Immunity against infection

1. Immunity against infection • Institute of Immunology • 2nd Faculty of Medicine • Prague 5- Motol Janeway’s Immunobiology 8th Edition / Kenneth Murphy

2. Pathogenic microorganisms Parasites Protozoa Helmints Fungi

3. Host-pathogen interaction Hostitel Microorganisms • mechanismsofpathogenicity • immuneescapemechanisms • numberofpathogens • genesregulatingimmuneresponses • healthconditionofthe host

4. 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 anti-microbial substances ) Bordetella pertussis

5. 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)

6. Oral tolerance • Default response to oral administrationofantigens (food) • Immuneunresponsivness • Itcanbeovercome by administrationofadjuvants Immunemechanismsof oral tolerance: • Activesuppression by T regulatorycellsproducing TGF-β, IL-10 • Clonalanergy • Tolerogenicdendriticcells (CD103+)

7. 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

8. Immunoglobulin A • IgA1 (respiratory tract, serum – 87% monomeric, bone marrow) • IgA2 (gastrointestinal tract, dimericform) • 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-inflammatoryeffect (IgA does not activate complement) • Sensitive to proteolysis by bacterial proteases (IgA1) (H.influenzae, N.gonorrheae)

9. 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)

10. 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 lectinpathwayofcomplementactivation • Productionofinterferons and cytokines • Localinflammatory response • Productionofacute-phaseproteins

11. 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

12. Localization of infection and type of immune response

13. Defence against extracellular bacteria • Bacteriaproducingtoxins (C.tetani, C.botulinum, C.diphtheriae) • Polysaccharidecapsule (Streptococci, Neisseria, Staphylococci) • Opsonization - complement, lectinorantibodies • Neutralization - antibodies • Phagocytosis – neutrophils, macrophages • B lymphocytes (IgM), Th2 response (IgA, IgG1) • Peoplewithdefect in phagocytosis, complement and antibodyproduction at risk • bacteriawithpolysaccharidecapsuledangerousforsmall children (up to 2y) and peoplewitha defective spleen function, oraftersplenectomy. Streptococcus pneumoniae

14. Defence against Streptococcus pyogenes • primarypathogenic, humanis a carrier • toxin production • neutralization • M protein – resistance to phagocytosis • opsonization • autoimmune-mediatedcomplications: cross-reactivityofantibodiesagainst M protein with host proteins • rheumaticfever, glumerulonephritis • Semmelweiss – childbedfever • antisepticprocedures

15. Defence against intracellular bacteria • Intracellularparasitese.gListeria, Mycobacterium, Brucella • Phagocytosis – macrophages • Antibodies are inefficient • Th1 response (IFN-γproduction to activatemacrophages) • Th17 response (IL-17 productionforneutrophilsrecruitment) • Cytotoxic T lymphocytes (Listeriamonocytogenes) • Peoplewithdefectsofinnate and adaptiveimmunityat risk Pathology: granulomas M. tuberculosis

16. Defence against viruses Influenza virus • Obligatoryintracellularparasites • Interferonsα and β • Neutralizingantibodies • Complementactivation (virolysis) • B lymphocytesa Th2 response • Activityof NK cells • Th1 response • Cytotoxic T lymphocytes (CTL) • Peoplewith T cell immunodeficiency, combinedimmunodeficiencies and defect in NK cell function (herpesviruses) at risk HIV

17. Defence against fungi • Opportunisticpathogens • Neutrophils, macrophages • Th1 response (IFN-γproduction to activatemacrophages) • Th17 response (IL-17 productionforneutrophilsrecruitment) • Antibodies are inefficient • Systemicdiseaseonly in immunocompromised individuals Aspergillus fumigatus Candida albicans Pneumocystis jirovecii (carinii)

18. Defence against protozoan infections • Chronic non-symptomaticlatentinfection • Antigenicvariation, differentdevelopmentalstages • Intracellular (Plasmodium, Trypanosoma, Leishmania, Toxoplasma) Th1 lymphocytes and activatedmacrophages • Extracellular (Entameba, Giardia, Trichomonas) Antibodies • Cytokine milieu determinestheoutcome ofinfection (Th1) • Clinicalmanifestationwhenimmunesystem iscompromisedorweakend Trypanosoma Trichomonas

19. Defence against helminths • chronicpersistentinfection (e.gtapeworm, roundworm, pinworms) • High morbidity, low mortality • reinfection • Mastocytes, eosinophils (extracellularbactericidalsubstances) • Th2 response, antibodyIgE • later Th1 response (macrophages), CTL Pathology: • Formationofimmunocomplexes • Auto-antibodies, granulomas • Allergicreactions tapeworm roundworm

20. Immune escape mechanisms of pathogens • Antigenicvariation (Influenza virus, S.pneumoniae, Trypanosoma) • Antigenicmimicry (mimicthestructuresof host cells) – M protein (the utility of host proteins – T. pallidum, B. burgdorferi) • Inhibitionofphagocytosis – capsule, protein M (Streptoccoci), toxins • Inhibitionofcomplement - (Borreliaburgdorferi – Factor H) • Hidinginsidethecells - (integrationinto genom - HIV, latency - herpesviruses) • Inhibitionof antigen presentation and MHC expression (Mycobacterium, viruses) • Secretionof inhibitory factors (IL-10 analogue) orproteolyticenzymes (IgA)

21. 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 • Immunotoxinscontainingbacterial toxin bound to anantibodyspecificallyrecognizingtumour-associated antigen (C.diphtheriaediphtheria toxin,P. aeruginosaexotoxin A)

22. Vaccination in the Czech Republic BCG-VACCINE SSI Live attenuatedM.bovis BCG Contraindicationimunodeficiency I. InfantrixHexa, Hexavac inactivatedviruses and toxins, antigens Prevenar (S. pneumoniae) Polysaccharideantigens II. III. I. Priorix (measels,mumps,rubella) Live attenuatedviruses Contraindicationimunodeficiency IV. II. Silgard Non-infectious VLP (virus likeparticles)