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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