Toxoplasma gondii, Leishmania, Trypanosoma
• defense against protozoa parasites is similar to
  bacteria
• extracellular parasites - antibodies
• intracellular parasites - TH1 lymphocytes and
  activated macrophages

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Defense against multicellular parasites
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Defense against multicellular parasites

• IgE, mast cells, basophils and eosinophils
• TH2 stimulation under the influence of IL-4 (mast
  cells and other APC stimulated by parasite)
• TH2 stimulate B cells with BCR-specific parasite
  antigens
• isotype switching under the influence of IL-4 to
  IgE
• IgE bind to FceRI on mast cells and basophils

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Defense against multicellular parasites

• multicellular parasite binds to IgE on mast cell?
  cross-linking of several molecules Fc?RI
• initiate mast cell degranulation (release of
  histamin, tryptase, serotonin)
• activation of arachidonic acid metabolism
  (leukotriene C4, prostaglandin PGD2) -
  amplification of inflammatory responses
• cytokine production by mast cell (TNF, TGF?,
  IL-4, 5, 6)

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Defense against multicellular parasites

• Histamine
• vasodilatation, increase vascular permeability
  (erythema, edema, itching)
• bronchoconstriction (cough)
• increases intestinal peristalsis (diarrhea)
• increased mucus secretionThis helps eliminate
  the parasite.

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Mast cell activation
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Defense against multicellular parasites

• eosinophils fagocyte complexes of parasitic
  particles with IgE via their receptors for IgE
• eosinophils use against parasites extracellular
  bactericidal substances released from granules
  (ECP- eosinophil cationic protein, MBP-major
  basic protein)

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Defense against multicellular parasites -
eosinophils
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Thank you for your attention
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