Carina Krüger Weiner Övertandläkare, Käkkirurg, Med. Dr ... · Defense mechanisms of the mucosa...

Carina Krüger Weiner

Övertandläkare, Käkkirurg, Med. Dr

Kliniska aspekter; Karin Garming-Legert,

Bitr Övertandläkare, Oral medicin, Med. Dr

SlemhinneimmunologiT3

Aktivering av immunsvar

SIgA

Immunbrist

Oral immunologi

Vaccinologi

Slemhinnan

400 m2 mekanisk barriär

Kroppens utsida

Olika funktioner

Skydd

Transport

Aktivering immunsvar

Slemhinnans immunförsvar Ospecifik

Mekanisk barriär, peristaltik, sekret, normal mikroflora

Specifik

Cellmedierat, T-celler

Humoralt, antikroppar

Defense mechanisms of the mucosa Non specific defense (innate)

Mucosa and mechanical movement Secretions

Acid, bile, saliva, mucus Antimicrobial factors:

Mucin, lysozyme, peroxydase, lactoferrin, defensin, complement

Endogenous microbiota Phagocytosis

Macrophages and neutrophiles (PMN)

Specific immune defense (adaptive) Cellular: T and B cells Humoral: antibodies

SIgA first line of defense

Figure 10-20

Organisation

Induction site: Aktivering av immunsvar

Upptag av antigen

Organized lymphoid tissues (O-MALT):

GALT, BALT, NALT

Forts. Organisation

Effector site: Expression av immunsvar

Production av SIgA

Diffus lymfoid vävnad

Lamina propria tarm, genitalia, luftvägar

Saliv-, bröst och tårkörtlar

Gut associated lymphoid tissues:-Organized lymphoid structure

Peyer’s patches and isolated lymphoid follicles (ILF) (inductive site)

-Diffuse tissue of the lamina propria and epithelium (effector site)

DC

CD8+ cytotoxic

CD4+ cellsTh1, Th2, Th3, or Tr1

B cells

IgA+

Plasma cells

IgA

Figure 10-19Upptag av antigen

Figure 10-24

Figure 4-23Sekretoriska

antikroppar

Secretory IgA

–Deletion of 13 amino acid in the hinge region of IgA2

–IgA1 more susceptible to bacterial IgA proteases

–Serum: 90% IgA1, 10% IgA2

–Secretions: IgA2 (30-60%)

2 IgA monomer

J-chain: linker

SC: transport

Secretory IgA

Transport of IgA

1) Binding to polymeric Ig receptor (PIgR)

2) Internalization into endocytic vesicle

3) PIgR is cleaved

4) Dimeric IgA bound to secretory component released in secretions

12

3

4

Antikroppars funktion på mukosan

Neutralisera enzymer, toxiner

Blockera adhesion

Agglutinera bakterier

IgA brist Vanligast: 1/500

Sjukdomar associerade med IgA brist Luftvägsinfektioner Intestinal disorders: infections, IBD Allergier Autoimmune sjukdomar

IgM kompensation

IgA proteaser

Extracellulära enzymer produceras av bakterier

Klyver ”hinge” regionen IgA1 resp. sIgA1

Virulensfaktor

Action of IgA1 proteases on IgA

•S. pneumoniae, Neisseria spp., Haemophilus influenzae

•S. sanguis, S. oralis, S. mitis, Prevotella spp., Capnocytophaga spp

IgA1

Loss of protection conferred by Fc-Fab can still bind to the antigen

-No aggregation

-No binding to other defense factors

Oral tolerans

”Att äta utan inflammation”

Terapi tex äta kollagen vid reumatoid artrit

Immunsvar eller tolerans? Koncentration eller

administrationssätt

Anergi- T-celler, B-celler

Klonal deletion

Oral immunology Defense mechanisms

Salivary SIgA

Induction

Mechanisms of action

Role in protection against caries

Immunotherapy against caries

Gingival sulcusGingival fluid flow

PMNs

Antibodies (IgG)

Complement

Defensins

GingivaT and B cells

Macrophages

DC

PMNs

Complement

Antibodies

Defensin

Supra-gingival environment Mechanical cleansing, mucin, lysozyme,

agglutinin, lactoferrin, peroxydase,

histatin, defensin, SIgA, SIgM,

antibodies from gingival fluid

Tooth

• Saliva

(salivary glands)

– Mucin

– Lysozyme

– Lactoferrin

– Peroxydase

– Defensin

– SIgA

• Gingival fluid

(plasma)– PMNs

– T- and B-cells

– Macrophages

– Serum IgG, IgM, IgA

– complement

Whole salivaGingival

crevice

Supragingival

environment

Defense mechanisms in the oral cavity

SalivenAntimikrobiella funktioner

Mekanisk rengöring

Lysozym- bacteriocid (bryter cellvägg)

Peroxidas- antibakteriell

Laktoferrin- bakteriostatiskt protein

Leukocyter- från blod via tandköttsfickan

Sekretoriskt IgA- plasmaceller i salivkörtlarna

Secretory IgA Major immunoglobulin in saliva

More resistant to bacterial proteases

SIgA against microbes associated with oral diseases

S. mutans, P. gingivalis, A. actinomycetemcomitans, C. albicans

Bacteria in the oral cavity coated with SIgA

SIgA in the oral cavity Main role:

Control colonization by commensalmicroorganisms and invasion by pathogens

Block adhesins Adherence to acquired pellicle

Adherence to other bacteria (coaggregation)

Aggregation in saliva

Inhibition of enzymes and toxins

Interaction with other defense factors

Oral antigens

-Bacteria-Protein

–lipid

–Polysaccharide

–Lipoteichoic acid

–LPS

–Virus

–Yeast

Induction of SIgA response

in the oral cavity

1) Salivary glands

2) GALT (Peyer patches)

3) NALT (tonsils and adenoid))1

3

2

Role of SIgA in the development of periodontal diseases

SIgA does not penetrate the crevice or pocket

By modulating the formation of supragingival plaque,

Prevent periodontopathogens that inhibit the tongue to colonize the gingival sulcus

Prevent transmission of periodontopathogens from infected to healthy gingival site

Studies on the role of SIgA in the control of caries

Contradictory results: +, - or no correlation between

Level of S. mutans

Caries (DMFS, DMFT, active lesions)

IgA deficiency: No major difference in Level of S. mutans and putative

periodontopathogens

Plaque accumulation, gingivitis and periodontaldestruction

Figure 1-1

Figure 1-2

Mukosa vaccinologi

Vaccination

Active immunization (antigen) Systemic

Mucosal

Passive immunization (antikroppar)

Oral antigens

-Bacteria-Protein

–lipid

–Polysaccharide

–Lipoteichoic acid

–LPS

–Virus

–Yeast

Induction of SIgA response

in the oral cavity

1) Salivary glands

2) GALT (Peyer patches)

3) NALT (tonsils and adenoid))1

3

2

Passive immunization

Vaccination

Active immunization (antigen) Systemic

Mucosal

Passive immunization (antikroppar)

2015-09-01 Namn Efternamn 37

Kariesvaccin

”1986”

Hela celler av S. mutans injicerades

Korsreagerande antikroppar mot

hjärtmuskelvävnad.

AKTIV IMMUNISERING

Streptococcus

mutans

•Polyclonal antibodies

–S. mutans (rat, human)

–GTF (rat, human)

–SAI/II (rat)

•Monoclonal antibodies

–GTF (?)

–SAI/II (rat, monkey,

human)

Streptococcus mutans

target antigen

Aim

Develop and evaluate an

efficient and safe oral

passive vaccine against

dental caries

Lactobacillus

S. mutans

SAI/II

1) Lactobacillus

• Gram positive rods

• Aciduric (pH 5.0 or less)

• Normal resident

• Food industry

• Probiotics

• Balancing of resident microbiota

• Prevention of infectious diseases

• Immune response

• Bowel motility and mucosal integrity

• GRAS

Agglutination

Transformed L. zeae and S. mutans Empty vector control L. zeae and S. mutans

Lactobacilli n S.

mutansa

P value Dental

cariesb

P value

- 6 2900 - 4 (67%) -

pLP402 6 2350 n.s. 4 (67%) n.s.

pLP402-

scFv-long

anchor

7 75 <0.05c 1 (14%) <0.05d

Table 3. Therapeutic in vivo effect of transformed lactobacilli

In desalivated rats

a. Summary of two screenings of all individual animals during the final week of the therapeutic experiment. Results are given as median numbers of

b. Number of animals with dentinal (slight and moderate) caries at term of the experiment.

c. Mann-Whitney test.

d. c2 test.

Heavy chain antibodies (Collaboration with Unilever)

•Acid resistant

•Heat resistant

•Bind with high affinity

Passive immunity in the oral cavity