Immunity against infection

• • •

Institute of Immunology 2

nd

Faculty of Medicine Prague 5- Motol

Janeway’s Immunobiology 8 th 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 or tears, pepsin in the gut, low pH, anti-bacterial peptides) (skin - fatty acids, enzymes - lysozym in saliva Microbiological (normal microbiota – competition for nutrients, blocking of adhesion, production of anti microbial substances )

Bordetella pertussis

• 400 m 2

Mucosal immunity

• 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)

M-cells

IgA 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

• Obligatory intracellular parasites

Influenza virus

• • • • 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) • Clinical manifestation when immune system is compromised or weakend

Trypanosoma 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

Tab. 28 Očkovací kalendář v České Republice

Od 4. dne do 6. týdne Očkování proti

tuberkulóze (pouze u rizikových dětí s indikací)

Infantrix Hexa, Hexavac inactivated viruses and toxins, antigens Prevenar (S. pneumoniae) Polysaccharide antigens I.

II.

Od 9. týdne (2. měsíc) 3. měsíc III.

4. měsíc Očkování proti

záškrtu, tetanu, dávivému kašli, dětské obrně, Haemophilus influenzae typu b, virové hepatitidě typu B

(hexavakcína, 1. dávka) + konjugovaná vakcína proti

pneumokokům

* Očkování proti

záškrtu, tetanu, dávivému kašli, dětské obrně, Haemophilus influenzae typu b, virové hepatitidě typu B

vakcína proti

pneumokokům

* (hexavakcína, 2. dávka- za měsíc po 1.dávce) + konjugovaná Očkování proti

záškrtu, tetanu, dávivému kašli, dětské obrně, Haemophilus influenzae typu b, virové hepatitidě typu B

vakcína proti

pneumokokům

* (hexavakcína, 3. dávka- za měsíc po 2.dávce) + konjugovaná Priorix (measels,mumps,rubella) Live attenuated viruses Contraindication imunodeficiency I.

IV.

II.

Silgard Non-infectious VLP (virus like particles) 11.-15. měsíc 15. měsíc do 18. měsíce věku Očkování konjugovanou vakcínou proti pneumokokům (4.dávka) * Očkování proti

spalničkám, příušnicím, zarděnkám

(1.dávka) 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) Očkování proti

spalničkám, příušnicím, zarděnkám

(2.dávka) 21.-25. měsíc 5.- 6. rok 10.-11. rok 13. rok (jen dívky) Přeočkování proti

záškrtu, tetanu a dávivému kašli

Přeočkování proti

záškrtu, tetanu, dávivému kašli a dětské obrně

Očkování proti karcinomu děložního čípku (lidský papilomavirus) celkem 3 dávky * Přeočkování proti

tetanu

Každých 10- 15 let * nepovinné očkování hrazené ze zdravotního pojištění Očkovací kalendář platný dle vyhlášky 537/2006 Sb. ve znění pozdějších předpisů, platný od 1.1.2013