Jitka BrazovaJitka Brazova

Immunity Immunity against infectionagainst infection

Entrance

• Pathogenicity mechanisms• Escape mechanisms• Amount • Genes regulating immune reaction

• Actual state of host organism

Epithelial bariers against infections

• Mechanic (intact epithelial surface, longitudinal airand liquids flow)

• Chemical (fatty acids on the skin surface, enzymes –lysozyme in saliva, sweat and tears, pepsin in gut, low pH in stomach, antibacterial peptides in gut)

• Microbial (normal flora – compete, prevention of adhesion, production of antibacterial substances)

Recognition of pathogen

• Receptors on innate immune cells (APC) - Direct: Toll Like Receptors (TLR - 11),

lectin receptors, - Indirect: Fc receptors, complement

receptors (CR3,CR4)• Humoral factors: complement, CRP, MBL

Use of host receptorsSurface molecule Physiological ligand;

(function) Microorganism

CD4 MHC gp II, IL-16 HIV, herpersvirus 7

CD21 (CR2) C3dg, CD23 EBV

CD46 (MCP) (complement regulation) Measles virus, herpesvirus 6

CD54 (ICAM-1) LFA-1 (CD11a/CD18) Rhinoviruses, Plasmodium malariae

CD55 (DAF) (complement regulation) Echovirus R

CD71 Transferin Hepatitis B virus

CD150 (SLAM) CD150 Mesles virus

β1 integrins Extracellular matrix proteins Yersinia, patgogenic E. coli

CR3 (αMβ2 integrin) C3b, CD23 aj. Mykobakterie, Legionella, Bordetella, Leishmania

β3 integrines (αΙΙβ3) Fibronectin Borrelia

Erythrocyte P antigen ? Parvovirus B19

LDL receptor LDL Rhinovirus HRV2

Adhesion of the pathogen andbeginning of immune response

Innate immunity components in infection defence

• alternative and lectin complement pathwayactivation – opsonisation, lysis

• phagocytosis - local inflammatory reaction• production of cytokines and acute phase

reactants• antigens presentation to specific immune

components (macrophages, DC, APC)

Innate immunity components in infection defence II.

• Interferons production• NK cells activity• gamma/delta T lymphocytes• B1 lymphocytes CD5+,

production of IgM antibodies

Specific immune components in infection defence

• APC• Activation of T lymphocytes• Th1 and Th2 subtype diferenciation of T

lymphocytes • efector mechanisms - cellular

- humoral• imunologic memory (afinit maturation,

CD45RO, persist IC on FDC)

Immune components in infection defence

• Extracelullar microorganisms (extracellular phase of microorganism life) – humoral immunity

• Intracellular microorganisms – cellularimmunity

Mucous immunity

• 400 m2

• MALT, GALT , BALT, NALT• o-MALT (places of immune reaction

induction, Payer´s patches, lymphoidfolicules)

• d-MALT (efector places, IEL, lamina propria B and T lymphocytes, neutrophils, eosinophils, mast cells)

Immunoglobulin A

• IgA dimer binds to secretory componentand is transepithelialtransported

• Secretory IgA isresistant to protheolysis by mucous enzymes

• Nonspecific bind bacteria

• Antiinflammatoryefect (opsonin, neutralisation,phagocytes inhibition, do not activatecomplement)

• Sensitive to bacterial protease splitting(IgA1)

Immunoglobulin A - II.

• IgA1• IgA2• synthesis 24 mg/kg/day

(IgG 33 mg/kg/day)• liver transport and

catabolism

• 80 % serum IgA (87 % IgA monomer)

• Bown marrow (A2) andmucous (A1)

Oral tolerance

• Do not react to protein antigenes administeredto mucous tissue

• It is possible to change it by adding ofadjuvance

Mechanisms: • active supression by T

cells – secretion of TGF-b (Th3) and Treglymphocytes –secretion of IL-10

• clonal anergy

Immunity against extracelullar bacteria

• antibodies• complement• lectins+ phagocytosis and

killing (NADPHoxidase) by neutrophils

• Bacteria produce toxins(neutralisating Ab), capsulated bacteria(Streptococckai, Hi), polysascharide Ag (pneumococcai, H., meningococcai)

• Neisseriae (sensitive to complement MLC)

• Staphylococcai

Opsonisation by

Endotoxin shock - SEPSIS

Defence against S. pneumonie

• Adhesion to epithelial cell surface

• Complementactivation via alternative and classical pathway

• opsonisation • Spleen function

Pathogenicity is caused by: • Mucous damage• Complement defects and

granulocyte defects infunction and number

• Ab defects

• Status after splenectomy

Defence against Str. pyogenes (A)

• Semmelweiss –puerperal sepsis, childbed fever

• M protein - resistence to phagocytosis

• Toxins production• cross antibodies

reactivity against M proteins

• antisepsis

• opsonisation• neutralisation• Rheumatic fever,

glomerulonefritis• (genetic determine

sensibility)

Defence against intracellular bacteria

Pathogens characteristics• intracelullar parasites• low toxicity• Mycobacteria, ListeriaLegionela

Defence mechanisms• In lysosomes -Th1, IFNg• macrophages,

granulomatous reaction• In cytoplasm – CD8• Antibodies play no role• Defence is almost always

connected with disease

TH1 – Macrophage interactionTCR

CD3γ

εζ

ZAP-70

cytokine receptor

γJAK-3

WASP

p56lckCD4

CD154CD40L

SLAM

NFAT

• IL-12 receptor

Mo/Mf

•IL-12

•IFNg

BCGitis in a patient with SCID

Defence against virusesPathogenicity mechanisms• using receptors• Obligate intracellular

parasites• Production of inhibiting

factors

Defence mechanisms• inteferons• NK cells• antibodies• Regional lymphnodes

- APC, T and B lymphocytes

• effector CD8 i CD4 lymphocytes

Use of host receptorsSurface molecule Physiological ligand;

(function) Microorganism

CD4 MHC gp II, IL-16 HIV, herpersvirus 7

CD21 (CR2) C3dg, CD23 EBV

CD46 (MCP) (complement regulation) Measles virus, herpesvirus 6

CD54 (ICAM-1) LFA-1 (CD11a/CD18) Rhinoviruses, Plasmodium malariae

CD55 (DAF) (complement regulation) Echovirus R

CD71 Transferin Hepatitis B virus

CD150 (SLAM) CD150 Mesles virus

β1 integrins Extracellular matrix proteins Yersinia, patgogenic E. coli

CR3 (αMβ2 integrin) C3b, CD23 aj. Mykobakterie, Legionella, Bordetella, Leishmania

β3 integrines (αΙΙβ3) Fibronectin Borrelia

Erythrocyte P antigen ? Parvovirus B19

LDL receptor LDL Rhinovirus HRV2

Different types of virus infectionsInitial infection consequences example

acute Recovery and elimination of virus

Inluenza virus, rotavirus

acute Latency (non-infectious virus); on

reactivation, new viruses are shed

Varicella zoster virus, herpes simplex

virus

acute Persistence with continuance or

intermittent shedding

Hepatitis B virus, EBV

not acute Persistent slow infection

Creutzfeld-Jacob disease, scrapie

Defence against viruses

Pathogenicity mechanisms• using receptors• Obligate intracellular

parasites• Production of inhibiting

factors

Defence mechanisms• inteferons• NK cells• antibodies• Regional lymphnodes

- APC, T and B lymphocytes

• effector CD8 i CD4 lymphocytesInfluenza

Ag driftInfluenzaAg shift

Antv.mov

Defence against fungi

Characteristics:• oportunne pathogens• Systemic disease only

in immunodeficiencies(Candida, Aspergillus,

Nocardia)

Defence mechanisms• neutrophils• monocytes and

macrophages• Th1 lymphocytes• Antibodies plays no

role

Lung aspergilosis, peripheral parenchyme condensation, nodules. Patient with chronic granulomatous disease, CGD, (inherited defect of phagocytosis – NADPH oxidase

• Lung nocardiosis, Dg CID• Brain - 2001• recidive 2002 (exitus)

Patient AJ,1983

ring saturation in occipit. Left lobe – nocardiosisabscessus

Nodule in right upper lobe dorsal With cavitation in lung nocardiosis

Immunity against protozoa

Character of the infection: chronic latente asymtomatic reactionhost specific

Antigenne variation, different development stage with different Ag

(Plasmodium,Entamoeba,Giardia,Trypanosoma,Leishmania,Toxoplasma,

Trichomonas...)

Protective immunity: cytokinebalance/dysbalance leads to infection character(Th1)

Decrease resistance of organism leads to clinicalmanifestation

Immunity against Spirochettes

Course of infection:primaresecundareterciare(Treponema, Borrelia,

Leptospira)

Defence mechanisms:antibody reactionTh1Failure of immune

mechanismsimunopathology: CIC,

autoantibodies

Immunity against multicell parasites

Pathogen• chronic infections with

long persistance• high morbidity, low

mortality• Do not multiply in

final organism - cycles• Reinfection(Toxocara, Taenia,

Enterobius, etc.)

Escape mechanisms• secvestration• Molecular mimicres• No expresion of

surfice molecules• secretion inhibiting

factors or proteases• Blocking antibodies

Immunity against multicell parasites II.

Pathology• Imunocomplexes

production• autoantibodies• granulomatous

reaction• alergic reactions

Physiology• Mechanic eviction• Mast cells• eosinophils• Th2• IgE • monocytes• Th1, CD8+

Hygiene hypothesis – more parasites, less alergies??

Localisation of infection and type of immune response

Vaccination

= Active immunizationSpecific immune reaction to given antigen to reach long term immune memory (protective circulatingantibodies, memory lymphocytes –quicker immune response)

Types of vaccines• live attenuated microorganisms (polio oral-Sabin, BCG, MMR, yellow fever, VZV)• inactivated whole microorganisms (polio-Salk, rabies, VHA, influenza, typhus, pertussis, typhoid, cholera)• subunit vaccines – capsular polysaccharides (pneumococcus, meningococcus, Hib)

- surface antigen (VHB)• recombinant vaccines – gene cloned and expressed (VHB)• toxoids (tetanus, diphtheria)•Adjuvans – enlargement vaccine immunogenicity (aluminium salts, Bordetella pertussis), enhance Ab production,stimulation of inflammation, DC activation, antigen longer time in organism

Memory B cell

Stimulated T-lymphocyte

T cell

Stimulated B-lymphocyte

Stimulated B-lymphocyte

differentiation

Plasmatic cellStimulated

B-lymphocyte

proliferation

proliferation

3. T-D (Thymus dependent exodogenous antigen), complex, live and atenuated vaccines (BCG, polio)

2. T-D (Thymus dependent endogenous antigen), protein, most of vaccines

1. T-I (Thymus independentendogenous antigen), polysaccharide (Pneumococcal vaccine, Meningococcus)

B-cell

TypesTypes of of vaccinationvaccination in CZin CZ

•• Compulsory Compulsory by by lawlaw ((§§ 258/2000 sb.)258/2000 sb.)regularregular ((vaccination calendarvaccination calendar))special special ((people at higherpeople at higher risk)risk)extraordinaryextraordinary (severe(severe epidemiological epidemiological situationsituation))

•• VaccinationVaccination onon requestrequest

Compulsory vaccinationCompulsory vaccination in CZin CZ

• TBCTBC•• PertussisPertussis, tetanus, , tetanus, diphtheriadiphtheria,, Haemophilus Haemophilus

influenzaeinfluenzae serotypeserotype b (b (HibHib))•• Hepatitis BHepatitis B•• RubellaRubella,, measlesmeasles,, mumpsmumps•• Polio Polio

Advantagages of vaccination before getting infection

• lower pathogenicity of vaccine than infectious agens

• avoid severe demage of target organs• timing of aplication• vaccine combination

ContraindicationsContraindications forfor vaccinationvaccination•• ForFor inactive vaccinesinactive vaccines:: acute illnessesacute illnesses, , during andduring and 2 2 weeksweeksafter illnesses with high feversafter illnesses with high fevers, , severe severe allergic reactions after previous vaccinationsallergic reactions after previous vaccinations,,pregnancypregnancy•• ForFor live vaccineslive vaccines:: the same abovethe same above++ immunodeficiencyimmunodeficiencytherapy with glucocorticoidstherapy with glucocorticoids,, antimetabolitsantimetabolits,,radiationradiation, ACTH, ACTH3 3 month after blood transfusionmonth after blood transfusion, plasma, plasma or Ig or Ig substitution substitution bone bone marrow malignanciesmarrow malignancies

VaysVays ofof applicationsapplications

OrallyOrallyPolioPolio

IntradermalyIntradermalyTBCTBC

SubcutaneouslySubcutaneouslyrubellarubella,, measlesmeasles,,mumpsmumps

IntramuscularlyIntramuscularlyperthussisperthussis, tetanus,, tetanus,diptheriadiptheria,, Haemophilus influenzae Haemophilus influenzae serotypeserotype b (b (HibHib), Hepatitis B ), Hepatitis B

Vaccination in future

• recombinant vaccines (food like vaccines)• using genes and vectors to deliver Ag• vaccines against chronic infections (EBV, HIV, malaria)

• eradication of severe infections• decrease infection mortality and morbidity • vaccinating against cancer