Download External regulation of immune response

Antiinfection immunity
J. Ochotná
Defence against
extracellular pathogens
Defence against extracellular pathogens
• Neutrophils
• Opsonins (C3b, IgG, lectins, CRP, SAP…)
• Antibodies (IgM, IgG, IgA)
Defence against extracellular pathogens
 bacteria (gram-negative, gram-positive cocci, bacilli),
unicellular parasites
 neutrophilic granulocytes are attracted to the site of the
infection by chemokines (C5a, C3a and chemotactic products
of bacteria)
 phagocytes recognized pathogens via PRR and receptor for
opsonins
Opsonization
Defence against extracellular pathogens
• absorbed 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) that induce an increase in temperature,
metabolic response of the organism and synthesis of
acute phase proteins
Defence against extracellular pathogens
 IgM (complement activation, neutralization)
 IgG (complement activation, opsonisation,
neutralization)
 sIgA protect against intestinal and respiratory infections
by bacteria
 after infection persist IgG, IgA (protective effect) and
memory T and B lymphocytes
Defence against extracellular pathogens
 bacteria with a polysaccharide capsule may cause
T-independent IgM antibody production (after the establishment to
the bacteria activate the classical complement path)
 in the defense against bacterial toxins apply neutralizing antibodies
(Clostridium tetani and botulinum ...)
 "indirect toxins - bacterial Lipopolysaccharide (LPS) stimulates big
number of monocytes to release TNF, which can cause septic shock
Defence against extracellular pathogens
 individuals with disorders in the function of phagocytes,
complement and antibody production are especially at
risk extracellular bacterial infections
Defence against
intracellular pathogens
Defense against intracellular pathogens
• Macrophages activated by TH1 cells
• Cytotoxic T cells
Defense against intracellular pathogens
 certain 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 induction of iNOS
Defense against intracellular pathogens
Defense against intracellular pathogens
 in the defense against intracelular parasites, which
escape from phagolysosomes apply TC lymphocytes
 intracellular microorganisms infections are at risk
individuals with certain disorders of phagocytes and
defects of T lymphocytes
Defense against intracellular pathogens
Anti-viral defence
Anti-viral defence
• Interferons (IFNa, IFNb)
• NK cells
• Cytotoxic T cells
• Antibodies (IgM, IgG, IgA)
Anti-viral defence
 interferons : production of IFNa and IFNb is induced in
infected cells (prevent viral replication in uninfected
cells); IFNg activates macrophages (iNOS)
Anti-viral defence
• Interferons:
• The antiviral effect
• NK cells stimulation
• Increase the expression of HLA I → enhance the
presentation to cytotoxic T cells
Anti-viral defence
• Viral-infected cell can be recognized by NK cell
• Natural killer cell activation depends on the balance
of inhibitory and activating receptor stimulation
Anti-viral defence
ADCC (Antibody-dependent cell-mediated cytotoxicity)
Antibodies that bind to antigens can be recognised by
FcϒRIII (CD16) receptors expressed on NK cells,
resulting in NK activation, release of cytolytic granules
and consequent cell apoptosis.
Anti-viral defence
• Effector cytotoxic T cells destroy infected cells in
direct contact (granzym/perforin; FasL) and by produced
cytokines (lymfotoxin)
Anti-viral defence
Anti-viral defence
 in the defense against cytopathic viruses mostly applied
antibodies:
 sIgA inhibit mucosal adhesion of viruses (defense
against respiratory viruses and enteroviruses)
 neutralizing IgG and IgM antibodies activate
the classical way of complement, which is capable
of some viruses lysis
 IgA and IgG derived in viral infection have
a preventive effect in secondary infection
Anti-viral defence - antibodies
Anti-viral defence
 some viruses after infection integrate into the host genome,
where persist for years (varicella zoster, EBV, papillomavirus)
 by these infections are at risk individuals with T lymphocyte
immunodeficiency and with combined immune disorders
 increased susceptibility to herpes infections in individuals with
dysfunction of NK cells
Defense against
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
• Mast cells
• Basophils
• Eosinophils
• IgE antibodies
Defense against multicellular parasites
 contact of mast cells, basophils and eosinophils with
parasite antigens
 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 binds to FceRI on mast cells and basophils
Defense against multicellular parasites
 establish of multivalent antigen (multicellular parasite)
using the IgE to highafinity Fc receptor for IgE (FceRI)
aggregation of several molecules FceRI
 initiate mast cell degranulation (cytoplasmic granules
mergers with the surface membrane and release their
contents) - histamine
 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 helps eliminate the parasite, causes:
 vasodilation, increased vascular permeability →
erythema, edema, itching
 increased mucus secretion in the respiratory tract
and GIT
 contraction of bronchial smooth muscle
 increases intestinal peristalsis
Activation of mast cell
Defense against multicellular parasites
 eosinophils use against parasites extracellular
bactericidal substances released from granules
(eosinophil cationic protein, protease)
 eosinophils fagocyte complexes of parasitic particles with
IgE via their receptors for IgE
External regulation of
immune response
Causal treatment
a) Stem cell transplantation
 for serious congenital disorders of the immune system and some
lymphoproliferative and myeloproliferative disorders
 complications: infectious complications
Graft-versus-host disease
 obtaining stem cells - collection from shovel hip bone
- from umbilical cord blood
- from peripheral blood after stimulation
with GM-CSF
b) Gene therapy
 with a suitable expression vector is introduced functional
gene (to replace dysfunctional gen) into the lymphocytes
or stem cells
 used as a treatment for some cases 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 immunosuppressive therapy
 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, severe allergic
conditions and for organ transplantation
Non-specific immunosuppressive therapy
 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 immunosuppressive therapy
• immunosuppressants affecting the metabolism of
DNA
- cyclophosphamide (alkylating agent)
- methotrexate (antimetabolite)
- azathioprine (purine analogue)
Non-specific immunosuppressive therapy
 immunosuppressant selectively inhibiting T lymphocytes
- immunosuppressive ATB: cyclosporine A, tacrolimus,
rapamycin (suppressing the expression of IL-2 and
IL-2R in activated T lymphocytes)
- monoclonal antibody anti-CD3 (Immunosuppression
after transplantation, treatment of rejection crises)
Non-specific immunosuppressive therapy
• 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
molecules
- reduce the secretion of histamine ...
 inhibitors of inflammatory cytokine
- receptor antagonist for IL-1
- monoclonal antibodies against TNF
- thalidomide (TNF inhibitor)
 enzyme therapy - in the enzyme mixture has a major
effect trypsin and bromelain
- anti-inflammatory
and immunomodulatory effects
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 immunomodulatory
therapy
 specific immunomodulation = induce an immune
response or tolerance against a specific antigen
A) active immunization
B) passive immunization
C) specific immunosuppression
a) active immunization
= induction of immune response after exposure to an
antigen, that can later protect against a pathogen
bearing this antigen (or similar antigen)
 immunization vaccines are made from inactivated
or attenuated microorganisms or their antigens
(polysaccharide capsule, toxins)
 creates long-term immunity
 activates specific cellular and humoral immunity
 administration of antigen injectable or oral
 prophylaxis
 risk of infection or anaphylactic reactions
b) 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 - preventing
maternal immunization with RhD+ fetus
 provides a temporary (3 weeks) specific humoral
immunity
 the risk anaphylactic reactions
c) specific immunosuppression
= induction of tolerance to a specific antigen
 ongoing clinical studies
 induction of tolerance by oral administration of
antigen (treatment of certain autoimmune
diseases)
 allergen immunotherapy (pollen, insect poisons)
d) vaccination against cancer
 immunization by dendritic cells
Thank you for your attention
• Phagocytosis
http://www.youtube.com/watch?v=7VQU28itVVw
http://www.youtube.com/watch?v=r4-g6tVyUAU
• NK cells
http://www.youtube.com/watch?v=HNP1EAYLhOs
• Tc
http://www.youtube.com/watch?v=4_e93zRSHco
• Mast cells and eosinophils
http://www.youtube.com/watch?v=MWh-zig8liE
http://www.youtube.com/watch?v=gafekFEbUg4