LIGHT protein gingival crevicular fluid biomarker and periodontal disease activity

Introduction

LIGHT protein (Lymphotoxin-beta receptor Interacting with G Protein-coupled Receptor), is a significant cytokine involved in immune regulation and inflammation. It plays a critical role in various physiological and pathological processes, particularly those related to immune responses and inflammation. Understanding LIGHT’s structure, function, and interactions is crucial for grasping its role in diseases, including periodontal disease, where it serves as a potential biomarker in gingival crevicular fluid (GCF). LIGHT is a member of the TNF superfamily, which comprises several cytokines involved in immune system regulation. The protein is encoded by the TNFSF14 gene located on chromosome 19p13.3 in humans. LIGHT exists as a type II transmembrane protein but can also be found in a soluble form after being cleaved by specific proteases.

Structure and molecular characteristics

Structurally, LIGHT protein is a type II transmembrane protein with a structure that includes several key regions:

Amino Acid Sequence and Domains

LIGHT is composed of 240 amino acids, with a molecular weight of approximately 30 kDa. It contains a TNF homology domain (THD) responsible for its receptor-binding activities. The protein has three main domains:

• Intracellular Domain: Involved in signal transduction.
• Transmembrane Domain: Anchors the protein to the cell membrane.
• Extracellular Domain: Contains the THD and is involved in receptor binding.

Oligomerization

LIGHT typically functions as a homotrimer, which is essential for its interaction with receptors. This trimerization is a common feature among TNF superfamily members and is critical for their biological activity.

Receptors and interactions

LIGHT exerts its effects by binding to specific receptors on the surface of target cells. It interacts primarily with two receptors:

HVEM (Herpesvirus Entry Mediator):

HVEM, also known as TNFRSF14, is a receptor that belongs to the TNF receptor superfamily. It is expressed on various immune cells, including T cells, B cells, and dendritic cells. LIGHT binding to HVEM can trigger multiple signaling pathways that lead to the activation of nuclear factor-kappa B (NF-κB) and the production of pro-inflammatory cytokines. This interaction is crucial in immune responses, particularly in the activation and differentiation of T cells.

LTβR (Lymphotoxin Beta Receptor):

LTβR is another member of the TNF receptor family and is expressed on non-lymphoid cells, such as epithelial and stromal cells. The interaction between LIGHT and LTβR is involved in the development of secondary lymphoid organs and the maintenance of tissue homeostasis. It also plays a role in inflammation, particularly in chronic inflammatory diseases.

Additionally, LIGHT can interact with the decoy receptor, DcR3 (Decoy Receptor 3), which binds LIGHT but does not transduce signals, thereby modulating LIGHT’s activity by preventing it from interacting with HVEM or LTβR.

Biological Functions

LIGHT plays a pivotal role in various immune and inflammatory responses. Its biological functions are diverse and include:

T Cell activation and co-stimulation

As discussed in “cell mediated immune response”, T cells, a critical component of the adaptive immune system, are essential for recognizing and responding to specific antigens presented by infected or abnormal cells. T cell activation is a tightly regulated process that involves multiple signals to ensure an appropriate immune response. This process generally requires two signals:

Signal 1: Antigen recognition through the T cell receptor (TCR) after it binds to a specific peptide presented by the major histocompatibility complex (MHC) on the surface of antigen-presenting cells (APCs).

Signal 2: Co-stimulatory signals provided by the interaction between co-stimulatory molecules on the T cell and their ligands on the APC. Without this co-stimulation, T cells may become anergic or undergo apoptosis, preventing an inappropriate immune response.

LIGHT protein (TNFSF14) is one of the key molecules involved in providing the crucial co-stimulatory signals required for T cell activation. By engaging with its receptors, LIGHT plays an important role in modulating T cell responses, influencing both the magnitude and nature of the immune response. As discussed earlier, LIGHT primarily interacts with two receptors- HVEM (Herpesvirus Entry Mediator) and LTβR (Lymphotoxin Beta Receptor). It exerts its co-stimulatory effects on T cells by these interactions.

HVEM (Herpesvirus Entry Mediator) mediated activation

When LIGHT binds to HVEM on T cells, it initiates several intracellular signaling cascades that enhance T cell activation. This interaction leads to the upregulation of key signaling pathways, such as NF-κB, which promotes the transcription of genes involved in T cell proliferation, survival, and cytokine production. LIGHT-HVEM interaction provides a potent co-stimulatory signal that enhances T cell activation beyond the signal provided by TCR-MHC interaction alone. This co-stimulation is crucial for the full activation of T cells, enabling them to effectively proliferate and differentiate into effector cells capable of responding to infections or tumors.

LTβR (Lymphotoxin Beta Receptor) mediated activation

While LTβR is more involved in the development and organization of lymphoid tissues, its engagement by LIGHT can indirectly influence T cell activation by modulating the microenvironment in which T cells are activated. This receptor’s role in T cell co-stimulation is less direct than HVEM, but it contributes to creating a supportive environment for immune responses. The binding of LIGHT to HVEM initiates several key signaling pathways that drive T cell activation and function. NF-κB is a central transcription factor that regulates the expression of genes involved in immune responses, including those encoding cytokines, chemokines, and cell survival proteins. Upon binding to HVEM, LIGHT triggers the activation of the NF-κB pathway, leading to the transcription of genes that promote T cell survival, proliferation, and differentiation. This pathway is essential for sustaining the activation of T cells during an immune response.

Upregulation of Co-stimulatory Molecules

LIGHT-HVEM interaction leads to the upregulation of additional co-stimulatory molecules, such as CD80 and CD86, on APCs. This amplifies the co-stimulatory signals available to T cells, further enhancing their activation. This amplification is critical in settings where T cell activation needs to be robust, such as in responses to viral infections or tumor cells.

Promotion of Cytokine Production

As we know that, cytokines are small proteins released by cells, particularly those of the immune system, which play crucial roles in cell signaling. They are key regulators of the immune response, influencing the behavior of cells in the immune system as well as those in other tissues. The promotion of cytokine production by LIGHT primarily occurs through its interactions with specific receptors on the surface of target cells i.e. HVEM and, LTβR. The interaction of LIGHT with its receptors leads to the production of several key cytokines, each playing a unique role in the immune response and inflammation:

Tumor Necrosis Factor-alpha (TNF-α)

TNF-α is a potent pro-inflammatory cytokine that plays a central role in inflammation and immune regulation. It is involved in the activation of other immune cells, induction of fever, and the acute phase response. LIGHT enhances TNF-α production primarily through the NF-κB pathway, contributing to the amplification of inflammatory responses. Elevated TNF-α levels are associated with chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.

Interleukin-6 (IL-6)

IL-6 is a multifunctional cytokine involved in the regulation of immune responses, inflammation, and hematopoiesis. It plays a role in the acute phase response and is crucial for the differentiation of T cells into effector and memory subsets. The LIGHT-HVEM interaction significantly upregulates IL-6 production. IL-6 contributes to the chronicity of inflammation and has been implicated in various autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis.

Interferon-gamma (IFN-γ)

IFN-γ is a key cytokine produced by T cells and natural killer (NK) cells, and it is crucial for innate and adaptive immunity against viral and intracellular bacterial infections. It also plays a role in tumor surveillance. LIGHT promotes IFN-γ production, particularly in Th1 cells and cytotoxic T lymphocytes (CTLs). This production is essential for activating macrophages and enhancing their microbial killing capacity. IFN-γ also contributes to the differentiation of T cells into Th1 cells, thus promoting a type 1 immune response.

Interleukin-2 (IL-2)

IL-2 is critical for T cell proliferation and the expansion of the immune response. It is also involved in the development of regulatory T cells (Tregs), which help maintain immune tolerance and prevent autoimmunity. Through its co-stimulatory effect, LIGHT enhances IL-2 production in activated T cells. The increased IL-2 levels support the clonal expansion of T cells during an immune response, enabling the immune system to effectively respond to pathogens or tumors.

Interleukin-1β (IL-1β)

IL-1β is a major pro-inflammatory cytokine that plays a pivotal role in the inflammatory response. It is involved in the induction of fever, recruitment of immune cells to sites of infection, and activation of various inflammatory pathways. LIGHT can induce the production of IL-1β, particularly in macrophages and dendritic cells. This contributes to the initiation and propagation of the inflammatory response in conditions like periodontal disease and atherosclerosis.

T Cell survival and memory formation

T cell survival and the formation of memory T cells are critical components of the immune system’s ability to provide long-term protection against pathogens and malignancies. After an initial immune response, a subset of activated T cells differentiates into memory T cells, which persist long after the antigen has been cleared. These memory T cells can rapidly respond to subsequent exposures to the same antigen, providing faster and more effective immunity. LIGHT protein (TNFSF14) influences several signaling pathways that are crucial for maintaining T cell survival and facilitating the development of long-lived memory T cells.

The binding of LIGHT to HVEM triggers a series of intracellular signaling pathways that enhance T cell survival. Key pathways involved include the activation of nuclear factor-kappa B (NF-κB), phosphoinositide 3-kinase (PI3K)/Akt, and mitogen-activated protein kinases (MAPKs). The NF-κB pathway is a central regulator of cell survival. When LIGHT binds to HVEM, it activates NF-κB, leading to the transcription of genes that promote T cell survival. These genes include those encoding anti-apoptotic proteins such as Bcl-2 and Bcl-xL, which help protect T cells from apoptosis during and after activation. NF-κB activation also promotes the production of cytokines such as IL-2, which further supports T cell proliferation and survival by acting in an autocrine and paracrine manner. The PI3K/Akt pathway, activated by LIGHT-HVEM signaling, is crucial for promoting T cell survival by enhancing cellular metabolism, nutrient uptake, and growth. Akt phosphorylates and inactivates pro-apoptotic factors such as Bad and promotes the activity of mTOR (mammalian target of rapamycin), which supports cellular growth and survival. Akt activation also inhibits the activity of pro-apoptotic proteins, ensuring that T cells remain viable during their expansion phase and while transitioning into memory cells. The MAPK pathway, which includes ERK1/2 (extracellular signal-regulated kinases), is another pathway activated by LIGHT-HVEM interaction. It plays a role in cell proliferation and survival, further contributing to the maintenance of T cells during the immune response. This pathway also modulates the expression of genes involved in apoptosis, providing an additional layer of protection against cell death during T cell activation and differentiation.

Memory T cells are a specialized subset of T cells that provide long-term immunity by “remembering” past encounters with antigens. LIGHT plays a role in the differentiation and maintenance of these memory T cells through the various mechanisms. After the initial immune response, a portion of effector T cells transitions into memory T cells. LIGHT signaling through HVEM contributes to this transition by promoting the survival of T cells and preventing their apoptosis, allowing them to persist long enough to differentiate into memory cells. LIGHT-induced cytokines, such as IL-2 and IL-15, are important for the differentiation and maintenance of memory T cells. IL-2 is crucial during the early phase of memory formation, while IL-15 supports the long-term survival of memory T cells. Memory T cells need to survive for extended periods, often for the lifetime of the host. LIGHT contributes to the long-term survival of memory T cells by activating survival pathways, such as NF-κB and PI3K/Akt, which prevent apoptosis and maintain cellular metabolism. Memory T cells undergo low-level proliferation to maintain their numbers over time, a process known as homeostatic proliferation. LIGHT signaling can support this proliferation by providing survival signals and promoting the expression of receptors that respond to homeostatic cytokines like IL-7 and IL-15. It should be noted here that central memory T cells reside in lymphoid tissues and have a high proliferative capacity. LIGHT signaling may influence the formation and maintenance of Tcm by promoting survival and responsiveness to homeostatic cytokines. Effector memory T cells circulate in peripheral tissues and provide immediate protection upon re-exposure to antigens. LIGHT may support the survival and function of Tem by enhancing the expression of survival genes and cytokine receptors.

Th1/Th2 Differentiation

As discussed in chapter 7, “Cell mediated immune response”, T helper cells (Th cells) are a subset of CD4+ T cells that play a central role in orchestrating the immune response. Upon activation, naive CD4+ T cells can differentiate into various subsets, including Th1 and Th2 cells, each characterized by distinct cytokine profiles and functions. Th1 cells are primarily involved in cellular immunity. They produce cytokines such as interferon-gamma (IFN-γ) and interleukin-2 (IL-2), which activate macrophages and cytotoxic T lymphocytes, thereby enhancing the immune response against intracellular pathogens (e.g., viruses and certain bacteria) and tumors. Th2 cells are associated with humoral immunity. They secrete cytokines like interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), which promote B cell proliferation, antibody production, and the activation of eosinophils, playing a critical role in defense against extracellular parasites and in allergic responses. LIGHT binds to HVEM on T cells and dendritic cells, leading to the activation of intracellular signaling pathways that favor Th1 differentiation. HVEM signaling activates the nuclear factor-kappa B (NF-κB) pathway and the mitogen-activated protein kinase (MAPK) pathway, both of which are important for the expression of Th1-associated genes. LIGHT-HVEM interaction promotes the production of IFN-γ by T cells. IFN-γ is a key cytokine that drives Th1 differentiation by activating the transcription factor T-bet, which upregulates genes involved in the Th1 program. This positive feedback loop further enhances the Th1 response. Along with this, LIGHT can enhance the production of IL-12 by dendritic cells and macrophages through its interaction with HVEM and LTβR. IL-12 is a critical cytokine for Th1 differentiation, as it induces the expression of T-bet and supports the production of IFN-γ by T cells. By promoting IL-12 production, LIGHT indirectly favors the polarization of naive T cells toward the Th1 lineage. This is particularly important in the context of infections that require a strong cellular immune response, such as viral and intracellular bacterial infections.

While LIGHT primarily promotes Th1 differentiation, it can also suppress Th2 differentiation. This suppression is partly due to the enhanced production of IFN-γ, which inhibits the expression of GATA3, the master transcription factor for Th2 differentiation. LIGHT signaling through HVEM reduces the production of Th2-associated cytokines such as IL-4 and IL-13. By favoring a Th1-biased response, LIGHT helps to suppress Th2-mediated immune responses, which are important in conditions like allergies and asthma. Th2 cells are central to the pathogenesis of allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis. LIGHT’s ability to suppress Th2 differentiation may have therapeutic potential in treating these conditions by reducing the production of Th2 cytokines that drive allergic inflammation. Enhancing LIGHT signaling could be a strategy to shift the immune response from a Th2-dominant profile to a Th1-dominant one, potentially benefiting patients with Th2-mediated disorders.

The immune system requires a balance between Th1 and Th2 responses to function properly. LIGHT’s role in promoting Th1 differentiation and suppressing Th2 responses helps maintain this balance, ensuring that the immune system can effectively respond to different types of pathogens while avoiding excessive inflammation or autoimmunity. The effect of LIGHT on Th1/Th2 differentiation can vary depending on the context, including the presence of other cytokines and the type of immune challenge. In some cases, LIGHT may have a more nuanced role, modulating the balance between Th1 and Th2 responses in a way that is appropriate for the specific immune challenge.

Cytotoxic T Lymphocyte (CTL) Activity

Cytotoxic T lymphocytes (CTLs) are a subset of CD8+ T cells that play a vital role in the immune system’s ability to target and destroy cells infected with viruses, as well as cancerous cells. CTLs exert their effects by recognizing and binding to antigen-presenting cells via their T cell receptor (TCR), which is specific to peptides presented by MHC class I molecules. Upon activation, CTLs release cytotoxic granules containing perforin and granzymes, leading to the apoptosis of target cells. HVEM is expressed on a variety of immune cells, including CTLs. LIGHT binding to HVEM on CTLs provides a co-stimulatory signal that enhances their activation. LIGHT-HVEM interaction strengthens TCR signaling in CTLs, which is crucial for their full activation. This enhanced signaling leads to increased expression of activation markers such as CD25 (IL-2 receptor alpha) and CD69, as well as the production of cytokines like IFN-γ and TNF-α, which are essential for CTL function.

LIGHT promotes the production of IL-2, a critical cytokine for CTL proliferation and survival. IL-2 acts in both an autocrine and paracrine manner, ensuring that activated CTLs expand robustly and maintain their effector functions. The increased availability of IL-2 due to LIGHT signaling enhances the proliferation and activity of CTLs, allowing them to mount a stronger and more sustained immune response against infected or malignant cells. It should be noted here that LIGHT signaling through HVEM and LTβR increases the cytotoxic potential of CTLs by promoting the expression and release of granzyme B and perforin. These molecules are critical for inducing apoptosis in target cells. LIGHT also upregulates the expression of Fas ligand (FasL) on CTLs, which binds to Fas on target cells, triggering the extrinsic apoptotic pathway. This provides an additional mechanism for CTLs to eliminate infected or transformed cells. LIGHT enhances the production of IFN-γ by CTLs, which not only helps in directly killing target cells but also activates other components of the immune system, such as macrophages and natural killer (NK) cells, to further eliminate the pathogen or tumor. IFN-γ production, LIGHT indirectly contributes to a Th1-skewed immune response, which is more effective at dealing with intracellular pathogens and tumors.

LIGHT signaling through HVEM activates key survival pathways in CTLs, including the NF-κB and PI3K/Akt pathways. These pathways lead to the upregulation of anti-apoptotic proteins such as Bcl-2 and Bcl-xL, which protect CTLs from apoptosis during and after the effector phase. LIGHT contributes to the long-term survival of memory CTLs, ensuring that they persist and can respond rapidly upon re-exposure to the same antigen. This is crucial for long-lasting immunity, particularly in the context of chronic infections and cancer. LIGHT’s role in promoting the survival and homeostatic proliferation of CTLs helps maintain a stable pool of memory CTLs. These cells can undergo low-level proliferation in response to homeostatic cytokines like IL-15, ensuring that a ready population of CTLs is available for rapid response to recurrent infections or tumor cells.

Regulation of immune tolerance

Immune tolerance is the process by which the immune system distinguishes between self and non-self, allowing it to respond to pathogens while avoiding attacks on the body’s own tissues. This balance is crucial for preventing autoimmune diseases, where the immune system mistakenly targets and destroys healthy tissues. Immune tolerance can be broadly categorized into central tolerance, which occurs during lymphocyte development in the thymus and bone marrow, and peripheral tolerance, which occurs in the peripheral tissues and is crucial for controlling the activation of mature T cells. The LIGHT protein (TNFSF14) plays an important role in immune tolerance.

Central tolerance involves the elimination of autoreactive T cells during their development in the thymus through a process called negative selection. Although LIGHT’s role in thymic selection is not fully understood, its interactions with HVEM on thymic epithelial cells and developing T cells may influence this process. By modulating the signaling pathways involved in T cell maturation, LIGHT could contribute to the deletion of potentially autoreactive T cells, thereby preventing autoimmune responses. The thymus is also a critical site for the development of regulatory T cells (Tregs), which are essential for maintaining immune tolerance. LIGHT, through its receptor interactions, may influence the selection and development of Tregs in the thymus, although further research is needed to clarify these mechanisms.

LIGHT can deliver both activating and inhibitory signals to T cells, depending on the context and receptor engagement. While LIGHT binding to HVEM typically promotes T cell activation, HVEM can also interact with inhibitory ligands such as BTLA (B and T Lymphocyte Attenuator), which negatively regulate T cell responses. This dual signaling capability allows LIGHT to contribute to the fine-tuning of T cell activation, preventing excessive or inappropriate immune responses that could lead to autoimmunity. LIGHT-HVEM interaction can modulate TCR (T cell receptor) signaling strength, influencing whether a T cell becomes activated or anergic (non-responsive). By controlling the threshold for T cell activation, LIGHT helps maintain peripheral tolerance by ensuring that self-reactive T cells do not become fully activated.

Regulatory T cells are crucial for maintaining peripheral tolerance by suppressing the activation and proliferation of autoreactive T cells. LIGHT signaling through HVEM has been shown to enhance the suppressive function of Tregs. This interaction promotes the expression of key regulatory molecules, such as CTLA-4 and TGF-β, which are essential for Treg-mediated suppression of immune responses. LIGHT may also play a role in the expansion and stability of Tregs in the periphery. By supporting Treg survival and function, LIGHT contributes to the maintenance of a tolerogenic environment, preventing the onset of autoimmune diseases.

LIGHT protein and autoimmune diseases

Autoimmune diseases occur when the immune system mistakenly targets and attacks the body’s own tissues, leading to chronic inflammation and tissue damage. The breakdown of immune tolerance, which normally prevents the immune system from attacking self-antigens, is a hallmark of autoimmune disorders. Factors contributing to autoimmunity include genetic predisposition, environmental triggers, and dysregulation of immune signaling pathways. The LIGHT protein (TNFSF14) plays an important role in autoimmune diseases.

LIGHT signaling can promote the differentiation of T helper cells into pro-inflammatory Th1 and Th17 subsets. Th1 cells produce interferon-gamma (IFN-γ), while Th17 cells produce interleukin-17 (IL-17), both of which are implicated in the pathogenesis of autoimmune diseases. By enhancing the production of these cytokines, LIGHT contributes to the inflammatory environment that drives autoimmune tissue damage. LIGHT can also enhance the activation and cytotoxic functions of CD8+ T cells (CTLs). In autoimmune diseases, CTLs may target self-antigens, leading to direct tissue destruction. LIGHT’s role in boosting CTL activity could therefore exacerbate autoimmune pathology.

Tregs are essential for maintaining immune tolerance by suppressing autoreactive T cells. Dysregulated LIGHT signaling can impair Treg function or reduce their numbers, weakening the immune system’s ability to control autoreactive T cells. This loss of regulation can lead to the unchecked activation of autoreactive immune cells, promoting autoimmunity. LIGHT can interfere with mechanisms of peripheral tolerance, such as the induction of anergy in autoreactive T cells or the promotion of tolerogenic dendritic cells (DCs). Disruption of these processes can lead to the activation of self-reactive T cells and the development of autoimmune responses.

Gene Silencing

Gene silencing refers to the process by which the expression of a specific gene is reduced or completely inhibited. This can be achieved through various mechanisms, including RNA interference (RNAi), gene editing techniques (such as CRISPR/Cas9), and the use of gene-specific inhibitors. Gene silencing is a powerful tool in molecular biology and medicine for studying gene function, understanding disease mechanisms, and developing therapeutic interventions. Various gene silencing approaches have been developed targeting LIGHT protein. RNAi is a mechanism where small RNA molecules inhibit gene expression. siRNA molecules can be designed to specifically target the mRNA of the LIGHT gene, leading to its degradation and a subsequent decrease in LIGHT protein production. This approach allows for the transient and specific reduction of LIGHT expression, which can be useful for studying its role in various diseases and conditions. shRNA is another RNAi-based technique that involves the introduction of a plasmid or viral vector encoding a hairpin-shaped RNA sequence. This sequence is processed into siRNA within the cell, leading to the silencing of the LIGHT gene. shRNA can provide stable gene silencing over a longer period compared to siRNA.

Gene editing techniques have also been explored. The CRISPR/Cas9 system allows for precise editing of the genome by introducing double-strand breaks at specific locations. This technique can be used to create knockout models for the LIGHT gene, effectively silencing its expression by disrupting its coding sequence. CRISPR/Cas9 can provide permanent gene silencing and is useful for generating stable cell lines or animal models for studying the long-term effects of LIGHT disruption. A more recent advancement, base editing, allows for targeted nucleotide changes without creating double-strand breaks. This technique can be used to correct or disrupt specific mutations in the LIGHT gene, providing a more controlled approach to gene silencing.

Targeting of antisense oligonucleotides (ASOs). Antisense oligonucleotides are short, synthetic strands of nucleotides designed to bind to the mRNA of the target gene, preventing its translation into protein. ASOs targeting LIGHT mRNA can be used to reduce LIGHT protein levels and study its function. This approach offers high specificity and can be tailored to different aspects of gene expression regulation.

Periodontal Disease

Periodontal pathogens often exist in biofilms, which are complex communities of bacteria that are resistant to immune clearance and antimicrobial treatments. LIGHT’s role in promoting inflammation might indirectly affect the composition and stability of these biofilms, potentially influencing the progression of periodontal disease. LIGHT may influence the ability of the immune system to clear periodontal pathogens. By modulating the activation of immune cells such as macrophages and neutrophils, LIGHT could enhance the clearance of bacteria from the gingival crevicular fluid. However, excessive LIGHT signaling might also lead to a hyperactive immune response, causing collateral damage to periodontal tissues.

The immune response plays a central role in the pathogenesis of periodontal disease. While the immune system’s initial response aims to control bacterial infection, dysregulation can lead to excessive inflammation, resulting in tissue destruction. As discussed in the previous sections, LIGHT is known to induce the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, which are critical mediators in the inflammatory response observed in periodontal disease. These cytokines contribute to the recruitment of immune cells to the gingival tissues, leading to the characteristic swelling, redness, and bleeding of the gums. LIGHT has been shown to promote the differentiation of T helper cells into Th1 and Th17 subsets. Th1 cells produce IFN-γ, while Th17 cells produce IL-17, both of which are associated with the inflammatory processes in periodontal disease. Th17 cells, in particular, play a key role in the recruitment of neutrophils and other immune cells to the site of infection, contributing to the chronic inflammation and tissue damage characteristic of periodontal disease.

LIGHT interacts with receptors such as HVEM on T cells, enhancing their activation and promoting the release of inflammatory mediators. In the context of periodontal disease, this can lead to an amplified immune response, resulting in increased tissue destruction. The activation of cytotoxic T lymphocytes (CTLs) by LIGHT may also contribute to the direct damage of periodontal tissues. Neutrophils are among the first immune cells to respond to bacterial infection in the gums. LIGHT signaling can enhance the recruitment and activation of neutrophils, which, while essential for controlling bacterial infection, can also contribute to tissue damage through the release of proteolytic enzymes and reactive oxygen species.

Review of literature on LIGHT protein and periodontal diseases

Several studies have investigated LIGHT expression in periodontal tissues to understand its involvement in periodontal disease. Numerous studies have reported increased LIGHT expression in the gingival tissues of patients with periodontal disease. For instance, (Author reference available in book) demonstrated that LIGHT levels are significantly higher in gingival biopsies from patients with chronic periodontitis compared to healthy controls. This elevation in LIGHT expression is often correlated with increased levels of pro-inflammatory cytokines and markers of tissue destruction. Research has indicated that LIGHT expression correlates with the severity of periodontal disease. For example, (Author reference available in book) found that LIGHT levels were higher in patients with severe periodontitis compared to those with mild or moderate forms of the disease. This correlation suggests that LIGHT may contribute to disease progression and severity.

LIGHT has been shown to induce the production of several pro-inflammatory cytokines in periodontal tissues. Studies such as (Author reference available in book) have reported that LIGHT stimulates the secretion of TNF-α, IL-1β, and IL-6 in gingival fibroblasts and immune cells. These cytokines are crucial in driving the inflammatory response observed in periodontal disease. LIGHT also affects the production of matrix metalloproteinases, which are enzymes involved in the degradation of extracellular matrix components. For instance, (Author reference available in book) demonstrated that LIGHT upregulates MMP-9 and MMP-13 in periodontal ligament cells, leading to increased tissue breakdown and contributing to periodontal tissue destruction.

LIGHT interacts with its receptors on T cells, leading to their activation. Research by (Author reference available in book) has shown that LIGHT promotes the differentiation of T cells into Th1 and Th17 subsets, which are associated with chronic inflammation in periodontal disease. This interaction enhances the production of inflammatory cytokines and exacerbates tissue damage. LIGHT plays a role in the recruitment and activation of neutrophils to inflamed tissues. Studies such as (Author reference available in book) have found that LIGHT enhances neutrophil migration to gingival tissues, where these cells contribute to inflammation and tissue destruction through the release of proteolytic enzymes and reactive oxygen species. LIGHT contributes to bone resorption by promoting osteoclastogenesis. Research by (Author reference available in book) has shown that LIGHT increases RANKL (Receptor Activator of Nuclear Factor Kappa-B Ligand) expression in periodontal fibroblasts, leading to enhanced osteoclast differentiation and activity. This process contributes to alveolar bone loss observed in periodontal disease. Experimental studies have demonstrated that LIGHT signaling is associated with increased alveolar bone loss. For example, (Author reference available in book) used a LIGHT-overexpressing mouse model and observed greater bone loss compared to wild-type controls. This finding highlights LIGHT’s role in bone resorption and periodontal tissue destruction.

Conclusion

LIGHT protein (TNFSF14) is a crucial cytokine in the TNF superfamily, with significant roles in immune regulation, inflammation, and lymphoid organogenesis. Its involvement in various autoimmune and chronic inflammatory diseases, including periodontal disease, makes it a key molecule of interest in both research and clinical applications. As a biomarker in gingival crevicular fluid, LIGHT holds promise for improving the diagnosis, monitoring, and treatment of periodontal disease, potentially leading to more targeted and effective therapeutic strategies. Further research into LIGHT’s mechanisms and interactions could pave the way for novel treatments aimed at modulating its activity in disease contexts.

References

References are available in the hardcopy of the website “Periobasics a Textbook of Periodontics and Implantology”.