Immunity against infection • Institute of Immunology • 2nd Faculty of Medicine • Prague 5- Motol
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
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+)
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 lymfocyty)
IgA M-cells
IgA
Immunoglobulin A • • •
IgA1 (respiratory tract, serum – 87% monomeric, bone marrow) IgA2 (gastrointestinal tract, dimeric form) production 24 mg/kg/day
•
IgA binds to a secretory component and is transported by transcytosis to the luminal surface of the epithelium Secretory IgA is resistant to proteolytic enzymes IgA binds unspecifically to bacteria Main function is to neutralize toxins and to block adhesion of pathogens Anti-inflammatory effect (IgA does not activate complement)
• • • •
•
Sensitive to proteolysis by bacterial proteases (IgA1) (H.influenzae, N.gonorrheae)
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)
Innate immunity in defence against pathogens Cellular innate immunity • • • • • •
Phagocytes Antigen-presenting cells (APC) Cytotoxic activity of NK cells T lymphocytes gama/delta B1 lymphocytes CD5+ NK-T lymphocytes
Humoral innate immunity Phagocytosis of M.tuberculosis
• • • •
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 • • • • •
Antigen-presenting cells (APC) 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) • • • •
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 • • • • •
Phagocytosis – macrophages 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 • • • •
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 • • • •
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, 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 (measels,mumps,rubella) Live attenuated viruses Contraindication imunodeficiency IV.
II. Silgard 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
