NATURAL IMMUNITYNATURAL IMMUNITY

Immunology EPhImmunology EPh

2014.09.15.2014.09.15.

Dr. habil. Kőhidai László Dr. habil. Kőhidai László

Department of Genetics, Cell- and ImmunobiologyDepartment of Genetics, Cell- and Immunobiology

Semmelweis UniversitySemmelweis University

The immune responseThe immune response

Natural (innate)

Acquired (adaptive)

Provides immediate defense

Develops with time

Innate immunity

First line defense Limited specifity Immediate response (no latency) Linear amplification No memory Cellular and humoral defense

Immume homeostasis

Innate

dendritic cellmacrophage

T cellcomplement system

CD5+ B cellantibacterial peptides

NK cellgranulocytescytokines

Adaptive

T lymphocyte

cytokines

B lymphocyte

antibodies

Pathogen

Virus Viral

RNA, DNA

peptide

Bacteria, fungi etc.

Target Cell infected by virus

Macrophage Epithel Granulo-cyte

Complement

Signal IL12 TNFa Endothel C3a C5a

chemokines

Effector NK cell Phagocytes Defensins MAC-lysis

Target destroyed

Virus infected ell

Bacteria,

fungi

Bacteria, fungi Gram- bact.

viruses

Soluble recognition molecules of innate immune system

Defensins bacteria, fungi killing

PentraxinesC reactive protein (CRP) ECM protein, complementSerum amyloid protein (SAP) microbial cell wall

(polysacch., nucl. acids)

CollectinesMannose binding lectins Microbial cell wall complementFicolin (phosphoryl choline, Surface active proteins saccharides)

Lipopolysaccharide binding LPS LPS sens. proteins (LBP)

Barriers: skin,

mucous membranes, secretions

Cells: macrophages, neutrophils, NK cells, mast cells, dendritic cells

Molecules: complement system

MPS (mononuclear phagocyte system)

First line defence

Mechanical: skin, mucous membranes, cough, sneeze

Chemical: skin pH: 5,5 stomach pH: 1,2-3

Biological: in the mouth saliva contains antibacterial agents

lysozyme lactoperoxidase

lactoferrinantibody - IgA

First line barriers

in toothpaste

Limited specificity3 strategies in recognition

Pathogen

non-self

Altered

self

Characteristic markers of pathogens

(missing in the host)

Immunreaction is blocked in case of

self markers

(missing in microorganisms)

Non healthy self markers

Missing MHCI - NK cells active

Missing C3 convertase – alternative complement activation starts

Missing sialic acid – phagocytes, alternative complement activation

Missing

self

www.alergias.med.br/

immunolfig02.html

APOPTOSIS

NK CELLS: dual receptor system

Tumor or virus infected cell

KIR/KAR

no MHC

Limited specificity3 strategies in recognition

Pathogen

non-self

Altered

self

Characteristic markers of pathogens

(missing in the host)

Immunreaction is blocked in case of

self markers

(missing in microorganisms)

Non healthy self markers

Missing

self

Opsonic receptors: Fc and complement

receptors

Phagocytes have two types of receptors on their surfaces

Pattern Recognition Receptors (PRRs)

Opsonization

Facilitation of phagocytosis

vs.

complement protein

antibody

complement receptor

Fc receptor

phagocytebacteriumOPSONIZATION

Fc receptors

bind IgEhigh affinity receptor is expressed on mast cells and basophils role in allergy(low affinity receptor has regulatory function)

Fcε receptors

bind IgG facilitate phagocytosis (regulate B-cell activation)

Fcγ receptors

Fc region

Immunoglobulin = Ig IgG

Fc receptor mediated phagocytosis

Complement

protein

antibody

Complement receptor

Fc receptor

phagocyte

PAMP PRR

Limited specificity

bacteriumOPSONIZATION

PAMP PRRpathogen-associated molecular patterns

pattern recognition receptors

pattern recognition

Membrane receptors

Intracellular receptor

Secreted receptors

I. Scavenger receptors

- CD14: LPS receptor

II. Lectin receptors

- macrophage mannose receptor

III. Toll like receptors

- carbohydrates, lipids, nucleic acids

Membrane PRR

LPS receptor

Gay et al. Nature Reviews Immunology , 2006

Nucleic acid and lipid/protein TLR ligands are recognized in different cellular compartments.

Lipid or protein TLR ligands: recognized on the plasma membrane

e.g. LPS, flagellinNucleic acid TLR ligands: recognized by TLRs in the endosome.

www.natap.org/2006/AASLD/AASLD_57.htm

Toll-like receptors (TLR)

Intracellular cytoplasmatic PRRs

RIG-I-like helicases (RLHs, RLR) recognize viral 5’-Triphosphate ssRNA

-Nod-like Receptors (NLRs) recognize peptidoglycan constituent of Gram positive and Gram negative bacteria

Nature Reviews Microbiology 5, 491-504

Brown GD. Dectin-1: a signalling non-TLR pattern-recognition receptor. Nat Rev Immunol. 2006 Jan;6(1):33-43.

Recognition – at multiple levels

5.Intracellular PRR

1.Secreted PRR

3.Membrane PRR

2.Opsonisation

4. Multiplerecognition

Specificity of TLR

Inflammatory respponses

- expression of receptors

- release of mediators

- internalization of bacteria

- phagolysosome formation

Main steps of macrophage activity

Immediate response (no latency)

NADPH-ox =NADPH oxidase SOD

SOD =superoxide dismutase

MPO = myeloperoxidas

e

Microbicidal activity of professional phagocytes

Superoxide: O2 + e- O2-

Hydrogen peroxide: O2- + e- + 2H+ H2O2

Hydroxyl groups: H2O2 + e- + 2H+ OH- + H2O

www.uni-koeln.de/dictyostelium/07_human.shtml

Takes place even whithout PHAGOCYTOSIS !

IL-1

TNF-

FEVER

Fever is caused by exogenous (e.g. bacterial subst.) and endogenous pyrogenes (products of macrophages).

- Major endogenous pyrogens: IL-1, IL-6, TNF-alpha

- Minor endogenous pyrogens: IL-8, MIP-1, MIP-2, interferons

Brain: Circumventricular organs

Commensal bacterial flora

- all the natural bacteria that live on and in a healthy person (skin, oral cavity, upper respertory tract, lower GI  tract, the urogenital tract) = 1013 cells

- about 1012 bacteria living in the human gut

- in oral cavity e.g. Streptococcus species

Benefit to the host: Compete with pathogens for colonization

(by competing for nutrition and attachment sites to the epithelium)

Differential expression and compartmentalization

of TLRsNo TLR: commensal bacteria are tolerated– NO recognition

TLR: Bacteria passing the epithelia

Intracellular bacteria – intracellular TLR

Nature Reviews Immunology 8, 411-420 (June 2008)

All bacteria that cross the epithelium are recognized

by immune cells

DANGER !!!

How antigens reach lymph node?

Immature dendritic cell

Bridge between innate and adaptive immunity

Innate immunity Adaptive immunity

Dendritic cell

TLR

COSTIMULATION: required for initial activation of T cells

Adaptive immune system

NOT ONLY A SIMPLE FIRST LINE defence

TLR based CONNECTION between natural and adaptive immunity

Nature Reviews Immunology 8, 279-289 (April 2008)

PAMP:

Pathogen associated molecular

pattern

DAMP:

Damage associated molecular

pattern

Nature Reviews Immunology 8, 279-289 (April 2008)

Danger only in case of

necrotic cell death!

!

http://www.invivogen.com/family.php?ID=242&ID_cat=13&ID_sscat=107

RAGE: (Receptor for

advanced glycation

endproducts)

TREM:

Triggering receptor

expressed on myeloid

cells 1 synergize with TLR4

Aknowledgements

Dr. Holub, M. – for her lecture material „Natural Immunity” used as source