Mucosal Immunology: Overview—DM Walker 27

Review Article

Oral Mucosal Immunology: An Overview

DM Walker,1FRCPath, FFOP, RCPA

Abstract
The primary function of the immune system of the mouth is to protect the teeth, jaws, gingivae
and oral mucosa against infection. These host defences vary in the different oral microenviron-
ments or domains represented by the oral mucosa, saliva and gingival crevice. This review aims
to consider and contrast the main immune components in each domain and cites examples of oral
diseases where the immune response is defective.
Ann Acad Med Singapore 2004;33(Suppl):27S-30S
Key words: Antigen processing, Gingiva, Immunoglobulin A, Oral mucosa, Saliva

Introduction cytokines including interleukin-1 beta (IL-Iβ), interleukin-

The primary function of the immune system of the mouth 6, tumour necrosis factor-alpha (TNF-alpha) granulocyte-
is to protect the teeth, jaws, gingivae and the rest of the oral macrophage colony stimulating factor (GM-CSF) 2
mucosa against infection. The oral immune system is part transforming growth factor-beta (TGF-beta) and their
of an extensive and specialised compartmentalised mucosa- receptors and IL-8.3-6 Bacteria can be a stimulus for epithelial
associated lymphoid tissue (MALT).1 cell production of interleukins, for example IL-6. 7
Conversely, exogenous cytokines such as IL-8 may
The host defences against infection vary in the different
upregulate expression of MHC-I and II antigens by epithelial
oral micro-environments or domains represented by the
cells, which may therefore function as antigen-presenting
oral mucosa, salivary glands and saliva and the gingival
cells.8
crevice.
Cytokines can also be secreted by macrophages,
Oral Mucosa fibroblasts, dendritic cells, mast cells and intra-epithelial
The intact stratified squamous epithelium supported by lymphocytes in the oral mucosa.
the lamina propria presents a mechanical barrier to oral
Saliva and Salivary Glands
microorganisms. The continuous shedding by exfoliation
of epithelial squames limits microbial colonisation of the The flow of saliva has a mechanical effect, flushing
surface. Membrane-coating granules discharged extra- microorganisms from mucosal and tooth surfaces. Saliva
cellularly in the granular layer, transudation of antibody also contains important antimicrobial agents (Table 1)9 and
through the mucosa and the barrier presented by the patients with a significant xerostomia are prone to dental
basement membrane contribute to mucosal defences. Intra- caries and candida infections.
epithelial dendritic Langerhans cells are peripheral antigen- The main specialised immunoglobulin isotype of the
presenting cells which can process antigen in their secretory immune system is secretory immunoglobulin A
MHC-Class II abundant intracellular compartments. They (s-IgA), the major antibody in saliva. Two IgA molecules
migrate to the regional lymph nodes to present antigenic linked by a J-chain are synthesised by plasma cells associated
peptides complexed to MHC-II molecules to prime naïve with salivary glands. This dimeric IgA then binds by its J-
helper T cells. The oral epithelium also forms part of an chain to a receptor for polymeric immunoglobulin (pIgR)10,11
intercommunicating network of the immune system, in on the cell membrane of salivary gland epithelium. This
which signals are regularly exchanged in dynamic complex is transported across the epithelial cell in an
interactions. Oral epithelial cells produce a range of endocytic vacuole and enters the salivary duct by its

1
Faculty of Dentistry
University of Sydney, Australia
Address for Reprints: Professor DM Walker, Oral Pathology & Oral Medicine, Westmead Centre for Oral Health, Westmead Hospital, Wentworthville,
NSW 2145, Australia.

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28 Mucosal Immunology: Overview—DM Walker

Table 1. Antimicrobial Properties of Saliva neutrophils from gingival capillaries into the gingival
Antimicrobial agent Activity sulcus attracted by bacterial peptides from the biofilm of
dental plaque and interleukin-8 from gingival epithelium.17
Secretory IgA (also s-IgG, s-IgM) Inhibits adherence. Agglutinates
[Link] neutralisation. IgA is Circulating blood leukocytes accumulate in the gingival
the major antibody in saliva. tissues in response to dental plaque. The lymphocytes first
Lactoferrin Iron-binding. Bacteriostatic. become tethered to the endothelium of high-walled post-
Lysozyme Effective against S. mutans. capillary venules or other small blood vessels. This requires
Agglutinins Glycoproteins, mucins, fibronectin, specific coupling of lymphocyte membrane receptor
2-microglobulin, histatins, proline- integrins such as L-selectin or LPAM-1 binding to vascular
rich proteins.
endothelial ligands such as GlyCAM-1 (glycosylation-
Myeloperoxidase system Bactericidal in presence of
thiocyanate/halide-H202. dependent-adhesion-molecule) or MAd CAM-1 (mucosal
Salivary peroxidase system (enzyme-thioycyanate-H202) addressin cell adhesion molecule).18 Once tethered, the
Complement (trace amounts) C3 probably largely derived from lymphocytes then roll along the endothelial surface attached
gingival crevice fluid. by integrins such as VLA-4 (very late antigen) to fibronectin
Leukocytes >98% are neutrophils, but up to 50% and VCAM1 (vascular cell adhesion molecule) expressed
may not be capable of phagocytosis. by the blood vessels. In a second phase of this transmigration
of lymphocytes, LFA1-1, (lymphocyte function-associated
molecule), an integrin on the non-villous surface of
luminal surface where cleavage of the pIgR receptor lymphocytes, becomes activated and adheres to endothelial
releases secretory IgA into saliva, with a portion of the cell ICAM-1 (intercellular-adhesion molecule).19 The
pIgR receptor, the secretory piece, still attached. Of the 2 lymphocyte becomes flattened. Finally, LFA-1-ICAM-1
subclasses of IgA, IgA 1 and 2, IgA2 subclass predominates binding with PECAM-I (platelet endothelial cell adhesion
in secretions such as saliva. molecule CD3) is also involved in diapedesis of these
Secretory IgA antibody blocks by “immune exclusion”, flattened lymphocytes between endothelial cells to exit the
inhibiting adherence of microorganisms to oral epithelium12 vessel.
or teeth. Monoclonal antibody to streptococcus mutans, a Neutrophil polymorphs are induced to slow and then
cariogenic organism, painted on the teeth in human migrate through the blood vessel wall (diapedesis) by
volunteers and in animals, inhibits colonisation by the similar processes. In inflammation, histamine from mast
organism and could provide passive immune protection cells or thrombin are released, resulting in increased
against dental caries. S-IgA can also opsonise bacteria for expression of endothelial cell P-selectin and later E-selectin,
phagocytosis by polymorphs, activate complement by the which pair with specific ligands on the neutrophil membrane.
alternative pathway, and directly neutralise some viruses.13,14 Endothelial cell PAF-I is also upregulated and binds to a
The plasma cells synthesising s-IgA are involved in the specific neutrophil receptor.
mucosa-associated lymphoid tissue, which forms the Emigration of these activated neutrophils from the blood
secretory immune system of the alimentary tract. This vessels is driven by C5a fragments and leukotriene-B4.
functions as an independent unit. The mucosa-associated Subsequently, the inflammatory reaction is continued by
lymphoid tissue (MALT) contains B & T lymphocytes macrophages elaborating a spectrum of molecules including
whose origin, repertoire, products and probably function, interleukin-1 (IL-1) and tumour necrosis factor (TNF)
are distinct.1 S-IgA secretory precursor B cells are generated acting on the endothelial cells which form E-selectin and P-
in Peyer’s patches in the small bowel. They recirculate and selectin. In this later phase, neutrophil emigration is also
are selectively guided by adhesion molecules expressed by directed by IL-8 (CXCL8) and CXCL5. MCP-1 (CCL2) is
mucosal postcapillary venules to home to particular chemotactic for monocytes and is upregulated by IL-1 and
secretory sites in the alimentary tract15 including salivary TNF.
glands. This independent function of the secretory immune Most of the neutrophil polymorphs entering the gingival
system can be exploited diagnostically in celiac disease, in sulcus by these mechanisms are functionally active and
which the abnormal immune response to dietary gliadin in capable of phagocytosis and the killing of micro-
the small bowel is mirrored in the salivary glands and we organisms. 20 Conversely, quantitative neutrophil
developed an ELISA assay for salivary gliadin antibodies deficiencies, as in neutropenias, result in uncontrolled
for the diagnosis of celiac disease.16 apical extension of dental plaque and loss of periodontal
attachment. Oral candida infections such as thrush are also
Gingival Crevice common in neutropenia. Qualitative defects, some
Even in healthy gingiva, there is a continuous traffic of genetically determined, in neutrophil or monocyte

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 Mucosal Immunology: Overview—DM Walker 29

chemotaxis or phagocytosis, for example in diabetes mellitus Class II-peptide complex is then expressed on the cell
or tobacco smoking, are also associated with aggressive surface. Helper T cells can now recognise the antigen
forms of periodontitis.21,22 presented by the Class II molecules.
On activation, Type I helper cells characteristically secrete
Activation of the Oral Immune Response TNF-alpha, IFN-gamma and IL-2 and activate macrophages
This commences with phagocytosis of antigens by and cytotoxic lymphocytes.29 These helper cells are involved
macrophages and dendritic cells in lymphoid tissue or in delayed hypersensitivity reactions. They activate
mucosal Langerhans cells. These cells process the antigens macrophages and promote IgG2A opsonising and
internally and present antigen peptide fragments associated complement fixing antibody formation. TH2 cells have a
with cell surface MHC-II molecules. The antigen-presenting different cytokine secretion profile designed for their role
cells first non-specifically and briefly link up with any T in providing help for the humoral immune response,
cells they meet by means of intercellular adhesion molecules particularly IgG and IgE synthesis and mucosal immunity
ICAM 1 and 3 binding to LFA-1. Most T cells have surface including IgA in secretions and production of mast cells
receptors made up of a heterodimer alpha and beta chain and eosinophils. Using interferon-gamma, TH1 cells can
with highly variable regions, in an immunoglobulin-like inhibit TH2 cell function and reciprocally TH2 can suppress
configuration, conferring antigen specificity. A minority TH1 cells with IL-10.
of T cells have gamma and delta chain receptors23 instead In HIV infection, the virus usually gains entry by infecting
and this subset is relatively more numerous in sites such as Langerhans cells in the vaginal or rectal mucosa and is
the tongue. Recognition of antigen associated with the carried to regional lymph nodes where it proliferates.18 Via
MHC-class II molecules on the antigen-presenting cell by its envelope gp120 glycoprotein, the HIV virus binds to the
the T cell receptor provides a first signal, but for full CD4 surface molecules expressed by T helper cells and
activation of resting T helper cells,24 a second signal is also macrophages and microglia. The depletion of CD4 T
needed from a co-stimulatory B7 (CD80 & CD86) molecule cells due to this infection correlates with the susceptibility
on the antigen presenting cell (APC), a ligand for CD28 on of AIDS patients to oral opportunistic infections by candida,
the T cell25 and interleukin-1 from the antigen presenting HSV and cytomegalovirus.
cell. The helper T lymphocyte response is MHC restricted
and CD4 surface molecules on the T helper cells associate Cytotoxicity
with MHC-II molecules on the macrophages. T cell CD2 is Cytotoxic T cells have specific receptors which recognise
also always involved in this T cell – APC interaction. The viral antigens presented by MHC-1 on the membrane of
switched-on T cells now synthesise IL-2, which has an infected cells. Other T cell ligands such as LFA-1 and CD2
autocrine effect via specific receptors in triggering T cell help to attach the T cells to the target cell. Natural killer
proliferation. Other T cell cytokines released include IFN- (NK) cells can identify viral antigens on cells lacking
gamma, granulocyte macrophage-colony stimulating factor MHC-1 antigens, which is useful, for example, in herpes
(GM-CSF), IL-4 and TNF-beta. infection in which MHC-1 antigens may be suppressed.
The antigen-presenting cells also contribute to this phase T cells and NK cells may kill target cells by discharging
of cytokine signalling, producing IL-1, IL-6, TNF-alpha, granules containing perforins which punch holes in the
IL-12 and IL-15. Class I restricted T cells recognise membrane of the attacked cell. Serine esterases, collectively
endogenous viral or self-proteins within the target cell termed granzymes, then penetrate the target cells through
broken down into antigenic peptides within organelles these pores. Some cytotoxic T cells without granules
called proteasomes.26 These antigen peptides enter the upregulate ligands which in trimerised form can in turn
endoplasmic reticulum and are introduced to MHC-1 trimerise with Fas (CD95) TNF receptors on the target cell
molecules synthesised there.24,27 These complexes pass surface. This sends a signal through the cell membrane for
through the Golgi apparatus and are carried in transport the target cell to activate a family of caspase molecules,
vesicles to be displayed on the cell surface.28 resulting in apoptosis. Antibody-dependent cytotoxicity
MHC-II molecules in the endoplasmic reticulum combine and NK cell activity are major responses associated with
with polypeptide invariant chain Ii and this complex passes mucosal lymphocytes.30,31
via the Golgi apparatus to a MIIC vesicle where the Ii is This brief overview has attempted to show how the
cleaved to a smaller CLIP fragment (Class II associated various anatomical regions in the mouth, teeth and salivary
invariant peptide). Exogenous bacterial antigens enter the glands have different micro-environments with specialised
cell by endocytosis and after degradation to antigenic immune systems designed to maintain oral health. A better
peptides, displace the CLIP fragment from the antigen- understanding of oral immune mechanisms from future
binding groove in the MHC-II molecules and the resulting research should lead to improved control or prevention of

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30 Mucosal Immunology: Overview—DM Walker

viral and fungal oral infections, particularly in the in mice infected with influenza A virus by the respiratory route is
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16. al-Bayaty HF, Aldred MJ, Walker DM, Newcombe RG, Swift G, Smith
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