THE IMMUNE SYSTEM: PROTECTION FROMPATHOGEN CHALLENGE
A significant number of oral diseases result from defects or deficits in the immune system. The immune system is extremely complex, but is composed of both the innate and adaptive immune systems, served by diverse cell types that have the primary function of defending the body against infection. To achieve this, the immune system has to distinguish between self and non‐self and identify foreign invaders as distinct from self.1 In this way, the immune system can recognize and clear invading pathogens such as viruses, bacteria, or parasites, but tolerate antigens derived from innocuous proteins, and self‐antigens as well as commensal microbiota. When responding to an invading pathogen, the immune system is responsible for coordinating an effective immune response, which will not only neutralize the invading pathogen, but remove dead or damaged cells and turn itself off once the pathogen has been removed. Furthermore, the immune system is tasked with mediating responses to injury, cell death, and tumor surveillance. An appropriately functioning immune system is vital for life and its importance is highlighted by the fact that its dysfunction underpins a plethora of diseases, ranging from infection to cancer and autoimmunity; within the oral cavity, immune system dysfunction contributes to the pathology of gingivitis, periodontitis, oral infections, and autoimmune manifestations of systemic or local disease.
Immune responses in humans, and indeed all vertebrates, are mediated by two distinct yet connected systems: the innate and the adaptive immune systems.2 The innate immune system is immediately activated upon injury or pathogen encounter. This activation occurs in a nonspecific manner, but is often capable of independently eliminating the invading insult. However, when the innate immune response is unable to control the insult, it will recruit and activate an adaptive immune response. The adaptive immune system is highly targeted, not only ensuring that the right type of immune response is activated for the type of infection, for example viral verses parasitic, but also becoming targeted to the specific invader. Moreover, it will later provide memory for the specific pathogen, allowing a faster, more effective immune response to be mounted upon any subsequent encounter with the same pathogen. The two systems are heavily connected. However, the innate immune system is absolutely vital for effective protection against injury and infection, particularly at mucosal sites.
THE IMMUNE SYSTEM OF THE MOUTH
Successful defense of oral mucosal barriers requires secretion of saliva, an effective epithelial barrier, and activation of innate and adaptive immune cells. Indeed, we consider saliva, a mucosal barrier, and the immune cell network to be the pillars of the oral immune system (Figure 19‐1).
Saliva, the extracellular fluid secreted by salivary glands in the mouth, plays a critical role in immune protection at the oral mucosal barrier. Saliva contains 99% water, but also electrolytes, enzymes for digestion (amylase, lipase), mucus, and antimicrobial components. Key antimicrobial components in saliva are secretory immunoglobulin (Ig) A, microbiocidal enzymes such as lysozyme, lactoperoxidase, lactoferrin, proline‐rich proteins, and antimicrobial peptides (histatins, defensins, secretory leukocyte protease inhibitor [SLPI]). Saliva provides constant lubrication and ensures the health and integrity of the mucosal barrier. Indeed, patients with reduced or absent saliva (dry mouth to hyposalivation) suffer from mucosal inflammation and ulcerations, which lead to pain and difficulty eating. Saliva also clearly provides effective antimicrobial defense, particularly toward specific microbial pathogens. In fact, patients with xerostomia present predominantly with oral candidiasis (a mucosal infection with Candida albicans) as well as severe to rampant dental infections with “cariogenic” (dental caries–causing) bacteria, such as Streptococcus mutans.
The oral epithelial barrier is a key interface of the human body with the external environment, providing physical, structural, and immunologic protection to infectious challenge. The oral mucosa is lined with a multilayer squamous cell epithelium. This epithelium is fortified to a different extent depending on the area of the oral cavity and its functional needs. In the hard palate, dorsum of tongue, and gingiva, the epithelium is fully keratinized to withstand the constant mechanical damage induced during mastication. However, the majority of the oral epithelial barrier is composed of lining epithelium, a multilayered squamous cell epithelium with minimal keratinization. Such epithelium lines the buccal mucosa, the labial mucosa, the gingival crevice, and the floor of the mouth. These areas are more exposed to the outside environment, not only because of minimal keratinization, but because some of them have thinner epithelium and increased vascularity (such as the floor of the mouth).
However, possibly the most exposed and vulnerable site of the oral mucosal barrier is the junctional epithelium (the connection between teeth and mucosa). The junctional epithelium, which directly attaches to the surface of the tooth, is only three to four cells thick at its narrowest points near the teeth and is nonkeratinized. This means that the junctional epithelium is a weak point in the oral mucosal barrier. However, by being nonkeratinized, it is permeable, and therefore serves as the primary pathway for the transmigration of immune cells, particularly neutrophils, and fluid into the oral space. This fluid, termed gingival crevicular fluid, contains host‐defensive proteins that are then at a high concentration on the external side of the junctional epithelium. Thus, the oral epithelium is locally specialized, providing a physical barrier protecting underlying tissues. Alongside this, oral epithelial cells are key sources of pro‐inflammatory cytokines and chemokines and directly respond to pathogens; as such, disruption of the epithelium constitutes a risk factor for infection and aberrant inflammation.
The oral cavity is constantly exposed to environmental stimuli, including a resident commensal bacterial community, continuous damage from mastication, and pathogen challenge. The ceaseless nature of these local triggers requires active immune surveillance within the mouth. This means that in addition to saliva and specialized epithelium, immune cells are resident even within healthy oral mucosa to ensure effective barrier defense, regulation, and healing. Here we will introduce the main mediators of the immune system, first those of the innate and then the adaptive immune system, outlining how these systems play key roles in safeguarding health and driving pathology.
The major innate immune cells present within the oral mucosa are neutrophils. These are short‐lived (24–48 hours) cells that make up about 70% of peripheral blood white blood cells. Neutrophils are activated by bacterial products, exhibiting profound antimicrobicidal activity, through ingestion of bacteria (phagocytosis) and release of soluble and nonsoluble components that can trap and kill extracellular pathogens.3 These cells are rapidly mobilized to sites of pathogen invasion, being the first innate immune cells to extravasate from blood vessels, via a well‐defined series of events, and migrate toward the infection. Here, neutrophils release reactive oxygen species (ROS), granules containing cytotoxic compounds and antimicrobial peptides, and neutrophil extracellular traps (NETs), which combined create an environment proficient at pathogen killing, degradation, and removal.
Even in health, neutrophils constitute the majority of immune cells present in the gingival oral barrier. Neutrophils constantly traffic from the circulation, through gingival tissue and junctional epithelium, into the gingival crevice. It has been demonstrated that about 30,000 neutrophils undertake this journey every minute in humans, and as such neutrophils can be found within the oral cavity.4 The functional contributions of neutrophils outside the tissue, within the oral cavity, remain to be defined, but it is clear that effective neutrophil surveillance of the gingival barrier is vital for oral health, as oral inflammation routinely occurs when neutrophil functions and numbers are dysregulated.
Other innate immune cells resident within the oral mucosa include mononuclear phagocytes, phagocytic cells including monocytes, macrophages, and dendritic cells (DCs).5 The main function of monocytes, and their macrophage progeny, is to internalize pathogens and dead/dying cells and degrade them in an organelle that has a low pH and is filled with hydrolytic enzymes: the phagosome. In this way, monocytes and macrophages are considered functionally plastic, as they mediate key roles in both pathogen protection, but also tissue repair and healing. At other mucosal sites, macrophages are crucial for the maintenance of barrier homeostasis, adopting barrier‐specific functions that support health. For example, in the gastrointestinal tract, macrophages constitutively produce the anti‐inflammatory cytokine interleukin (IL)‐10. However, the functional characteristics and importance of macrophages within the oral barrier remain to be determined.
The main function of DCs is to internalize and process foreign particles to generate small peptide antigens that can be presented on their cell surface to T cells. Therefore, DCs are considered “professional” antigen‐presenting cells (APCs) and are key initiators of the adaptive immune response. Upon activation, barrier‐resident DCs become more effective at processing and presenting antigens and drain to local lymph nodes, where they interact with, and activate, T cells. Langerhans cells are perhaps the best studied of the oral DCs, residing in the oral epithelium, but multiple populations of DCs have been described, each of which exhibits enhanced capabilities at initiating specific types of T‐cell response. Although the DC populations at certain oral barriers have been well characterized, we are only just beginning to understand how distinct subsets contribute to the mounting of effective T‐cell responses within the oral cavity.
The complement system is a major arm of innate immunity that enhances pathogen clearance by promoting pathogen phagocytosis, antigen presentation, and immune cell activation, and can also attack the cell surface of any invader. The complement system consists of multiple plasma proteins (C1‐9), pattern‐recognition molecules, and proteases that operate in a cascade to opsonize pathogens and induce pro‐inflammatory responses. As such, complement plays a vital role in promoting effective immune responses upon pathogen challenge. However, complement can also become dysregulated and has been shown to contribute to pathology in diseases such as cancer and autoinflammatory diseases; in particular, excessive complement activation is seen in patients with periodontitis.
Alongside these key innate immune mediators are populations of cells that exhibit characteristics of both the innate and adaptive immune systems. These include innate lymphoid cells (ILCs), natural killer (NK) cells, and γδ‐T cells. Although lymphocytes, these cells are not activated by peptide antigens and instead rapidly respond to signals of tissue and cellular perturbation, either producing an array of immunomodulatory cytokines or inducing cell death of infected cells. In mediating such functions, ILCs, NK, and γδ‐T cells are all at low frequencies in peripheral blood but are enriched at mucosal barrier sites. Within the oral cavity all these immune cells have been identified,6 with specialized populations of ILCs and NK cells present in salivary glands and oral barrier‐resident γδ‐T cells being shown to safeguard gingival immune homeostasis and limit periodontitis development.
Activation of innate immunity culminates in the development of highly specific immune responses, which are antigen specific and coordinated by cells of the adaptive immune system, specifically lymphocytes. There are two types of lymphocytes, B cells and T cells, which express genetically rearranged and extremely diverse antigen receptors. These receptors allow the B or T cell to be activated in an antigen‐specific manner, thus imparting the specificity exhibited by these cells.
The B‐cell receptor is a surface‐bound immunoglobulin molecule, which recognizes both linear and conformation antigens. Recognition of antigen via this immunoglobulin receptor, alongside some additional activation signals, allows B cells to start producing soluble immunoglobulins, also known as antibodies. Antibodies can neutralize pathogens, for instance bind to viruses and prevent cell entry, activate immune cells, and activate the complement cascade. Initially B cells will produce IgM; however, as the immune response develops, B cells undergo class switching, a genetic rearrangement that allows B cells to produce other antibody isotypes: IgG, IgA, IgD, or IgE. The different isotypes have distinct constant regions that do not participate in antigen binding, but instead are important for the effector function of the antibody. For example, IgE will preferentially bind to antibody receptors expressed on mast cells, triggering the release of histamine during parasitic worm infection and allergy. IgG is the dominant antibody found in plasma and can be transported across the placenta to impart a degree of fetal protection.
The mouth is part of the mucosal immune system, embracing all mucosal epithelium including that of the gut, lungs, respiratory and genital tracts, breast, and eyes and with a total surface area of 400 m2. The surfaces are protected by mucins but adaptively by secretory IgA, which can be induced by immunization in the gut or nose and independently from serum IgA. Thus, antibodies found in secretions, such as saliva or bronchial secretions, are usually IgA (or sometimes IgM) produced by plasma cells within mucosal tissues. The IgA secreted by plasma cells in the lamina propria links to the secretory component, which facilitates antibody transport through the secretory epithelium. Mucosal IgA is mainly dimeric, in contrast to serum IgA. It protects by virus or enzyme neutralization, by aggregation of bacteria, and by preventing adherence of pathogens to the host.
Oral commensal bacteria‐specific antibodies, predominantly IgA, can be detected in the oral fluids of even healthy individuals and certain oral commensals have been shown to be coated in IgA. In addition, autoantibodies in various autoimmune diseases can be detected in saliva, which can be used as a diagnostic fluid. Serum antibodies against oral commensal bacteria have also been detected, and there are some indications that they may help regulate the bacterial communities on the surfaces of the teeth and more generally within the oral cavity, acting via crevicular fluid.
For T cells to become activated, antigen must be processed and bound to a class I or class II major histocompatibility complex (MHC) molecule on the surface of an APC. Antigens recognized by the T‐cell receptor are short linear peptide sequences, which are recognized in the context of the MHC in which they are presented. In terms of T‐cell activation, encounter of cognate antigen bound to MHC is considered “signal 1,” but an additional signal is required for full T‐cell activation. “Signal 2” is co‐stimulation, whereby ligand‐receptor pairs on the surface of the T cell and APC interact to further promote T‐cell activation; in this way T‐cell activation is strictly controlled.
There are two types of T cells: CD4+ and CD8+ T cells. CD8+ T cells are activated by peptide antigens of intracellular origin (therefore most likely viral antigens), which are presented by MHC class I molecules. Activated CD8+ T cells proliferate and differentiate to become cytotoxic lymphocytes (CTLs), which are highly effective killing machines capable of inducing the cell death of multiple target cells presenting their specific antigen. CD4+ T cells are activated by peptides bound to MHC class II molecules, whereupon they differentiate into different subsets of T‐helper (Th) cells.7 CD4+ T cells can be considered to require a “signal 3,” which drives the activated CD4+ T cell to differentiate into either a Th1, Th2, Th17, or regulatory T cell (Treg). Th1 and Th2 cells were the first CD4+ T cell subsets identified in the 1980s. Th1 cells help promote the clearance of bacteria and viruses, whereas Th2 cells are generated in response to parasitic worm infections and help fight off these large extracellular pathogens. Th1 cells predominantly produce the cytokine IFNγ, which activates macrophages, making them more effective at phagocytosing and killing pathogens and supports CD8+ T cell differentiation into CTLs. Th2 cells predominantly produce the cytokines IL‐4 and IL‐13. These cytokines subsequently promote a coordinated immune response that clears worm infection by promoting eosinophil recruitment and epithelial shedding.
More recently, Th17 cells have been identified, which are distinguished by their production of the cytokines IL‐17A and IL‐17F.8 This subset is vital for defending against fungal infection, and individuals with defects in the generation or function of this subset frequently present with persistent candidiasis. Th17 cells promote neutrophil recruitment to the site of infection and also enhance the production of antimicrobial peptides by epithelial cells. The final classical subset of CD4+ T cells is Tregs; unlike the other subsets, Tregs do not promote effective immunity, but instead play key roles in the suppression of immune responses. Tregs are defined by the expression of the transcription factor Foxp3 (or scurfin) and have been shown to be vital mediators of peripheral tolerance. Their importance to health is highlighted by the severe autoinflammatory disease that results in their absence; individuals with mutations in the Foxp3 gene develop IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X‐linked), a lymphoproliferative disease in which self‐reactive T cells target multiple bodily organs and inappropriate T‐cell responses are mounted to harmless antigens. Indeed, defects in Treg numbers and function have been identified in patients with a plethora of different inflammatory diseases. Of note from a therapeutic standpoint is that in experimental systems, increases in Tregs have been shown to limit the pathology of autoinflammatory diseases, including periodontitis.
Following the clearance of any invading organism, most activated, differentiated T‐cell populations undergo apoptosis as pathogen‐derived antigens are removed. However, a subset of antigen‐specific T cells survives and persists long‐term after pathogen clearance. These are known as memory T cells and remain within the body to rapidly respond should reinfection with the same pathogen occur. Different types of memory T cells exist. Some continuously circulate through the body similar to naïve T cells, awaiting reactivation. Others become resident in the tissues in which the pathogen challenge occurred. In this way, mucosal barriers show increased proportions of resident memory T cells, which promote rapid effector responses and site‐specific protection against pathogens.
Within oral barriers, most resident T cells exhibit a memory phenotype, and most are CD4+ T cells. In health, resident effector CD4+ T cells predominantly produce the cytokine IFNγ, as outlined earlier, the canonical Th1 cytokine. Alongside these effector cells, resident within the oral mucosa are Tregs, presumably to help regulate local inflammatory reactions. At other barrier sites, most notably the gastrointestinal tract and skin, Th17 cells are resident during health, help the host establish an appropriate dialogue with the commensal bacterial community, and also promote epithelial barrier function. This is not the case in the oral cavity, where Th17 numbers are low in healthy tissues but are dramatically expanded during periodontitis.8 Indeed, emerging studies indicate that Th17 cells are key mediators of pathology in periodontitis, and that targeting these cells could provide a novel opportunity in the treatment of this disease.
Maintenance of Immune Homeostasis in the Oral Cavity
Maintenance of immunologic health within the oral cavity is an active process, with local immune mediators of both the innate and adaptive arms of the immune system acting in coordination to reinforce barrier integrity and prevent pathogen invasion.9 This local immune activity will also shape and constrain the local commensal bacterial community.
Ongoing studies have begun to delineate the immune populations present at distinct oral sites and what is becoming clear is that a unique immune network polices oral mucosal barriers compared to other mucosal barrier sites. The unique aspects of immune functioning at oral barriers likely reflect the need for specific immune activities that are required to maintain homeostasis at these sites. For example, given that oral mucosal sites constantly experience mechanical damage as a result of mastication, there is a requirement for rapid and continuous healing; immune mediators within the oral cavity would promote this. The unique nature of the oral immune network can most readily be seen in the high numbers of neutrophils present at this site, as well as the continuous recruitment and extravasation of neutrophils through the oral epithelium that occur during health. Indeed, the continuous extravasation of neutrophils through the oral epithelium does not happen across any other healthy mucosal barrier. Ultimately, the combined activities of both innate and adaptive immune cells are required for effective defense of oral barriers. The complex nature of this defensive network is readily highlighted by the plethora of oral pathologies that result when any aspect of it malfunctions.
Primary immunodeficiencies (PIDs, also known as inborn errors of immunity) include a group of more than 300 genetic disorders, which are typically caused by single‐gene mutations and impair specific mechanisms of immune function. Although PIDs were previously thought to be very rare conditions, they are now known to affect 1 of every 1200–2000 individuals, with growing prevalence due to increased testing and recognition. The clinical presentation of PIDs is variable and often includes severe or unusual infections with a single type of infectious agent. Importantly, autoimmunity, autoinflammation, and malignancy are increasingly recognized as signs of PID disease. In 2015 the expert committee of the International Union of Immunological Societies (IUIS) developed an updated classification scheme10 to categorize PID diseases into nine categories based upon the segment of the immune system affected, and it provides a clinically oriented strategy for disease categorization that can facilitate diagnosis and management.11
Multiple PIDs present with significant oral manifestations, ranging from oral infections to severe periodontal disease, craniofacial anomalies, and malignancy. Recognition of such disease is key in oral medicine, as such patients often present with significant and challenging clinical needs and therefore diagnosis and disease understanding are necessary to provide specialized care in coordination with a multidisciplinary team of experts. From a scientific standpoint, understanding and characterization of relevant diseases provide insights into the role of specific arms of the immune system in oral health and disease.
This chapter will introduce the basic current classification scheme for PIDs, and present the main features of each major category as well as examples of genes implicated in these diseases (Table 19‐1). PIDs with significant oral manifestations will be given increased attention and summarized in the text and in table format (Table 19‐2).
Table 19‐1 Major categories of primary immunodeficiencies.
|Immune FunctionAffected||Genes Affected
||IL2RG, JAK3, IL7R, CD3D
|Broad range of life‐threatening infections|
||RAG1, RAG2||As above|
||CD40, CD40L, TAP1, TAP2
|Broad range of infections,
Milder than SCID
||LOF WAS||CID with low platelets|
||ATM||CID with intrauterine growth restriction, facial dysmorphisms|
||22q11.2 deletion||CID with structural heart defects, hypoparathyroidism, facial dysmorphisms|
||CID with skeletal anomalies|
||LOF STAT3||CID with hyper‐IgE, AD‐HIES, or Job’s syndrome (oral features)|
||Multiple gene targets||CID with syndromic features
DKC is associated with risk for oral cancer
||BTK, CD79A, CD79B||Severe bacterial infections|
||CD19, CD20, BAFF‐R||Recurrent infections|
||May be asymptomatic|
||FOXP3, IL2RA, CTLA4||Multiorgan inflammation and autoimmunity|
||FASLG, FADD, TNFRSF6||Spenomegaly, adenopathies, autoimmune cytopenias|
||IL10, IL10RA, IL10RB||Colitis|
||Fever and cytopenias|
||HAX1, ELANE/ELA2||Infections, periodontitis|
||ITGB2, CTSC, FPR1, RAC2||Infections, periodontitis|
||CYBB, CYBA, NCF1, NCF2||Infections, hyperinflammatory phenotype|
||IL12RB1, IL12B, INFGR1/2, TYK2||Mycobacterial infections and Salmonella|
||TMC6, TMC8, CORO1A, CXCR4||HPV infections|
||STAT1/2, IFNAR2||HSV, EBV, HHV, VZV|
||IRAK1/4, MYD88||Pyogenic bacterial infections|
||RORC, IL‐17RA, IL17F
||PSMB8 a||Fever, contractures, panniculitis|
||MEFV, NLRP3, NLRP12, NLRP1||Fevers, inflammatory tissue lesions (IBD or arthritis), rashes|
||PSTPIPI, IL1RN||Inflammatory tissue lesions|
|Affecting early complement components||C1‐C4
|Terminal classic components||C5‐C9||Neisserial infections|
|Autoimmune lympho‐leuko proliferation||TNFRSF6, KRAS, NRAS||Splenomegaly, lymphadenopathy, cytopenia|
|Autoantibody diseases||AIRE||Infections due to antibodies to cytokines|
AD‐HIES, autosomal dominant hyper‐immunoglobulin E syndrome; APECED, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; CID, combined immunodeficiencies; EBV, Epstein–Barr virus; HHV, human herpesvirus; HPV, human papillomavirus; HSV, herpes simplex virus; IBD, inflammatory bowel disease; Ig, immunoglobulin; NK, natural killer; PID, primary immunodeficiency; SCID, severe combined immunodeficiency; SLE, systemic lupus erythematosus; TLR, toll‐like receptor; VZV, varicella‐zoster virus; WHIM, warts, hypogammaglobulinemia, recurrent infections, and myelokathexis.
Table 19‐2 Common oral manifestations in primary immunodeficiency.
|Oral Manifestations||Immune Mechanism Involved||Specific Mutations/Syndromes|
|Recurrent herpetic infections
Human papilloma viruses
|T‐cell/NK T‐cell function||Tapasin genes/MHCI deficiency
Deletion chromosome 22q11.2/DiGeorge
|Odontogenic infections||B cells||BTK/BTK deficiency
Select IgG deficiencies
|Chronic mucocutaneous candidiasis||Defects in IL‐17‐dependent responses
|Aggressive periodontitis in children and young adults||Neutropenia
Defects in neutrophil motility
CXCR4 GOF (WHIM)
|Recurrent oral ulcers||Autoinflammatory syndromes
(periodic fevers, PFAPA, and others)
Neutropenia/defects in neutrophil motility/function
PID with HSV susceptibility
|DIRA, A20, GOF STAT1
ELANE, LAD, CGD
|Head and neck squamous
|Immunodeficiencies with severe HPV susceptibility
AD‐HIES, autosomal dominant hyper‐immunoglobulin E syndrome; APECED, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; CGD, chronic granulomatous disease; CID, combined immunodeficiencies; HPV, human papillomavirus; HSV, herpes simplex virus; Ig, immunoglobulin; LAD, leukocyte adhesion deficiency; LJP, localized juvenile periodontitis; NK, natural killer; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and adenitis; PID, primary immunodeficiency; SCID, severe combined immunodeficiency.
Immunodeficiencies Affecting Cellular and Humoral Immunity (T Cells/B Cells)
This group of diseases significantly affects adaptive immune responses by impairing the development and function of T cells and B cells. They are also called combined immunodeficiencies (CIDs), as they tend to affect the development and function of multiple cellular subtypes.11,12 The most severe example of CID is severe combined immunodeficiency (SCID). Patients with this condition are born with almost no T cells. Although many patients with SCID may have B cells, antibody production is absent because there is no T‐cell help. Patients present within the first few months of life with life‐threatening infections. Without curative therapy (hematopoietic stem‐cell transplantation or gene therapy), patients typically die from overwhelming infection before 1 year of age. Other CIDs are somewhat arbitrarily distinguished from SCID in that they typically do not lead to death in the first year of life and typically have higher T‐cell numbers and T‐cell function compared with SCID. Patients with CID defects can present with a broad range of infections, including viral, fungal, and/or bacterial infections. Such patients are also susceptible to opportunistic infections (e.g., Pneumocystis jirovecii pneumonia) and infections from live vaccinations (e.g., measles, mumps, and rubella [MMR] and varicella).
This category includes SCID, both with absence of T cells and NK cells but presence of B cells (T‐B+) as well as without T or B cells (T‐B‐); and milder forms of CID. Mutations associated with T‐B+ typically affect the maturation and survival of T cells and NK T cells by affecting either cell development or signaling through the T‐cell receptor (CD3D, CD3E), and T/NK cell survival and activation (IL2RG, IL7R, JAK3).13 Mutations leading to T‐B‐ SCID include those affecting the rearrangement of the T‐cell receptor and of immunoglobulins (RAG1/ RAG2). Milder forms of non‐SCID CID are caused by MHCI/II deficiencies (TAP1, TAP2), CD40 deficiency, or Dock8 deficiency.13
DOCK8 deficiency has been reported to present with significant oral manifestations. It is caused by loss‐of‐function (LOF) mutations in the DOCK8 gene, which encodes a guanine nucleotide exchange factor that regulates the actin cytoskeleton and is highly expressed in lymphocytes. Patients have impaired B‐, T‐, and NK T‐cell survival and long‐lived memory responses.14 Clinically such patients present with eczema, recurrent respiratory as well as persistent mucocutaneous viral infections: varicella‐zoster virus (VZV), molluscum contagiosum, herpes simplex virus (HSV), and human papillomavirus (HPV). Persistent infection, particularly with HPV, leads to increased risk of cancer (typically viral‐driven, squamous cell carcinomas), which affects up to 17% of patients. In the oral cavity, severe HPV and HSV infections have been reported in DOCK8 patients as well as susceptibility to HPV‐associated squamous cell carcinoma (Figure 19‐2).
Combined Immunodeficiency with Syndromic Features
This category includes diseases in which patients are affected by combined immunodeficiency in conjunction with other clinical features outside the immune system, such as congenital anomalies and manifestations in the skeletal system. It includes the following subcategories:
- CID with congenital thrombocytopenia. Disorders in this subcategory are characterized by CID with low platelets as a key clinical feature. A classic example is Wiskott–Aldrich syndrome (WAS, LOF mutation), characterized by thrombocytopenia with small platelets, bloody diarrhea, and eczema.15
- CID due to DNA repair defects. DNA repair defects can result in both T‐ and B‐cell abnormalities because it is essential for V(D)J recombination to generate T‐cell/B‐cell diversity and for effective class‐switch recombination. In addition to a CID phenotype, many of these conditions such as ataxia telangiectasia (caused by ATM mutations) are characterized by other clinical features including intrauterine growth restriction (IUGR), facial dysmorphisms, and increased radiosensitivity.
- CID due to thymic defects with additional congenital anomalies. Genetic disorders in this category result in impaired development of the thymus, which ultimately affects T‐cell development and can result in CID. One of the most common (1:3000 live births) and well‐characterized syndromes with underlying immunodeficiency is DiGeorge (22q11.2 deletion) syndrome. This syndrome is characterized by structural heart defects, hypoparathyroidism (resulting in hypocalcemia), characteristic facial features, and T‐cell immunodeficiency.
- CID with immuneosseous dysplasia. These disorders are characterized by CID features with skeletal abnormalities.
- Hyper‐IgE syndromes (HIES). These disorders are all characterized by CID and elevated IgE. One well‐characterized such PID with documented oral/craniofacial features is autosomal dominant hyper‐IgE syndrome (AD‐HIES/Job’s syndrome). AD‐HIES is caused by LOF mutations in the signal transducer and activator of transcription (STAT) 3 gene. Clinical manifestations occurring in >75% of patients are recurrent staphylococcal abscesses, recurrent airway infections, and increased concentration of IgE in serum.16 Patients also present with atopy and skeletal manifestations. In the craniofacial/oral region, manifestations include characteristic facial features, retention of primary teeth, and recurrent oral candidiasis (Figure 19‐3).
- Dyskeratosis congenita (DKC), myelodysplasia, defective telomere maintenance. Telomeres are structures that prevent the loss of genetic material that normally occurs with every cell division. Without proper telomere maintenance, cell senescence and apoptosis can occur, especially in highly proliferative cell types such as lymphocytes. As such, in the presence of defects in telomere maintenance, patients can present with CID combined with syndromic features affecting the skin, nails, and hair and leading to lung fibrosis and enteropathy.17 Such patients also have an increased risk for malignancy, including increased risk for oral cancer, and therefore oral cancer screening becomes particularly significant for this patient population.
Predominantly Antibody Deficiencies
B cells differentiate into plasma cells that produce antibodies or immunoglobulins. Human antibodies are classified into five isotypes (IgM, IgD, IgG, IgA, and IgE) according to their H chains, which provide each isotype with distinct characteristics and roles. IgG is the most abundant antibody isotype in the blood (plasma), accounting for 70–75% of human immunoglobulins. Antibody deficiencies are categorized into the following:
- Severe reduction in all serum Ig isotypes with absent B cells (e.g., BTK deficiency Bruton’s agammaglobulinemia, Igα and Igβ deficiency due to CD79A/B mutations).
- Severe reduction in at least two serum Ig isotypes with normal or low numbers of B cells (e.g., B‐cell deficiencies including mutations in CD19, CD20, and BAFF‐R).
- Severe reduction in serum IgG and IgA with increased IgM and normal numbers of B cells (UNG deficiency).
- Isotype or light‐chain deficiencies with normal numbers of B cells (such as Ig heavy‐chain mutations, K chain deficiency, and isolated IgG subclass deficiencies).
Patients with antibody deficiency commonly present with recurrent bacterial infections of the upper and lower respiratory tracts (ear infections, sinus infections, and pneumonia, including odontogenic infections) from encapsulated bacteria, such as Streptococcus pneumoniae. However, more invasive bacterial infections such as sepsis, meningitis, and osteomyelitis can occur. These patients have also been reported to be susceptible to severe odontogenic infections.
Diseases of Immune Dysregulation
It is increasingly recognized that numerous PIDs present with features of dysregulated inflammatory responses that often lead to autoimmune phenomena, including cytopenias and solid organ autoimmunity, in addition to lymphoproliferation and malignancy. The treatment of immune disorders with coexisting immune deficiency and immune dysregulation is challenging, as it requires careful balancing of immunosuppression and control of infection. Subcategories of PID with immune dysregulation include the following:
- Regulatory T‐cell defects. Tregs play a critical role in peripheral tolerance by suppressing autoreactive and activated T cells. Reduced or impaired function of Tregs results in systemic autoimmunity. Examples in this category include IPEX (due to FOXP3 mutations), CD25 deficiency (IL2RA), and cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA4) deficiency.
- Autoimmune lymphoproliferative syndrome (ALPS). ALPS results from defects in the
Fas/Fas ligand (FasL) pathway. This pathway normally eliminates autoreactive lymphocytes. Relevant mutations include FASLG, FADD, and TNFRSF6.18
- Immune dysregulation with colitis, classically associated with IL10 and IL10RA/RB mutations.
- Familial hemophagocytic lymphohistiocytosis syndromes are linked to decreased NK and CTL cells with increased activation of T cells. One disease in this category, Chédiak–Higashi Syndrome, is linked to severe periodontitis; it is caused by mutations in the lysosomal trafficking regulator gene (CHS1/LYST).19 Beyond aberrant inflammatory responses, these patients present with significant neutrophil defects, including destruction of neutrophils early in myelopoiesis, decreased chemotactic responses, and impaired diapedesis. Neutrophil defects in these patients have been linked to susceptibility to periodontal disease.
- Autoimmunity with/without lymphoproliferation, as seen in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED; mutations in AIRE) and ITCH syndrome (ITCH mutations). APECED is of increased interest to the oral medicine provider as these patients present with dental enamel defects, susceptibility to oral candidiasis, and have been reported to have an increased risk for oral squamous cell carcinoma.
Congenital Defects of Phagocyte Number and/or Function
Phagocytes such as neutrophils and macrophages act as a first line of defense to protect the body from harmful bacteria and fungi by phagocytosis and destruction of these pathogens and through initiation and engagement of adaptive immune responses. Through phagocytosis and release of immune mediators, these cells also play crucial roles in wound healing as well as in the resolution of inflammation.
Main subcategories in this section include the following:
- Congenital neutropenia (due to defective neutrophil development).
- Defects in neutrophil motility.
- Defects in myeloid respiratory burst.
- Nonlymphoid defects (which include defects in the development of monocyte/macrophages due to GATA2 mutations). Congenital neutrophil defects as well as defects in neutrophil motility and function have been linked to severe aggressive periodontitis at a young age as well as recurrent oral ulcerations, and thus specific examples of these diseases are discussed here.
Congenital neutropenia is caused by mutations in genes affecting granulopoiesis (development of neutrophils in the bone marrow), such as mutations in HAX1 (Kostman syndrome), in the elastase ELA2/ELANE gene, or in the (HCLS) 1‐associated gene X1. Patients with such mutations have peripheral neutrophil counts below 0.5 × 109/L (1.5– 1.8 × 109/L in health) and frequent bacterial/fungal infections, as well as severe periodontitis that begins in childhood. Granulocyte colony‐stimulating factor (G‐CSF) treatment leads to improvement of infection susceptibility with varying results in the resolution of periodontitis. Hematopoietic stem‐cell transplant has been shown to reverse the phenotype of periodontitis in these patients.
Leukocyte Adhesion Deficiency I
Leukocyte adhesion deficiency 1 (LAD‐1) is a rare disorder of leukocyte adhesion and transmigration, which results from mutations in the ITGB2 gene encoding for the β2 integrin component, CD18. Deficiency in CD18 prevents neutrophil adhesion to endothelial surfaces and extravasation into tissues. This results in severe tissue neutropenia. Patients with LAD‐1 suffer from recurrent infections, defective wound healing, and in the oral cavity present with severe to aggressive periodontitis and recurrent oral ulcers.20 Periodontitis in these patients has been shown to be recalcitrant to standard‐of‐care treatment with loss of dentition in the teenage years (Figure 19‐4).
Papillon–Lefèvre syndrome is a rare autosomal recessive genetic disorder, caused by mutations in the gene encoding lysosomal cysteine protease cathepsin C (CTSC). CTSC is necessary for post‐translational modification and activation of serine proteases stored primarily in azurophilic granules, such as neutrophil elastase, cathepsin G (CTSG), proteinase 3 (PR3), and neutrophil serine protease 4 (NSP4). It is thought that patients have defective antimicrobial responses at mucosal surfaces due to this defect. These patients also present with severe periodontitis at an early age, but have limited infection susceptibility.
Localized Juvenile Periodontitis
Localized juvenile periodontitis (LJP) is a genetic defect impairing formylpeptide‐induced chemotaxis of neutrophils (FPR1), which presents with specific predisposition to a severe but localized form of periodontitis in the teenage years.
Defects of Intrinsic and Innate Immunity
The innate immune system typically provides initial nonspecific immunity to pathogens, including initial recognition and responses, and is mediated primarily through phagocytes, APCs, and innate lymphocytes. Mendelian susceptibility to mycobacterial disease (MSMD) is related to defects in IL‐12 and INFγ signaling, which is important for clearance of intracellular pathogens. Examples of genes involved are IL12RB1, IL12B, INFGR1/2, and TYK2. Susceptibly to viral infection is most often related to defects in NK cells and innate lymphocytes that protect the body from HSV, VZV, Epstein–Barr virus (EBV), and cytomegalovirus (CMV) infections and also play a role in tumor surveillance. Three subcategories in this section are related to viral susceptibility: epidermodysplasia verruciformis (HPV susceptibility), predisposition to severe viral infection (NK/T cell deficiencies, STAT1/2, IFNAR2), and herpes simplex encephalitis due to defects in signaling in resident central nervous system (CNS) innate cells.
Predisposition to fungal disease is associated with defective recognition of fungi (CARD9 deficiency, leading to invasive fungal disease) or defective IL‐17 responses (leading to mucocutaneous candidiasis).21 Defects in microbial recognition through toll‐like receptors (TLRs) and related signaling (IRAK1/4, MYD88) and TLR signaling pathway deficiencies predispose to bacterial infections.
In this category, diseases with prominent oral manifestations are as follows:
- WHIM, which stands for warts, hypogammaglobulinemia, recurrent infections, and myelokathexis (impaired egress of mature neutrophils from bone marrow), is caused by gain‐of‐function mutations in the chemokine receptor CXCR4. Constituent expression of CXCR4 impairs immune cell egress from the bone marrow and these patients present with pan‐leukocytopenia. The signature pathogen in this disease is HPV. The dominant oral manifestation is severe periodontitis at an early age (teenage years), which is attributed to the neutropenia observed in these patients. Due to HPV susceptibility, these patients also are at increased risk for HPV‐associated mucosal squamous cell carcinomas.
- Mucocutaneus (oral) candidiasis. Defective responses to the IL‐17 cytokine have unequivocally been linked to oral fungal susceptibility.21 Patients with mutations in the IL‐17 receptor (IL17RA, IL17RC), the IL17 cytokine F (IL17F), IL‐17 signaling (TRAF3IP2), as well as defects in the development of IL‐17‐secreting cells (RORC, STAT3) all present with severe, recurrent oral candidiasis. IL‐17 responses have been shown to be critical for the induction of epithelial‐mucosal antifungal immunity (Table 19‐2, Figure 19‐5).
In the autoinflammatory disorders, overactivation of innate inflammatory pathways occurs in a nonspecific, antigen‐independent manner and most commonly will cause recurrent fevers, skin rashes, and tissue damage. In this category of disorders, recurrent inflammation occurs without evidence of other disorders (e.g., cyclic neutropenia) or infections. Genetic testing is necessary to confirm the diagnosis. Subcategories in this group include the following:
- Type I interferonopathies. Defective regulation of type I interferon response is associated with severe inflammatory phenotypes and autoimmunity, presenting as atypical, severe, early‐onset rheumatic diseases (e.g., CANDLE syndrome, PSMB8a mutation).22
- Defects affecting the inflammasome. The inflammasome is a multiprotein intracellular complex that detects microorganisms and cell damage–related mediators and acts to activate pro‐inflammatory cytokines such as IL‐1β and IL‐18. Hyperactivation of the inflammasome leads to classically recognized inflammasome disorders such as familial Mediterranean fever (MEFV), familial cold autoinflammatory syndrome 1 and 2 (NLRP3 and NLRP12), and neonatal onset multisystem inflammatory disease (NOMID, due to NLRP3 mutations).
- Non‐inflammatory‐related conditions, including PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, acne, due to PSTPIPI mutations) and DIRA syndrome (deficiency of IL‐1 receptor antagonist, due to IL1RN mutations).
A typical oral manifestation for many of the autoinflammatory syndromes is recurrent oral ulcers during periods of disease activity and inflammation (most prominent in periodic fever, aphthous stomatitis, pharyngitis, and adenitis [PFAPA] syndrome).23
The complement arm of the immune system protects the body from bacterial pathogens by opsonizing bacteria and leading to their phagocytosis and destruction. Additionally, complement proteins also play a role in clearance of apoptotic cell debris, which is necessary for the resolution of inflammation. Defective clearance of apoptotic cell debris is linked to persistent inflammation and autoimmunity. As such, patients with complement deficiencies can be predisposed both to bacterial infection and to autoimmunity. Interestingly, early classic complement component deficiencies (C1q, C1r, C1s, C2, C4, C3) present with systemic lupus erythematosus (SLE) and susceptibility to infections from encapsulated bacteria. Specific types of complement defects (C1R, C1S) are associated with severe periodontal disease. Terminal classic complement component deficiencies (C5, C6, C7, C8, C9) present with a unique susceptibility to recurrent Neisseria