Transcript T cell-mediated immunity

Immunity against infection
• Institute of Immunology
• 2nd Faculty of Medicine
• Prague 5- Motol
Irena Adkins, PhD
irena.adkins @lfmotol.cuni.cz
Janeway’s Immunobiology 8th Edition / Kenneth Murphy
Pathogenic microorganisms
Parasites
Protozoa
Helmints
Fungi
Host-pathogen interaction
• mechanisms of pathogenicity
• immune escape mechanisms
• number of pathogens
• genes regulating immune responses
• health condition of the host
Immune system
Cell-mediated immunity
Humoral immunity – cytokines, antibodies, complement
Antigen presenting cells
Antigen presenting cells
Pathogen-associated molecular patterns
TLR – Toll-like receptors… but also other molecules
Activation of co-stimulatory molecules on APCs
T cell-mediated immunity
CD8+ cytotoxic T cells
T cell-mediated immunity
CD8+ cytotoxic T cells
Signal 3 – cytokines produced by APCs determine
the type of CD4+ T cell response
CD4+ T cells
Subsets of CD4+ T cells
B cells
T-cell dependent
T-cell independent
antigens
Antibodies
IgM, IgD
IgG
IgA
IgE
humoral immunity
Cytokines
Complement
Antibodies
Epithelial barriers against infection
• Mechanical (intact epithelial surface, longitudinal flow of
air or fluid, movements of mucous by cilia)
• Chemical (skin - fatty acids, enzymes - lysozym in saliva
or tears, pepsin in the gut, low pH, anti-bacterial
peptides)
• Microbiological (normal microbiota – competition for
nutrients, blocking of adhesion, production of antimicrobial substances )
Bordetella pertussis
Mucosal immunity
• 400 m2
• defence against invasion of pathogenic microorganisms
• defence against harmful inflammatory reactions against pathogens,
…..but also against harmless environmental antigens
(oral tolerance)
Oral tolerance
• Default response to oral administration of antigens (food)
• Immune unresponsivness
• It can be overcome by administration of adjuvants
Immune mechanisms of oral tolerance:
• Active suppression by T regulatory cells producing TGF-β, IL-10
• Clonal anergy
• Tolerogenic dendritic cells (CD103+)
Development of immune response to pathogens
Host cellular receptors serve as portals of entry for pathogens
• mainly viruses (CD4 – HIV; CD21 – EBV)
• bacteria (CR3 – Mycobacterium, Bordetella; β1-integrins – Yersinia, E.coli)
104 – 106 antigen-specific T cells
Mucosal immune responses
• MALT (mucosa-associated lymphoid tissue) GALT, BALT, NALT
• o-MALT (organized, Peyer’s patches, lymphoid follicles, FAE)
• d-MALT (scattered, effector site, IEL, lamina propria lymphocytes)
IgA
M-cells
IgA
Effector cells
Mucosal immune responses
Effector cells – DC, macrophages, CD8+, CD4+ T cells
plasma cells
Lymphocyte imprinting – gut-homing molecules
Protective immunity at other mucosal surfaces - vaccination
Immunoglobulin A
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IgA1 (respiratory tract, serum – 87% monomeric, bone marrow)
IgA2 (gastrointestinal tract, dimeric form)
production 24 mg/kg/day
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IgA binds to a polymeric Ig receptor (pIgR) and is transported by transcytosis
to the luminal surface of the epithelium (secretory component)
Secretory IgA is resistant to proteolytic enzymes
Main function is to neutralize toxins and to block adhesion of pathogens
Anti-inflammatory effect (IgA does not activate complement)
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Sensitive to proteolysis by
bacterial proteases (IgA1)
(H.influenzae, N.gonorrheae)
Innate immunity in defence against pathogens
Cellular innate immunity
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Phagocytes (macrophages, neutrophils)
Antigen-presenting cells (APC)
Cytotoxic activity of NK cells
T lymphocytes gama/delta
NK-T lymphocytes
Humoral innate immunity
Phagocytosis of M.tuberculosis
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Alternative and lectin pathway of complement activation
Production of interferons and cytokines
Local inflammatory response
Production of acute-phase proteins
Adaptive immunity in defence against pathogens
Cellular adaptive immunity
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Antigen-presenting cells (APC – dendritic cells)
Activation of T and B lymphocytes
Functional differentiation of T lymphocytes (Th1, Th2, Th17)
Induction of cytotoxic T lymphocytes (CTL)
Immunological memory (affinity maturation, memory lymphocytes,
long-lasting presentation of immunocomplexes on FDC)
Humoral adaptive immunity
• antibodies
• cytokines
Localization of infection and type of immune response
Defence against extracellular bacteria
• Bacteria producing toxins (C.tetani, C.botulinum, C.diphtheriae)
• Polysaccharide capsule (Streptococci, Neisseria, Staphylococci)
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Opsonization - complement, lectin or antibodies
Neutralization - antibodies
Phagocytosis – neutrophils, macrophages
B lymphocytes (IgM), Th2 response (IgA, IgG1)
• People with defect in phagocytosis, complement and antibody production
at risk
• bacteria with polysaccharide capsule dangerous for small
children (up to 2y) and people with a defective spleen
function, or after splenectomy.
Streptococcus pneumoniae
Defence against Streptococcus pyogenes
• primary pathogenic, human is a carrier
• toxin production
• neutralization
• M protein – resistance to phagocytosis • opsonization
• autoimmune-mediated complications:
cross-reactivity of antibodies against M protein with host proteins
• rheumatic fever, glumerulonephritis
• Semmelweiss – childbed fever
• antiseptic procedures
Defence against intracellular bacteria
• Intracellular parasites e.g Listeria, Mycobacterium, Brucella
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Phagocytosis – macrophages, neutrophils
Antibodies are inefficient
Th1 response (IFN-γ production to activate macrophages)
Th17 response (IL-17 production for neutrophils recruitment)
Cytotoxic T lymphocytes (Listeria monocytogenes)
• People with defects of innate and adaptive immunity at risk
Pathology:
granulomas
M. tuberculosis
Defence against viruses
Influenza virus
• Obligatory intracellular parasites
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Interferons α and β
Neutralizing antibodies
Complement activation (virolysis)
B lymphocytes a Th2 response
• Activity of NK cells
• Th1 response
• Cytotoxic T lymphocytes (CTL)
HIV
• People with T cell immunodeficiency, combined immunodeficiencies
and defect in NK cell function (herpesviruses) at risk
Defence against fungi
• Opportunistic pathogens
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Neutrophils, macrophages
Th1 response (IFN-γ production to activate macrophages) Aspergillus fumigatus
Th17 response (IL-17 production for neutrophils recruitment)
Antibodies are inefficient
• Systemic disease only in immunocompromised
individuals
Candida albicans
Pneumocystis jirovecii (carinii)
Defence against protozoan infections
• Chronic non-symptomatic latent infection
• Antigenic variation, different developmental stages
• Intracellular (Plasmodium, Trypanosoma, Leishmania, Toxoplasma)
Th1 lymphocytes and activated macrophages
• Extracellular (Entameba, Giardia, Trichomonas)
Antibodies
• Cytokine milieu determines the outcome
of infection (Th1)
Trypanosoma
• Clinical manifestation when immune system
is compromised or weakend
Trichomonas
Defence against helminths
• chronic persistent infection (e.g tapeworm, roundworm, pinworms)
• High morbidity, low mortality
• reinfection
• Mastocytes, basophils, eosinophils
(extracellular bactericidal substances)
• Th2 response, antibody IgE
• later Th1 response (macrophages), CTL
Pathology:
• Formation of immunocomplexes
• Auto-antibodies, granulomas
• Allergic reactions
tapeworm
roundworm
Immune escape mechanisms of pathogens
• Antigenic variation (Influenza virus, S.pneumoniae, Trypanosoma)
• Antigenic mimicry (mimic the structures of host cells) – M protein
(the utility of host proteins – T. pallidum, B. burgdorferi)
• Inhibition of phagocytosis – capsule, protein M (Streptoccoci), toxins
• Inhibition of complement - (Borrelia burgdorferi – Factor H)
• Hiding inside the cells - (integration into genom - HIV, latency - herpesviruses)
• Inhibition of antigen presentation and MHC expression (Mycobacterium, viruses)
• Secretion of inhibitory factors (IL-10 analogue) or proteolytic enzymes (IgA)
Pathogens are not only bad….immunotherapy
Adjuvants
• Derivatives of bacterial cell walls (LPS)
• Bacterial toxins and their non-toxic variants (cholera toxin)
Vectors for antigen delivery
• Attenuated bacterial strains (Listeria, Salmonella)
• Bacterial toxins and their non-toxic variants with inserted
antigenic epitopes (B.pertussis ACT)
Cytotoxic effects
• Immunotoxins containing bacterial toxin bound to an antibody
specifically recognizing tumour-associated antigen
(C.diphtheriae diphtheria toxin, P. aeruginosa exotoxin A)
Vaccination in the Czech Republic
BCG-VACCINE SSI
Live attenuated M.bovis BCG
Contraindication imunodeficiency
Infantrix Hexa, Hexavac
inactivated viruses and
toxins, antigens
Prevenar (S. pneumoniae)
Polysaccharide antigens
Tab. 28 Očkovací kalendář v České Republice
Očkování proti tuberkulóze (pouze u rizikových dětí s indikací)
Od 9. týdne (2. měsíc)
Očkování proti záškrtu, tetanu, dávivému kašli, dětské obrně,
Haemophilus influenzae typu b, virové hepatitidě typu B
(hexavakcína, 1. dávka) + konjugovaná vakcína proti
pneumokokům *
3. měsíc
Očkování proti záškrtu, tetanu, dávivému kašli, dětské obrně,
Haemophilus influenzae typu b, virové hepatitidě typu B
(hexavakcína, 2. dávka- za měsíc po 1.dávce) + konjugovaná
vakcína proti pneumokokům *
4. měsíc
Očkování proti záškrtu, tetanu, dávivému kašli, dětské obrně,
Haemophilus influenzae typu b, virové hepatitidě typu B
(hexavakcína, 3. dávka- za měsíc po 2.dávce) + konjugovaná
vakcína proti pneumokokům *
11.-15. měsíc
Očkování konjugovanou vakcínou proti pneumokokům (4.dávka) *
15. měsíc
Očkování proti spalničkám, příušnicím, zarděnkám (1.dávka)
do 18. měsíce věku
Očkování proti záškrtu, tetanu, dávivému kašli, dětské obrně,
Haemophilus influenzae typu b, virové hepatitidě typu B
(hexavakcína, 4. dávka- nejdříve 6 měsíců po 3.dávce)
21.-25. měsíc
Očkování proti spalničkám, příušnicím, zarděnkám (2.dávka)
5.- 6. rok
Přeočkování proti záškrtu, tetanu a dávivému kašli
10.-11. rok
Přeočkování proti záškrtu, tetanu, dávivému kašli a dětské obrně
13. rok (jen dívky)
Očkování proti karcinomu děložního čípku (lidský papilomavirus)
celkem 3 dávky *
Každých 10- 15 let
Přeočkování proti tetanu
I.
II.
III.
I.
Priorix (measles,mumps,rubella)
Live attenuated viruses
Contraindication imunodeficiency IV.
II.
Silgard, Cervarix
Non-infectious VLP
(virus like particles)
Od 4. dne do 6. týdne
* nepovinné očkování hrazené ze zdravotního pojištění
Očkovací kalendář platný dle vyhlášky 537/2006 Sb. ve znění pozdějších předpisů, platný od
1.1.2013