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References
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103 Gary SE, Ryan E, Steward AM, Sidransky E. Recent advances in the diagnosis and management
of Gaucher disease. Expert Rev Endocrinol Metab. 2018;13(2):107– 18. https://doi.
org/10.1080/17446651.2018.
104 Patterson M Niemann- Pick Disease Type C. 2000Jane 26 [Updated 2020 December 10]. In: Adam
MP, Feldman J, Mirzaa GM, etal., editors. GeneReviews® [Internet]. Seattle (WA): University of
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106 Ramani PK, Parayil Sankaran B. Tay- Sachs Disease. [Updated 2023January 25]. In: StatPearls
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107 MacQueen GM, Rosebush PI, Mazurek MF. Neuropsychiatric aspects of the adult variant of
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108 Abbaspour N, Hurrell R, Kelishadi R. Review on iron and its importance for human health.
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111 Bermejo F, García- López S. A guide to diagnosing iron deficiency and iron deficiency anaemia in
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112 Warner MJ, Kamran MT. Iron Deficiency Anemia. [Updated 2023 August 7]. In: StatPearls
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113 Kumar A, Sharma E, Marley A, Samaan MA, Brookes MJ. Iron deficiency anaemia:
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114 Verma S, Mukherjee S. Plummer- Vinson Syndrome. [Updated 2023 February 7]. In: StatPearls
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115 Samad A, Mohan N, Balaji RV, Augustine D, Patil SG. Oral manifestations of plummer- vinson
syndrome: a classic report with literature review. J Int Oral Health. 2015;7(3):68– 71.
116 Novacek G. Plummer- Vinson syndrome. Orphanet J Rare Dis. 2006;1:36. https://doi.org/10.118
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117 Goel A, Bakshi SS, Soni N, Chhavi N. Iron deficiency anaemia and Plummer– Vinson syndrome:
current insights. J Blood Med. 2017;8:175– 84. https://doi.org/10.2147/JBM.S127801.
118 Lykstad J, Sharma S. Biochemistry, Water Soluble Vitamins. [Updated 2023March 6]. In:
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119 Reddy P, Jialal I. Biochemistry, Fat Soluble Vitamins. [Updated 2022 September 19]. In:
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120 Sahay M, Sahay R. Renal rickets- practical approach. Indian J Endocrinol Metab. 2013;17(Suppl 1):
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121 Acar S, Demir K, Shi Y. Genetic Causes of Rickets. J Clin Res Pediatr Endocrinol. 2017;9(Suppl 2):
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122 Cohen S, Becker GL. Origin, diagnosis, and treatment of the dental manifestations of vitamin
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123 Mornet E. Hypophosphatasia. Orphanet J Rare Dis. 2007;2:40. https://doi.org/10.1186/1750
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124 Bangura A, Wright L, Shuler T. Hypophosphatasia: current literature for pathophysiology, clinical
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Section 3
Defence Mechanisms Against Disease
133
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10
Immunity andHost Defence Mechanisms inOral Health andDisease
Irene Lafuente- Ibáñez de Mendoza and José M. Aguirre- Urizar
Department of Stomatology, University of the Basque Country UPV/EHU, Leioa, Spain
This chapter covers the most important immunological and defence mechanisms involved in the
oral cavity, outlining the main physiological responses to external pathogens, and the involvement
of the immune response in the development of autoimmune pathologies with intraoral involvement.
10.1 Immunity andHost Defence Mechanisms inthe Oral Cavity
135
The immune system is the primary defensive mechanism of the oral cavity against microbial
invasion and recognition of both endogenous and exogenous molecules. The oral immune response
comprises a set of cellular and molecular mechanisms that, under physiological conditions, are
driven by the innate (non- specific) and adaptive (specific agents) immune systems (1). Their
dysregulation can lead to immunopathological including even carcinogenic reactions.
10.1.1 Innate Immune Response (Non- specific)
In many cases, innate immunity modulates the initial immune response. This system encompasses
a broad set of protective elements such as physical– epithelial barriers, the monocyte– macrophage
system, polymorphonuclear and dendritic cells, soluble molecules (cytokines, chemokines, antibacterial peptides, etc.) and complement system proteins. It is a nonspecific response, which does
not increase with antigenic exposure(2, 3).
The oral mucosa plays a vital role in general innate immunity due to its proximity to the external
environment and antigenic exposure. The squamous epithelium and lamina propria create a solid
and resistant physical barrier against many toxic agents (4). Moreover, the oral cavity possesses
specific cellular elements (Langerhans dendritic cells and keratinocytes) and inflammatory- immune
mediators (α- defensins, IgA, etc.) located on the mucosal surface, crevicular fluid or saliva, which
have broad- spectrum antimicrobial activity and provide additional immune action. Local mucosaassociated lymphoid tissues (lymphoid nodules, salivary glands and Waldeyer’s ring lymphoid
tissue) also facilitate the uptake and processing of pathogens(4, 5).
Unlike the slower adaptive response, innate immunity is fast. To this end, specific antigenpresenting cells (APC), mainly immature myeloid basal and parabasal dendritic cells, through
Pathological Basis of Oral and Maxillofacial Diseases, First Edition. Edited by S. R. Prabhu, Syed Ali Khurram,
Omar Kujan and Merva Soluk Tekkesin.
© 2025 John Wiley & Sons Ltd. Published 2025 by John Wiley & Sons Ltd.
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136
their surface pattern recognition receptors (PRRs) (Toll- like receptors [TLRs], CD1a, etc.), induce
different immune responses to maintain the state of immune tolerance(2). These receptors identify pathogen- associated molecular pattern molecules (PAMPs) expressed by microbes or damageassociated molecular patterns (DAMPs) produced by injured or necrotic cells, which are then
processed and presented on major histocompatibility complex (MHC) molecules(3). Activation of
these receptors triggers an inflammatory response via secretion of cytokines and chemokines
(IL- 1β and IL- 8), transforming the phagocytic but immature dendritic cells into immunogenic
cells capable of generating lymphocytic responses, leading to the advanced- adaptive immune
response. Keratinocytes also express several families of PRRs like TLRs and Nod- like receptors
(NLRs), which also produce antimicrobial peptides (IL- 37, β- defensins, prostaglandin E2, NO, OH,
O2, C3b, C5a)(2, 3, 6).
A well- known example of non- specific innate immune response is that of cariogenic disease(7).
In the early stages of tooth decay, multiple cells (odontoblasts, macrophages, neutrophils or
immature Langerhans’ cells) group together to facilitate the repair of the dental pulp (reversible
pulpitis). The contact between the antigens of certain acidogenic bacteria such as Streptococcus
mutans (capsular lipopolysaccharides, lipoteichoic acid, etc.) and PRR triggers a proinflammatory
molecular magma (IL- 1, IL- 6, IL- 8, tumour necrosis factor- a [TNF- α], interferon γ [IFNγ],
histamine, etc.) that induces plasma extravasation, oedema and increased intrapulpal pressure.
These molecular mediators also stimulate pulpal afferent nerve fibres, causing pain(5, 7).
10.1.2 Adaptive Immune Response (Specific)
The adaptive immune response is regulated by lymphocytic cells characterised by the expression
of specific antigen receptors. Each lymphocyte only recognises one antigenic configuration;
however, the human lymphocyte population can recognise more than 100 antigens(8).
Cells of the immune system are organised into two defined tissues: lymphoid generative organs
that produce mature lymphocytes (bone marrow and thymus) and peripheral lymphoid organs
where the immune reaction occurs. In the head and neck region, these areas correspond to
the cervical lymph nodes, Waldeyer’s ring and lymphoid foci located in the lamina propria of the
mucosa(4). Under inflammatory or infectious conditions, plasmacytoid and myeloid cells migrate
towards the oral mucosa to perform their activity.
There are two types of adaptive immune response: cellular and humoral. Cell- mediated adaptive
immunity fights against cells expressing foreign cytoplasmic antigens (phagocytosed microbes,
+
intracellular pathogens and tumour cells) via cytotoxic T lymphocytes (CD8
T cells) regulated by
cytokines. Humoral adaptive immunity battles extracellular pathogens through B- lymphocytes
+
that produce antibodies with the aid of helper T lymphocytes (CD4
T cells). Later, these
immunoglobulins activate macrophages to destroy ingested microbes and stimulate leukocyte
recruitment(9).
Thymus- derived T cells express antigenic T- cell receptors (TCR), which recognise peptide fragments of protein antigens on the surface of APC, preferentially dendritic cells and macrophages(9).
Dendritic cells involved in adaptive immunity are distinct from innate immunity in their expression of PRR, cytokine release and ability to induce antigen- specific responses. Furthermore, these
cells sometimes depend on the help of natural killer (NK) lymphocytes. After identification, APCs
transport the different pathogenic and antigenic elements to lymphoid organs via MHC molecules
named ‘human leukocyte antigens’ (HLA) and deploy them for recognition by T lymphocytes. This
process induces the activation, proliferation and differentiation of effector and memory cells and
the clonal expansion of antigen- specific T- cell responses(10).
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Periodontal health Periodontitis
(a) (b) (f)
Bone marrow- derived B lymphocytes identify antigens by membrane- bound antibodies, which are
later activated and transformed into plasma cells capable of secreting antibodies. The immunoglobulin isotype involved in the humoral immune response of the oral mucosa is immunoglobulin A
(IgA)(4). The maturation of B cells diversifies their immunoglobulin gene repertoire, making them
highly susceptible to pathogenic microorganisms and their toxins. Antibodies secreted by plasma
cells neutralise microbes and block their infectivity, enabling their phagocytosis and destruction(11).
Periodontal disease is a good model of interaction between innate and adaptive immunity(12).
In order to maintain periodontal health, receptors located in the Langerhans cells, macrophages,
keratinocytes, fibroblasts, osteoblasts, osteoclasts or cementoblasts, together with cytoplasmic
infected cell receptors (NLR) and the complement system, recognise specific intracellular and
extracellular pathogens like Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis and
Tannerella forsythia. This interplay sets off different intracellular signalling pathways for pathogenic elimination through phagocytosis and opsonisation. Increased numbers of commensal
microorganisms, secretion of proinflammatory cytokines and stimulation of TLRs lead to gingivitis(7). In more advanced stages of periodontal disease, overstimulation of TLR pathways leads
to an exaggerated production of strong proinflammatory cytokines (IL- 1, IL- 6, IL- 18, TNF- α,
prostaglandins, thromboxanes, leukotrienes, matrix metalloproteinases [MMPs], cathelicidin,
β- defensins, receptor activator for nuclear factor κB ligand [RANKL], oxygen free radicals, etc.),
which provokes mucosal inflammation and bone resorption(12) (Figure10.1).
Due to the multitude of infectious, traumatic, irritative, etc., factors affecting the oral cavity, the
host immune system works in a coordinated manner to guarantee a homeostatic physiological
137
(c)
Figure10.1 (a) Gingiva with periodontal health; (b) periodontal microbiome complex (plaque);
(c)interaction of microbes with periodontal defence elements; (d) periodontal cell and tissue activation
andproliferation; (e) secretion of inflammatory mediators which lead to clinical attachments loss, swelling
and bone resorption; (f) periodontitis.
t.me/Dr_Mouayyad_AlbtousH
(d)
(e)
IL-1, IL-6, IL-18
TNF-α
Prostaglandins
Thromboxanes
Leukotrienes
MMPs
Cathelicidin
β-defensins
RANKL
Oxygen free
radicals
........
138
balance. Immature immune cells stay in a silent- latent manner (immune tolerance), migrating to
the draining lymph nodes to suppress unnecessary immune response (anergy), and IgA mutes
foreign antigens, limiting microbial colonisation and providing non- inflammatory protection to
the oral cavity(4, 13).
10.2 Hypersensitivity
10.2.1 What Is It?
Hypersensitivity reactions are harmful and excessive immune responses towards an antigenic
stimulus due to an imbalance of effector and regulatory mechanisms. These immune- related pathologies result from exogenous environmental antigens or endogenous self- antigens ( autoimmune
disease)(14).
10.2.2 Types ofHypersensitivity andAutoimmune Diseases inthe Oral Cavity
Immune reactions against self- antigens (autoimmunity) are caused by the disruption of selftolerance, i.e. the normal state of not responding to self- antigens. Autoimmune diseases are
mediated by autoantibodies and/or autoreactive T lymphocytes(15).
Central tolerance is when T cells that recognise self- antigens are rendered harmless (negative
selection), and B cells rearrange their immunoglobulin profile to generate new non- reactive receptors (receptor editing). If the lymphocyte clonal elimination is imperfect and peripheral tolerance
is ineffective, ‘normal’ T and B cells generate responses against self- antigens that lead to autoimmune diseases(16). On the contrary, peripheral tolerance refers to the mechanism by which
self- reactive cells that have escaped central regulatory systems can be eliminated or inactivated
through (i) anergy (irreversible functional inactivation), (ii) suppression by CD4
T cells, (iii) elimination by apoptosis (Bim and FasL) and (iv) tissue antigenic sequestration
( physical barrier)(15).
Autoimmunity is conditioned by predisposing genes and environmental triggering factors.
Multigene alterations are not the only cause, but the presence of specific gene alleles, such as HLA,
is strongly associated with the aetiopathogenesis of many autoimmune disorders (diabetes
mellitus I, rheumatoid arthritis, inflammatory bowel disease, etc.) (15, 17). On the other hand,
positive stimulating factors, such as infectious processes or solar radiation, can overcome
peripheral control and break tolerance by molecular mimicry, altering the structure of the
self- antigens, which, in turn, generates a new lymphocyte response(16).
All autoimmune diseases respond to the following phases: (i) defective immune response
tolerance, (ii) abnormal deployment of self- antigens and (iii) inflammatory lymphocyte activation.
Once induced, these pathologies tend to be progressive, with activation and remission episodes(15).
The clinical and pathological consequences of a specific autoimmune disease will depend on the
nature of the response; nevertheless, it can show many overlaps, making it difficult to classify
some disorders into a single type of hypersensitivity(14).
+
regulatory
10.2.2.1 Immediate Hypersensitivity (Type I)
Immediate hypersensitivity or ‘allergy’ is mediated by immunoglobulin E (IgE) antibodies directed
against specific antigens (allergens), systemically or site- specifically located. IgE synthesis results
+
from the release of IL- 4 and IL- 13 by helper CD4
t.me/Dr_Mouayyad_AlbtousH
cells(18).
10.2 Hypersensitivity
IgE antibodies bind to mast cells via specific surface receptors, and upon exposure, the allergen
binds to these receptors, resulting in an immediate reaction (5– 30 minutes), with the release
(degranulation) of preformed vesicles (primary mediators) and vasodilatation. Subsequently, a late
reaction (2– 34 hours) occurs, characterised by an inflammatory infiltrate of B cells that secrete
IL- 5, activates eosinophils and generates a new tissue injury with the release of secondary mediators (leukotrienes, prostaglandin, TNF- a, IL- 1, etc.)(19).
More than 20% of the population is considered to suffer from immediate hypersensitivity
reactions. However, oral IgE- mediated reactions are uncommon, and these are usually related to
contact with drugs, food, dental materials, cosmetics or metals(20). Acute signs appear hours after
contact as erythematous, pruritic and urticarial lesions on the oral mucosa or facial surrounding
skin. In the case of angioneurotic oedema, excessive mast cell and histamine degranulation induces
a diffuse oedematous swelling of submucosal soft tissue, including the oral cavity(21).
10.2.2.2 Antibody- Mediated Hypersensitivity (Type II)
Antibody- mediated hypersensitivity occurs due to antibodies against extrinsic or endogenous antigens of the cell surface or extracellular matrix. This type of immune response encompasses three
different mechanisms: (i) opsonisation and phagocytosis (via the C3b complex of the complement
system), (ii) inflammation (via neutrophils, macrophages and harmful reactive oxygen species)
and (iii) cellular dysfunction(14, 22).
Important diseases associated with antibody- mediated hypersensitivity can appear in the oral
cavity. Pemphigus is a mucocutaneous intraepithelial blistering disorder associated with circulating IgG antibodies to desmoglein, which has different clinicopathological subtypes: vulgar,
foliaceous, paraneoplastic and erythematous. The binding of these autoantibodies disrupts the
epithelial intercellular junction and activates intercellular proteases(23). The most common variant is pemphigus vulgaris, whose antibodies bind to desmosomal desmoglein one and three, and
in which oral mucosal lesions can be the first sign of the disease in many cases (>50% of patients).
Pemphigus also affects the scalp skin, face, trunk and intertriginous areas(24). Microscopically,
intraepithelial blisters show acantholysis, intercellular clefts and adherence of basal cells alongside a variable inflammatory infiltrate. Immunofluorescence shows a reticular pattern of IgG, IgM
and C3 deposition within the intercellular spaces of the keratinocytes(23). Oral blistering lesions
rupture rapidly leaving irregular ‘fresh blood’ ulcerations, situated on the palate, buccal mucosa,
lips or tongue. Gingival involvement is called ‘desquamative gingivitis’, a non- specific clinical
lesion that also appears in other oral immune disorders, mainly mucous pemphigoid and oral
lichenoid reactions and lichen planus(25) (Figure10.2).
Pemphigoid entitles a group of chronic mucocutaneous autoimmune disorders distinguished by
the development of subepithelial blistering lesions. Patients with mucous pemphigoid generate
autoantibodies against basement membrane components such as laminin five and six. Direct
immunofluorescence studies of the perilesional mucosa show deposits of IgG, C3, IgA and IgM in
the basement membrane, resulting in a diagnostic linear pattern(26). When the subepithelial oral
blisters of pemphigoid rupture, these usually leave large, painful ulcerated areas. Other regions
arealso commonly affected, including nasal, oesophageal, laryngeal, vaginal and ocular mucosa;
scarring in the latter can even lead to blindness(25, 27).
139
10.2.2.3 Immunocomplex- Mediated Hypersensitivity (Type III)
Immunocomplex- mediated hypersensitivity is caused by antigen– antibody complexes formed in
the systemic circulation (systemic disease) or at antigen deposition sites (local disease). These
t.me/Dr_Mouayyad_AlbtousH
(a) (b) (c) (d)
(e)
140
(f) (g) (h)
Figure10.2 (a) Oral pemphigus vulgaris with buccal and palatal ulcerations, some with a characteristic
‘fresh meat’ appearance; (b) scheme of an intraepithelial mucous pemphigus blister; (c) immune- mediated
acantholysis with suprabasal separation of keratinocytes and blister formation (H&E); (d) direct
immunofluorescence of pemphigus with IgG deposits arranged in a reticular pattern; (e) gingival mucous
pemphigoid with an ulcerated lesion and blister roof; (f) scheme of a subepithelial blister of mucous
pemphigoid; (g) subepithelial blister with complete separation of the epithelium and subepithelial
inflammation (H&E); (h) direct immunofluorescence of pemphigoid with linear IgG deposits.
antigenic structures can either be exogenous (infectious microorganisms) or endogenous
(lupuserythematosus, rheumatoid arthritis, etc.)(14).
The immune response of type III hypersensitivity has three phases: (i) immune complex formation, in which newly synthesised antibodies appear one week after antigen inoculation, forming
circulating immune complexes; (ii) deposition of the immune complex, depending on its physicochemical nature and local vascular characteristics; and (iii) injury caused by the immune complex.
This tissue damage is caused by activation of the complement cascade and perivascular neutrophilic
inflammatory infiltration (vasculitis). Hereby, necrosis and proteinaceous accumulation lead to
fibrinoid necrosis. Over time, repeated antigen exposure induces chronic and recurrent tissue
injury with fibrosis and loss of vascular function(22).
The classic immunocomplex- mediated hypersensitivity disease is lupus, which is more frequent
in women (9:1) and shows a high incidence (1/2500inhabitants) and multiple clinicopathological
forms (28). Aetiopathogenesis of this collagen- vascular disease involves genetic, immune and
environmental factors (ultraviolet light, oestrogens, etc.). Defective elimination of autoreactive
B- lymphocytes and ineffective peripheral tolerance mechanisms contribute to inappropriate activation of B lymphocytes, producing autoantibodies against antinuclear antigens (ANA): anticDNA and Smith antigen. The resulting immunocomplexes are taken up by B cells and plasmacytoid
dendritic cells, which produce cytokines and further autoantibodies(29). The clinical manifestations of lupus are quite variable and may begin insidiously as a febrile illness or as nonspecific
joint, skin or renal symptoms. Oral lesions are rare and usually appear in patients with discoid
lupus erythematosus as atrophic and erosive lesions with peripheral striations, similar to oral
lichenoid disease (30). Histopathology of the oral lesions shows hyperkeratosis, atrophy, basal
degeneration and classic chronic perivascular inflammatory foci in the submucosa.
Another important oral disorder within this group of immune pathologies is Sjögren syndrome,
which mainly affects young adult women (40– 50 years) and is characterised by oral hyposialia
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