Immunity against infection

• Institute of Immunology• 2nd Faculty of Medicine• Prague 5- Motol

Janeway’s Immunobiology 8th Edition / Kenneth Murphy

Pathogenic microorganisms

ParasitesProtozoa

Helmints

Fungi

• mechanisms of pathogenicity• immune escape mechanisms• number of pathogens

• genes regulating immune responses• health condition of the host

Host-pathogen interaction

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

Mucosal immunity

• defence against invasion of pathogenic microorganisms

• defence against harmful inflammatory reactions against pathogens,

…..but also against harmless environmental antigens (oral tolerance)

• 400 m2

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

• 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)

• IgA1 (respiratory tract, serum – 87% monomeric, bone marrow)• IgA2 (gastrointestinal tract, dimeric form)• production 24 mg/kg/day

Immunoglobulin A

Development of immune response to pathogensHost 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

• Alternative and lectin pathway of complement activation

• Production of interferons and cytokines• Local inflammatory response• Production of acute-phase proteins

• Phagocytes• Antigen-presenting cells (APC) • Cytotoxic activity of NK cells• T lymphocytes gama/delta• B1 lymphocytes CD5+• NK-T lymphocytes

Humoral innate immunity

Cellular innate immunity

Phagocytosis of M.tuberculosis

Adaptive immunity in defence against pathogens

• 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

Cellular 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

• Interferons α and β• Neutralizing antibodies• Complement activation (virolysis)• B lymphocytes a Th2 response

• Activity of NK cells• Th1 response• Cytotoxic T lymphocytes (CTL)

• People with T cell immunodeficiency, combined immunodeficiencies

and defect in NK cell function (herpesviruses) at risk

Influenza virus

HIV

Defence against fungi

Aspergillus fumigatus

Candida albicans

• Opportunistic pathogens

• Neutrophils, macrophages• Th1 response (IFN-γ production to activate macrophages)• Th17 response (IL-17 production for neutrophils recruitment)• Antibodies are inefficient

• Systemic disease only in immunocompromised individuals

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

• Derivatives of bacterial cell walls (LPS)• Bacterial toxins and their non-toxic variants (cholera

toxin)

Cytotoxic effects

Adjuvants

Vectors for antigen delivery

• Attenuated bacterial strains (Listeria, Salmonella)• Bacterial toxins and their non-toxic variants with

inserted antigenic epitopes (B.pertussis ACT)

• Immunotoxins containing bacterial toxin bound to an antibody specifically recognizing tumour-associated antigen (C.diphtheriae diphtheria toxin, P. aeruginosa exotoxin A)

Tab. 28 Očkovací kalendář v České Republice

Od 4. dne do 6. týdne 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

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

Vaccination in the Czech Republic

I.

II.

III.

IV.

I.

II.

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

Priorix (measels,mumps,rubella)Live attenuated virusesContraindication imunodeficiency

BCG-VACCINE SSILive attenuated M.bovis BCGContraindication imunodeficiency

SilgardNon-infectious VLP(virus like particles)