Download Cytokines

Physiological mechanisms
of regulation of the immune
system
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
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
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
Regulation by cytokines and cellular contact
Interaction between APC and T cell
T cell:
TCR - 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)
Regulation by cytokines and cellular contact
Interaction between TH1 and TH2 cells
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
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
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
Cytokines
(Tissue hormones)
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 ..)
Cytokines
 Pleiotropic effect
 Operates in a cascade
 Cytokine network
 Cytokine system is redundant
 Effects of cytokines- autocrine
- paracrine
- endocrine
 Are known as interleukins (IL-1…IL-38)
(except: TNF, lymphotoxin, TGF, interferons, CSF and growth factors)
B cells communicate via cytokines with other cells,
such as T cells and macrophages
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
Clasification of cytokines by functions
 Proinflammatory cytokines (IL-1, IL-6,IL- 8,IL- 12,IL- 18, TNF)
 Antiinflammatory cytokines (IL-4, IL-10, TGFb)
 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, IFNg, GM-CSF, lymphotoxin)
 Cytokines with anti-viral effect (IFN-a, IFN-b , IFN- g)
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
Possibilities of therapeutic
affecting of the immune
system
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
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
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
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
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
Non-specific immunosuppression
Immunosuppressants affecting the metabolism
of DNA (cytostatics)
• cyclophosphamide (alkylating agent)
• methotrexate (antimetabolite)
• azathioprine (purine analogue)
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)
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
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
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
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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
Antigen-specific immunomodulation
 specific immunomodulation = induce of an immune
response or tolerance to a specific antigen
• active immunization
• passive immunization
• specific immunosuppression
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)
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
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
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
Antiinfection immunity
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...)
Defence against extracellular pathogens
Opsonisation and phagocytosis
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)
Defence against extracellular pathogens
 IgM - complement activation
 IgG - complement activation, opsonization
 IgA - opsonization
sIgA prevents against infection by intestinal and respiratory bacteria
 in the defense against bacterial toxins apply neutralizing
antibodies (Clostridium tetani and botulinum …)
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
Defense against
intracellular pathogens
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
Defense against intracellular pathogens
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
Defense against intracellular pathogens
Anti-viral defense
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
Anti-viral defence - interferons
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)
Anti-viral defence - NK cell activation
ADCC
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
Anti-viral defence - antibodies
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
Anti-viral defence – NK cells and Tc lymphocytes
Defense against protozoa
parasites
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
Defense against
multicellular parasites
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
Defense against multicellular parasites
 multicellular parasite binds to IgE on mast cell→ crosslinking of several molecules FceRI
 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, TGFb, IL-4, 5, 6)
Defense against multicellular parasites
Histamine
 vasodilatation, increase vascular permeability (erythema,
edema, itching)
 bronchoconstriction (cough)
 increases intestinal peristalsis (diarrhea)
 increased mucus secretion
This helps eliminate the parasite.
Mast cell activation
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…)
Defense against multicellular parasites - eosinophils
Thank you for your attention
• Phagocytosis
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