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