The Initial Lesion.

The initial lesion is typically said to develop within 2 to 4 days of the accumulation of plaque at a site that was otherwise free of plaque and at which there was no inflammation evident microscopically. However, this situation is probably never encountered in reality, and the gingival tissues always have characteristics of a low-grade chronic inflammatory response as a result of the continual presence of the subgingival biofilm. In other words, the initial lesion corresponds with the histologic picture that is evident in clinically healthy gingival tissues. This low-grade inflammation is characterized by dilation of the vascular network and increased vascular permeability, thus permitting the neutrophils and monocytes from the gingival vasculature to migrate through the connective tissues toward the source of the chemotactic stimulus: the bacterial products in the gingival sulcus. The upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and E-selectin in the gingival vasculature facilitates the migration of neutrophils from the capillaries into the connective tissues. The increased leakage of fluid from the vessels increases the hydrostatic pressure in the local microcirculation, and, as a result, GCF flow increases. Increased GCF flow has the effect of diluting bacterial products, and it also potentially has a flushing action to remove bacteria and their products from the crevice. However, given the nature of the bacterial biofilm, it is likely that only planktonic (free-floating) bacteria are removed in this way.

The Early Lesion.

The early lesion develops after about 1 week of continued plaque accumulation and corresponds with the early clinical signs of gingivitis. The gingiva are erythematous in appearance as a result of the proliferation of capillaries, the opening up of microvascular beds, and continued vasodilation.¹⁰⁵ Increasing vascular permeability leads to increased GCF flow, and transmigrating neutrophils increase significantly in number. The predominant infiltrating cell types are neutrophils and lymphocytes (primarily thymic lymphocytes [T cells]),¹³⁶ and the neutrophils migrate through the tissues to the sulcus and phagocytose bacteria. Fibroblasts degenerate, primarily via apoptosis (programmed cell death), which increases the space available for infiltrating leukocytes. Collagen destruction occurs, which results in collagen depletion in the areas apical and lateral to the junctional and sulcular epithelium. The basal cells of these epithelial structures begin to proliferate to maintain an intact barrier against the bacteria and their products, and the epithelium can then be seen proliferating into the collagen-depleted areas of the connective tissues (Figure 5-2).¹⁵² As a result of edema of the gingival tissues, the gingiva may appear slightly swollen, and, accordingly, the gingival sulcus becomes slightly deeper. The subgingival biofilm exploits this ecologic niche and proliferates apically (thereby rendering effective plaque control more difficult). The early gingival lesion may persist indefinitely, or it may progress further.

The Established Lesion.

The established lesion roughly corresponds with what clinicians would refer to as “chronic gingivitis.” The progression from the early lesion to the established lesion depends on many factors, including the plaque challenge (the composition and quantity of the biofilm), host susceptibility factors, and risk factors (both local and systemic). In the initial work by Page and Schroeder, the established lesion was defined as being dominated by plasma cells.¹³² In human studies, reports have suggested that plasma cells predominate in established gingivitis in older subjects,⁵¹ whereas lymphocytes predominate in younger individuals, although the relevance of these findings is not clear.^23,51 What is clear from all of the studies is that there is a significant inflammatory cell infiltrate in established gingivitis that occupies a considerable volume of the inflamed connective tissues. Large numbers of infiltrating cells can be identified adjacent and lateral to the junctional and sulcular epithelium, around blood vessels, and between collagen fiber bundles.²² Collagen depletion continues, with further proliferation of the epithelium into the connective tissue spaces. Neutrophils accumulate in the tissues and release their lysosomal contents extracellularly (in an attempt to kill bacteria that are not phagocytosed), thereby resulting in further tissue destruction. Neutrophils are also a major source of matrix metalloproteinase-8 (MMP-8; neutrophil collagenase) and MMP-9 (gelatinase B), and these enzymes are produced in large quantities in the inflamed gingival tissues as the neutrophils migrate through the densely packed collagen fiber bundles to enter the sulcus. The junctional and sulcular epithelium form a pocket epithelium that is not firmly attached to the tooth surface, that contains large numbers of neutrophils, and that is more permeable to the passage of substances into or out of the underlying connective tissue. The pocket epithelium may be ulcerated and less able to resist the passage of the periodontal probe, so bleeding on probing is a common feature of chronic gingivitis. It is important to remember that these inflammatory changes are still completely reversible if effective plaque control is reinstituted.

The Advanced Lesion.

The advanced lesion marks the transition from gingivitis to periodontitis. This transition is determined by many factors, the relative importance of which is currently unknown but which includes the bacterial challenge (both the composition and the quantity of the biofilm), the host inflammatory response, and susceptibility factors, including environmental and genetic risk factors. Histologic examination reveals continued evidence of collagen destruction that extends into the periodontal ligament and the alveolar bone. Neutrophils predominate in the pocket epithelium and the periodontal pocket, and plasma cells dominate in the connective tissues. The junctional epithelium migrates apically along the root surface into the collagen-depleted areas to maintain an intact epithelial barrier. Osteoclastic bone resorption commences, and the bone retreats from the advancing inflammatory front as a defense mechanism to the prevent spread of bacteria into the bone (Figure 5-3). As the pocket deepens, plaque bacteria proliferate apically into a niche, which is very favorable for many of the species that are regarded as periodontal pathogens. The pocket presents a protected, warm, moist, and anaerobic environment with a ready nutrient supply, and, because the bacteria are effectively outside of the body (even though they are in the periodontal pocket), they are not significantly eliminated by the inflammatory response. Thus, a cycle develops in which chronic inflammation and associated tissue damage continue. The tissue damage is mainly caused by the inflammatory response, yet the initiating factor—the biofilm—is not eliminated. The destruction of collagen fibers in the periodontal ligament continues, bone resorption progresses, the junctional epithelium migrates apically to maintain an intact barrier, and as a result, the pocket deepens fractionally. This makes it even more difficult to remove the bacteria and to disrupt the biofilm through oral hygiene techniques, and thus the cycle is perpetuated.

Lipopolysaccharide.

Lipopolysaccharides (LPSs) are large molecules composed of a lipid component (lipid A) and a polysaccharide component. They are found in the outer membrane of gram-negative bacteria, they act as endotoxins (LPSs are frequently referred to as endotoxins), and they elicit strong immune responses in animals. LPSs are highly conserved in gram-negative bacterial species, which reflects their importance in maintaining the structural integrity of the bacterial cells. Immune systems in animals have evolved to recognize LPS via Toll-like receptors (TLRs), a family of cell surface molecules that are highly conserved in animal species ranging from Drosophila (a genus of fruit flies) to humans, thereby reflecting their importance in innate immune responses. TLRs are also present in lower animals and are in fact more varied than in higher species.²⁶ TLRs are cell surface receptors that recognize microbe-associated molecular patterns (MAMPs), which are conserved molecular structures located on diverse pathogens. TLR-4 recognizes LPSs from gram-negative bacteria and functions as part of a complex of cell surface molecules, including CD14 and MD-2 (also known as lymphocyte antigen 96). The interaction of this CD14/TLR-4/MD-2 complex with LPSs triggers a series of intracellular events, the net result of which is the increased production of inflammatory mediators (most notably cytokines) and the differentiation of immune cells (e.g., dendritic cells) for the development of effective immune responses against the pathogens. It is particularly interesting to the periodontist that the pathogen Porphyromonas gingivalis has an atypical form of LPSs that are recognized by both TLR-2 and TLR-4.^38,45

It is important to remember that a component of gram-positive cell walls, lipoteichoic acid, also stimulates immune responses, although less potently than LPSs. Lipoteichoic acid signals through TLR-2. Both LPSs and lipoteichoic acid are released from the bacteria present in the biofilm and stimulate inflammatory responses in the tissues, thereby resulting in increased vasodilation and vascular permeability, the recruitment of inflammatory cells by chemotaxis, and the release of proinflammatory mediators by the leukocytes that are recruited to the area. LPSs in particular are of key importance for initiating and sustaining inflammatory responses in the gingival and periodontal tissues.

Bacterial Enzymes and Noxious Products.

Plaque bacteria produce a number of metabolic waste products that contribute directly to tissue damage. These include noxious agents such as ammonia (NH₃) and hydrogen sulfide (H₂S) as well as short-chain carboxylic acids such as butyric acid and propionic acid. These acids are detectable in GCF and found in increasing concentrations as the severity of periodontal disease increases. These substances have profound effects on host cells (e.g., butyric acid induces apoptosis in T cells, B cells, fibroblasts, and gingival epithelial cells).95,96,166 The short-chain fatty acids may aid P. gingivalis infection through tissue destruction, and they may also create a nutrient supply for the organism by increasing bleeding into the periodontal pocket. The short-chain fatty acids also influence cytokine secretion by immune cells, and they may potentiate inflammatory responses after exposure to proinflammatory stimuli such as LPS, interleukin-1β (IL-1β), and tumor necrosis factor alpha (TNF-α).¹²³

Plaque bacteria produce proteases, which are capable of breaking down structural proteins of the periodontium such as collagen, elastin, and fibronectin. Bacteria produce these proteases to digest proteins and thereby provide peptides for bacterial nutrition. Bacterial proteases disrupt host responses, compromise tissue integrity, and facilitate the microbial invasion of the tissues. P. gingivalis produces two classes of cysteine proteases that have been implicated in periodontal pathogenesis. These are known as gingipains, and they include the lysine-specific gingipain Kgp and the arginine-specific gingipains RgpA and RgpB. The gingipains can modulate the immune system and disrupt immune–inflammatory responses, potentially leading to increased tissue breakdown.¹³⁸ Gingipains can reduce the concentrations of cytokines in cell culture systems,⁷ and they digest and inactivate TNF-α.²⁵ The gingipains can also stimulate cytokine secretion via the activation of protease-activated receptors (PARs). For example, RgpB activates two different PARs (PAR-1 and PAR-2), thereby stimulating cytokine secretion,¹⁰⁸ and both Rgp and Kgp gingipains stimulate IL-6 and IL-8 secretion by monocytes via the activation of PAR-1, PAR-2 and PAR-3.¹⁸⁴

Microbial Invasion.

Microbial invasion of the periodontal tissues has long been a contentious topic. In histologic specimens, bacteria (including cocci, filaments, and rods) have been identified in the intercellular spaces of the epithelium.⁵⁰ Periodontal pathogens such as P. gingivalis and Aggregatibacter actinomycetemcomitans have been reported to invade the gingival tissues,^30,76,148 including the connective tissues.¹⁴⁷ Fusobacterium nucleatum can invade oral epithelial cells, and bacteria that routinely invade host cells may facilitate the entry of noninvasive bacteria by coaggregating with them (Figure 5-4).⁴⁷ It has also been shown that A. actinomycetemcomitans can invade epithelial cells and persist intracellularly.⁴⁹ The clinical relevance of these findings is unclear, however. Some investigators have suggested that tissue invasion by subgingival bacteria is an active process, whereas others have considered it to be an artifact or simply a passive translocation process.

The reports of bacteria present in the tissues have sometimes been used to justify the use of antibiotics for the treatment of periodontitis as a means of attempting to eliminate those organisms that are located in the tissues and that are therefore “protected” from mechanical disruption by root surface debridement. It has also been reported that bacteria in the tissues represent a “reservoir for reinfection” after nonsurgical management. However, until the clinical relevance of bacteria being present in the tissues is better defined, it is inappropriate to make clinical treatment decisions (e.g., whether to use adjunctive systemic antibiotics) on this premise alone.

Fimbriae.

The fimbriae of certain bacterial species, particularly P. gingivalis, may also play a role in periodontal pathogenesis. P. gingivalis fimbriae stimulate immune responses, such as IL-6 secretion,97,128 and the major fimbrial structural component of P. gingivalis, FimA, has been shown to stimulate nuclear factor (NF)-κβ and IL-8 in a gingival epithelial cell line via TLR-2.⁵. Monocytes are also stimulated by P. gingivalis FimA, secreting IL-6, IL-8, and TNF-α.⁴⁸ P. gingivalis fimbriae also interact with complement receptor-3 (CR-3) to activate intracellular signaling pathways that inhibit IL-12 production mediated by TLR-2 signalling.⁶⁶ This may be of clinical relevance, because IL-12 is important in the activation of natural killer (NK) cells and CD8+ cytotoxic T cells, which themselves may be important in killing P. gingivalis–infected host cells, such as epithelial cells. Indeed, the blockade of the CR-3 receptor promotes IL-12–mediated clearance of P. gingivalis and negates its virulence.⁶⁶ Bacterial fimbriae are therefore important for modifying and stimulating immune responses in the periodontium.

Bacterial Deoxyribonucleic Acid and Extracellular Deoxyribonucleic Acid.

Bacterial deoxyribonucleic acid (DNA) stimulates immune cells via TLR-9, which recognizes hypomethylated CpG regions of the DNA.⁹³ CpG sites are regions of DNA at which a cytosine nucleotide is found next to a guanine nucleotide (separated by a phosphate molecule, which links the C and G nucleotides together, hence “CpG”). Extracellular DNA (eDNA) is likely to play a role in the development and structure of the biofilms formed by oral bacteria, and it has been identified as an important component of the matrix in a number of bacterial biofilms.^169,196 eDNA is derived from the chromosomal DNA of bacteria in biofilms, and the majority of eDNA is released after bacterial cell lysis.^2,178 However, there is also evidence that eDNA secretion may occur from bacterial cells by mechanisms that are independent of cell lysis.^68,142 The significance of this finding is not yet clear, but such “donated” DNA may be used by bacterial species as a means of increasing genetic diversity (if taken up by other bacteria), thereby contributing to antigenic variation and the spread of antibiotic resistance, and it may also modulate the host immune response. Thus eDNA may function as a source of genetic information for naturally transformable bacteria in the biofilm¹⁹¹ or as a stimulus for host immunity. Little is known about the role of eDNA in oral biofilms, however. It has been demonstrated that DNA isolated from P. gingivalis, A. actinomycetemcomitans, and Peptostreptococcus micros stimulates macrophages and gingival fibroblasts to produce TNF-α and IL-6 in a dose-dependent manner; therefore, immune stimulation by bacterial DNA from subgingival species could contribute to periodontal pathogenesis.¹²⁴

Cytokines.

Cytokines play a fundamental role in inflammation, and they are key inflammatory mediators in periodontal disease.140,161 They are soluble proteins, and they act as messengers to transmit signals from one cell to another. Cytokines bind to specific receptors on target cells, and they initiate intracellular signaling cascades that result in phenotypic changes in the cell via altered gene regulation.^17,176 Cytokines are effective in very low concentrations, they are produced transiently in the tissues, and they primarily act locally in the tissues in which they are produced. Cytokines are able to induce their own expression in either an autocrine or paracrine fashion, and they have pleiotropic effects (i.e., multiple biologic activities) on a large number of cell types. (Autocrine signaling means that the autocrine agent [in this case cytokines] binds to receptors on the cell that secreted the agent, whereas paracrine signaling affects other nearby cells.) Simply put, cytokines bind to cell surface receptors and trigger a sequence of intracellular events that lead ultimately to the production of protein by the target cell, which alters that cell’s behavior and could result in, for example, the increased secretion of more cytokines in a positive feedback cycle that leads to inflammation.

Cytokines are produced by a large number of cell types, including infiltrating inflammatory cells (e.g., neutrophils, macrophages, lymphocytes) as well as resident cells in the periodontium (e.g., fibroblasts, epithelial cells).¹⁷² Cytokines signal, broadcast, and amplify immune responses, and they are fundamentally important for regulating immune–inflammatory responses and for combating infections. However, they also have profound biologic effects that lead to tissue damage with chronic inflammation; the prolonged and excessive production of cytokines and other inflammatory mediators in the periodontium leads to the tissue damage that characterizes the clinical signs of the disease. For example, cytokines mediate connective tissue and alveolar bone destruction through the induction of fibroblasts and osteoclasts to produce proteolytic enzymes (i.e., MMPs) that break down structural components of these connective tissues.¹²

There is significant overlap and redundancy between the function of individual cytokines. Cytokines do not act in isolation; rather, they function in flexible and complex networks that involve both proinflammatory and anti-inflammatory effects and that bring together aspects of both innate and acquired immunity.⁸ Cytokines play a key role at all stages of the immune response in periodontal disease.¹⁴⁰ Among the most studied (and probably the most important) cytokines in periodontal pathogenesis are the proinflammatory cytokines IL-1β and TNF-α. Both of these cytokines play a key role in the initiation, regulation, and perpetuation of innate immune responses in the periodontium, thereby resulting in vascular changes and the migration of effector cells such as neutrophils into the periodontium as part of a normal immune response to the presence of subgingival bacteria.⁵⁷

Prostaglandins.

The prostaglandins (PGs) are a group of lipid compounds derived from arachidonic acid, a polyunsaturated fatty acid found in the plasma membrane of most cells. Arachidonic acid is metabolized by cyclooxygenase-1 and -2 (COX-1 and COX-2) to generate a series of related compounds called the prostanoids, which includes the PGs, the thromboxanes, and the prostacyclins. PGs are important mediators of inflammation, particularly prostaglandin E₂ (PGE₂), which results in vasodilation and induces cytokine production by a variety of cell types. COX-2 is upregulated by IL-1β, TNF-α, and bacterial LPS, resulting in increased production of PGE₂ in inflamed tissues. PGE₂ is produced by various types of cells and most significantly in the periodontium by macrophages and fibroblasts. PGE₂ results in the induction of MMPs and osteoclastic bone resorption, and it has a major role in contributing to the tissue damage that characterizes periodontitis.

Matrix Metalloproteinases.

MMPs are a family of proteolytic enzymes that degrade extracellular matrix molecules such as collagen, gelatin, and elastin. They are produced by a variety of cell types, including neutrophils, macrophages, fibroblasts, epithelial cells, osteoblasts, and osteoclasts. The names and functions of key MMPs are shown in Table 5-1. The nomenclature of MMPs has been based on the perception that each enzyme has its own specific substrate; for example, MMP-8 and MMP-1 are both collagenases (i.e., they break down collagen). However, it is now appreciated that MMPs usually degrade multiple substrates, with significant substrate overlap between individual MMPs.⁷⁰ The substrate-based classification is still used, however, and MMPs can be divided into collagenases, gelatinases/type IV collagenases, stromelysins, matrilysins, membrane-type metalloproteinases, and others.

MMPs are secreted in a latent form (inactive) and are activated by the proteolytic cleavage of a portion of the latent enzyme. This is achieved by proteases, such as cathepsin G, produced by neutrophils. MMPs are inhibited by proteinase inhibitors, which have anti-inflammatory properties. Key inhibitors of MMPs found in the serum include the glycoprotein α₁-antitrypsin and α₂-macroglobulin, a large plasma protein produced by the liver that is capable of inactivating a wide variety of proteinases. Inhibitors of MMPs that are found in the tissues include the tissue inhibitors of metalloproteinases (TIMPs), which are produced by many cell types; the most important in periodontal disease is TIMP-1.¹⁸ MMPs are also inhibited by the tetracycline class of antibiotics, which has led to the development of a subantimicrobial formulation of doxycycline as a licensed systemic adjunctive drug treatment for periodontitis that exploits the anti-MMP properties of this molecule (see Chapter 50).

Other Interleukin-1 Family Cytokines.

Six new members of the IL-1 family (IL-1F) of cytokines have been identified on the basis of their sequence homology, structure, gene location, and receptor binding.4,10 Several of these cytokines were identified by different groups, who gave them a variety of names, and proposals were suggested for renaming all of the IL-1F cytokines in a more consistent manner, as indicated in Table 5-2. Our knowledge of the role of these cytokines in inflammation and immunity is very limited at present, and some of these cytokines may be evolutionarily redundant. IL-1F6, IL-1F8, and IL-1F9 are potential agonists (stimulating proinflammatory responses),^19,182 whereas IL-1F5 and IL-1F10 are potential antagonists.^19,33,103 IL-1F7 appears to have anti-inflammatory action.⁴⁴ It has five splice variants and one isoform, IL-1F7b, which is highly expressed by monocytes and upregulated by LPS.²⁴ An intracellular mode of action has been suggested for IL-1F7b; it translocates to the nucleus of macrophages, and it may act as a transcriptional modulator by reducing the production of LPS-stimulated proinflammatory cytokines, thus supporting an anti-inflammatory role for this cytokine.¹⁶³

These novel IL-1F cytokines have limited tissue expression. For example, the agonists IL-1F6, IL-1F8, and IL-1F9 are mainly expressed in skin.¹⁸² Therefore, although the primary cellular sources of IL-1β and IL-18 are hematopoietic cells (e.g., neutrophils, macrophages, monocytes, lymphocytes), IL-1F5 through IL-1F10 are mainly expressed outside of these lineages. At present, there are no data to support a role for IL-1F5 through IL-1F10 in periodontal pathogenesis. However, given that they are expressed mainly by epithelial cells, it will be interesting to learn whether they may play a role in inflammatory responses in the gingiva. This is relevant given the continual exposure of gingival epithelial cells to bacterial challenge, and these cytokines also have properties similar to the primary cytokines (e.g., IL-1β). For example, LPS results in the upregulation of IL-1F6, IL-1F8, and IL-1F9, and these cytokines also stimulate the secretion of IL-6 and IL-8.¹⁸² P. gingivalis LPS upregulates IL-1F9 mRNA expression in monocytes, although it does not have an effect on IL-1F6, IL-1F7, IL-1F8, or IL-1F10.¹⁰

IL-33, which is also known as IL-1F11, is of particular interest because, uniquely among the IL-1 cytokines, it stimulates the production of Th2 cytokines (e.g., IL-5, IL-13), it activates Th2 cells, and it plays a role in mast cell development and function.1,77,90,117,151 IL-33 is mainly found in nonimmune cells such as bronchial and arterial smooth muscle cells and epithelial cells from the bronchus.¹⁵¹ It is constitutively expressed in the endothelial cells of small and large blood vessels, in the fibroblastic reticular cells of lymphoid tissues, and in epithelial cells.^27,118 Our knowledge of the expression of IL-33 in myeloid immune cells is very limited, and there are no data to support a role for IL-33 in periodontal pathogenesis. However, it has been reported that IL-33 activates Th2 cells¹⁵¹ and that it is chemoattractant for these cells.⁹⁰ Given that Th2 cells are likely to play a role in the destructive phases of periodontal disease and that the balance of T-cell subsets is an important factor in determining disease progression,⁵⁸ IL-33 may yet prove to play a role in periodontal pathogenesis.

Tumor Necrosis Factor-α.

TNF-α is a key inflammatory mediator in periodontal disease, and it shares many of the cellular actions of IL-1β.⁶⁴ It plays a fundamental role in immune responses, it increases neutrophil activity, and it mediates cell and tissue turnover by inducing MMP secretion. TNF-α stimulates the development of osteoclasts and limits tissue repair via the induction of apoptosis in fibroblasts. TNF-α is secreted by activated macrophages as well as by other cell types, particularly in response to bacterial LPS. The proinflammatory effects of TNF-α include the stimulation of endothelial cells to express selectins that facilitate leukocyte recruitment, the activation of macrophage IL-1β production, and the induction of PGE₂ by macrophages and gingival fibroblasts.¹³⁴ TNF-α—although it possesses similar activity to IL-1β—has a less potent effect on osteoclasts, and it is present at lower levels in inflamed gingival tissues than IL-1β.¹⁶⁸ GCF levels of TNF-α increase as gingival inflammation develops, and higher levels are found in individuals with periodontitis.^64,73 The importance of TNF-α (and IL-1β) in periodontal pathogenesis is unquestioned, and it has particularly been highlighted by studies showing that the application of antagonists to IL-1β and TNF-α resulted in an 80% reduction in recruitment of inflammatory cells in proximity to the alveolar bone and a 60% reduction in bone loss.⁶

Interleukin-6 and Related Cytokines.

The cytokines in this group—which include IL-6, IL-11, leukemia-inhibitory factor (LIF), and oncostatin M—share common signaling pathways via signal transducers glycoprotein (gp) 130.⁷⁴ IL-6 is the most extensively studied of this group, and it has pleiotropic proinflammatory properties.⁸⁷ IL-6 secretion is stimulated by cytokines such as IL-1β and TNF-α, and it is produced by a range of immune cells (e.g., T cells, B cells, macrophages, dendritic cells) as well as resident cells (e.g., keratinocytes, endothelial cells, fibroblasts).¹⁸⁸ IL-6 is also secreted by osteoblasts, and it stimulates bone resorption and the development of osteoclasts.^81,94 IL-6 is elevated in the cells, tissues, and GCF of patients with periodontal disease.^56,104 IL-6 may have an influence on monocyte differentiation into osteoclasts and a role in bone resorption in patients with periodontal disease.¹²⁹ IL-6 also has a key role in regulating the proliferation and differentiation of B cells and T cells, particularly the Th17 subset.⁸⁷ IL-6 therefore has an important role in periodontal pathogenesis, although it is less than that of IL-1β or TNF-α.

IL-6 also has many activities outside of the immune system, such as in the cardiovascular and nervous systems. It has an important role in hematopoiesis and in signaling the production of C-reactive protein in the liver. Furthermore, IL-6 stimulates T-cell differentiation and function, and it is important in the regulation of the balance of T-cell subsets, particularly the activation of Th17 cells (a subset of T cells that produce IL-17) and the balance with regulatory T cells (T_reg cells).