Download T cell-mediated immune response

Defense against pathogens,
possibilities of therapeutic
affecting of the immune system
Martin Liška
Extracellular microorganisms
• Typically bacteria or parasites
• For defense against extracellular microbes
and their toxins, specific humoral immune
response is important
Humoral immune response
• Recognition of antigen by specific Ig, bound i
cell membrane of naive B lymphocyte
• The binding of antigen cross-links Ig receptors of
specific B cells and then biochemical signal is
delivered to the inside B cell; a breakdown
product of the complement protein C3 provides
necessary „second signal“
• Clonal expansion of B cell and secretion of low
levels of IgM
Humoral immune response
• Protein antigens activate CD4+ T helper cells
after presentation of specific antigen
• T helper cells exprime CD40L on their surface
and secrete cytokines → proliferation and
differentiation of antigen-specific B cells,
isotype switching, affinity maturation
Phases of humoral immune
response
Effector functions of antibodies
• Neutralization of microbes (incl.viruses) and
their toxins
• Opsonization of microbec (binding to Fc
receptors on phagocytes; at the same time,
stimulation of microbicidal activities of
phagocytes)
• ADCC (Antibody-dependent cell-mediated
cytotoxicity) – IgG opsonized microb is destroyed
by NK cells after its binding to IC
• Activation of the complement system (classical
pathway)
Defense against extracellular pathogens
(bacteria and unicellular parasites)
a/ non-specific (innate) immune system
- monocytes/macrophages, neutrophils,
complement system, acute phase proteins
(e.g.CRP)
b/ specific (adaptive) immune system
- antibodies (opsonization, neutralization)
Defense against multicellular
parasites
• Production of IgE → coating and
opsonization of parasites
• Activation of eosinophils - they recognize
Fc regions of the bound IgE, then they are
activated and release their granule contents,
which kill the parasites
• Th2-lymphocytes support this type of
immune response
Intracellular microorganisms
• Initially: non-specific immune response (ingestion
by phagocytes)
• Some microorganisms are able to survive inside
phagocytes (e.g. some bacteria, fungi, unicellular
parasites, viruses) – they survive inside
phagosomes or enter the cytoplasm and multiply
in this compartment
• The elimination of these microorganisms is the
main function of T cells (specific cell-mediated
response)
Processing and presentation of
antigen
• Professional antigen-presenting cells: macrophages,
dendritic cells, B lymphocytes (they express
constitutionally class II MHC)
a/ exogenous antigens – e.g. bacterial,
parasitic, viral (if they are ingested in IC or
during the processing of infected cells)
- hydrolysed in endosomes to linear peptides →
presentation on the cell surface together with class II
MHC to CD4+ T lymphocytes
Processing and presentation of
antigen
b/ endogenous antigens – e.g. autoantigens,
foreign antigens from i.c. parasites or
tumorous antigens
- hydrolysed to peptides → transportation
into ER → in Golgi complex they are
associated with class I MHC →
presentation on the cell surface to CD8+ T
lymphocytes
T cell-mediated immune response
• Presentation of peptides to naive T lymphocytes
in peripheral lymphoid organs → recognition of
antigen by naive T lymphocytes
• At the same time, T lymphocytes receive
additional signals from microbe or from innate
immune reactions → production of cytokines →
clonal expansion → differentiation → effector
& memory cells → effector cells die after
elimination of infection
T cell-mediated immune response
• TCR (T cell receptor) – T cell antigen-specific
receptor
- TCR recognizes (together with co-receptors - CD4
or CD8) the complex of antigen and MHC
- a signal is delivered into the cell through
molecules associated with TCR and co-receptors
(CD4 or CD8) after antigen recognition
T cell-mediated immune response
• APC exposed to microbes or to cytokines
produced as part of innate immune reactions to
microbes express costimulators that are
recognized by receptors on T cells and delivered
necessary „second signals“ for T cell activation
• Activated macrophages kill ingested bacteria by
reactive oxygen intermediates, NO and lysosomal
enzymes
T cell-mediated immune response
• Naive CD4+ T (helper) cells → effector cells
(activation of macrophages for killing of ingested
microbes, activation of B cells for production of
antibodie, activation of other cells)
- Th1 lymphocytes: production of IFN-g, activation
of phagocytes, stimulation of production of
opsonizing a complement binding antibodies;
support defense against i.c. microbes
T cell-mediated immune response
- Th2 lymphocytes: production of IL-4 and
IL-5, stimulation of IgE production,
activation of eosinophils (= defense against
multicellular parasites); they suppress
defense reactions against i.c. microbes
T cell-mediated immune response
• Naive CD8+ T (cytotoxic) lymphocytes →
effector cells (killing of target cells, activation of
macrophages)
- differentiation into CTL – their function is killing
of cells producing cytoplasmic microbial antigens
- Killing the cells mainly by induction of DNA
fragmentation and induction of apoptosis
Mechanisms of resistance of
intracellular microbes to cell-mediated
immune response
• Inhibiting phagolysosome fusion
• Escaping from the vesicles of phagocytes
• Inhibiting the assembly of class I MHCpeptide complexes
• Production of inhibitory cytokines
• Production of decoy cytokine receptors
Defense against intracellular
pathogens (bacteria and unicellular
parasites)
• Intracellular bacteria (Mycobacteria,
Listeria monocytogenes, Legionella
pneumophila), parasites (Cryptococcus
neoformans, Plasmodium falciparum), fungi
(Leishmania, Trypanosoma cruzei)
• Specific immune response is necessary
Anti-viral defense
• Viruses may bind to receptors on a wide
variety of cells and are able to infect and
replicate in the cytoplasm of these cells,
which do not possess intrinsic mechanisms
for destroying the viruses
• Some viruses can integrate viral DNA into
host genome and viral proteins are produced
in the infected cells (e.g. Retroviruses)
Possibilities of therapeutic
affecting of the immune system
• Immunomodulation = therapeutic approach to
modulation of affected immune function
• Based on their effect, we can distinguish following
immunomodulators:
- immunostimulants
- immunosuppressives
- immunomodulators with the complex effect
Immunostimulants
• They stimulate the immune system
• Methisoprinol (Isoprinosine) – used for the
treatment of severe or recurrent viral
infections
• Cytokines – IL-2 (anti-tumour therapy),
colony-stimulating factors (e.g. treatment of
severe granulocytopenia)
Immunosuppressives
• They are used for the treatment of autoimmune or
allergic diseases, in transplantology
• Corticosteroids – anti-inflammatory,
immunosuppressive effect
• Cytostatics, antimetabolites (cyclofosfamide,
methotrexate, cyclosporine A) – lymfocytotoxic
effect
• Monoclonal antibodies – antiCD3
Immunomodulator with the
complex effect
• Bacterial lysates (Broncho-Vaxom,
Ribomunyl)
• Transferfactor
• Antihistamines – esp. 3rd generation
Substitution
• Typically substitution therapy with
intravenous Ig (IVIG) in primary or
secondary hypo- or agamaglobulinemia
• Life-long substitution
• IVIG 200-300 mg/kg every 3 weeks
Active and passive immunization
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a/ active immunization
immunization with vaccines made from killed or
attenuated microorganisms or their products
the immunity is long-lasting
both B cell and T cell based immunity are
activated
injective, oral administration
prophylactic procedure
Active immunization
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DTP (diphtheria, pertussis, tetanus)
H.influenzae
N.meningitidis
Pneumococci
BCG
MMR (measles, mumps, rubella)
Poliomyelitis
Hepatitis A,B
Active and passive immunization
b/ passive immunization
- provides humoral temporary (approximately
3 weeks)
- prophylactic or therapeutic