8: The immune system and the oral cavity

Chapter 8 The immune system and the oral cavity

The immune system: general considerations

Immunology is the branch of biology concerned with the body’s defence reactions. The word ‘immunity’ is derived from the Latin word immunis, meaning ‘free of burden’. In essence, the immune system exists to maintain the integrity of the body by excluding or removing the myriad of potentially burdensome or threatening microorganisms, which could invade from the environment. Internally derived threats, mutant cells with malignant potential, may also be attacked by the immune system.

There are two kinds of immunological defence:

During its development, the immune system must be educated specifically to avoid reacting against all normal components of the body (tolerance). Immunology can be considered ‘the science of self-non-self discrimination’.

The vital importance of the immune system is evident in the life-threatening infections suffered by patients with immune defects (immunodeficiency). In other situations, there may be too much immunity. A by-product of a successful immune response may be damage to normal ‘bystander’ cells, but this is normally limited by stringent immune regulatory mechanisms. Deficiencies of immunoregulation may be the root causes of hypersensitivity diseases such as autoimmunity and allergy.

These concepts are summarized in Figure 8.1.

The innate immune system

These intrinsic defence mechanisms are present at birth prior to exposure to pathogens or other foreign macromolecules. They are not enhanced by such exposures and are not specific to a particular pathogen.

Defensins and cathelicidins

Defensins and cathelicidins are two major families of mammalian antimicrobial proteins. They contribute to host innate antimicrobial defences by disrupting the integrity of the bacterial cell membrane. Further, several members of defensins and cathelicidins have been shown recently to have chemotactic effects on host cells. Their capacity to mobilize various types of phagocytic leukocytes, immature dendritic cells and lymphocytes, together with their other effects, such as stimulating interleukin-8 production and mast cell degranulation, provides evidence for their participation in alerting, mobilizing and amplifying innate and adaptive antimicrobial immunity of the host (Table 8.1). In brief, upon microbial invasion, epithelial cells/keratinocytes and tissue macrophages are induced to produce β-defensins (especially HBD2 and 3) and cathelicidin/LI-37. The defensins and cathelicidin form gradients that, in tandem with other chemotactic mediators (e.g. chemokines), lead to extravasation of various types of leukocytes to the site of infection in order to overcome the invading pathogens (Table 8.2).

Table 8.1 Antigen-non-specific defence chemicals in oral secretions

Chemical Antimicrobial function(s) Major cell source(s)
Calprotectin Divalent cation chelator, restricts microbe nutrition Oral epithelial cells and neutrophils
Defensins (α and β types) Membrane pore-forming peptides, cause osmotic lysis Leukocytes and epithelial cells
Cathelicidins Lysosomal antimicrobial polypeptides Macrophages and neutrophils
Saliva Ig, lysozyme, lactoferrin, peroxidases and GCF Salivary acinar cells
Lysozyme Muramidase activity, aggregates microbes and amphipathic sequences Macrophages, epithelial cells and neutrophils
Peroxidase Oxidizes bacterial enzymes in glycolytic pathways Salivary acinar cells, neutrophils, eosinophils
His-, Cis- statins Various effects Salivary acinar cells
SLPI, PRP Antiviral activities Various cell types
GCF Provides blood components Various cell types
Mucins Aggregates bacteria, various effects, homotypic and heterotypic complexes Salivary acinar cells

SLPI, secretory leukocyte protease inhibitor; PRP, proline-rich proteins; GCF, gingival crevicular fluid; Ig, immunoglobulin.

Pathogen-associated molecular patterns, pattern-recognition receptors and Toll-like receptors

Unlike adaptive immunity, innate immunity does not recognize every possible antigen. The cells involved in innate immune responses such as phagocytes (neutrophils, monocytes, macrophages) and cells that release inflammatory mediators (basophils, mast cells and eosinophils) are designed to recognize only a few highly conserved structures present in many different microorganisms. These cells recognize microbial structures called pathogen-associated molecular patterns (PAMPs) in order to activate the innate immune response. PAMPs are molecular components common to a variety of microorganisms but not found as a part of eukaryotic cells and include:

This promotes the attachment of microbes to phagocytes and their subsequent engulfment and destruction. Most defence cells (macrophages, dendritic cells, endothelial cells, mucosal epithelial cells, lymphocytes) have on their surface a variety of receptors called pattern-recognition receptors (PRRs) capable of binding specifically to conserved portions of PAMPs so there is an immediate response against invading microbes. These receptors enable phagocytes to attach to microbes so they can be engulfed and destroyed by lysosomes. There are two functionally different classes of PRRs:

Signalling PRRs bind a number of microbial molecules such as flagellin, pilin, glycolipids, zymosan from fungi and viral double-stranded RNA. A major class of signalling PRRs is Toll-like receptors (TLRs), so named because of their similarity to the protein coded by the Toll gene identified in Drosophila melanogaster.

Binding of PAMPs to signalling PRRs promotes the synthesis and secretion of regulatory molecules such as cytokines that are crucial to initiating innate immunity. Various types of TLRs bind different PAMPs and initiate different types of innate immune responses (Fig. 8.2). PAMPs can also be recognized by a series of soluble PRRs in the blood that function as opsonins and initiate the complement pathway.

Natural killer cells

Natural killer (NK) cells are non-phagocytic lymphocytes that account for up to 15% of blood lymphocytes and have a special role in the killing of virus-infected and malignant cells (Fig. 8.3). These cells have two kinds of receptors with opposing action: antigen receptors able to recognize specific molecules on target cells, through which activation signals are transmitted, and receptors that recognize self major histocompatibility complex I (MHC I) antigens (see below) through which inactivation signals are transmitted. Activation of NK cells can only occur when there is no inactivation signal, so virus-infected and tumour cells with downregulated MHC I antigens are susceptible to NK cytotoxicity, but normal MHC I-positive cells are protected. The killing mechanism is activated by cytokines released by virus-infected cells, tissue cells, lymphocytes and NK cells themselves. The NK cells are also important in the adaptive immune response, being the effector cells for killing antibody-coated microorganisms.

Acute-phase proteins

Acute-phase proteins are serum proteins produced by the liver in response to tissue-damaging infections and other inflammatory stimuli such as cytokines (e.g. interleukins-1 and -6). Although the physiological role of the acute-phase proteins is not fully understood, it has been recognized to enhance the efficiency of innate immunity. Positive acute-phase proteins increase in plasma concentration in the acute-phase response to inhibit or kill microbes through opsonization, coagulation, antiprotease activity and/or complement activation. Negative acute-phase proteins including human serum albumin and transferrin are reduced in concentration in the acute-phase response and act to limit inflammation. Together acute-phase proteins provide immediate defence and enable the body to recognize and react to foreign substances prior to more extensive activation of the immune response. The concentration of the following positive acute-phase proteins in body fluids increases rapidly during tissue injury or infection:

Alternative activation

Complement factor C3 is the central component of both the classical and alternative pathways (Fig. 8.4). Products of C3 activation, C3b and inactivated C3b (iC3b) bind to microorganisms and are recognized by complement receptors (CRs) on phagocytes. If any C3b molecules bind to a normal host cell surface, they can then bind the next component in the sequence, factor B. Factor D (the only complement factor present in body fluids as an active enzyme) splits off a small fragment, Ba, leaving an active C3 convertase, C3bBb, on the cell surface. However, the normal host cell is able actively to dissociate and inactivate C3bBb. This is achieved by the concerted action of regulatory proteins decay-accelerating factor (DAF), membrane cofactor protein (MCP), β1H globulin (factor H), CR1 and factor I.

Activator surfaces are those that inhibit the regulatory proteins, allowing C3bBb to remain intact. For example, bacterial endotoxins and LPSs inhibit factor H. The enzyme C3bBb converts C3 into C3a and C3b. The latter is incorporated, along with properdin (factor P), to form PC3bBbC3b. This is a stable enzyme whose substrates are C3 and C5. It amplifies C3b production and activates the membrane attack pathway.

Membrane attack

The peptides Bb and C2b, bound into their respective alternative (PC3bBbC3b) and classical (C4b2b3b) pathway enzymatic complexes, initiate membrane attack (Fig. 8.6) by splitting a small peptide, C5a, from C5 to form C5b. This molecule binds C6 and C7. Cell-bound C5b67 acts as a template for the binding of one molecule of C8 and up to 18 molecules of C9. Normal cells in the body are largely protected from bystander lysis by homologous restriction factor (HRF), which intercepts C8 and C9 before they can be properly assembled into the membrane attack complex (MAC). The MAC, with a molecular weight of 1–2 × 106, forms transmembrane channels, which permit osmotic influx so that the target cell swells up and bursts.

Cells of the immune system

All the cells of the immune system (Fig. 8.8) are derived from self-regenerating haematopoietic stem cells present in bone marrow and foetal liver. These differentiate along either the myeloid or the lymphoid pathway. Myeloid precursor cells give rise to mast cells, erythrocytes, platelets, dendritic cells, polymorphs (eosinophils, basophils, neutrophils) and mononuclear phagocytes (monocytes in the blood, macrophages in the tissues). Lymphoid precursor differentiation gives rise to T (thymus-dependent) lymphocytes, B (bone marrow-derived) lymphocytes and NK lymphocytes.

During post-natal life, B cell genesis takes place in the bone marrow. Each newly formed B cell expresses a unique B cell receptor (BCR) on its membrane for antigen-binding. Although T lymphocytes also arise in the bone marrow, they migrate to the thymus to mature. During its maturation, the T lymphocyte expresses a specific antigen-binding molecule known as the T cell receptor (TCR) on its membrane.

The B lymphocytes are responsible for secreting Ig antibodies and can also function as highly efficient antigen-presenting cells (APCs) for T lymphocytes. The latter are divided into two major subsets: T-helper cells, which usually bear the ‘cluster of differentiation’ marker CD4, and T-cytotoxic cells, which usually carry CD8. The T-helper cells are required for activating the effector function of B cells, other T cells, NK cells and macrophages. They do this by transmitting signals via cell-to-cell contact interactions and/or via soluble hormone-like factors called lymphokines. The T-cytotoxic cells kill target cells such as virus-infected host cells. Another functional property of some T lymphocytes is to downregulate immune responses. These T-suppressor cells are usually CD8-positive. Dendritic cells and monocytes/macrophages play key roles in the immune system as APCs.

The lymphoid organs

The primary sites of lymphocyte production are the bone marrow and thymus. Immature lymphocytes produced from stem cells in the bone marrow may continue their development within the bone marrow (B lymphocytes, NK cells) or migrate to the thymus and develop into T lymphocytes. ‘Education’ within the primary lymphoid organs ensures that emerging lymphocytes can discriminate self from non-self. They migrate through the blood and lymphatic systems to the secondary lymphoid organs – spleen, lymph nodes and mucosa-associated lymphoid tissue (MALT) of the alimentary, respiratory and urogenital tracts. Here, lymphocytes encounter foreign antigens and become activated effector cells of the immune response.

The spleen acts as a filter for blood and is the major site for clearance of opsonized particles. It is an important site for production of antibodies against intravenous antigens. The lymph nodes form a network of strategically placed filters, which drain fluids from the tissues and concentrate foreign antigen on to APCs and subsequently to lymphocytes. Spleen and lymph nodes are encapsulated organs, whereas MALT is non-encapsulated dispersed aggregates of lymphoid cells positioned to protect the main passages by which microorganisms gain entry into the body. Gut-associated lymphoid tissue (GALT) includes Peyer’s patches of the lower ileum, accumulations of lymphoid tissue in the lamina propria of the intestinal wall and the tonsils.

Mature lymphoid cells continuously circulate between the blood, lymph, lymphoid organs and tissues until they encounter an antigen, which will cause them to become activated (see Chapter 9).

Jan 4, 2015 | Posted by in General Dentistry | Comments Off on 8: The immune system and the oral cavity
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