Download slides#5 - DENTISTRY 2012

ORAL
Immunology
Faculty of Medicine/University Of Jordan
April 9th 2015
Mohammed El-Khateeb
Outline
• The Origin of Immune Concept
• Overview of Immunity to Microbes
• Features & Components of Innate &
Adaptive Immunity
• Hallmarks of the Immune Response
 Self/Non-self Discrimination
 Memory
 Specificity
Blood Cells and their Precursors
Figure 1-3 part 1 of 4
 Totipotent
 Pluripotent
 Multipotent
 Unipotent
White
Blood
Cells
(WBCs)
Figure 1-3 part 4 of 4
Antigen Processing cells
Immune Cells
Molecules
IMMUNE SYSTEM COMPNENTS
Aaptive IS
Innate IS
• Organs:
• Organs,
– RES
• Cell: Monocytes
/Macrophages, PNL,
Eosinophiles, Basophils, NK
• Molecules: Acute phase
proteins, interferone,
interleukins , kimokines
– Primary organs (Bone Marrow
+ Thymus)
– Secondery organs ( LN,
Spleen, MLAT)
• Cells : B cells, T cells
• Molecules: Igs, Lymphokine
Cytokine
The immune system
Innate (non-specific) immunity
Adaptive (specific) immunity
 Anatomic barriers (Skin,mucous
membranes)
 Antigen specificity
 Physological barriers
(temperature, pH)
 Immunological memory
 Phagocytic Barriers (cells that
eat invaders)
 Inflammatory barriers (redness,
swelling, heat and pain)
 Diversity
 Self/nonself recognition
Innate and Adaptive Immunity
INNATE IMMUNITY
ACQUIRED
• A summary of
innate
and
acquired
Rapid responses to a
IMMUNITY
Slower responses to
immunity broad range of microbes
specific microbes
External defenses
Invading
microbes
(pathogens)
Internal defenses
Skin
Phagocytic cells
Mucous membranes
Antimicrobial proteins
Secretions
Inflammatory response
Natural killer cells
Humoral response
(antibodies)
Cell-mediated
response
(cytotoxic
lymphocytes)
Figure 2-2 part 2 of 2
Three-phase
Response
to2Initial
Figure
2-1 part
of 2 Infection
0 – 4 hours
4 - 96 hours
Late > 96 hours
RESPONSES
• Activation of Complement
• Activation of Acute Phase Proteins
• Activate Phagocytosis
C’
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Human Acute Phase Protein
• Antiproteases
 α1-Protease inhibitor
 α1-Antichymotrypsin (ACT)
 Pancreatic secretory
trypsin inhibitor
 Inter- α-trypsin inhibitor
• Tranport proteins
 Ceroloplasmin
 Haptoglobin
 Hemopexin
• Inflammatory response
 Phopholipase A2
 Lipopolysaccharide-binding
protein
 Interleukin-1-receptor
antogonist
 Granulocyte colonystimulating factor
• Others
 C-reactive protein
 Serum amyloid A
Phagocytosis
Phagocytosis
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Immune cell Receptors
Ig
TCR
Overview of the stages of lymphocyte development and function
Antigen
Indpendeny
Development
Antigen
Dependent
Responses
18
Functions of Antibodies
Functions of T-Cells
After activation the cell divides to form:
T-helper cells – secrete CYTOKINES
 help B cells divide
 stimulate macrophages
Cytotoxic T cells (killer T cells)
 Kill body cells displaying
antigen
Memory T cells
 remain in body
B- Cells:
 Plasma cell Abs
 Memory B cells
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Dynamics of Adaptive Immunity
This chapter tries to integrate much of what we have
already covered so we can better understand how the
immune system protects from infection.
• How infectious agents cause disease
• The course of an adaptive immune response
• Immunological memory
Mucosal Immune System
Introduction
• Mucosal Defence
• Mucosal Immune system
Antigen - induced expansion of lymphoid tissue
 Lymphocyte homing
 Functional and phenotypic diversity
 Regulatory T cells
 Immunoglobulin IgA
 Immunity thru’ Vaccination

COMPONENTS OF THE MUCOSAASSOCIATED
LYMPHOID TISSUE
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Gastrointestinal tract (GALT)
Bronchial Tree (BALT)
Nasopharyngeal area (NALT)
Mammary gland
Salivary and lacrimal glands
Genitourinary organs
Inner ear
Mucosal
NALT
BALT
***
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GALT
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RALT
***
The secondary lymphoid organs can be sub-divided
into the Systemic (***) and Mucosal immune systems
Tonsillar Tissues form a ring around
entrance to GI tract
Mucosal Immune System
• Immune response
– Induction & Expression within same system
• Mucosal Lymphocytes
– Remain within the mucosal immune system
– Lymphocyte migration / homing / retention
• Special T cells
– CD8 α/β, γ/λ , and regulatory T cells
– Th17 cells Produce IL-17
Examples of mucosal
diseases- role for Th17 cells
 Gut: IBD – autoimmune diseases of the gut
 Vaginal mucosa:Th17 cells are protective
against Neisseria gonnorrheae
 Lung: Th17 cells are protective against various
pneumoniaes, TB, etc., promote airway
hyperreactivity/allergy
 Mouth: Th17 cells promote Sjogren’s
(autoimmune disease of salivary gland, tear
ducts), but protective in oropharyngeal
candidiasis (“thrush”)
Mouth
Contains organisms that survive mechanical
removal by adhering to gums and teeth
 Excellent growth environment with water, nutrients,
temperature, etc.
 Both aerobes and anaerobes present (biofilms)
 Streptococci, especially S. mutans attach to enamel
by glycocalyx
 Contribute to formation of dental plaque, dental
caries, gingivitis, and periodontal disease
Mucosa
• The intact oral mucosa is a barrier against
infecting organisms.
• Superficial squamous cells may be colonized
with bacteria in the same way as squamous
cells on the skin,
• Intact bacteria can cross a damaged epithelial
barrier.
• The undamaged oral mucosa is permeable to
a range of substances smaller than bacteria
Oral mucosal secretions
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Mucin
Lysozyme
Lactoferrin
Salivary peroxidase
Histatins
PRPs
Statherin
Cystatins
Epithelial cell derived antimicrobial peptides
Saliva
• Saliva is a dynamic barrier in the mouth,
•
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constantly flowing backwards to the
oesophagus.
Micro-organisms become entrapped and are
carried via the oesophagus to the hydrochloric
acid and pepsin of the stomach.
Saliva also acts as an additional barrier to the
penetration of materials into the oral mucosa.
Saliva
• Saliva contains a number of materials which afford
non-specific protection to the individual.
 Lysozyme, a mucolytic enzyme: is capable of splitting
sugars off the glycopeptides of the cell wall of many Grampositive bacteria, leading to their lysis.
 Lactoferrin, which reduces the amount of free iron
available for bacterial metabolism,
 Unidentified basic polypeptides, which exert antimicrobial
activity,
 Lactoperoxidase which can cross-link proteins and hence
damage certain bacteria and viruses.
 Mucins : have some carbohydrate side chains in common
with epithelial cells and competitively inhibit the binding of
viruses to the epithelial cells
Salivary constituents and their functions
defensins
defensins
Mucins
defensins
Gingival Crevice
• Since the gingival crevice may harbor micro-organisms
and their products, the ability of the junctional epithelium
to withstand penetration may be of considerable
importance.
• The junctional epithelium is apparently more permeable
than other non-keratinized oral mucosa.
• The flow of fluid is increased with gingival inflammation.
• The major immunoglobulin classes are represented in
gingival crevice fluid.
Cellular Components
The cells involved in the immune response in the
mouth are widely distributed in the following
sites,
 Submucosal tissue
 Gingiva,
 Salivary glands,
 Epithelium,
 Gingival crevice fluid,
 Tonsils,
 Extra oral lymph nodes, which drain lymph
from the oral cavity
Oral Tolerance
• Oral tolerance is
– A general immunosuppressive state in the oral
mucosa to prevent reaction to harmless Ags
such as commensals or foods
– the generation of systemic immune
unresponsiveness by feeding of antigen
• Necessary to prevent excessive response to
normal flora and food antigens
Limitations to Oral Tolerance
• Can be overcome with mucosal adjuvant (e.g.
Cholera toxin)
• Alter physical characteristics of antigen:
antigen in micro-spheres that target PP
• Feeding of attenuated enteric pathogen
expressing the antigen (Salmonella)
Oral Antigen Induces IgA
• Ingestion of killed Streptococcus mutans
• IgA antibody producing cells
– Peripheral blood by day 7, peak day 10 – 12
• Secretory IgA antibodies
– Saliva & Tears by 2 weeks, peak 3 weeks
Natural development of sIgA
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At birth: no sIgA in saliva
Predentate infants (16-28 wks):
 Detected against “1st wave” of strep. organisms: S. mitis, S.
salivarius (Smith and Taubman, 1992)
 These organisms initially colonize mucosal surfaces
 No Abs to S. mutans detected
Dentate children:
 Tooth eruption brings “2nd wave” of strep. organisms: S. sanguis, S.
mutans
 Antibodies (Abs) against S. mutans observed in 1 yr old children
 Abs against: serotype specific carbohydrate, protein I/II,
glucosyltransferase, glucans, teichoic acids
 w/i 10 yrs the child has IgA levels comparable to an adult (adult
parotid saliva contains 30-160 g/ml IgA)
sIgA
 Major salivary glands produce 70% of total salivary sIgA
 30% comes from minor salivary glands
 sIgA system is what we attempt to manipulate to prevent
dental caries and certain microbial infections
 3 X as much IgA is produced/day than IgG
 ~2/3 of IgA produced is sIgA
 Primary function to prevent microbial adherence
(serum)
 Bacterial IgA-specific proteases found in
S. sanguis;
periodontal pathogens.
Secretory IgA - Production
• IgA in blood is monomeric, >90% IgA1
• Secretory IgA
♦ polymeric, IgA1 upper respiratory & GI tract IgA2 in
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♦
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♦
colon & rectum
Induction by antigen in Peyer’s patches
Production by IgA plasma cells in lamina propria
J chain polymerisation of IgA
Binds polymeric Ig-receptor for trans-epithelial
transport, cleaved to release secretory IgA
Secretory IgA - Function
• Specificity
♦ 2 – 5% reacts with specific Ag after immunisation
♦ Commensal flora? Dietary antigens?
• Resists proteolysis
• Inhibits microbial adherence
• Neutralisation of viruses, toxins (cholera)
• Activates complement (alternative pathway)
• Antigen exclusion
• Modulation of enzyme activity
Possible Causes of Immunologically
Mediated Mucosal Damage
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Antigens: Local microbial flora or food
Accumulation of cirvulating antigen
B cell mitogens: Microorganisms and food
Mitogenic complement split products
Blastogenic factors from locally activated T and B cells
Lymphostimulatory factors from macrophages and
neutophils
Altered autologous IgG-Immune complexes
Endogenous tissue antigens cross-reacting with microbial
componenets
IgA Multiple Properties Adopted
to GI Tract
• Relatively resistant to proteolytic effect (IgA2>IgA1)
• Poor activator of complement
• Inhibits:
– Bacterial adhesion
– Macromolecule absorption
– Inflammatory affects of other immunoglobulins
• Neutralizes Viruses and Toxins
• Enhances nonspecific defense mechanisms
– Lectofernin
– Lactoperoxidase
• Mediate antibody dependent cytotoxicity (ADCC)
Origin and Flow of Cervicular Fluid
• CF mainly derived from
tissue fluids in blood
capillaries
• It flows into the lamina
propria through the JE
and into the GCF
• Passes into saliva at the
rate of 0.3 /tooth/hr
SPECIFIC ORAL DISEASES
• Dental Carries
• Peridontal Disease
• Aphthous Ulceration
• Oral menifestations of Systemic
Immunological Diseases
Mutans streptococci
 Group of strep species most closely associated with caries of
smooth surfaces, pits, fissures
 6 serotypes of ms that are associated with man
 S. mutans serotype C, predominant group associated with
enamel surfaces; 80-87% of cases in U.S.
 Swedish kids; smooth surface caries, 36% presence of serotype c,
54% serotype d/g
Specific immunity against DCs
 Caries correlated with sIgA titers and
serum IgM to S. mutans.
 Elevation in titer is due to exposure
 Are these antibodies protective??
 Association between sIgA antibodies and
resistance to dental infection by S. mutans has
still to be convincingly demonstrated.
Serum Abs to Strp. mutans in Man
DMF: Index of decayed, missing or filled tooth
Active: High DMF group with one or more carious lesion
Reduction of Caries in Monkey Model
• Immunization against
dental caries in Monkey
• Subcutaneous
immunization with S.
mutans MO or purified
Ag.
• Both gave the same
reduction in dental
caries
GENETIC FACTORS
• Respond to low dose of S. mutans Ag (SA I/II)
1-10ng, positive for HLA-DRw6
• Needs 1000ng/ml negative for HLA-DRw6
• High Ab level to S mutans
Subjects Low carries subjects
SA I/II Ag
HLA
Ab Level
Caries prone
low Dose 1-10ng
High Dose 1000ng
DRw6 Positive DRw6 Negative
High
Low
Stages of Periodontal Disease
Some Types of Oral Ulcerations
May Mimics RAS
Recurrent aphthous stomatitis
♦ Behcet’s Syndrome
♦ Clinical Neuropenia
♦ Coeliac disease
♦ Iron deficiency
♦ Folate deficiency
♦ Ulcerative colitis
Do not Usually Mimics
RAS
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Pemphigus
Mucus membrane pemphigoid
Erythema multiforme
Erosive lichen planus
Chron’s disease
Wagner’s granuloma
Carcinoma
Leukemia
APHTHOUS ULCERATION
Minor eleptical shape aphtous
ulceration, and defined periulcer erythema, effects the
non-keratinized mucosa
Major aphthous ulceration
In the mucosa, may grow up
To 2cm in diameter
Oral Manifestations of
Systemic Immunological
Diseases GI DISEASE
Coeliac Disease
Crohn’s Disease
Ulcerative Colitis
Food Allergy and Oral Disease
Oral Manifestations of
Systemic Immunological
Diseases DERMATOLOGICAL
DISEASES
Lichen Planus
Pemphigus
Benign Mucous Membrane Pemphigoid
(BMMP)
Erythema Multiforme
Oral Manifestations of
Systemic Immunological
Diseases CONNECTIVE
TISSUE DISEASES
Sjogren’s Syndrome
Wagners’s Granulomatosis
Malignant Midline Granuloma
(Stewart’s Granuloma)
Conclusion
• Mucosal Immune system
◙ Antigen - induced expansion of lymphoid tissue
◙ Lymphocyte homing
◙ Functional and phenotypic diversity
◙ Regulatory T cells
◙ Immunoglobulin IgA